TCID | Description | Domain | Kingdom/Phylum | Example | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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1.A.1.1.1 | Two TMS K+ and water channel (conducts K+ (KD = 8 mM); blocked by Na+ (190 mM) (Renart et al., 2006) and tetrabutylammonium (Iwamoto et al., 2006)). Ion permeation occurs by ion-ion contacts in single file fashion through the selectivity filter (Köpfer et al. 2014). A narrow pore lined with four arrays of carbonyl groups is responsible for ion selectivity, whereas a conformational change of the four inner transmembrane helices (TMS2) is involved in gating (Baker et al. 2007). Two gates have been identified; one is located at the inner bundle crossing and is activated by H+ while the second gate is in the selectivity filter (Rauh et al. 2017). The C-terminal domain mediates pH modulation (Hirano et al., 2011; Pau et al., 2007). KcsA exhibits a global twisting motion upon gating (Shimizu et al., 2008). Activity is influenced by the phase of the lipid bilayer (Seeger et al. 2010), and occupancy of nonannular lipid binding sites increases the stability of the tetrameric complex (Triano et al. 2010). The open conformation of KcsA can disturb the bilayer integrity and catalyze the flipping of phospholipids (Nakao et al. 2014). This protein is identical to the KcsA orthologue (P0A333) in Streptomyces coelicolor. The stability of the pre domain in KcsA is stabilized by GCN4 (Yuchi et al. 2008). The potential role of pore hydration in channel gating has been evaluated (Blasic et al. 2015). Having multiple K+ ions bound simultaneously is required for selective K+ conduction, and a reduction in the number of bound K+ ions destroys the multi-ion selectivity mechanism utilized by K+ channels (Medovoy et al. 2016). The channel accomodates K+ and H2O molecules alternately in a K+-H2O-K+-H2O series through the channel (Kratochvil et al. 2016). Insertion of KcsA is spontaneous and directional as the cytosolic part of the protein does not translocate across the membrane barrier. Charged residues, not hydrophobic residues, are crucial for insertion of the unfolded protein into the membrane via electrostatic interactions between membrane and protein. A two-step mechanism was proposed. An initial electrostatic attraction between membrane and protein represents the first step prior to insertion of hydrophobic residues into the hydrocarbon core of the membrane (Altrichter et al. 2016). Bend, splay, and twist distinguish KcsA gate opening, filter opening, and filter-gate coupling, respectively (Mitchell and Leibler 2017). Details of the water permeability have been presented. Water flow through KcsA is halved by 200 mM K+ in the aqueous solution, which indicates an effective K+ dissociation constant in that range for a singly occupied channel. (Hoomann et al. 2013). A parameterized MARTINI program can be used to predict the hinging motions of the protein (Li et al. 2019). Activation of KcsA is initiated by proton binding to the pH gate upon an intracellular drop in pH which prompts a conformational switch, leading to a loss of affinity for potassium ions at the selectivity filter and therefore to channel inactivation (Rivera-Torres et al. 2016). An alteration in the conformational equilibrium of the intracellular K+-gate is one of the fundamental mechanisms underlying the dysfunctions of K+ channels caused by disease-related mutations (Iwahashi et al. 2020). Folding and misfolding of KcsA monomers during assembly and tetramerization has been examined (Song et al. 2021). The flexible C-terminus stabilizes KcsA tetramers at a neutral pH with decreased stabilization at acidic pH (Howarth and McDermott 2022). Under equilibrium conditions, in the absence of a transmembrane voltage, both water and K+ occupy the selectivity filter of the KcsA channel in the closed conductive state (Ryan et al. 2023). |
Bacteria | Actinomycetota | Skc1 (KcsA) of Streptomyces lividans |
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1.A.1.10.1 | Voltage-sensitive Na+ channel, NaV1.7 (Cox et al., 2006). The human orthologue, SCN3A or Nav1.3, when mutated causes cryptogenic pediatric partial epilepsy (Holland et al., 2008; Zaman et al. 2020). Batrachotoxin (BTX) is a steroidal alkaloid neurotoxin that activates NaV channels through interacting with transmembrane domain-I-segment 6 (IS6) of these channels. Ginsenoside inhibits BTX binding (Lee et al. 2008). VGSCs are heterotrimeric complexes consisting of a single pore-forming alpha subunit joined by two beta subunits, a noncovalently linked beta1 or beta3 and a covalently linked beta2 or beta4 subunit (Hull and Isom 2017). The binding mode and functional components of the analgesic-antitumour peptide from Buthus martensii Karsch to human voltage-gated sodium channel 1.7 have been characterized (Zhao et al. 2019). Dvorak et al. 2021 developed allosteric modulators of ion channels by targeting their PPI interfaces, particularly in the C-terminal domain of the Nav, with auxiliary proteins. Fenestrations are key functional regions of Nav that modulate drug binding, lipid binding, and influence gating behaviors (Gamal El-Din and Lenaeus 2022). Compartment-specific localizations and trafficking mechanisms for VGSCs are regulated separately to modulate membrane excitability in the brain (Liu et al. 2022). Naview is a library for drawing and annotating voltage-gated sodium channel membrane diagrams (Afonso et al. 2022). Deltamethrin (DLT) is a type-II pyrethroid ester insecticide used in agricultural and domestic applications as well as in public health. Exposure to DLT produced a differential and dose-dependent stimulation of peak Na+ currents, Conversely, tefluthrin (Tef), a type-I pyrethroid insecticide, accentuates I(Na) with a slowing in inactivation time course of the current (Lin et al. 2022). MicroRNA-335-5p suppresses voltage-gated sodium channel expression and may be a target for seizure control (Heiland et al. 2023). Voltage-gated sodium channels are enhancing factors in the metastasis of metastatic prostate cancer cells (Yildirim-Kahriman 2023). Decreasing microtubule detyrosination modulates Nav1.5 subcellular distribution and restores sodium current in Mdx cardiomyocytes (Nasilli et al. 2024). Multiple gating processes are associated with the distal end of TMS6 of domain II in Nav channels (Chen et al. 2025). |
Eukaryota | Metazoa, Chordata | Voltage-sensitive Na+ channel of Rattus norvegicus |
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1.A.1.10.10 |
The insect (cockroach) Na+ channel. Batrachotoxin, pyrethroids, and BTG 502 share overlapping binding sites (Du et al., 2011). Insecticides tagetting Na+ channels include indoxacarb and metaflumizone (Casida and Durkin 2013). They preferably bind to and trap sodium channels in the slow-inactivated non-conducting state, a mode of action similar to that of local anesthetics (Jiang et al. 2015). Asp802 is involved in gating and action, but not binding, of pyrethroid insecticides (Du et al. 2010). |
Eukaryota | Metazoa, Arthropoda | Na+ channel of Blattella germanica (O01307) |
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1.A.1.10.11 | Sodium channel of 2215 aas and 24 TMSs, VmNa. An L925V mutation in the channel domain renders the honey bee mites resistant to pyrethroids such as tau- fluvalinate and flumethrin (González-Cabrera et al. 2013).
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Eukaryota | Metazoa, Arthropoda | VmNa of Varroa destructor |
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1.A.1.10.12 | Type 2 Na+ channel, SCN2A or NaV1.2, of 2,005 aas and 24 TMSs. Mutations give rise to epileptic encephalophathy, Ohtahara syndrome (Nakamura et al. 2013). They may also give rise to autism (ASD) (Tavassoli et al. 2014). This protein is orthologous to the rat Na+ channel, TC# 1.A.1.10.1 and very similar to the type 1 Na+ channel (1.A.1.10.7). NaV1.2 has a single pore-forming alpha-subunit and two transmembrane beta-subunits. Expressed primarily in the brain, NaV1.2 is critical for initiation and propagation of action potentials. Milliseconds after the pore opens, sodium influx is terminated by inactivation processes mediated by regulatory proteins including calmodulin (CaM). Both calcium-free (apo) CaM and calcium-saturated CaM bind tightly to an IQ motif in the C-terminal tail of the alpha-subunit. Thermodynamic studies and solution structure (2KXW) of a C-domain fragment of apo 13C,15N- CaM (CaMC) bound to an unlabeled peptide with the sequence of the rat NaV1.2 IQ motif showed that apo CaMC (a) was necessary and sufficient for binding, and (b) bound more favorably than calcium-saturated CaMC. CaMN apparently does not influence apo CaM binding to NaV1.2IQp (Mahling et al. 2017). The phenotypic spectrum of SCN2A-related epilepsy is broad, ranging from benign epilepsy in neonate and infancy to severe epileptic encephalopathy. Oxcarbazepine and valproate are the most effective drugs in epilepsy patients with SCN2A variants. Sodium channel blockers often worsen seizures in patients with seizure onset beyond 1 year of age. Abnormal brain MRI findings and de novo variations are often related to poor prognosis. Most SCN2A variants located in transmembrane regions were related to patients with developmental delay (Zeng et al. 2022). The beta4-subunit and PRRT2 form a push-pull system that finely tunes the membrane expression and function of NaV channels and the intrinsic neuronal excitability (Valente et al. 2022). Icariin can be used to treat epilepsy by inhibiting neuroinflammation via promoting microglial polarization to the M2 phenotype (Wang et al. 2023). Scn2a gene knockouts with a substantial reduction of voltage-gated sodium channel Nav 1.2 expression have been isolated (Eaton et al. 2021). |
Eukaryota | Metazoa, Chordata | SCN2A of Homo sapiens |
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1.A.1.10.13 | Voltage-sensitive Na+ channel of 2821 or 2844 aas (see Uniprot Q9W0Y8) aas and 24 TMSs (Cohen et al. 2009). Pyrethroid, an insecticide, binds to insect Na+ channels at two sites called pyrethroid,receptors, PyR1 (initial) and PyR2, located in the domain interfaces II/III and I/II, respectively, and binding residues have been identified (Du et al. 2015). It's homologue in honeybees, CaV4, has distinct permeation, inactivation, and pharmacology from homologous NaV channels (Bertaud et al. 2024). Specifically, honeybee CaV4 has distinct permeation, being specific for Ca2+, and exhibits inactivation, and pharmacology differing from homologous NaV channels (Bertaud et al. 2024). |
Eukaryota | Metazoa, Arthropoda | Na+ channel of Drosophila melanogaster |
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1.A.1.10.14 | The voltage-gated Ca2+ channel (VDCC; CAV2), α-subunit of 2027 aas and 24 TMSs in four domains, each with six transmembrane segments and EEEE loci in the ion-selective filter, typical of VDCCs in vertebrates. CAV2 primarily localizes in the distal part of flagella and is transported toward the flagellar tip via intraflagellar transport (IFT) although CAV2 accumulates near the flagellar base when IFT is blocked. Thus, Ca2+ influx into Chlamydomonas flagella is mediated by the VDCC, CAV2, whose distribution is biased to the distal region of the flagellum, and this is required for flagellar waveform conversion (Fujiu et al. 2009). |
Eukaryota | Viridiplantae, Chlorophyta | CAV2 of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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1.A.1.10.15 | The sodium channel of 1989 aas and 24 TMSs. 80% identical to the characterized channel of the crayfish (Astacus leptodactylus (Turkish narrow-clawed crayfish) (Pontastacus leptodactylus)) in which functional regions responsible for the selectivity filter, inactivation gate, voltage sensor, and phosphorylation have been identified (Coskun and Purali 2016). |
Metazoa, Arthropoda | Na+ channel of Cancer borealis (Jonah crab) |
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1.A.1.10.16 | The voltage-gated sodium channel of 2147 aas and 24 TMSs. Several mutations in the structural gene give rise to pyrethroid resistance (kdr) (Saavedra-Rodriguez et al. 2007). A novel strategy for screening mutations in the voltage-gated sodium channel gene of Aedes albopictus based on multiplex PCR-mass spectrometry minisequencing technology, has appeared (Mu et al. 2023). |
Eukaryota | Metazoa, Arthropoda | Na+ channel of Aedes aegypti (Yellowfever mosquito) (Culex aegypti), the most prevalent vector of dengue and yellow fever viruses. |
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1.A.1.10.17 | Voltage-gated Na+ Channel protein of 2,139 aas and 24 TMSs. Mediates voltage-dependent sodium ion permeability of excitable membranes. 3-d modeling revealed spacial clustering of evolutionarily conserved acidic residues at extracellular sites (Vinekar and Sowdhamini 2016). |
Eukaryota | Metazoa, Arthropoda | PARA sodium channel of Anopheles gambiae (African malaria mosquito) |
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1.A.1.10.18 | Sodium channel protein, α-subunit, FPC1, of 2050 aas and 24 TMSs. The 3-d structure has been solved by cryoEM to 3.8 Å resolution (Shen et al. 2017). One residue at the corresponding selectivity filter (SF) locus in each repeat, Asp/Glu/Lys/Ala (DEKA), determines Na+ selectivity. The S1 to S4 segments in each repeat form a voltage-sensing domain (VSD), wherein S4 carries repetitively occurring positive residues essential for voltage sensing. There are seven extracellular glycosylation sites (Shen et al. 2017). |
Eukaryota | Metazoa, Arthropoda | FPC1 of Periplaneta americana (American cockroach) (Blatta americana) |
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1.A.1.10.19 | Sodium channel Nav1.4-beta complex of 1820 and 209 aas, respectively. Voltage-gated sodium (Nav) channels initiate and propagate action potentials. Yan et al. 2017 presented the cryo-EM structure of EeNav1.4, the Nav channel from electric eel, in complex with the beta1 subunit at 4.0 Å resolution. The immunoglobulin domain of beta1 docks onto the extracellular L5I and L6IV loops of EeNav1.4 via extensive polar interactions, and the single transmembrane helix interacts with the third voltage-sensing domain (VSDIII). The VSDs exhibit ""up"" conformations, while the intracellular gate of the pore domain is kept open by a digitonin-like molecule. Structural comparison with closed NavPaS shows that the outward transfer of gating charges is coupled to the iris-like pore domain dilation through intricate force transmissions involving multiple channel segments. The IFM fast inactivation motif on the III-IV linker is plugged into the corner enclosed by the outer S4-S5 and inner S6 segments in repeats III and IV, suggesting a potential allosteric blocking mechanism for fast inactivation (Yan et al. 2017). The PDB# for the complex is 5XSY, and that for the two subunits are 5XSY_A and 5XSY_B. Domain 4 TMS 6 of Nav1.4 plays a key role in channel gating regulation, and is targeted by the neurotoxin, veratridine (VTD) (Niitsu et al. 2018). |
Eukaryota | Metazoa, Chordata | Nav1.4-beta subunits of Electrophorus electricus (Electric eel) (Gymnotus electricus) |
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1.A.1.10.2 | Na+ channel, α-subunit, SCAP1, of 1993 aas and 24 TMSs (Dyer et al. 1997). |
Eukaryota | Metazoa, Mollusca | SCAP1 from Aplysia californica (P90670) |
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1.A.1.10.20 | Voltage-gated sodium channel of 1836 aas and 24 TMSs, PaFPC1. The 3-d structure has been determined (Shen et al. 2017). It mediates the voltage-dependent sodium ion permeability in excitable membranes. |
Eukaryota | Metazoa, Arthropoda | PaFPC1 of Periplaneta americana (American cockroach) (Blatta americana) |
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1.A.1.10.21 | Putative two component voltage-gated Na+ channel, subunit 1 of 1149 aas and subunit 2 of 958 aas. Decreased expression of these genes, encoding this system, gives rise to mortality of the peach-potato aphid, Myzus persicae (Tariq et al. 2019). |
Eukaryota | Metazoa, Arthropoda | NaV of Myzus persicae. |
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1.A.1.10.22 | The Na+-activated Na+ channel (Nax; also called SCN7A; of 1737 aas and ~24 TMSs) and salt-inducible kinase (SIK, see TC# 8.A.104.1.14) are stimulated by increases in local Na+ concentration, affecting the Na+,K+-ATPase activity (see TC# 3.A.3.1.1). It mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na+ ions may pass in accordance with their electrochemical gradient (Gonsalez et al. 2023). Rare SCG genetic variants may contribute to the development of painful neuropathy (Almomani et al. 2023). |
Eukaryota | Metazoa, Chordata | Nax of Homo sapiens |
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1.A.1.10.3 | Ca2+-regulated heart Na+ channel, Nav1.5, SCN5A or INa channel of 2016 aas. The COOH terminus functions in the control of channel inactivation and in pathologies caused by inherited mutations that disrupt it (Glaaser et al., 2006); regulated by ProTx-II Toxin (Smith et al. 2007), telethonin, the titin cap protein (167aas; secreted protein; O15273) (Mazzone et al., 2008), and the Mog1 protein, a central component of the channel complex (Wu et al., 2008). Nav1.5, the principal Na+ channel in the heart, possesses an ankyrin binding site, and direct interaction with ankyrin-G is required for the expression of Nav1.5 at the cardiomyocyte cell surface (Bennett and Healy, 2008; Lowe et al., 2008). Mutations cause type 3 long QT syndrome and type 1 Brugada syndrome, two distinct heritable arrhythmia syndromes (Mazzone et al., 2008; Kapplinger et al. 2010; Wang et al. 2015). SCN5A mutations causing arrhythmic dilated cardiomyopathy, commonly localized to the voltage-sensing mechanism, and giving rise to gating pore currents (currents that go through the voltage sensor) have been identified (McNair et al., 2011; Moreau et al., 2014). Patients with Brugada syndrome are prone to develop ventricular tachyarrhythmias that may lead to syncope, cardiac arrest or sudden cardiac death (Sheikh and Ranjan 2014) and (Kapplinger et al. 2015). Mutations causing disease have been identified (Qureshi et al. 2015). These give rise to arrhythias and cardiomyopathies (Moreau et al. 2015). Mutations that cause relative resistance to slow inactivation have been identified (Chancey et al. 2007). Green tea catechins are potential anti-arrhythmics because of the significant effect of Epigallocatechin-3-Gallate (E3G) on cardiac sodium channelopathies that display a hyperexcitability phenotype (Boukhabza et al. 2016). A mutatioin, R367G, causes the familial cardiac conductioin disease (Yu et al. 2017). The C-terminal domain of calmodulin (CaM) binds to an IQ motif in the C-terminal tail of the alpha-subunit of all NaV isoforms, and contributes to calcium-dependent pore-gating in some (Isbell et al. 2018). Ventricular fibrillation in patients with Brugada syndrome (BrS) is often initiated by premature ventricular contractions, and the presence of SCN5A mutations increases the risk upon exposure to sodium channel blockers in patients with or without baseline type-1 ECG (Amin et al. 2018). A mutation (R367G) is associated with familial cardiac conduction disease (Yu et al. 2017). Among ranolazine, flecainide, and mexiletine, only mexiletine restored inactivation kinetics of the currents of the mutant protein, A1656D (Kim et al. 2019). Epigallocatechin-3-gallate (EGCG) is protective against cardiovascular disorders due in part to its action on multiple molecular pathways and transmembrane proteins, including the cardiac Nav1.5 channels (Amarouch et al. 2020). An SCN1B variant affects both cardiac-type (NaV1.5) and brain-type (NaV1.1) sodium currents and contributes to complex concomitant brain and cardiac disorders (Martinez-Moreno et al. 2020). Mice null for Scn1b, which encodes NaV beta1 and beta1b subunits, have defects in neuronal development and excitability, spontaneous generalized seizures, cardiac arrhythmias, and early mortality (Martinez-Moreno et al., 2020; Martinez-Moreno et al. 2020). The structural basis of cytoplasmic NaV1.5 and NaV1.4 regulation has been reviewed (Nathan et al. 2021). Fibroblast growth factor 21 ameliorates NaV1.5 and Kir2.1 channel dysregulation in human AC16 cardiomyocytes (Li et al. 2021). The interaction of Nav1.5 with MOG1 (RANGRF), a Ran guanine nucleotide release factor and chaparone, provides a possible molecular mechanism for Brugada syndrome (Xiong et al. 2021). Arrhythmic phenotypes are a defining feature of dilated cardiomyopathy-associated SCN5A variants (Peters et al. 2021). A SCN5A genetic variant, Y739D, is associated with Brugada syndrome (Zaytseva et al. 2022). Melatonin treatment causes an increase of conduction via enhancement of sodium channel protein expression and increases of sodium current in the ventricular myocytes (Durkina et al. 2022). Quantification of Nav1.5 expression has been published (Adams et al. 2022). Cardiac sodium channel complexes play a role in arrhythmia, and the structural and functional roles of the beta1 and beta3 subunits have been determined (Salvage et al. 2022). Brugada Syndrome (BrS) treatment is electrocardiography with ST-segment elevation in the direct precordial derivations. The clinical presentation of the disease is highly variable. Patients can remain completely asymptomatic, but they can also develop episodes of syncope, atrial fibrillation (AF), sinus node dysfunction (SNF), conduction disorders, asystole, and ventricular fibrillation (VF). This disease is caused by mutations in the genes responsible for the potential action of cardiac cells. The most commonly involved gene is SCN5A, which controls the structure and function of the heart's sodium channel (Brugada 2023). Postoperative supraventricular tachycardia and polymorphic ventricular tachycardia can be due to SCN5A variants (Kato et al. 2020). The importance of understanding Nav1.5 pharmacology in the context of drug development and cardiac risk assessment has been reviewed (Chaudhary et al. 2024). A point mutation can give rise to atrial flutter (Cadena-Ullauri et al. 2024). Many more mutations can give rise to Long QT syndrome type 3 (Zhang et al. 2024). NEDD4L (a HECT-type E3 ligase that catalyzes the addition of ubiquitin to intracellular substrates such as the cardiac voltage-gated sodium channel, NaV1.5, has intramolecular interactions that regulate its auto and substrate NaV1.5 ubiquitination (Wright et al. 2024).
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Eukaryota | Metazoa, Chordata | Nav1.5 of Homo sapiens (Q14524) |
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1.A.1.10.4 | The skeletal muscle Na+ channel, NaV1.4 of 1836 aas and 24 TMSs. Mutations in charged residues in the S4 segment cause hypokalemic periodic paralysis (HypoPP)) due to sustained sarcolemmal depolarization (Struyk and Cannon 2007; Sokolov et al., 2007; Groome et al. 2014). Also causes myotonia; regulated by calmodulin which binds to the C-terminus of Nav1.4 (Biswas et al., 2008). NaV1.4 gating pores are permeable to guanidine as well as Na+ and H+ (Sokolov et al., 2010). The R669H mutation allows transmembrane permeation of protons, but not larger cations, similar to the conductance displayed by histidine substitution at Shaker K+ channel S4 sites (Struyk and Cannon 2007). The mechanism of inactivation involves transient interactions between intracellular domains resulting in direct pore occlusion by the IFM motif and concomitant extracellular interactions with the beta1 subunit (Sánchez-Solano et al. 2016). Potassium-sensitive hypokalaemic and normokalaemic periodic paralysis are inherited skeletal muscle diseases in humans, characterized by episodes of flaccid muscle weakness. They are caused by single mutations in positively charged residues ('gating charges') in the S4 transmembrane segment of the voltage sensor of the voltage-gated sodium channel Nav1.4 or the calcium channel Cav1.1. Mutations of the outermost gating charges (R1 and R2) cause hypokalaemic periodic paralysis by creating a pathogenic gating pore in the voltage sensor through which cations leak in the resting state. Mutations of the third gating charge (R3) cause normokalaemic periodic paralysis owing to cation leak in both activated and inactivated states (Jiang et al. 2018). The neurotoxic cone snail peptide μ-GIIIA specifically blocks skeletal muscle voltage-gated sodium (NaV1.4) channels (Leipold et al. 2017). the cryo-electron microscopy structure of the human Nav1.4-β1 complex at 3.2-Å resolution. Accurate model building was made for the pore domain, the voltage-sensing domains, and the β1 subunit (Pan et al. 2018) provided insight into the molecular basis for Na+ permeation and kinetic asymmetry of the four repeats. Structural analysis of reported functional residues and disease mutations corroborates an allosteric blocking mechanism for fast inactivation of Nav channels. the S4-S5L of the DI, DII and DIII domains allosterically modulate the activation gate and stabilize its open state (Malak et al. 2020). The structural basis of cytoplasmic NaV1.5 and NaV1.4 regulation has been reviewed (Nathan et al. 2021). Mutations in SCN4A give rise to a variety of pathological conditions (Sun et al. 2021). Hypokalemic periodic paralysis (HypoPP) is a rare autosomal dominant disease caused by mutations in either calcium or sodium transmembrane voltage-gated ion channels in the ER of skeletal muscle (Calise et al. 2023). Diverse biophysical mechanisms for the voltage-gated sodium channel Nav1.4 variants are associated with myotonia (Tikhonova et al. 2024).
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Eukaryota | Metazoa, Chordata | NaV1.4 of Homo sapiens (P35499) |
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1.A.1.10.5 |
Voltage-sensitive Na+ channel, type 9, α-subunit, Nav1.7 or SCN9A (orthologous to 1.A.1.10.1). Loss of function, resulting from point mutations, results in a channelopathy called Congenital Insensitivity to Pain (CIP) (He et al. 2018), that causes the congenital inability to experience pain (Cregg et al., 2010; Kleopa, 2011). An S241T mutation causes inherited erythromelalgia IEM; erythermalgia, an autosomal dominant neuropathy characterized by burning pain in the extremities in response to mild warmth (due to altered gating) (Lampert et al., 2006; Drenth and Waxman, 2007). Gain-of-function mutations in the Na(v)1.7 channel lead to DRG neuron hyperexcitability associated with severe pain, whereas loss of the Na(v)1.7 channel in patients leads to indifference to pain (Dib-Hajj et al., 2007). Blocked by 1-benzazepin-2-one (Kd = 1.6 nM) (Williams et al., 2007). Mutations in the Nav1.7 Na channel α-subunit give rise to familial pain syndromes called chronic non-paoxysmal neuropathic pain (Catterall et al., 2008; Fischer and Waxman, 2010; Dabby et al. 2011 ). It interacts with the sodium channel beta3 (Scn3b), rather than the beta1 subunit, as well as the collapsing-response mediator protein (Crmp2) through which the analgesic drug lacosamide regulates Nav1.7 current (Kanellopoulos et al. 2018). The R1488 variant is totally inactive (He et al. 2018). Nav1.7 is inhibited by knottins (see TC# 8.B.19.2) (Agwa et al. 2018). Nav1.7 interacts with the following proteins: syn3b (TC# 8.a.17.1.2; the β3 subunit), Crmp2, Syt2 (Q8N9I0) and Tmed10 (P49755), and it also regulates opioid receptor efficacy (Kanellopoulos et al. 2018). Mutations in TRPA1 and Nav1.7 to insensitivity to pain-promoting algogens such as capsaicin, acid, and allyl isothiocyanate (AITC), have been documented (Eigenbrod et al. 2019). Nav1.7 is associated with endometrial cancer (Liu et al. 2019) and fever-associated seizures or epilepsy (FASE) (Ding et al. 2019). Nav1.7 and Nav1.8 peripheral nerve sodium channels are modulated by protein kinases A and C (Vijayaragavan et al. 2004). Sodium channel NaV1.7 and potassium channel KV7.2 promote and oppose excitability in nociceptors, respectively. Inflammation differentially controls transport of depolarizing Nav versus hyperpolarizing Kv channels to drive rat nociceptor activity (Higerd-Rusli et al. 2023). The structural basis for severe pain, caused by mutations in the S4-S5 linkers of voltage-gated sodium channel NaV1.7, have been revealed (Wisedchaisri et al. 2023). Cyclopentane carboxylic acids are potent and selective inhibitors of NaV1.7 (Sun et al. 2025). Non-synonymous functional SNPs in the human SCN9A gene have been identified (Waheed et al. 2024). Nav1.7, encoded by the SCN9A gene, has been linked to diverse painful peripheral neuropathies, represented by the inherited erythromelalgia (EM) and paroxysmal extreme pain disorder (PEPD) (Yuan et al. 2023). For example, mutations have given rise to paroxysmal extreme pain disorder (PEPD) (Hua et al. 2022). |
Eukaryota | Metazoa, Chordata | Nav1.7 of Homo sapiens (Q15858) |
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1.A.1.10.6 | Tetrodotoxin-resistant voltage-gated Na+ channel of dorsal ganglion sensory neurons, Nav1.8, plays a crucial role in the occurrence and development of chronic pain (Akopian et al., 1996) and is essential for pain at low temperatures (Zimmermann et al., 2007). Nav1.8 is the sole electrical impulse generator in a nociceptor that transmits information to the central nervous system. Bark scorpion venom induces pain in many mammals (house mice, rats, humans) by activating Nav1.7 but has no effect on Nav1.8. Grasshopper mice Nav1.8 has amino acid variants that bind bark scorpion toxins and inhibit Na+ currents, blocking action potential propagation and inducing analgesia. These mice thereby can use scorpions as a food source (Zhu et al. 2013; Rowe et al. 2013). Nav1.8 is involved in bull spermatozoa dynamics including motility, membrane integrity, acrosome integrity, capacitation and mitochondrial transmembrane potential (Chauhan et al. 2017). Selective inhibition of NaV1.8 with VX-548 aleviates acute pain in humans (Jones et al. 2023). N-(((1S,3R,5S)-adamantan-1-yl)methyl)-3-((4-chlorophenyl)sulfonyl)benzenesulfonamide is a novel Nav1.8 inhibitor with an analgesic profile (Song et al. 2024). |
Eukaryota | Metazoa, Chordata | Nav1.8 of Rattus norvegicus |
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1.A.1.10.7 | Voltage-sensitive Na+ channel, Nav1.1 or SCN1A (causes epilepsy when mutated) (Rusconi et al., 2007). Mutations are associated with a wide range of mild to severe epileptic syndromes with phenotypes ranging from the relatively mild generalized epilepsy with febrile seizures to other severe epileptic encephalopathies (Colosimo et al. 2007), including myoclonic epilepsy in infancy (SMEI), cryptogenic focal epilepsy (CFE), cryptogenic generalized epilepsy (CGE) and a distinctive subgroup termed as severe infantile multifocal epilepsy (SIMFE) (Ben Mahmoud et al. 2015). Mutations can give rise to familial sporadic hemiplegic migranes (Prontera et al. 2018). An SCN1B variant affects both cardiac-type (NaV1.5) and brain-type (NaV1.1) sodium currents and contributes to complex concomitant brain and cardiac disorders (Martinez-Moreno et al. 2020). Mice null for Scn1b, which encodes NaV beta1 and beta1b subunits, have defects in neuronal development and excitability, spontaneous generalized seizures, cardiac arrhythmias, and early mortality (Martinez-Moreno et al. 2020). The Melkersson-Rosenthal Syndrome and Migraine may be associated with SCN1A variants (Azzarà et al. 2023). A variant in the SCN1A gene confirms Dravet syndrome in a Moroccan child (El Mouhi et al. 2024). Biallelic SCN1A variants show divergent epilepsy phenotypes (Pentz et al. 2025). |
Eukaryota | Metazoa, Chordata | Nav1.1 of Homo sapiens (P35498) |
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1.A.1.10.8 | The Voltage-gated Na+ channel α-subunit, Nav1.6, encoded by the Scn8a gene which when defective gives rise to the ENU-induced neurological mutant ataxia3 which gives rise to ataxia, tremors, and juvenile lethality. 75% identical to 1.A.1.10.7. Nav1.6 is the dendritic, voltage-gated sodium channel (responsible for dendritic excitability (Lorincz and Nusser, 2010)). Nav1.6 (SCN8A) interacts with microtubule-associated protein (O'Brien et al., 2012). Scorpion alpha toxins bind at receptor site-3 and inhibit channel inactivation, whereas beta toxins bind at receptor site-4 and shift the voltage-dependent activation toward more hyperpolarizing potentials (Gurevitz, 2012). Mutations give rise to epileptic encephalopathy and intellectual disability (O'Brien and Meisler 2013). A gain-of-function mutation gave rise to increased channel activation and infantile epileptic encephalopathy (Estacion et al. 2014). Benign familial infantile seizures (BFIS), paroxysmal kinesigenic dyskinesia (PKD), and their combination - known as infantile convulsions and paroxysmal choreoathetosis (ICCA) - are related autosomal dominant diseases involving SCN8A (Gardella et al. 2015). Mutations can lead to chronic movement disorder in the mouse (Jones et al. 2016), and loss of function mutations in humans can lead to intellectual disability without seizures (Wagnon et al. 2017). Nav1.6 has been quantitated in mouse brain and proved to be present in 2-fold decreased amounts in epileptic mice (Sojo et al. 2019). SCN8A developmental and epileptic encephalopathy results in intractable seizures including spasms, focal seizures, neonatal status epilepticus, and nonconvulsive status epilepticus (Kim et al. 2019). Mutations in the SCN8A gene causes early infantile epileptic encephalopathy (Pan and Cummins 2020). Amitriptyline is a tricyclic antidepressant that binds to the anesthetic binding site in the α-subunit of the channel protein (Wang et al. 2004). A heterobivalent ligand (mu-conotoxin KIIIA, which occludes the pore of the NaV channels, and an analogue of huwentoxin-IV, a spider-venom peptide that allosterically modulates channel gating (TC#8.B.3.1.3)) slows ligand dissociation and enhances potency (Peschel et al. 2020). Several FDA‑approved drugs that are highly correlated with Nav1.6 could be candidate drugs for patients with glioma (Ai et al. 2023). Clinical and electrophysiological features of SCN8A variants cause episodic or chronic ataxia (Lyu et al. 2023). Epilepsy can be due to variants of the SCN8A gene (Zhang et al. 2024). |
Eukaryota | Metazoa, Chordata | Nav1.6 of Homo sapiens (Q9UQD0) |
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1.A.1.10.9 | The voltage-gated Na+ channel α-subunit, Nav1.9. It is present in excitable membranes and is resistant to tetrodotoxin and saxitoxin (Bosmans et al., 2011). The mutation, S360Y, makes NaV1.9 channels sensitive to tetrodotoxin and saxitoxin, and the unusual slow open-state inactivation of NaV1.9 is mediated by the isoleucine-phenylalanine-methionine inactivation motif located in the linker connecting domains III and IV (Goral et al. 2015). Gain-of function mutations can lead to heritable pain disorders, and painful small-fibre neuropathy (Han et al. 2016). It is a threshold channel that regulates action potential firing, and is preferentially expressed in myenteric neurons, the small-diameter dorsal root ganglion (DRG) and trigeminal ganglion neurons including nociceptors. There is a monogenic Mendelian link of Nav1.9 to human pain disorders including episodic pain due to a N816K mutation (Huang et al. 2019). The human neuronal sodium channel Nav1.9 is inhibitied by ACEA (arachidonyl-2-chloroethylamide), an analogue of anandamide (Marchese-Rojas et al. 2022). .
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Eukaryota | Metazoa, Chordata | Nav1.9 of Homo sapiens (Q9UI33) |
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1.A.1.11.1 | Voltage-sensitive Ca2+ channel (transports Ca2+, Ba2+ and Sr2+) | Eukaryota | Metazoa, Chordata | Voltage-sensitive Ca2+ channel, α-1 chain of Rattus norvegicus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.1.11.10 |
Plasma membrane voltage-gated, high affinity Ca2+ channel, Cch1/Mid1; activated by mating pheromones and environmental stresses; required for growth in low Ca2+ (Locke et al., 2000; Paidhungat and Garrett, 1997). Also essential for tolerance to cold stress and iron toxicity (Peiter et al., 2005). Ecm7, (448aas; 4 TMS; TC# 1.H.1.4.6), a member of the PMP-22/EMP/MP20 Claudin superfamily of transmembrane proteins that includes gamma-subunits of voltage-gated calcium channels appears to interact with Mid1 TC# 8.A.41.1.1) and regulate the activity of the Cch1/Mid1 channel (Martin et al., 2011). Ecm7p is related to members of TC families 1.H.1, 1.H.2 and 1.A.81. The two indispensable subunits, Cch1 and Mid1 are equivalent to the mammalian pore-forming α1 and auxiliary α2 /δ subunits, respectively. Cho et al. 2016 screened candidate proteins that interact with Mid1 and identified the plasma membrane H+-ATPase, Pma1 (TC#3.A.3.3.6). Mid1 co-immunoprecipitated with Pma1. At the nonpermiss, and Mid1-EGFP colocalized with Pma1-mCherry at the plasma membrane. Using a temperature-sensitive mutant, pma1-10, the membrane potential was less negative, and Ca2+ uptake was lower than in wild-type cells. Thus, Pma1 interacts physically with Cch1/Mid1 Ca2+ channels to enhance their activity via its H+-pumping activity (Cho et al. 2016). |
Eukaryota | Fungi, Ascomycota | Cch1/Mid1 of Saccharomyces cerevisiae |
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1.A.1.11.11 | The Cav1.4 L-type Ca2+ channel (gene CACNA1F). Mutations resulting in increased activity cause x-linked incomplete congenital stationary night blindness (CSNB2) (Hemara-Wahanui et al., 2005; Peloquin et al., 2007). Aland Island eye disease (AIED), also known as Forsius-Eriksson syndrome, is an X-linked recessive retinal disease characterized by a combination of fundus hypopigmentation, decreased visual acuity, nystagmus, astigmatism, protan color vision defect, progressive myopia, and defective dark adaptation. Since the clinical picture of AIED is quite similar to CSNB2, these disorders are allelic or form a single entity. Thus, AIED is also caused by CACNA1F gene mutations (Jalkanen et al. 2007). Cav1.4 calcium channels play roles in the pathophysiology of psoriasis (Pelletier and Savignac 2022). Cav1.4 L-type calcium channels are predominantly expressed at the photoreceptor terminals and in bipolar cells, mediating neurotransmitter release. Mutations in its gene, CACNA1F, can cause congenital stationary night-blindness type 2 (CSNB2). Water wires in both, resting and active channel states have been proposed (Heigl et al. 2023). |
Eukaryota | Metazoa, Chordata | Cav1.4 of Homo sapiens |
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1.A.1.11.12 | T-type Ca2+ channel (CACNA1G; Cav3.1d), (σ1G T-type Ca2+ channel) in developing heart (fetal myocardium (Cribbs et al., 2001)) and elsewhere. Both Cav3.1 and Cav3.2 are permeated by divalent metal ions, such as Fe2+ and Mn2+, and possibly Cd2+ (Thévenod, 2010). CaV3.1 channels are activated at low votage and regulate neuronal excitability in the spinal cord (Canto-Bustos et al. 2014). It is regulated by protein kinase C (PKC) and the RanBPM protein (Q96S59) (Kim et al. 2009). T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by mibefradil. A particularity of this type of channel is an opening at quite negative potentials and voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells, and support calcium signaling in secretory cells and vascular smooth muscle (Coutelier et al. 2015). The human ortholog is 85% identical to the mouse protein. These channels also determines the angiogenic potential of pulmonary microvascular endothelial cells (Zheng et al. 2019). Selective inhibition of T-type calcium channels preserves ischemic pre-conditioning mediated neuroprotection during cerebral ischemia reperfusion injury in diabetic mice (Sharma et al. 2024).
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Eukaryota | Metazoa, Chordata | Cav3.1d of Mus musculus (Q9WUT2) |
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1.A.1.11.13 | Two-pore Ca2+ channel protein 1, TPC1 (Km(Ca2+))=50 µM; voltage gated; 461 aas; 12 TMSs) (Hashimoto et al., 2004; Kurusu et al, 2004; 2005). Each TPC subunit contains 12 TMSs that can be divided into two homologous copies of an S1-S6 Shaker-like 6-TMS domain. A functional TPC channel assembles as a dimer. The plant TPC channel is localized in the vacuolar membrane and is also called the SV channel for generating the slow vacuolar (SV) current. Three subfamilies of mammalian TPC channels have been defined - TPC1, 2, and 3 - with the first two being ubiquitously expressed in animals and TPC3 being expressed in some animals, but not in humans. Mammalian TPC1 and TPC2 are localized to endolysosomal membranes (She et al. 2022). |
Eukaryota | Viridiplantae, Streptophyta | TPC1 of Oryza sativa (Q5QM84) |
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1.A.1.11.14 | Voltage-dependent calcium channel, α-1 subunit (1911aas), CyCaα1 | Eukaryota | Metazoa, Cnidaria | CyCaα1 of Cyanea capillata (O02038) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.1.11.15 | Neuronal nonselective cation channel, NALCN (forms background leak conductance and controls neuronal excitability; Lu et al., 2007). It is also found in the pancreatic β-cell (Swayne et al. 2010). NALCN serves as a variable sensor that responds to calcium or sodium ion flux, depending on whether the total cellular current density is generated more from calcium-selective or sodium-selective channels (Senatore and Spafford 2013). It functions in a complex with Unc80 (3258 aas; Q8N2C7) and Unc79 (2635 aas; Q9P2D8) (Bramswig et al. 2018). Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (Bramswig et al. 2018). Overexpression of the NALCN gene ablates allyl isothiocyanate-promoting pain reception by nociceptors (Eigenbrod et al. 2019). |
Eukaryota | Metazoa, Chordata | NALCN of Homo sapiens (Q6P2S6) |
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1.A.1.11.16 | 4 domain-type voltage-gated ion channel, α-1 subunit NCA-2 (Jospin et al., 2007) (dependent on Unc-80 (3225aas; CAB042172) for proper localization). | Eukaryota | Metazoa, Nematoda | NCA-2 of Caenorhabditis elegans (Q06AY4) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.1.11.17 | The high affinity Ca2+ channel; associates with elongation factor 3 (EF3) to target Cch1/Mid1 to the plasma membrane (Liu and Gelli, 2008). |
Eukaryota | Fungi, Basidiomycota | Cch1/Mid1 of Cryptococcus neoformans |
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1.A.1.11.18 | The nicotinic acid adenine dinucleotide phosphate (NAADP)- dependent two pore Ca2+- channel, TPC3 (Brailoiu et al., 2010). Phosphoinositides regulate dynamic movement of the S4 voltage sensor in the second repeat in two-pore channel 3 (Hirazawa et al. 2021). Each TPC subunit contains 12 TMSs that can be divided into two homologous copies of an S1-S6 Shaker-like 6-TMS domain. A functional TPC channel assembles as a dimer. The plant TPC channel is localized in the vacuolar membrane and is also called the SV channel for generating the slow vacuolar (SV) current. Three subfamilies of mammalian TPC channels have been defined - TPC1, 2, and 3 - with the first two being ubiquitously expressed in animals and TPC3 being expressed in some animals, but not in humans. Mammalian TPC1 and TPC2 are localized to endolysosomal membranes (She et al. 2022).
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Eukaryota | Metazoa, Chordata | Two pore Ca2+ channel 3, TPC3 of Bos taurus (C4IXV8) |
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1.A.1.11.19 |
The phosphoinositide (PI(3,5)P2)-activated Na+ two pore channel-2, TPC2, in endosomes and lysosomes (Wang et al. 2012). Previously thought, incorectly, according to Wang et al. 2012, to be a nicotinic acid adenine dinucleotide phosphate (NAADP)-dependent two pore Ca2+ channel. TPC2, like TPC1, has a 12 TMS topology (two channel units) (Hooper et al., 2011). The two domains of human TPCs can insert into the membrane independently (Churamani et al., 2012). Cang et al. (2013), showed that TPC1 and TPC2 together form an ATP-sensitive two-pore Na+ channel that senses the metabolic state of the cell. The channel complex detects nutrient status, becomes constitutively open upon nutrient removal, and controls the lysosome's membrane potential, pH stability, and amino acid homeostasis. Essential for Ebola virus (EBOV) host entry. Several inhibitors of TPC2 that act in the nM (tetrandrine) or μM (verapamil; Ned19) range block channel activity, prevent Ebola Virus from escaping cell vesicles and may be used to treat the disease (Sakurai et al. 2015). TPC2 may transport both Na+ and Ca2+ (Sakurai et al. 2015). Lipid-gated monovalent ion fluxes, mediated by TPC1 and TPC2 in mice, regulate endocytic traffic and support immune surveillance. This is in part achieved by catalyzing Na+ export from visicles derived from the plasma membrane by phagocytosis or pinocytosis, causing contraction and allowing the maintenance of a uniform cell volume (Freeman et al. 2020). This system is important for melanocyte function (Wiriyasermkul et al. 2020). Convergent activation of two-pore channels mediated by the NAADP-binding proteins JPT2 and LSM12 has been reported (Gunaratne et al. 2023). The lysosomal two-pore channels 2 (TPC2) and IP3 receptors (IP3Rs) located in the endoplasmic reticulum may be coupled (Yuan et al. 2024). Plasticity of the selectivity filter is essential for permeation in lysosomal TPC2 channels (Zaki et al. 2024). |
Eukaryota | Metazoa, Chordata | TPC2 of Homo sapiens (Q8NHX9) |
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1.A.1.11.2 | Muscle plasmalemma, voltage-gated, L-type dihydropyridine receptor Ca2+ channel, α-1 subunit (DHPR) (Ba2+ > Ca2+), Cav1.1, CACNA1S,CACH1 CDCN1, CACNL1A3 of 1873 aas in the human orthologue. Distinc voltage sensor domains control voltage sensitivity and kinetics of current activation (Tuluc et al. 2016). Rapid changes in the transmembrane potential are detected by the voltage-gated Ca2+ channel, dihydropyridine receptor (DHPR), embedded in the sarcolemma. DHPR transmits the contractile signal to another Ca2+ channel, the ryanodine receptor (RyR1), embedded in the membrane of the sarcoplasmic reticulum (SR), which releases a large amounts of Ca2+ from the SR that initiate muscle contraction (Shishmarev 2020). |
Eukaryota | Metazoa, Chordata | DHPR of Oryctolagus cuniculus |
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1.A.1.11.20 | The voltage-gated Ca2+ channel, L-type α-subunit, Eg1-19 regulated by Macoilin (8.A.38.1.2) |
Eukaryota | Metazoa, Nematoda | Eg1-19 of Caenorhabditis elegans (A8PYS5) |
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1.A.1.11.21 | Voltage-gated L-type Ca2+ channel, Egl-19, isoform a. There are three isoforms encoded by the same gene, isoforms a, b and c, and all are expressed in all types of muscle (McDonald et al. 2023). |
Eukaryota | Metazoa, Nematoda | Egl-19 of C. elegans (G5EG02) |
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1.A.1.11.22 |
The phosphoinositide (PI(3,5)P2)-activated Na+ two pore channel-1, TPC1 of endosomes and lysosomes (Wang et al. 2012). Previously thought, incorectly, according to Wang et al. (2012), to be an NAADP-activated two pore voltage-dependent calcium channel protein. However, Cang et al. (2013), showed that TPC1 and TPC2 (TC# 1.A.1.11.19) together form an ATP-sensitive two-pore Na+ channel that senses the metabolic state of the cell. The channel complex detects nutrient status, becomes constitutively open upon nutrient removal, and controls the lysosome's membrane potential, pH stability, and amino acid homeostasis. May be regulated by the HCLS-associated X-1 (HAX-1) protein (Lam et al. 2013). The cryoEM 3-D structure has been ellucidated (She et al. 2018). This voltage-dependent, phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2)-activated Na+ channel was solved in both the apo closed state and ligand-bound open state. The channel has a coin-slot-shaped ion pathway in the filter that defines the selectivity of mammalian TPCs. Only the voltage-sensing domain from the second 6-TMS domain confers voltage dependence while endolysosome-specific PtdIns(3,5)P2 binds to the first 6-TMS domain and activates the channel under conditions of depolarizing membrane potential. Structural comparisons between the apo and PtdIns(3,5)P2-bound structures show the interplay between voltage and ligand activation. These MmTPC1 structures reveal lipid binding and regulation in a 6-TMS voltage-gated channel (She et al. 2018). |
Eukaryota | Metazoa, Chordata | Tpcn1 of Mus musculus |
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1.A.1.11.23 | Cch1 calcium channel, alpha subunit; acts with Mid1 (8.A.41.1.7) which is required for function. |
Eukaryota | Fungi, Ascomycota | Mid1 of Schizosaccharomyces pombe |
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1.A.1.11.24 | Voltage-sensitive calcium channel of 2693 aas (Docampo et al. 2013). Found to be essential for bloodstream-form Trypanosoma brucei through a genome-wide RNAi screen (Schmidt et al. 2018). |
Eukaryota | Kinetoplastida | Calcium channel of Trypanosoma brucei |
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1.A.1.11.25 | Endosomal/lysosomal, two pore Na+and Ca2+-release channel (Na+> Ca2+) protein of 816 aas and 12 TMSs, TPC1 or TPCN1 (Guo et al. 2017). Endosomes and lysosomes are electrically excitable organelles (Cang et al. 2014). In a subpopulation of endolysosomes, a brief electrical stimulus elicits a prolonged membrane potential depolarization spike. The organelles have a depolarization-activated, non-inactivating Na+ channel (lysoNaV). The channel is formed by a two-repeat six-transmembrane-spanning (2x6 TMS) protein, TPC1, which represents the evolutionary transition between 6 TMS and 4x6 TMS voltage-gated channels. Luminal alkalization also opens lysoNaV by markedly shifting the channel's voltage dependence of activation toward hyperpolarization. Thus, TPC1 is a voltage-gated Na+ channel that senses pH changes and confers electrical excitability to organelles (Cang et al. 2014). Essential for Ebola virus (EBOV) host entry. Several inhibitors act in the nM (tetrandrine) or μM (verapamil; Ned19) range to block Na+ and Ca2+ channel activity, inhibit virus escape from membrane vesicles and may possibly be used to treat the disease (Sakurai et al. 2015). A cluster of arginine residues in the first domain required for selective voltage-gating of TPC1 map not to the voltage-sensing fourth transmembrane region (S4) but to a cytosolic downstream region (S4-S5 linker). These residues are conserved between TPC isoforms suggesting a generic role in TPC activation. Accordingly, mutation of residues in TPC1 but not the analogous region in the second domain prevents Ca2+ release by NAADP in intact cells (Patel et al. 2017). Dramatic conformational changes in the cytoplasmic domains communicate directly with the VSD during activation (Kintzer et al. 2018). PGRMC1 (the progesterone receptor membrane component1), an ER transmembrane protein that undergoes a unique heme-dependent dimerization, is an interactor of the endosomal two pore channel, TPC1. It regulates ER-endosomal coupling with functional implications for cellular Ca2+ dynamics (Gunaratne et al. 2023). Convergent activation of two-pore channels mediated by the NAADP-binding proteins JPT2 and LSM12 has been reported (Gunaratne et al. 2023). |
Eukaryota | Metazoa, Chordata | TPC1 of Homo sapiens |
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1.A.1.11.26 | Two pore Ca2+ > Na+, Li+ or K+ (non-selective for these three monovalen caions) channel protein of 733 aas and 12 TMSs, TPC1 (Guo et al. 2017). The crystal structure of this vacuolar two-pore channel, a homodimer, has been solved (Guo et al. 2015) (Kintzer and Stroud 2016). Activation requires both voltage and cytosolic Ca2+. Ca2+ binding to the cytosolic EF-hand domain triggers conformational changes coupled to the pair of pore-lining inner helices from the first 6-TMS domains, whereas membrane potential only activates the second voltage-sensing domain, the conformational changes of which are coupled to the pair of inner helices from the second 6-TMS domains. Luminal Ca2+ or Ba2+ modulates voltage activation by stabilizing the second voltage-sensing domain in the resting state and shift voltage activation towards more positive potentials. The basis for understanding ion permeation, channel activation, the location of voltage-sensing domains and regulatory ion-binding sites is partially explained by the 3-d structure (Kintzer and Stroud 2016). Only the second Shaker domain senses voltage (Jaślan et al. 2016). It has a selectivity filter that is passable by hydrated divalent cations (Demidchik et al. 2018). Dickinson et al. 2022 determined structures at different stages along its activation coordinate. These structures of activation intermediates, when compared with the resting-state structure, portray a mechanism in which the voltage-sensing domain undergoes dilation and in-membrane plane rotation about the gating charge-bearing helix, followed by charge translocation across the charge transfer seal. These structures, in concert with patch-clamp electrophysiology, showed that residues in the pore mouth sense inhibitory Ca2+ and are allosterically coupled to the voltage sensor. These conformational changes provide insight into the mechanism of voltage-sensor domain activation in which activation occurs vectorially over a series of elementary steps (Dickinson et al. 2022). Inhibition of the Akt/PKB kinase increases Nav1.6-mediated currents and neuronal excitability in CA1 hippocampal pyramidal neurons (Marosi et al. 2022). |
Eukaryota | Viridiplantae, Streptophyta | TPC1 of Arabidopsis thaliana |
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1.A.1.11.27 | Voltage-dependent P/Q-type Ca2+ channel subunit α1A, CACNA1A (CACH4; CACN3; CACNL1A4) of 2,505 aas. The CACNA1A gene is widely expressed throughout the CNS. The encoding protein is 90% identical to 1.A.1.11.8. Associated with four neurological phenotypes: familial and sporadic hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), spinocerebellar ataxia type 6 (SCA6) and epileptic encephalopathy with nerve atrophy (Reinson et al. 2016). A gain of function mutation gave symptoms of congenital ataxia, abnormal eye movements and developmental delay with severe attacks of hemiplegic migraine (García Segarra et al. 2014). Mutations can cause F/SHM with high penitrance (Prontera et al. 2018). CACNA1A variants lead to a wide spectrum of neurological disorders including epileptic or non-epileptic paroxysmal events, cerebellar ataxia, and developmental delay. The variants are either gain of function GOF) or loss of function (LOF) mutations (Zhang et al. 2020). CACNA1A pathogenic variants have been linked to several neurological disorders including severe early onset developmental encephalopathies and cerebellar atrophy. Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation (Gandini et al. 2021). Patients with CACNA1A mutational variants located in the transmembrane region may be at high risk of status epilepticus (Niu et al. 2022). Patients with ataxia in the absence of epilepsy can be caused by a CACNA1A mutationand respond to pyridoxine (Du et al. 2017). lamotrigine can be used to treat patients with refractory epilepsy due to calcium channel mutations (Hu et al. 2022; De Romanis and Sopranzi 2018). Eupatilin depresses glutamate exocytosis from cerebrocortical synaptosomes by decreasing P/Q-type Ca2+ channels and synapsin I phosphorylation and alleviates glutamate excitotoxicity caused by kainic acid by preventing glutamatergic alterations in the mamalian cortex. Thus, eupatilin is a potential therapeutic agent in the treatment of brain impairment associated with glutamate excitotoxicity (Lu et al. 2022). Episodic ataxia (EA2) is caused by mutations in CACNA1A, encoding a neuronal voltage-gated calcium channel (Graves et al. 2024). Albiflorin decreases glutamate release from rat cerebral cortex nerve terminals (synaptosomes) through depressing P/Q-type calcium channels and protein kinase A activity (Lu et al. 2024). Phenotypic variability has been reported in cases with CACNA1A mutations (Bozkaya-Yilmaz et al. 2025). |
Eukaryota | Metazoa, Chordata | CACNA1A Ca2+ channel of Homo sapiens |
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1.A.1.11.28 | Voltage-dependent L-type calcium channel subunit α, VDCC, CCA-1 or CaACNa1S, of 1873 aas and 24 TMSs. Ca2+ channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle. They are regulated by dystrophin-1 (Zhan et al. 2014). |
Eukaryota | Metazoa, Nematoda | VDCC of Caenorhabditis elegans |
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1.A.1.11.29 | Voltage-gated calcium channel (VDCC) of 3097 aas and 24 TMSs, Cav7 (Wheeler and Brownlee 2008). The photoreceptor potential in Chlamydomonas triggers the generation of all or no flagellar Ca2+ currents that cause membrane depolarization across the eyespot and flagella (Sanyal et al. 2023). Modulation in membrane potential causes changes in the flagellar waveform, and hence, alters the beating patterns of Chlamydomonas flagella. The eyespot membrane potential is rhodopsin-mediated and is generated by the photoreceptor Ca2+ current or P-current. However, flagellar Ca2+ currents are mediated by unidentified voltage-gated calcium (VGCC or CaV) and potassium channels (VGKC). The voltage-dependent ion channel that associates with ChRs to generate Ca2+ influx across the flagella and its cellular distribution has been identified. Sanyal et al. 2023 presented evidence on Chlamydomonas reinhardtii predicting that CrVGCC4 localizes to the eyespot and flagella and associates with channelrhodopsins. Further in silico interactome analysis of CrVGCCs suggested that they interact with photoreceptor proteins, calcium signaling, and intraflagellar transport components. Expression analysis indicated that these VGCCs and their putative interactors can be perturbed by light stimuli. Thus, VGCCs in general, and VGCC4 in particular, might be involved in the regulation of the phototactic response of Chlamydomonas. |
Viridiplantae, Chlorophyta | Cav7 of Chlamydomonas reinhardtii |
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1.A.1.11.3 | Voltage-dependent R-type Ca2+ channel, α-1E subunit (Cav2.3) (brain Ca2+ channel type II) (Ca2+ > Ba2+). Interacts with V-type ATPases (3.A.2), specifically, the G1-subunit, to regulate its activity (Radhakrishnan et al., 2011). Syntaxin-3 (Syn-3) interacts directly with Cav2.3 to regulate its activity (Xie et al. 2016). A Cav3.2 calcium channel missense variant is associated with epilepsy and hearing loss (Stringer et al. 2023). Structural insights into the allosteric effects of the antiepileptic drug topiramate on the CaV2.3 channel have been published (Gao et al. 2024). |
Eukaryota | Metazoa, Chordata | R-type Ca2+ channel of Mus musculus |
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1.A.1.11.30 | TPC calcium channel protein with two transmembrane domains of 6 TMSs each (720 aas and 12 TMSs) (Wheeler and Brownlee 2008). |
Viridiplantae, Streptophyta | TPC of Physcomitrella patens |
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1.A.1.11.31 | Voltage-sensitive calcium channel (VSCC), CAV1.3, encoded by the CACNA1D gene, of 2161 aas and 24 TMSs (Singh et al. 2008). CaV1.3-R990H channels conduct omega-currents at hyperpolarizing potentials, but not upon membrane depolarization compared with wild-type channels (Monteleone et al. 2017). A CACNA1D de novo mutation causes a severe neurodevelopmental disorder (Hofer et al. 2020). Snapin (a synaptic junction complex (see TC# 1.F.1.1.1) directly interacts with the C-terminal extension (long) of Cav1.3L, leading to up-regulation of Cav1.3L channel activity via facilitating channel opening probability (Jeong et al. 2021). Germline gain-of-function missense variants in the Cav1.3 alpha1-subunit (CACNA1D gene) confer high risk for a severe neurodevelopmental disorder (Török et al. 2023). |
Bacteria | Metazoa, Chordata | CAv1.3 of Homo sapiens |
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1.A.1.11.32 | Pore-forming, alpha-1S subunit of the voltage-gated calcium channel, of 1873 aas and 24 TMSs, Cav1.1; CACNA1S; CACN1; CACH1; CACNL1A3, that gives rise to L-type calcium currents in skeletal muscle. Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle via their interaction with RYR1, which triggers Ca2+ release from the sarcplasmic reticulum and ultimately results in muscle contraction. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group (Jiang et al. 2018). The 3-d structure of a bacterial homologue has been solved (Jiang et al. 2018). Mutations in arginly residues in the TMS4 voltage lead to increased leak currently that may be responsible for hypokalaemic periodic paralysis (Kubota et al. 2020). Mutations in the voltage sensor domain of CaV1.1, the alpha1S subunit of the L-type calcium channel in skeletal muscle cause hypokalemic periodic paralysis (HypoPP), and these mutations give rise to gating pore currents (Wu et al. 2021). The voltage-gated T-type calcium channel is modulated by kinases and phosphatases (Sharma et al. 2023). Advances in CaV1.1 gating, dealing with permeation and voltage-sensing mechanisms, have been reviewed (Bibollet et al. 2023). It is possible to prevent calcium leak associated with short-coupled polymorphic ventricular tachycardia in patient-derived cardiomyocytes (Sleiman et al. 2023). Far-infrared ameliorates Pb-induced renal toxicity via voltage-gated calcium channel-mediated calcium influx (Ko et al. 2023). Verapamil mitigates chloride and calcium bi-channelopathy in a myotonic dystrophy mouse model (Cisco et al. 2024).
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Metazoa, Chordata | Cav1.1 of Homo sapiens |
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1.A.1.11.33 | Calcium channel protein of 2556 aas and 24 TMSs. Inhibited by 1,4-dihydrophyridines such as nifedipine (Tempone et al. 2009). The effects of nifedipine and calcium ions on cellular electrophysiology have been examined (Tsai et al. 2021). |
Eukaryota | Euglenozoa | Ca2+ channel of Leishmania donovani |
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1.A.1.11.34 | Calcium channel of 913 aas and 12 TMSs. Ca2+ channels in trophozoites are inhibited by Amlodipine (Baig et al. 2013). |
Eukaryota | Discosea | Calcium channel of Acanthamoeba castellanii |
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1.A.1.11.35 | Calcium channel of 2725 aas and 24 TMSs. T. cruzi calcium channels are inhibited by fendiline and bepridil (Reimão et al. 2011). |
Eukaryota | Euglenozoa | Ca2+ channel of Trypanosoma cruzi |
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1.A.1.11.36 | Two pore segment channel 1 of 790 aas and 12 TMSs in a 3 + 3 (N-terminal half) + 2 + 2 + 2 (C-terminal half) TMS arrangement. In the trunk of developing zebrafish embryos, adjacent myotome blocks transmit contractile force via myoseptal junctions (MJs), dynamic structures that connect the actin cytoskeleton of skeletal muscle cells to extracellular matrix components via transmembrane protein complexes in the sarcolemma. Rice et al. 2022 reported that the endolysosomal ion channel, TPC1, generates highly localized, non-propagating Ca2+ transients that play a distinct and required role in the capture and attachment of superficial slow skeletal muscle cells (SMCs) at MJs. Disruption of the tpcn1 gene resulted in abnormal MJ phenotypes including SMCs detaching from or crossing the myosepta. TPC1-decorated endolysosomes are dynamically associated with MJs in a microtubule-dependent manner, and attenuating tpcn1 expression or function disrupted endolysosomal trafficking and resulted in an abnormal distribution of beta-dystroglycan (a key transmembrane component of the dystrophin-associated protein complex). Thus, localized TPC1-generated Ca2+ signals facilitate essential endolysosomal trafficking and membrane contact events, which help form and maintain MJs following the onset of SMC contractile activity (Rice et al. 2022). |
Eukaryota | Metazoa, Chordata | TPC1 of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.A.1.11.4 | The voltage-dependent L-type Ca2+ channel α-subunit-1C (L-type Cav1.2), CACNA1C (CACH2, CACN2, CACNL1A1, CCHL1A1) of 2221 aa. Mutations cause Timothy's syndrome, a disorder associated with autism (Splawski et al., 2006). The C-terminus of Cav1.2 encodes a transcription factor (Gomez-Ospina et al., 2006). Cav1.2 associates with the α-2, δ-1, β and γ subunits (Yang et al., 2011). The CRAC channel activator STIM1 binds and inhibits L-type voltage-gated calcium channel, Cav1.2 (Park et al., 2010). This channel appears to function as the molecular switch for synaptic transmission (Atlas 2013). Intramembrane signalling occurs with syntaxin 1A for catecholamine release in chromaffin cells (Bachnoff et al. 2013). miR-153 intron RNA is a negative regulator of both insulin and dopamine secretion through its effect on Cacna1c expression, suggesting that IA-2beta and miR-153 have opposite functional effects on the secretory pathway (Xu et al. 2015). Co-localizes with Syntaxin-1A in nano clusters at the plasma membrane (Sajman et al. 2017). It is a high voltage-activated Ca2+ channel in contrast to Cav3.3 which is a low voltage-activated Ca2+ channel (Sanchez-Sandoval et al. 2018). Nifedipine blocks and potentiates this and other L-type VIC Ca2+ channels (Wang et al. 2018). Cav1.2 is upregulated when STIM1 is deficient (Pascual-Caro et al. 2018). CaV1.2 regulates chondrogenesis during limb development (Atsuta et al. 2019). CACNA1C may be a prognostic predictor of survival in ovarian cancer (Chang and Dong 2021). Kinase and phosphatase modulation of T-type Ca2+ channel (TTCC) isoforms Cav3.1, Cav3.2, and Cav3.3, are mostly described for roles unrelated to cellular excitability (Sharma et al. 2023), and potential modulations that are yet to be explored are also discussed. Palmitoylation of the pore-forming subunit of Ca(v)1.2 controls channel voltage sensitivity and calcium transients in cardiac myocytes (Kuo et al. 2023). A novel binding site between the voltage-dependent calcium channel CaV1.2 subunit and the CaVβ2 subunit has been discovered using a new analysis method for protein-protein interactions (Murakami et al. 2023). CACNA1C is one of the top risk genes for schizophrenia; A novel 17-variant block across introns 36-45 of CACNA1C was significantly associated with schizophrenia; a novel 17-variant block across introns 36-45 of CACNA1C was responsible (Guo et al. 2023). A novel binding site has been found between the voltage-dependent calcium channel CaV1.2 subunit and CaVβ2 subunit (Murakami et al. 2023). The CaV1.2 distal carboxy terminus functions in the regulation of L-type current (Arancibia et al. 2024). A bi-functional compound acting as CaV1.2 channel blockers and K+ channel stimulators (an effective therapy for hypertension) 3,3'-O-dimethylquercetin was isolated from Brazilian Caatinga green propolis and had this property (Son et al. 2024). Biginelli dihydropyrimidines and their acetylated derivatives are L-/T-type calcium channel blockers (Gündüz et al. 2025). A CACNA1C pathogenic variant may cause a neurodevelopmental disorder (Stringer et al. 2025). |
Eukaryota | Metazoa, Chordata | CACNA1C of Homo sapiens (2221 aas; Q13936) |
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1.A.1.11.5 | The voltage-dependent L-type Ca2+ channel α-subunit-1H (T-type Cav3.2), CACNA1H (mutations can cause an increased propensity for autism spectrum disorders (ASD) characterized by impaired social interactions, communication skills and restricted and repetitive behaviors) (Splawski et al., 2006). Also called Cav3.2 or VSCC. Involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1H gives rise to T-type calcium currents, ''low-voltage activated'' currents blocked by nickel and mibefradil. Defective in Childhood Absence Epilepsy. Are permeated by divalent metal ions, such as Fe2+ and Mn2+ , and possibly Cd2+ (Thévenod, 2010). Patented inhibitors of T-type calcium channels have been reviewed (Giordanetto et al. 2011). Regulated by Syntaxin-1A (Xie et al. 2016). T-type calcium channel blockade induces apoptosis in C2C12 myotubes and skeletal muscle via endoplasmic reticulum stress activation (Chen et al. 2020). Gabapentin disrupts binding of perlecan to the α2δ1 voltage-sensitive calcium channel subunit and impairs skeletal mechanosensation (Reyes Fernandez et al. 2022). Kinase and phosphatase modulation of T-type Ca2+ channel (TTCC) isoforms Cav3.1, Cav3.2, and Cav3.3, are mostly described for roles unrelated to cellular excitability (Sharma et al. 2023), and potential modulations that are yet to be explored are also discussed. A subtle role for T-type calcium channels in regulating lymphatic contraction has been established (Davis et al. 2023). A Cav3.2 calcium channel missense variant is associated with epilepsy and hearing loss (Stringer et al. 2023). |
Eukaryota | Metazoa, Chordata | CACNA1H of Homo sapiens (2353 aas; Q95180) |
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1.A.1.11.6 | Voltage-dependent L-type Ca2+ channel subunit α-1C (αCav1.2) of cardiac muscle [A C-terminal fragment of Cav1.2 translocates to the nucleus and regulates transcription, explaining how a channel can directly activate transcription and differentiation of excitable cells.] (Gomez-Ospina et al., 2006). Cav1.2 associates with the α-2, δ-1, β and γ subunits (Yang et al., 2011). Voltage-gated Ca2+ influx and mitochondrial Ca2+ initiate secretion from Aplysia neuroendocrine cells (Hickey et al. 2013). |
Eukaryota | Metazoa, Chordata | α-Cav1.2 of Mus musculus (2139 aas; Q01815) |
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1.A.1.11.7 | The voltage-dependent Ca2+ channel subunit α-1I, Cav3.3, CACNA1I (isoform CRA_c (2223 aas and 24 TMSs)) (Hamid et al. 2006). It is a low voltage-activated Ca2+ channel in contrast to Cav1.2 (TC# 1.A.1.11.4) which is a high voltage-activated Ca2+ channel (Sanchez-Sandoval et al. 2018). The homolog in Cynops pyrrhogaster (85% identical) is inhibited by Ni2+ and may play a role in the sperm acrosome reaction (Kon et al. 2019). Kinase and phosphatase modulation of T-type Ca2+ channel (TTCC) isoforms Cav3.1, Cav3.2, and Cav3.3, are mostly described for roles unrelated to cellular excitability (Sharma et al. 2023), and potential modulations that are yet to be explored are also discussed. A possible involvement of CaV3 in carcinogenic processes and is a potential pharmacological target in new therapies for breast cancer treatment (Aguiar et al. 2023). G protein β subunits regulate Cav3.3 T-type channel activity and current kinetics via interaction with the Cav3.3 C-terminus (Jeong et al. 2024).
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Eukaryota | Metazoa, Chordata | Ca2+ channel CRA_c of Homo sapiens (Q9P0X4) |
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1.A.1.11.8 | Voltage-dependent Ca2+ channel α-1A subunit (2212 aas), Cav2.1 (P/Q-type) (when mutated in humans, leads to a human channelopathy (episodic ataxia type-2 (EA2)) due to protein misfolding and retention in the E.R. (Mezghrani et al., 2008; Kleopa, 2011). Mutations give rise to familial and sporadic hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6) (García Segarra et al. 2014). Syntaxin 1A (Sx1A), SNAP-25 and synaptotagmin (Syt1), either alone or in combination, modify the kinetic properties of voltage-gated Ca2+ channels (VGCCs) including Cav2.1 (Cohen-Kutner et al. 2010). Terahertz waves promote Ca2+ transport via the Cav2.1 channel (Sun et al. 2025). |
Eukaryota | Metazoa, Chordata | Cav2.1 of Rattus norvegicus (P54282) |
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1.A.1.11.9 | Voltage-dependent Ca2+ channel -subunit 1B (2339 aas), Cav2.2 (N-type) or NCC receptor of 2237 aas. Anchorin B interacts with Cav2.2 in the loop between TMSs 2 and 3. TSPAN-13 specifically interacts with the α-subunit and modulates the efficiency of coupling between voltage sensor activation and pore opening of the channel while accelerating the voltage-dependent activation and inactivation of the Ba2+ current through CaV2.2 (Mallmann et al. 2013). The structure of the closed state in the pore forming domains have been modeled (Pandey et al. 2012). Amlodipine, cilnidipine and nifedipine compounds are potent channel antagonists. CaV2.2 also interacts with reticulon 1 (RTN1) (TC# 8.A.102), member 1 of solute carrier family 38 (SLC38, TC#2.A.18), prostaglandin D2 synthase (PTGDS) and transmembrane protein 223 (TMEM223; TC#8.A.115). Of these, TMEM223 and, to a lesser extent, PTGDS, negatively modulate Ca2+ entry, required for transmitter release and/or for dendritic plasticity under physiological conditions (Mallmann et al. 2019). Phillygenin suppresses glutamate exocytosis in rat cerebrocortical nerve terminals (synaptosomes) through the inhibition of Cav2.2 calcium channels (Lee et al. 2024). |
Eukaryota | Metazoa, Chordata | Cav2.2 of Mus musculus (O55017) |
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1.A.1.12.1 | Paramecium bursaria Chlorella virus 1 (PBCV-1) K+ channel, Kcv1. (The viral-encoded K+ channel inserts into the green algal host membrane to aid ejection of DNA from the viral particle into the cytoplasm (Neupartl et al., 2007)). It may mediate host cell membrane depolarization and K+ loss (Agarkova et al., 2008; Balss et al., 2008). It is inhibited by Ba2+ and amantidine. (Reviewed by Thiel et al., 2010). The presence of charged amino acids which form dynamic inter- and intra- subunit salt bridges is crucial for channel activity (Hertel et al. 2010). |
Viruses | Bamfordvirae, Nucleocytoviricota | Kcv1 K+ channel of Chlorella virus PBCV-1 |
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1.A.1.12.2 | Acanthocystis turfacea chlorella virus cation, K+-preferring, channel, ATCV1 (82aas and 2 TMSs) (Gazzarrini et al., 2009; Siotto et al. 2014). The difference in open probability between close isoforms is caused by one long closed state in KcvS versus KcvNTS. This state is structurally created in the tetrameric channel by a transient, Ser mediated, intrahelical hydrogen bond. The resulting kink in the inner transmembrane domain swings the aromatic rings from downstream Phenylalanines in the cavity of the channel, which blocks ion flux. The most conserved region of the Kcv protein is the filter, the turret and the pore helix, and the outer and the inner transmembrane domains of the protein are the most variable (Murry et al. 2020). |
Viruses | Bamfordvirae, Nucleocytoviricota | ATCV1 (KCVS/KCVNTS) of Acanthocystis turfacea chlorella virus (A7K9J5) |
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1.A.1.12.3 | The viral K+ channel, Kesv of 124 aas. It is inhibited by Ba2+ and amantidine. It is important for infection and replication in marine brown algae (Chen et al. 2005; Balss et al., 2008; Siotto et al. 2014). A combination of hydrophobicity and codon usage bias determines sorting of the Kesv K+ channel protein to either mitochondria or the endoplasmic reticulum (Engel et al. 2023). |
Viruses | Bamfordvirae, Nucleocytoviricota | Kesv of Ectocarpus siliculosus virus 1 (Q8QN67) |
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1.A.1.12.4 | Viral K+ channel of 96 aas and 2 TMSs, Kcv (Siotto et al. 2014). Mechanical perturbation of the N-terminus can be transmitted to the C-terminal channel gates (Hoffgaard et al. 2015). |
Viruses | Bamfordvirae, Nucleocytoviricota | Kcv of Paramecium bursaria Chlorella virus |
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1.A.1.12.5 | Potassium ion channel protein of 86 aas and 2 TMSs (Greiner et al. 2018). |
Viruses | Bamfordvirae, Nucleocytoviricota | K+ channel protein of Micromonas pusilla virus SP1 |
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1.A.1.12.6 | Potassium channel of 101 aas and 2 TMSs (Kukovetz et al. 2020). |
Viruses | K+ channel of Rhizochromulina virus RhiV-SA1 |
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1.A.1.13.1 | 6TMS K+ channel (Munsey et al. 2002; Kuo et al., 2003). The kch gene, the only known potassium channel gene in E. coli, has the property to express both full-length Kch and its cytosolic domain (RCK) due to a methionine at position 240. The RCK domains form an octameric ring structure and regulate the gating of the potassium channels after having bound certain ligands. Several different gating ring structures have been reported for the soluble RCK domains. The octameric structure of Kch may be composed of two tetrameric full-length proteins through RCK interaction (Kuang et al. 2013). The RCK domains face the solution, and an RCK octameric gating ring arrangement does not form under certain conditions (Kuang et al. 2015). |
Bacteria | Pseudomonadota | Kch of E. coli |
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1.A.1.13.10 | K+ channel protein with 343 aas and 2 N-terminal TMSs, MjK2. Binding of the MjK2 RCK domain to membranes takes place via an electrostatic interaction with anionic lipid surfaces (Ptak et al. 2005). |
Archaea | Euryarchaeota | MjK2 of Methanocaldococcus jannaschii (Methanococcus jannaschii) |
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1.A.1.13.2 |
2 TMS ( P-loop) Ca2+-gated K+ channel, MthK (see Jiang et al., 2002 for the crystal structure, and Parfenova et al., 2006 for mutations affecting open probability). For the studies of ion permeation and Ca2+ blockage, see Derebe et al., 2011. (structures: 3LDD_A and 2OGU_A.). Voltage-dependent K+ channels including MthK which lacks a canonical voltage sensor can undergo a gating process known as C-type inactivation, which involves entry into a nonconducting state through conformational changes near the channel's selectivity filter (Thomson and Rothberg, 2010). C-type inactivation may involve movements of transmembrane voltage sensor domains. In the absence of Ca2+, a single structure in a closed state was observed by cryoEM that was highly flexible with large rocking motions of the gating ring and bending of pore-lining helices (Fan et al. 2020). In Ca2+-bound conditions, several open-inactivated conformations were present with the different channel conformations being distinguished by rocking of the gating rings with respect to the transmembrane region. In all conformations displaying open channel pores, the N-terminus of one subunit of the channel tetramer sticks into the pore and plugs it. Deletion of this N terminus led to non-inactivating channels with structures of open states without a pore plug, indicating that this N-terminal peptide is responsible for a ball-and-chain inactivation mechanism (Fan et al. 2020). Lipid-protein interactions influence the conformational equilibrium between two states of the channel that differ according to whether a TMS has a kink. Two key residues in the kink region mediate crosstalk between two gates at the selectivity filter and the central cavity, respectively. Opening of one gate eventually leads to closure of the other (Gu and de Groot 2020). Activation of MthK is exquisitely regulated by temperature (Jiang et al. 2020).
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Archaea | Euryarchaeota | MthK of Methanothermobacter thermoautotrophicus (Methanobacterium thermoautotrophicum)(O27564) |
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1.A.1.13.3 | Divalent cation (Ca2+, Mg2+, Mn2+, Ni2+)-activated K+ channel, TuoK (contains a RCK domain) (Parfenova et al., 2007) | Archaea | Candidatus Thermoplasmatota | TuoK of Thermoplasma volcanium (Q979Z2)
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1.A.1.13.4 | The Biofilm-inducing putative K+ channel, BikC or YugO (Prindle et al. 2015). BikC has an N-terminal 2 TMS + P-loop channel domain and a C-terminal NADB_Rossman superfamily domain (TrkA domain). YugO is in a two cistronic operon where Mistic (MstX; 9.A.66; Debnath et al., 2011; Roosild et al., 2005) is encoded by the gene that precedes yugO. Both play a role in biofilm formation, probably by functioning together (Lundberg et al. 2013; Marino et al. 2015). These K+ channels in bacterial biofilms provide an active, long-range electrical signalling for cellular communities (Prindle et al. 2015). Metabolic co-dependency gives rise to collective electrical oscillations in biofilms (Liu et al. 2015). This oscillatory electrical signalling, due to periodic release of K+, giving rise to K+ gradients, increasing as swimming cells approach the biofilm that generates the gradiens, allows cells of the same and different speices to find and then incorporate themselves into existing biofilms (Humphries et al. 2017). |
Bacteria | Bacillota | BikC of Bacillus subtilis (Q795M8) |
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1.A.1.13.5 | Putative 2 TMS ion channel protein (N-terminus) with C-terminal TrkA_N (NADB Rossman) domain. |
Bacteria | Actinomycetota | Ion channel protein of Streptomyces coelicolor |
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1.A.1.13.6 | Ca2+-activated K+ channel, SynCaK. Functions in the regulation of photosynthesis (Checchetto et al. 2013; Checchetto et al. 2013). |
Bacteria | Cyanobacteriota | K+ channel of Synechocystis PCC6803 |
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1.A.1.13.7 | Putative K+ channel, TrkA1, of 365 aas and 2 N-terminal TMSs, with a C-terminal NAD binding domain. |
Bacteria | Cyanobacteriota | K+ channel of Synechocystis PCC6803 |
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1.A.1.13.8 | Potassium channel protein, MjK1 of 333 aas and 6 TMSs. Seems to conduct potassium at low membrane potentials (Hellmer and Zeilinger 2003). Also called TrkA3, a Trk channel with a C-terminal NAD-binding domain.
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Archaea | Euryarchaeota | MjK1 of Methanocaldococcus jannaschii (Methanococcus jannaschii) |
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1.A.1.13.9 | K+ channel of 387 aas and 2 TMSs, KchA. KchA is essential for growth at low concentrations of K+. This K+ uptake system is essential for gastric colonization and the persistence of H. pyloriin the stomach (Stingl et al. 2007). This protein is of the two-transmembrane RCK (regulation of K+ conductance) domain family (Stingl et al. 2007). |
Bacteria | Campylobacterota | KchA of Helicobacter pylori |
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1.A.1.14.1 | Voltage-activated, Ca2+ channel blocker-inhibited, Na+ channel, NaChBac (Ren et al., 2001; Zhao et al., 2004; Nurani et al, 2008; Charalambous and Wallace, 2011). Arginine residues in the S4 segment play a role in voltage-sensing (Chahine et al. 2004). Transmembrane and extramembrane regions contribute to thermal stability (Powl et al., 2012). Deprotonation of arginines in S4 is involved in NaChBac gating (Paldi, 2012). Hinge-bending motions in the pore domain of NaChBac have been reported (Barber et al., 2012). The C-terminal coiled-coli stabilizes subunit interactions (Mio et al. 2010). Within the 4 TMS voltage sensor, coupling between residues in S1 and S4 determines its resting conformation (Paldi and Gurevitz 2010). The conserved asparagine was changed to aspartate, N225D, and this substitution shifted the voltage-dependence of inactivation by 25 mV to more hyperpolarized potentials. The mutant also displays greater thermostability (O'Reilly et al. 2017). Possibly, the side-chain amido group of asn225 forms one or more hydrogen bonds with different channel elements, and these interactions are important for normal channel function. The T1-tetramerization domain of Kv1.2 (TC# 1.A.1.2.10) rescues expression and preserves the function of a truncated form of the NaChBac sodium channel (D'Avanzo et al. 2022). The structure of NaChBac embedded in liposomes has been solved by cryo electron tomography (Chang et al. 2023). The small channel has most of its residues embedded in the membrane, and these are flexible, determining the channel dimensions. |
Bacteria | Bacillota | NaChBac of Bacillus halodurans |
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1.A.1.14.2 | Voltage-gated Na+ channel, NavPZ (Koishi et al., 2004) | Bacteria | Pseudomonadota | NavPZ of Paracoccus zeaxanthinifaciens (CAD24429) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.1.14.3 | Na+ channel, NavBP, involved in motility, chemotaxis and pH homeostasis (Ito et al., 2004). NavBP colocalizes with a methyl-accepting chemotaxis protein (MCP) at the cell poles (Fujinami et al., 2007). | Bacteria | Bacillota | NavBP of Bacillus pseudofirmus (AAT21291) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.1.14.4 | Voltage-gated Na+ channel, VGSC (Koishi et al., 2004; McCusker et al., 2011) Changing the selectivity filter from LESSM to LDDWSD yielded a Calcium-selective channel (Shaya et al., 2011). |
Bacteria | Pseudomonadota | VGSC of Silicibacter pomeroyi (56676695) |
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1.A.1.14.5 | Voltage-gated Na+ channel, NavCh or NavAb. The 3d-structure is known (3ROW; Payandeh et al., 2011; 4MW3A-D; 4+ selectivity through partial dehydration of Na+ via its direct interaction with conserved glutamate side chains). The pore is preferentially occupied by two ions, which can switch between different configurations by crossing low free-energy barriers (Furini and Domene, 2012). Jiang et al. 2018 presented high-resolution structures of NavAb with the analogous gating-charge mutations that have similar functional effects as in the human channels that cause hypokalaemic and normokalaemic periodic paralysis. Wisedchaisri et al. 2019 presented a cryo-EM structure of the resting state and a complete voltage-dependent gating mechanism via the voltage sensor (VS). The S4 segment of the VS is drawn intracellularly, with three gating charges passing through the transmembrane electric field. This movement forms an elbow connecting S4 to the S4-S5 linker, tightens the collar around the S6 activation gate, and prevents its opening. This structure supports the classical "sliding helix" mechanism of voltage sensing and provides a complete gating mechanism for voltage sensor function, pore opening, and activation-gate closure based on high-resolution structures of a single sodium channel protein (Wisedchaisri et al. 2019). (see also TC#s 1.A.1.10.4 and 1.A.1.11.32). The transport reaction catalyzed by NavCh is: Na+ (in) ⇌ Na+ (out) |
Bacteria | Campylobacterota | NavCh of Arcobacter butzleri (A8EVM5) |
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1.A.1.14.6 |
Bacterial voltage-gated sodium channel, Nav. 3-d crystal structures of vaious conformations are known (4P_3A A-D; 4PA7_A-D; 4P9P_A-D. etc.) (McCusker et al. 2012). It has its internal cavity accessible to the cytoplasmic surface as a result of a bend/rotation about a central residue in the carboxy-terminal TMS that opens the gate to allow entry of hydrated sodium ions. The molecular dynamics of ion transport through the open conformation has been analyzed (Ulmschneider et al. 2013). The C-terminal four helix coiled coil bundle domain couples inactivation with channel opening, depedent on the negatively charged linker region (Bagnéris et al. 2013). A NaVSp1-specific S4-S5 linker peptide induced both an increase in NaVSp1 current density and a negative shift in the activation curve, consistent with the S4-S5 linker stabilizing the open state (Malak et al. 2020). |
Bacteria | Pseudomonadota | Nav of Magnetococcus marinus (also called sp. strain MC-1) |
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1.A.1.14.7 | Tetrameric 6 TMS subunit Na+ channel protein, NaV. Two low resolution cyroEM structures revealed two conformations reconstituted in lipid bilayers (Tsai et al. 2013). Despite a voltage sensor arrangement identical with that in the activated form, Tsai et al. 2013 observed two distinct pore domain structures: a prominent form with a relatively open inner gate, and a closed inner-gate conformation similar to the first prokaryotic Nav structure. Structural differences, together with mutational and electrophysiological analyses, indicated that widening of the inner gate was dependent on interactions among the S4-S5 linker, the N-terminal part of S5 and its adjoining part in S6, and on interhelical repulsion by a negatively charged C-terminal region subsequent to S6 (Tsai et al. 2013). |
Bacteria | Bacillota | Nav of Caldalkalibacillus thermarum |
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1.A.1.14.8 | Voltage-gated Na+ channel, Nsv, of 277 aas and 6 TMSs with a structually defined C-terminal regulatory domain (Miller et al. 2016). Voltage-gated sodium channels (NaVs) are activated by transiting the voltage sensor from the deactivated to the activated state. Tang et al. 2017 identified peptide toxins stabilizing the deactivated VSM of bacterial NaVs. A cystine knot toxin, called JZTx-27, from the venom of the tarantula Chilobrachys jingzhao proved to be a high-affinity antagonist. JZTx-27 stabilizes the inactive form of the voltage sensor, thereby inhibiting channel activity (Tang et al. 2017). The chemistry of electrical signaling in sodium channels from bacteria has been reviewed (Catterall et al. 2024). |
Bacillota | Nsv of Bacillus alcalophilus |
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1.A.1.14.9 | Bacterial type voltage-activated sodium channel of 718 aas, NaV. |
Eukaryota | Bacillariophyta | NaV of Phaeodactylum tricornutum |
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1.A.1.15.1 | 6 TMS basolateral tracheal epithelial cell/voltage-gated, small conductance, K+ α-chain, KCNQ1, [acts with the KCNE3 β-chain]. Mutations in human Kv7 genes lead to severe cardiovascular and neurological disorders such as the cardiac long QT syndrome and neonatal epilepsy (Haitin and Attali, 2008). KCNE3 can co-assemble with KCNQ1 (1.A.1.15.6) (Kang et al., 2010). KCNQ1 regulates insulin secretion in the MIN6 beta-cell line (Yamagata et al., 2011). The S4-S5 linker of KCNQ1 forms a scaffold with S6 controlling gate closure (Labro et al. 2011). The KCNQ1 channel is differentially regulated by KCNE1 and KCNE2 (Li et al. 2014. Slow-activating channel complexes formed by KCNQ1 and KCNE1 are essential for human ventricular myocyte repolarization, while constitutively active KCNQ1-KCNE3 channels are important in the intestine. Inherited sequence variants in human KCNE1 and KCNE3 cause cardiac arrhythmias but by different mechanisms, and each is important for hearing in unique ways (Abbott 2015). The topology and dynamics of the voltage sensor domain of KCNQ1 reconstituted in a lipid bilayer environment has been studied (Dixit et al. 2019). KCNQ1 (Kv 7.1) alpha-subunits and KCNE1 beta-subunits co-assemble to form channels that conduct the slow delayed rectifier K+ current (IKs) in the heart. Mutations in either subunit cause long QT syndrome (LQTS), an inherited disorder of cardiac repolarization (Seebohm et al. 2005). KCNE1 modulates KCNQ1 potassium channel activation by an allosteric mechanism (Kuenze et al. 2020). The membrane electric field regulates the PIP2-binding site to gate the KCNQ1 channel (Mandala and MacKinnon 2023). Dynamic protein-protein interactions of KCNQ1 and KCNE1 have been measured by EPR line shape analysis (Stowe et al. 2024). |
Eukaryota | Metazoa, Chordata | KCNQ1 K+ channel of Mus musculus |
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1.A.1.15.2 |
6 TMS voltage-gated K+ channel, KCNQ2 or Kv7.2. Mutations cause benign familial neonatal convulsions (BNFC; epilepsy; Maljevic et al. 2016; Soldovieri et al. 2019). It forms homotetramers or heterotetramers with KCNQ3/Kv7.3) (Soldovieri et al., 2006; Uehara et al., 2008)). Like all other Kv7.2 channels, it is activated by phosphatidyl inositol-4,5-bisphosphate and hence can be regulated by various neurotransmitters and hormones (Telezhkin et al. 2013). Gating pore currents that go through the gating pores in TMSs1-4 (the voltage sensor) may give rise to peripheral nerve hyperexcitability (Moreau et al. 2014). Retigabine and ICA73, two anti-epileptic drugs, act via distinct mechanisms due to interactions with specific residues that underlie subtype specificity of KCNQ channel openers (Wang et al. 2016). A tight spatial and functional relationship between the DAT/GLT-1 transporters and the Kv7.2/7.3 potassium channel immediately readjusts the membrane potential of the neuron, probably to limit the neurotransmitter-mediated neuronal depolarization (Bartolomé-Martín et al. 2019). E-2-dodecenal from cilantro (Coriandrum sativum) is a potent activator and anticonvulsant that binds with an affinity of 60 nM to TMS5 in several KCNQ channels including KCNQ2 and 3 (Manville and Abbott 2019). The activities of Kv7 channels are modulated by polyunsaturated fatty acids (Larsson et al. 2020). Anticancer effects of FS48 from salivary glands of Xenopsylla cheopis via its blockage of voltage-gated K+ channels has been demonstrated (Xiong et al. 2023). The drug, ezogabine restoresnormal activity ,decreasing depressive symptoms in major depressive disorder patients (Costi et al. 2021). Both L- and D-isomers of S-nitrosocysteine (CSNO) can bind to the intracellular domain of voltage-gated potassium channels in vitro. CSNO binding inhibits these channels in the carotid body, leading to increased minute ventilation in vivo (Krasinkiewicz et al. 2023). KCNQ2 variants relate to a variable phenotypic spectrum range from epilepsy with auditory features to severe developmental and epileptic encephalopathies (Talarico et al. 2024). |
Eukaryota | Metazoa, Chordata | KCNQ2 K+ channel of Homo sapiens (O43526) |
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1.A.1.15.3 | 6 TMS voltage-gated K+ channel, KCNQ3 or Kv7.3. Mutations cause benign familial neonatal convulsions (BNFC; epilepsy; Maljevic et al. 2016). Forms homotetramers or heterotetramers with KCNQ2 (Soldovieri et al., 2006; Uehara et al., 2008). Retigabine and ICA73, two anti-epileptic drugs, act via distinct mechanisms due to interactions with specific residues that underlie subtype specificity of KCNQ channel openers (Wang et al. 2016). Gabapentin at low concentrations is a activator of KCNQ3, KCNQ2/3 and KCNQ5 but not KCNQ2 or KCNQ4 (Manville and Abbott 2018). At high concentrations it can be inhibitory. A tight spatial and functional relationship between the DAT/GLT-1 transporters and the Kv7.2/7.3 potassium channel immediately readjusts the membrane potential of the neuron, probably to limit the neurotransmitter-mediated neuronal depolarization (Bartolomé-Martín et al. 2019). E-2-dodecenal from cilantro (Coriandrum sativum) is a potent activator and anticonvulsant that binds with an affinity of 60 nM to TMS5 in several KCNQ channels including KCNQ2 and 3 (Manville and Abbott 2019). Pathogenic variants in KCNQ2 and KCNQ3, paralogous genes encoding Kv7.2 and Kv7.3 voltage-gated K+ channel subunits, are responsible for early-onset developmental/epileptic disorders characterized by heterogeneous clinical phenotypes ranging from benign familial neonatal epilepsy (BFNE) to early-onset developmental and epileptic encephalopathy (DEE). KCNQ2 variants account for the majority of pedigrees with BFNE, and KCNQ3 variants are responsible for a much smaller subgroup (Miceli et al. 2020). The M240R variant mainly affects the voltage sensitivity, in contrast to previously analyzed BFNE Kv7.3 variants that reduce current density (Miceli et al. 2020). |
Eukaryota | Metazoa, Chordata | KCNQ3 K+ channel of Homo sapiens (O43525) |
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1.A.1.15.4 | 6 TMS cell volume sensitive, voltage-gated K+ channel, KCNQ4 or Kv7.4 (mutations cause DFNA2, an autosomal dominant form of progressive hearing loss) (forms homomers or heteromers with KCNQ3) (localized to the basal membrane of cochlear outer hair cells and in several nuclei of the central auditory pathway in the brainstem). Four splice variants form heterotetramers; each subunit has different voltage and calmodulin-sensitivities (Xu et al., 2007). Autosomal dominant mutant forms leading to progressive hearing loss (DFNA2) have been characterized (Kim et al. 2011). Phosphatidylinositol 4,5-bisphosphate (PIP2) and polyunsaturated fatty acids (PUFAs) impact ion channel function (Taylor and Sanders 2016). This channel may be present in mitochondria (Parrasia et al. 2019). Polyunsaturated fatty acids are modulators of KV7 channels (Larsson et al. 2020). The pathogenicity classification of KCNQ4 missense variants in clinical genetic testing has been described (Zheng et al. 2022). KCNQ4 potassium channel subunit deletion leads to exaggerated acoustic startle reflex in mice (Maamrah et al. 2023). |
Eukaryota | Metazoa, Chordata | KCNQ4 K+ channel of Homo sapiens |
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1.A.1.15.5 |
The KCNQ5 K+ channel (modulated by Zn2+ , pH and volume change) (Jensen et al., 2005). A triple cysteine module within M-type K+ channels mediates reciptrocal channel modulation by nitric oxide and reactive oxygen species (Ooi et al. 2013). Gabapentin at low concentrations is a activator of KCNQ3, KCNQ2/3 and KCNQ5 but not of KCNQ2 or KCNQ4 (Manville and Abbott 2018). At high concentrations, it can be inhibitory. KCNQ5 controls perivascular adipose tissue-mediated vasodilation (Tsvetkov et al. 2024). |
Eukaryota | Metazoa, Chordata | KCNQ5 of Mus musculus |
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1.A.1.15.6 | K+ voltage-gated channel, LQT-like subfamily; Kv7.1; KvLQT1. KCNQ1 (regulated by KCNE peptides (TC# 8.A.58) affect voltage sensor equilibrium (Rocheleau and Kobertz, 2007). Almost 300 mutations of KCNQ1 have been identified in patients, and most are linked to the long QT syndrome (LQT1), some in the voltage sensor (Peroz et al., 2008; Eldstrom et al. 2010; Qureshi et al. 2013; Ikrar et al. 2008). KCNQ1-KCNE1 complexes may interact intermittently with the actin cytoskeleton via the C-terminal region (Mashanov et al., 2010). The stoichiometry of the KCNQ1 - KCNE1 complex is flexible, with up to four KCNE1 subunits associating with the four KCNQ1 subunits of the channel (Nakajo et al., 2010). A familial mutation in the voltage-sensor of the KCNQ1 channel results in a cardiac phenotype (Henrion et al., 2012). KCNQ1 regulates insulin secretion in the MIN6 beta-cell line (Yamagata et al., 2011; Gofman et al., 2012). Electrostatic interactions of S4 arginines with E1 and S2 contribute to gating movements of S4, but coupling requires the lipid phosphatidylinositol 4,5-bisphosphate (PIP2) as voltage-sensing domain activation failed to open the pore in the absence of PIP2 (Zaydman et al. 2013). The D242N mutation causes impaired action potential adaptation to exercise and an increase in heart rate. Moreover, the D242 amino acyl position is involved in the KCNE1-mediated regulation of the voltage-dependence of activation of the KV7.1 channel (Moreno et al. 2017). The KCNQ1 channel interacts with MinK (KCNE1) to cause pore constriction, generating the slow delayed rectifier (IKs) current in the heart (Jalily Hasani et al. 2018). KCNQ1 rescues TMC1 plasma membrane expression but not mechanosensitive channel activity (Harkcom et al. 2019). Activation of the neuronal Kv7/KCNQ/M-current represents an attractive therapeutic strategy for treatment of hyperexcitability-related neuropsychiatric disorders such as epilepsy, pain, and depression, and channel openers for treatment of antiepilepsy have been developed (Zhang et al. 2019). The relationship between mutation locations in KCNQ1, which is a major gene in long QT syndrome (LQTS), and phenotype has been analyzed and used for risk stratification (Yagi et al. 2018). The proximal C-terminal regions of KCNQ1 and KCNE1 participate in a physical and functional interaction during channel opening that is sensitive to perturbation (Chen et al. 2019). Retigabine analogs are activators of Kv7 channels (Ostacolo et al. 2020). People with borderline QTc prolongations were carriers of KCNQ1 mutations in TMSs 2 and 5, leading to haploinsufficiency, and they are potentially at risk of developing drug-induced arrhythmia (Gouas et al. 2004). Collision induced unfolding differentiates functional variants of the KCNQ1 voltage sensor domain (Fantin et al. 2020). The activated KCNQ1 channel promotes a fibrogenic response in hereditary gingival fibromatosis via clustering and activation of Ras (Gao et al. 2020). QT syndrome (LQTS) increases the risk of life-threatening arrhythmia in young individuals with structurally normal hearts. It may involve sixteen genes such as the KCNQ1, KCNH2, and SCN5A (Lin et al. 2020). The human KCNQ1 voltage sensing domain (VSD) has been studied in lipodisq nanoparticles by electron paramagnetic resonance (EPR) spectroscopy (Sahu et al. 2020). Structural mechanisms for the activation of the human cardiac KCNQ1 channel by electro-mechanical coupling enhancers have been reviewed (Ma et al. 2022). The pathogenicity of KCNQ1 variants using zebrafish as a model has been reviewed (Cui et al. 2023). Phosphatidyl-inositol-4,5-bisphosphate (PIP2) is required for coupling between the voltage sensor and the pore of the potassium voltage-gated KV7 channel family, especially the KV7.1 channel. Modulation of the I(KS) channel by PIP2 requires two binding sites per monomer (Kongmeneck et al. 2023). Divergent regulation of the KCNQ1/E1 channel can be accomplished by targeted recruitment of protein kinase A to distinct sites on the channel complex (Zou et al. 2023). Rare missense variants with a clear phenotype of Long QT Syndrome, type 1 (LQTS) have a high likelihood to be present within the pore and adjacent TMSs (S5-Pore-S6) (Novelli et al. 2023). LHFPL5 is a key element in force transmission from the tip link to the hair cell mechanotransducer channel (Beurg et al. 2024). A biomimetic K+ ion channel shortens the QT interval of type 2 long QT syndrome through efficient transmembrane transport of potassium ions (Sun et al. 2024). A novel compound QO-83 alleviates acute and chronic epileptic seizures in rodents by modulating KV7 channel activity (Wang et al. 2025). |
Eukaryota | Metazoa, Chordata | KCNQ1 of Homo sapiens (P51787) |
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1.A.1.15.7 | Ion channel transporter of 296 aas and 5 putative TMSs. |
Bacteria | Mycoplasmatota | Ion channel of Mycoplasma sp. Pen4
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1.A.1.15.8 | KCNQ1 of 647 aas and 6 TMSs. Xiong et al. 2022 characterized KCNQ1 which functions in shell biomineralisation of pearl oyster, Pinctada fucata martensii. |
Eukaryota | Metazoa, Mollusca | KCNQ1 of Pinctada fucata martensii |
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1.A.1.16.1 | The small conductance Ca2+-activated K+ channel, SkCa2, Sk2 or Kcnn2 (not inhibited by arachidonate) (activated by three small organic molecules, the 1-EBIO and N5309 channel enhancers and the DCEBIO channel modulation (Pedarzani et al., 2005)). It is inhibited by protonation of outer pore histidine residues (Goodchild et al., 2009). The same is true for SK3 (K(Ca) 2.3 (Q9UGI6)). Regulates endothelial vascular function (Sonkusare et al., 2012). Distinct subcellular mechanisms enhance the surface membrane expression by its interacting proteins, α-actinin 2 (TC# 8.A.66.1.3) and filamin A (TC# 8.A.66.1.4) (Zhang et al. 2016). SK channel activators can compensate for age-related changes of the autorhythmic functions of the cerebellum (Karelina et al. 2017). SK2 proteins are more abundant in Purkinje cells than in the ventricular myocytes of normal rabbit ventricles (Reher et al. 2017). Apamin inhibits and isoproterenol activates this and other SK (KCNN) channels, and activation by isoproterenol is sex-dependent (Chen et al. 2018). Diverse interactions between KCa and TRP channels integrate cytoplasmic Ca2+, oxidative, and electrical signaling affecting cardiovascular physiology and pathology (Behringer and Hakim 2019). This channel may be present in mitochondria (Parrasia et al. 2019). A non-neuronal hSK3 isoform has a dominant-negative effect on hSK3 currents (Wittekindt et al. 2004). Medicinal plant products can interact with SKCa (Rajabian et al. 2022). Varients may cause conformational changes that alter the ability of the protein to modulate ion channel activities (d'Apolito et al. 2023). The role of KCa channel modulators in therapeutic medicine has been reviewed (Van et al. 2024). Mechanisms for the regulation of small-conductance Ca2+-activated K+ channel (SK2) by PIP2 have been reviewed (Woltz et al. 2024). |
Eukaryota | Metazoa, Chordata | SkCa2 of Homo sapiens |
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1.A.1.16.2 | The intermediate conductance, Ca2+-activated K+ channel, IKCa, Kcnn4, SK4, Sk4, Smik, Ik1 hIK1, IKCa or KCa3.1, also called the Gardos channel, of 543 aas and 6 TMSs. It is inhibited by 1 μM arachidonate which binds in the pore (Hamilton et al., 2003)). Nucleoside diphosphate kinase B (NDPK-B) activates KCa3.1 via histidine phosphorylation, resulting in receptor-stimulated Ca2+ flux and T cell activation (Di et al., 2010). It regulates endothelial vascular function (Sonkusare et al., 2012). Tissue-specific expression of splice variants of the orthologous rat KCNN4 protein have been reported (Barmeyer et al. 2010). Residues involved in gating have been identified (Garneau et al. 2014). It is also present in the inner mitochondrial membrane where increases of mitochondrial matrix [Ca2+] cause mtKCa3.1 opening, thus linking inner membrane K+ permeability and transmembrane potential to Ca2+ signalling (De Marchi et al. 2009). KCa3.1 (IKCa) channels are expressed in CA1 hippocampal pyramidal cells and contribute to the slow afterhyperpolarization that regulates spike accommodation (Turner et al. 2016). SK channel activators can compensate for age-related changes of the autorhythmic functions of the cerebellum (Karelina et al. 2017). The activation mechanism has been revealed by the cryoEM structure of the SK4-calmodulin complex (Lee and MacKinnon 2018). It is responsible for hyperpolarization in some tumor cells (Lazzari-Dean et al. 2019). Mutations are linked to dehydrated hereditary stomatocytosis (xerocytosis) (Andolfo et al. 2015). This channel is present in mitochondria (Parrasia et al. 2019). KCNN4 promotes the progression of lung adenocarcinoma by activating the AKT and ERK signaling pathways (Xu et al. 2021). KCa3.1 channels in human microglia link extracellular ATP-evoked Ca2+ transients to changes in membrane conductance with an inflammation-dependent mechanism, and suggests that during brain inflammation, the KCa3.1-mediated microglial response to purinergic signaling may be reduced (Palomba et al. 2021). Both IK(Ca) and BK(Ca) regulate cell volume in human glioblastoma cells (Michelucci et al. 2023). Lysosomal Ca2+ release is sustained by ER→lysosome Ca2+ refilling and K+ efflux through the KCa3.1 channel in inflammasome activation and metabolic inflammation (Kang et al. 2024). GJB2 (TC# 1.A.24.1.3), KCNH6 (TC# 1.A.1.20.2, and KCNN4 are oncogenic, and GJB2 and KCNN4 were upregulated, while KCNH6 was downregulated in a high risk group and glioblastoma (GBM) cells (Huang et al. 2024). The regulatory network showed that KCNH6 was targeted by more miRNAs and transcription factors while KCNN4 interacted with more drugs (Huang et al. 2024).
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Eukaryota | Metazoa, Chordata | hIK1 of Homo sapiens (AAC23541) |
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1.A.1.16.3 | Small conductance calcium-gated potassium (SK) channel. Three charged residues in TMS S6 of SK channels near the inner mouth of the pore collectively control the conductance and rectification through an electrostatic mechanism (Li and Aldrich, 2011). The SK channel inhibitors NS8593 and UCL1684 prevent the development of atrial fibrillation via atrial-selective inhibition of sodium channel activity (Burashnikov et al. 2020). SK channel positive modulators prevent ferroptosis and excitotoxicity in neuronal cells (Zhang et al. 2024). |
Eukaryota | Metazoa, Arthropoda | SK of Drosophila melanogaster (Q7KVW5) |
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1.A.1.16.4 | Small conductance Ca2+-activated K+ channel, KCNL-2 of 672 aas. Plays a role in the rate of egg laying (Chotoo et al. 2013). |
Eukaryota | Metazoa, Nematoda | KCNL-2 of Caenorhabditis elegans |
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1.A.1.16.5 | Plasma membrane small conductance calcium-activated K+ channel of 396 aas, TSKCa; probably involved in immunoregulation (Cong et al. 2009). |
Eukaryota | Metazoa, Chordata | TSKCa of Psetta maxima (Turbot) (Pleuronectes maximus) |
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1.A.1.16.6 | Small conductance calcium-activated K+ channel, KCNN1 or SK, of 543 aas and 6 TMSs. It is a druggable risk factor for opioid use disorder (OUD) (Kember et al. 2022).
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Eukaryota | Metazoa, Chordata | SK of Homo sapiens |
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1.A.1.16.7 | Small conductance calcium-activated potassium channel protein 3 of 736 aas and 6 TMSs, SK3 or KCNN3. It forms a voltage-independent potassium channel, activated by intracellular calcium (Bauer et al. 2019). Activation is followed by membrane hyperpolarization and is thought to regulate neuronal excitability by contributing to the slow component of synaptic after-hyperpolarization. The channel is blocked by apamin. Contrary to its bradycardic effect in the sinus node, blockage of its current by apamin accelerates ventricular automaticity and causes repeated, nonsustained, ventricular tachycardia in normal ventricles. Ryanodine receptor 2 blockage reversed the apamin effects on ventricular automaticity (Wan et al. 2019). Dextran sodium sulfate treatment causes loss of transient relaxation due to downregulation of SK3 channels and may increase contractile responses due to increased Ca2+ sensitization of smooth muscle cells via protease-activated receptor_1 (PAR1) [TC# P25116; TC# 9.A.14.13.37] activation (Sung et al. 2022). The specificity of Ca2+-activated K+ channel modulation in atherosclerosis and aerobic exercise training has been discussed (Mokelke et al. 2022). Small conductance calcium-activated potassium (SK) channel-positive modulators prevent ferroptosis and excitotoxicity in neuronal cells (Zhang et al. 2024). |
Eukaryota | Metazoa, Chordata | KCNN3 of Homo sapiens |
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1.A.1.16.8 | Small conductance plasma membrane calcium-activated potassium channel of 553 aas and 6 TMSs (Paul et al. 2021). |
Eukaryota | Euglenozoa | BK channel of Leishmania donovani |
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1.A.1.17.1 | The archaeal voltage-regulated K channel, KvAP (Ruta et al., 2003). X-ray and solution structures are available. The latter shows phospholipid interactions with the isolated voltage sensor domain (Butterwick and MacKinnon 2010; Li et al. 2014). The gating-charge arginine in TMS4 of the voltage sensor forms part of the helical hairpin "paddle", and it moves 15-20 Å through the membrane to open the pore (Ruta et al., 2005). The orientation and depth of insertion of the voltage-sensing S4 helix has been determined (Doherty et al., 2010). A synthetic S6 segment derived from the KvAP channel self-assembles, permeabilizes lipid vesicles, and exhibits ion channel activity in bilayer lipid membrane (Verma et al., 2011). Thus the gating mechanism combines structural rearrangements and electric-field remodeling ( Li et al. 2014). KvAP has been reconstituted in Giant Unilamellar Vesicles (GUVs) (Garten et al. 2015). TMS4 (S4) which senses voltage also promotes membrane insertion of the voltage-sensor domain (Mishima et al. 2016). KvAP has a configuration consistent with a water channel, possibly underlying the conductance of protons, and other cations, through voltage-sensor domains (Freites et al. 2006). The structural dynamics of the paddle motif loop in the activated conformation of the KvAP voltage sensor have been studied from biophysical standpoints (Das et al. 2019). The S4 alpha-helix, which is straight in the experimental crystal structure solved under depolarized conditions (Vm approximately 0), breaks into two segments when the cell membrane is hyperpolarized (Vm << 0) and reversibly forms a single straight helix following depolarization (Vm = 0) ((Bignucolo and Bernèche 2020). The outermost segment of S4 translates along the normal to the membrane, bringing new perspective to previously paradoxical accessibility experiments that were initially thought to imply the displacement of the whole VSD across the membrane. The breakage of S4 under (hyper)polarization could be a general feature of Kv channels with a non-swapped topology. The surface charge of the membrane does not significantly affect the topology and structural dynamics of the sensor loop in membranes (Das and Raghuraman 2021). The dynamic variability of the sensor loop is preserved in both zwitterionic (POPC) and anionic (POPC/POPG) lipid membranes. The lifetime distribution analysis for the NBD-labelled residues by the maximum entropy method (MEM) demonstrates that, in contrast to micelles, the membrane environment not only reduces the relative discrete population of sensor loop conformations, but also broadens the lifetime distribution peaks. The local curvature of cellular membranes acts as a driving force for the targeting of membrane-associated proteins to specific membrane domains, as well as a sorting mechanism for transmembrane proteins, as demonstrated for KvAP (Kluge et al. 2022). Conformational heterogeneity of the voltage sensor loop of the K+ channel, KvAP, in micelles and membranes has been documented (Das and Raghuraman 2021). |
Archaea | Thermoproteota | KvAP of Aeropyrum pernix (Q9YDF8) |
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1.A.1.17.2 | Voltage-gated K+ channel, Kv (Santos et al., 2008). | Bacteria | Bacillota | Kv of Listeria monocytogenes (Q8Y5K1) |
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1.A.1.18.1 | The two-pore domain potassium channel, TRESK-1 (Czirjak et al., 2004) (provides the background K+ current in mouse DRG neurons (Dobler et al., 2007)) TRESK (TWIK-related spinal cord K+ channel) is reversibly activated by the calcium/calmodulin-dependent protein phosphatase, calcineurin. Czirjak et al. 2008 reported that 14-3-3 proteins directly bind to the intracellular loop to TRESK and control the kinetics of the calcium-dependent regulation. Cloxyquin (5-chloroquinolin-8-ol) is an activator (Wright et al. 2013). A cytoplasmic loop binds tubulin (Enyedi et al. 2014). Channel activity is modified by phosphorylation (inactive) and dephosphorylation (active) of the unusually long intracellular loop between the 2nd and 3rd TMS (Lengyel et al. 2018). The distal short intracellular C-terminal region (iCtr) following the fourth TMS is a major positive determinant of TRESK function (Debreczeni et al. 2023). |
Eukaryota | Metazoa, Chordata | TRESK-1 of Mus musculus (AAQ91836) |
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1.A.1.18.2 | TRESK-2 or potassium channel subfamily K member 18 of 348 aas and 6 TMSs. TRESK-2 is a functional member of the K(2P) channel family and contributes to the background K+ conductance in many types of cells (Kang et al. 2004). The distal short intracellular C-terminal region (iCtr) following the fourth TMS is a major positive determinant of TRESK function (Debreczeni et al. 2023). Cloxyquin activates hTRESK by allosteric modulation of the selectivity filter (Schreiber et al. 2023). Two small molecules (Q6F and Q5F) are activators that affect TREK1 by increasing its open probability in single-channel current measurements. The ligands increase the probability of permeation by modulating the dynamics of carbonyl flipping, influenced by a threonine residue at the bottom of the selectivity filter (Mendez-Otalvaro et al. 2024). |
Eukaryota | Metazoa, Chordata | TRESK-2 of Homo sapiens |
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1.A.1.19.1 | Alkalinizatioin-activated Ca2+-selective channel, sperm-associated cation channel, CatSper, required for male fertility and the hyperactivated motility of spermatozoa (Kirichok et al. 2006). These channels require auxiliary subunits, CatSperβ, γ and δ for activity (Chung et al., 2011). The primary channel protein is CatSper1 (Liu et al., 2007), and it may be a target for immunocontraception (Li et al. 2009). CatSper channels have been reported to regulate sperm motility (Vicente-Carrillo et al. 2017). Sperm competition is selective for a disulfide-crosslinked macromolecular architecture. CatSper channel opening occurs in response to pH, 2-arachidonoylglycerol, and mechanical force. A flippase function is hypothesized, and a source of the concomitant disulfide isomerase activity is found in CatSper-associated proteins beta, delta and epsilon (Bystroff 2018). More recently, it has been reported that rotational motion and rheotaxis of human sperm do not require functional CatSper channels or transmembrane Ca2+ signaling (Schiffer et al. 2020). Instead, passive biomechanical and hydrodynamic processes may enable sperm rolling and rheotaxis, rather than calcium signaling mediated by CatSper or other mechanisms controlling transmembrane Ca2+ flux. The Ca2+ channel CatSper is not activated by cAMP/PKA signaling but directly affected by chemicals used to probe the action of cAMP and PKA (Wang et al. 2020). The cation channel of sperm (CatSper) is essential for sperm motility and fertility. CatSper comprises the pore-forming proteins CATSPER1-4 and multiple auxiliary subunits, including CATSPERbeta, gamma, delta, epsilon, zeta, and EFCAB9. Lin et al. 2021 reported the cryo-EM structure of the CatSper complex isolated from mouse sperm. CATSPER1-4 conform to the conventional domain-swapped voltage-gated ion channel fold, following a counterclockwise arrangement. The auxiliary subunits CATSPERbeta, gamma, delta and epsilon - each of which contains a single transmembrane segment and a large extracellular domain - constitute a pavilion-like structure that stabilizes the entire complex through interactions with CATSPER4, 1, 3 and 2, respectively. The EM map revealed several previously uncharacterized components, exemplified by the organic anion transporter SLCO6C1. Lin et al. 2021 named this channel-transporter ultracomplex the CatSpermasome. The assembly and organizational details of the CatSpermasome lay the foundation for the development of CatSpermasome-related treatments for male infertility and non-hormonal contraceptives. CatSper is a target for inhibition, for use in male contraception, causing inhibition of sperm motility (Mariani et al. 2023). A CUG-initiated CATSPERθ functions in the CatSper channel assembly and serves as a checkpoint for flagellar trafficking (Huang et al. 2023). A CatSper-uninvolved mechanism to induce forward sperm motility during internal fertilization has been described (Goto et al. 2024). |
Eukaryota | Metazoa, Chordata | CatSper of Homo sapiens |
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1.A.1.19.2 | Sperm-associated cation channel, CatSper2 with 530 aas and 6 TMSs; it is a voltage-gated calcium channel that plays a central role in calcium-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the oocyte (Strünker et al. 2011). The CatSper calcium channel is indirectly activated by extracellular progesterone and prostaglandins following the sequence: progesterone > PGF1-alpha = PGE1 > PGA1 > PGE2 >> PGD2 (Lishko et al. 2011). |
Eukaryota | Metazoa, Chordata | CatSper2 of Homo sapiens (26051223) |
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1.A.1.19.3 |
Alkalinization-activated, Ca2+-selective cation channel of sperm 1, CatSper1, required for male fertility and the hyperactivated motility of spermatozoa. These channels require auxiliary subunits, CatSper β, γ and δ for activity (Chung et al., 2011; Liu et al., 2007). |
Eukaryota | Metazoa, Chordata | CatSper of Mus musculus |
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1.A.1.2.1 | Voltage-sensitive K+ channel (PNa+/PK+ ≈ 0.1) Shaker and Shab K+ channels are blocked by quinidine (Gomez-Lagunas, 2010). |
Eukaryota | Metazoa, Arthropoda | Shab11 of Drosophila melanogaster |
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1.A.1.2.10 | Voltage-gated K+ channel, chain A, Shaker-related, Kv1.2 or KCNA2 (Crystal structure known, Long et al., 2007; Chen et al. 2010). It functions with the auxiliary subunit, Ivβ1.2; 8.A.5.1.1) (Peters et al. 2009). Delemotte et al. (2010) described the effects of sensor domain mutations on molecular dynamics of Kv1.2. The Sigma 1 receptor (Q99720; Sigma non-opioid intracellular receptor 1) interacts with Kv1.2 to shape neuronal and behavioral responses to cocaine (Kourrich et al. 2013). Amino acid substitutions cause Shaker to become heat-sensing (opens with increasing temperature as for TrpV1) or cold-sensing (opens with decreasing temperature as for TrpM8) (Chowdhury et al. 2014). The Shaker Kv channel was truncated after the 4th transmembrane helix S4 (Shaker-iVSD) which showed altered gating kinetics and formed a cation-selective ion channel with a strong preference for protons (Zhao and Blunck 2016). Direct axon-to-myelin linkage by abundant KV1/Cx29 (TC# 1.A.24.1.12) channel interactions in rodent axons supports the idea of an electrically active role for myelin in increasing both the saltatory conduction velocity and the maximal propagation frequency in mammalian myelinated axons (Rash et al. 2016). A cryoEM structure (3 - 4 Å resolution; paddle chimeric channel; closed form) in nanodiscs has been determined (Matthies et al. 2018). Possible gating mechanisms have been discussed (Kariev and Green 2018; Infield et al. 2018). Pathogenic variants in KCNA2, encoding the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction (Döring et al. 2021). In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. Biophysical properties of a delayed rectifier K+ current can contribute to its role in generating spontaneous myogenic activity (Hu et al. 2021). The local curvature of cellular membranes acts as a driving force for the targeting of membrane-associated proteins to specific membrane domains, as well as a sorting mechanism for transmembrane proteins, as demonstrated for the chimeric channel, Kv1.2/2.1; KvChim induces strong positive membrane curvature (Kluge et al. 2022). 2-Aminoethoxydiphenyl borate (2-APB) has inhibitory effects on three KV1 channels, Kv1.2, Kv1.3 and Kv1.4 (Zhao et al. 2023). Voltage-gated K+ channels have two distinct gates that regulate ion flux: the activation gate (A-gate) formed by the bundle crossing of the S6 TMSs and the slow inactivation gate in the selectivity filter. These two gates are bidirectionally coupled. Szanto et al. 2023 suggested that the coupling between the A-gate and the slow inactivation gate is mediated by rearrangements in the S6 segment. S6 rearrangements are consistent with a rigid rod-like rotation of S6 around its longitudinal axis upon inactivation. Regulators of KV1.2 include the neutral amino acid transporter Slc7a5 which causes a dramatic hyperpolarizing shift of channel activation. In contrast, the transmembrane lectin LMAN2 is a regulator that has the opposite effect on gating: large depolarizing voltages are required to activate KV1.2 channels co-expressed with LMAN2. Slc7a5 and LMAN2 compete for interaction with the KV1.2 voltage sensor (Das et al. 2024). CryoEM structures of Kv1.2 potassium channels, in conducting and non-conducting states, have appeared (Wu et al. 2025). |
Eukaryota | Metazoa, Chordata | Kv1.2 of Homo sapiens (P16389) |
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1.A.1.2.11 | Voltage-gated K+ channel, Shab-related, Kv2.1, Delayed rectifier potassium channel 1, DRK1 or KCNB1 (858aas) The crystal structure is known (Long et al., 2007). Rat Kv2.1 and Kv2.2 (long) are colocalized in the somata and proximal dendrites of cortical pyramidal neurons and are capable of forming functional heteromeric delayed rectifier channels. The delayed rectifer currents, which regulate action potential firing, are encoded by heteromeric Kv2 channels in cortical neurons (Kihira et al., 2010). Phosphorylation by AMP-activated protein kinase regulates membrane excitability (Ikematsu et al., 2011). Functional interactions between residues in the S1, S4, and S5 domains of Kv2.1 have been identified (Bocksteins et al., 2011). Missense variants in the ion channel domain and loss-of-function variants in this domain and the C-terminus cause neurodevelopmental disorders, sometimes with seizures (de Kovel et al. 2017). Kv2.1 channels consist of two types of alpha-subunits: (1) electrically-active Kcnb1 alpha-subunits and (2) silent or modulatory alpha-subunits plus beta-subunits that, similar to silent alpha-subunits, regulate electrically-active subunits (Jędrychowska and Korzh 2019). It plays a role in neurodevelopmental disorders, such as epileptic encephalopathy. The N- and C-terminal domains of the alpha-subunits interact to form the cytoplasmic subunit of hetero-tetrameric potassium channels. Kcnb1-containing channels are involved in brain development and reproduction. Modification of Kv2.1 K+ currents is mediated by the silent Kv10 subunits (Vega-Saenz de Miera 2004). The clinical expression of KCNB1 encephalopathy is variable (Púa-Torrejón et al. 2021). Variants of KCNB1, located in the S1 segment, may be associated with a milder outcome of seizures (Hiraide et al. 2022). Altered neurological and neurobehavioral phenotypes have been observed in a mouse model of the recurrent KCNB1 -p.R306C voltage-sensor variant (Kang et al. 2023). A point mutation (M340I) in KV2.1 may cause severe and treatment-resistant obsessive-compulsive disorder (trOCD) (Chen et al. 2023; Ji et al. 2023). It may play a role in Parkinson's Disease (Zhou et al. 2023). An autism-associated KCNB1 mutation dramatically slows Kv2.1 potassium channel activation, deactivation and inactivation (Manville et al. 2024; Manville et al. 2024). |
Eukaryota | Metazoa, Chordata | Kv2.1/Kv2.2 of Homo sapiens |
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1.A.1.2.12 | Voltage-gated K+ channel, Kv1.1 or KCNA1. It is palmitoylated, modulating voltage sensing (Gubitosi-Klug et al. 2005). It is regulated by syntaxin (TC family 8.A.91) through dual action on channel surface expression and conductance (Feinshreiber et al., 2009). Defects cause episodic ataxia type 1 (EA1), an autosomal dominant K+ channelopathy accompanied by short attacks of cerebellar ataxia and dysarthria (D'Adamo et al. 2014; Yuan et al. 2020). Direct axon-to-myelin linkage by abundant KV1/Cx29 channel interactions in rodent axons supports the idea of an electrically active role for myelin in increasing both the saltatory conduction velocity and the maximal propagation frequency in mammalian myelinated axons (Rash et al. 2016). Kv1.1 is present in bull sperm where it is necessary for normal sperm progressive motility, percent capacitated spermatozoa (B-pattern) and the acrosome reaction (Gupta et al. 2018). Gating induces large aqueous volumetric remodeling (Díaz-Franulic et al. 2018). Paulhus et al. 2020 have reviewed the pathology of mutants in this protein and showed that epilepsy or seizure-related variants tend to cluster in the S1/S2 transmembrane domains and in the pore region of Kv1.1, whereas EA1-associated variants occur along the whole length of the protein, but variants at the C-terminus are more likely to suffer from seizures and neurodevelopmental disorders (Yuan et al. 2020). Mutation in KCNA1 has been identified that impairs voltage sensitivity (Imbrici et al. 2021). Altering expression of the genes encoding Kv1.1, Piezo2, and TRPA1 regulate the response of mechanosensitive muscle nociceptors (Nagaraja et al. 2021). Genetic variants have expanded the functional, molecular, and pathological diversity of KCNA1 channelopathies (Paulhus and Glasscock 2023). Carbamazepine suppresses the impaired startle response and brain hyperexcitability in kcna1a(-/-) zebrafish but had no effect on the seizure frequency in Kcna1(-/-) mice, suggesting that this EA1 zebrafish model might better translate to humans than rodents (Dogra et al. 2023). A lthough they are present at low levels and only generate small currents in the sinoatrial node, Kv1.1 channels have a significant impact on cardiac pacemaking (Short 2024). Episodic ataxia 1 (EA1) is caused by mutations in KCNA1 encoding a neuronal voltage-gated potassium channel (Graves et al. 2024).
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Eukaryota | Metazoa, Chordata | Kv1.1 of Homo sapiens (Q09470) |
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1.A.1.2.13 | Voltage-gated K+ channel subfamily C member 3,KCNC3 or Kv3.3. It is negatively modulated by protein kinase C (Desai et al., 2008). Phosphorylation of Kv3.3 by PKC may allow neurons to maintain action potential height during stimulation at high frequencies, and therefore contributes to stimulus-induced changes in the intrinsic excitability of neurons such as those of the auditory brainstem (Desai et al., 2008). N-glycosylation impacts the sub-plasma membrane localization and activity of Kv3.1b-containing channels, and N-glycosylation processing of Kv3.1b-containing channels contributes to neuronal excitability (Hall et al. 2017). Spinocerebellar ataxia (SCA), a genetically heterogeneous disease characterized by cerebellar ataxia, involves the abnormal expansion of repeat sequences as well as the mutation of K+ and Ca2+ channel genes (Tada et al. 2020). A missense mutation in Kcnc3 causes hippocampal learning deficits in mice (Xu et al. 2022). Thus, Kv3.3 expression is enhanced by a variant in the Kozak sequence of KCNC3 (Reis et al. 2024). |
Eukaryota | Metazoa, Chordata | Kv3.3 of Homo sapiens (Q14003) |
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1.A.1.2.14 | Voltage-gated delayed rectifier K+ channel, Kv1 of the octopus. RNA editing underlies adaption (Garrett and Rosenthal, 2012). 94% identical to the squid giant axon delayed rectifier voltage-dependent potassium channel, SqKv1A (Q25376). |
Eukaryota | Metazoa, Mollusca | Kv1 of Octopus vulgaris (H2EZS9) |
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1.A.1.2.15 | Potassium voltage-gated channel subfamily S member 3 (Delayed-rectifier K(+) channel alpha subunit 3) (Voltage-gated potassium channel subunit Kv9.3) | Eukaryota | Metazoa, Chordata | KCNS3 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.1.2.16 | Potassium voltage-gated channel subfamily S member 2 (Delayed-rectifier K(+) channel alpha subunit 2) (Voltage-gated potassium channel subunit Kv9.2) | Eukaryota | Metazoa, Chordata | KCNS2 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.1.2.17 | Potassium voltage-gated channel (KCNH) subfamily G member 3 (Voltage-gated potassium channel subunit Kv10.1) (Voltage-gated potassium channel subunit Kv6.3). Splice variants have different properties and can activate cyclin-dependent protein kinases (Ramos Gomes et al. 2015). Control of transport (pore) function by the voltage sensor may involve more than one mechanism (Tomczak et al. 2017). The silent (non transporting) behaviour of Kv6.3 in the ER is caused by the C-terminal part of its sixth transmembrane domain that causes ER retention (Ottschytsch et al. 2005). De novo missense variants in KCNH1 encoding Kv10.1 are responsible for two clinically recognisable phenotypes: Temple-Baraitser syndrome (TBS) and Zimmermann-Laband syndrome (ZLS) (Aubert Mucca et al. 2022). The clinical overlap between these two syndromes suggests that they belong to a spectrum of KCNH1-related encephalopathies. Affected patients have severe intellectual disability (ID) with or without epilepsy, hypertrichosis and distinctive features such as gingival hyperplasia and nail hypoplasia/aplasia (Aubert Mucca et al. 2022). |
Eukaryota | Metazoa, Chordata | Kcng3 or Kv10.1of Rattus norvegicus |
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1.A.1.2.18 | Potassium voltage-gated channel subfamily F member 1 (Voltage-gated potassium channel subunit Kv5.1) (kH1) | Eukaryota | Metazoa, Chordata | KCNF1 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.1.2.19 | The voltage-gated K+ channel subfamily D member 3, KCND3 or Kv4.3. Mutations cause spinocerebellar ataxia type 19 (Duarri et al. 2012). Positively charged residues in S4 contribute to channel inactivation and recovery (Skerritt and Campbell 2007). The crystal structure of Kv4.3 with its regulatory subunit, Kchip1, has been solved (2NZ0) (Wang et al. 2007). A KCND3 variant in the N-terminus impairs the ionic current of Kv4.3 and is associated with SCA19/22 (Reis et al. 2024). |
Eukaryota | Metazoa, Chordata | KCND3 of Homo sapiens |
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1.A.1.2.2 | Voltage-sensitive K+ channel of 498 aas and 6 TMSs, SHAW2. Modulation of the Drosophila Shaw2 Kv channel by 1-alkanols and inhaled anesthetics correlates with the involvement of the S4-S5 linker and C-terminus of S6, consistent with stabilization of the channel's closed state (Zhang et al. 2013). |
Eukaryota | Metazoa, Arthropoda | Shaw2 of Drosophila melanogaster |
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1.A.1.2.20 | Shaker K+ channel, Shk-1, Shk1, Kv1 of 536 aas and 6 TMSs. Mediates the voltage-dependent potassium ion permeability of excitable membranes. It plays a role in repolarization and in regulating the pattern of action potential firing. Isoform a expresses currents in a more depolarized voltage range than isoform d (Liu et al. 2011). |
Eukaryota | Metazoa, Nematoda | Shk-1 of Caenorhabditis elegans |
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1.A.1.2.21 | Shal (SHL-1, Kv4) K+ channels of 578 aas and 6 TMSs are the predominant transient outward current in C. elegans muscle. SHL-1 expression occurs in a subset of neurons, body wall muscle and in male-specific diagonal muscles (Fawcett et al. 2006) and control the excitability of neurons and cardiac myocytes by conducting rapidly activating-inactivating currents. Activity is modulated by three K+ channel interacting (KChIP) soluble auxiliary subunits, NCS-4, NCS-5, and NCS-7. All three ceKChIPs alter electrical characteristics of SHL-1 currents by slowing down inactivation kinetics and shifting voltage dependence of activation to more hyperpolarizing potentials. Native SHL-1 current is completely abolished in cultured myocytes of Triple KO worms in which all three KChIP genes are deleted (Chen et al. 2015). |
Eukaryota | Metazoa, Nematoda | Shal of Caenorhabditis elegans |
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1.A.1.2.22 | K+ channel, jShak1 of 487 aas and 6 TMSs. Intramolecular interactions control voltage sensitivity (Sharmin and Gallin 2016). |
Eukaryota | Metazoa, Cnidaria | jShak1 of Polyorchis penicillatus (Hydromedusa; jellyfish) |
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1.A.1.2.23 | Voltage-gated potassium channel subunit Kv8.2, KCNC2, of 545 aas and 6 TMSs. Mutation causes central ellipsoid loss which involves cone dystrophy with supernormal rod electroretinogram. It is a monogenic disease due to KCNV2 gene mutations that affect KCNC2 channel function in rod and cone photoreceptors (Xu et al. 2017). |
Eukaryota | Metazoa, Chordata | KCNC2 of Homo sapiens |
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1.A.1.2.24 | Voltage-gated K+ channel, KCNC1 (Kv3.1) of 511 aas and 6 TMSs. It plays an important role in the rapid repolarization of fast-firing brain neurons. The channel opens in response to the voltage difference across the membrane, forming a potassium-selective channel through which potassium ions pass in accordance with their electrochemical gradient (Muona et al. 2015). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNC2 (TC# 1.A.1.2.23), and possibly other family members as well. Contributes to fire sustained trains of very brief action potentials at high frequency in pallidal neurons. Causes various genetic neurological disorders when functioning abnormally such as attention deficit/hyperactivity (Yuan et al. 2017), myoclonus epilepsy and ataxia (Oliver et al. 2017) and intellectual disability (Poirier et al. 2017). The lipid environment, including 7-ketocholesterol (7KC), 24S-hydroxycholesterol (24S-OHC) and tetracosanoic acid (C24:0) affects Kv3.1b channel expression/functionality (Bezine et al. 2018).
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Eukaryota | Metazoa, Chordata | KCNC1 of Homo sapiens |
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1.A.1.2.25 | Potassium voltage-gated channel subfamily B member 2, Kv2.2 or KCNB2 of 911 aas and 6 TMSs. Selective expression of HERG (TC# 1.A.1.20.1) and Kv2 channels influences proliferation of uterine cancer cells (Suzuki and Takimoto 2004). |
Eukaryota | Metazoa, Chordata | Kv2.2 of Homo sapiens |
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1.A.1.2.26 | Potassium voltage-gated channel subfamily G member 4, KCNG4, of 519 aas and 6 TMSs. Potassium channel subunit that does not
form functional channels by itself, but can form functional heterotetrameric
channels with KCNB1; modulates the delayed rectifier voltage-gated
potassium channel activation and deactivation rates of KCNB1 (Mederos Y Schnitzler et al. 2009). |
Eukaryota | Metazoa, Chordata | KCNG4 of Homo sapiens |
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1.A.1.2.27 | Potassium voltage-gated channel subfamily G member 1, KCNG1, of 513 aas and 6 TMSs. Expressed in brain and placenta, and at much lower levels in kidney and pancreas (Su et al. 1997). This potassium channel subunit does not form functional channels by itself, but can form functional heterotetrameric channels with KCNB1. It modulates the delayed rectifier voltage-gated potassium channel activation and deactivation rates of KCNB1 (Mederos Y Schnitzler et al. 2009). KCNG1 mutations cause a syndromic form of congenital neuromuscular channelopathy (Jacinto et al. 2021).
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Eukaryota | Metazoa, Chordata | KCNG1 of Homo sapiens |
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1.A.1.2.28 | Potassium voltage-gated channel subfamily D member 1, Kv4.1 of 647 aas and 6 TMSs. It is the pore-forming α-subunit of a voltage-gated rapidly inactivating A-type potassium channel. It may contribute to I(To) current in the heart and I(Sa) current in neurons. Channel properties are modulated by interactions with other α-subunits and with regulatory subunits, KChIP-1 and DPPX-S. The complex voltage-dependent gating rearrangements are not limited to the membrane-spanning core but include the intracellular T1-T1 tetramerization domains interface (Wang and Covarrubias 2006). Artemisinin has an antiarrhythmic effect on wedge preparation models of Brugada syndrome (BrS). It may work by inhibiting potassium channels including I(to) channels, subsequently suppressing ventricular tachycardia/ventricular fibrillation (Jeong et al. 2023). The Kv4 potassium channel modulator NS5806 attenuates cardiac hypertrophy (Cai et al. 2024). KCND1 variants play roles in an X-linked neurodevelopmental disorder with variable expressivity (Kalm et al. 2024).
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Eukaryota | Metazoa, Chordata | Kv4.1 of Homo sapiens |
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1.A.1.2.29 | K+ channel of 529 aas and 6 TMSs, Kv1.6 or KCNA6. It can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA6, and possibly other family members (). channel properties depend on the type of alpha subunits that are part of the channel. Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation (By similarity). Homotetrameric channels display rapid activation and slow inactivation (Grupe et al. 1990). It is inhibited by 0.6 μM β-defensin 3 (BD3) (Zhang et al. 2018) as well as by neurotoxic cone snail peptide μ-GIIIA and other conotoxins (Leipold et al. 2017). An artificial pore blocker acts specifically on voltage-gated potassium channel isoform KV1.6 (Gigolaev et al. 2022). |
Eukaryota | Metazoa, Chordata | Kv1.6 of Homo sapiens |
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1.A.1.2.3 | Voltage-sensitive fast transient outward current K+ channel in neurons and muscle of flies and worms (Fawcett et al., 2006) |
Eukaryota | Metazoa, Arthropoda | Shal2 of Drosophila melanogaster |
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1.A.1.2.30 | Potassium channel protein of 542 aas and 10 TMSs in a 2 + 2 + 6 TMS toplogy, where the last 6 TMSs comprise the voltage-gated K+ channel. |
Bacteria | Mycoplasmatota | K+ channel of Haloplasma contractile |
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1.A.1.2.31 | The KCNA4 OR Kv1.4 K+ channel of 653 aas and 6 TMSs (potassium voltage-gated channel subfamily A member 4). The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (Ramaswami et al. 1990); Po et al. 1993).It can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, and possibly other family members; channel properties depend on the type of alpha subunits that are part of the channel (Po et al. 1993). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes. The molecular basis for the inactivation of the channel by the antidepressant, metergoline, has been presented (Bai et al. 2018).
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Eukaryota | Metazoa, Chordata | KCNA4 of Homo sapiens |
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1.A.1.2.32 | Potassium voltage-gated channel subfamily G member 4 of 535 aas and 6 TMSs + P-loop between TMSs 5 and 6, where the entire channel domain is between residues 220 - 460. The voltage gated (Kv) slow-inactivating delayed rectifier channel regulates the development of hollow organs of the zebrafish. The functional channel consists of the tetramer of electrically active Kcnb1 (Kv2.1) subunits and Kcng4b (Kv6.4) modulatory or electrically silent subunits (Jędrychowska et al. 2024). This channel is found in fish but not mammals. |
Eukaryota | Metazoa, Chordata | Kcng4a of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.A.1.2.4 | Margatoxin-sensitive voltage-gated K+ channel, Kv1.3 (in plasma and mitochondrial membranes of T lymphocytes) (Szabò et al., 2005). Kv1.3 associates with the sequence similar (>80%) Kv1.5 protein in macrophage forming heteromers that like Kv1.3 homomers are r-margatoxin sensitive (Vicente et al., 2006). However, the heteromers have different biophysical and pharmacological properties. The Kv1.3 mitochondrial potassium channel is involved in apoptotic signalling in lymphocytes (Gulbins et al., 2010). Interactions between the C-terminus of Kv1.5 and Kvβ regulate pyridine nucleotide-dependent changes in channel gating (Tipparaju et al., 2012). Intracellular trafficking of the KV1.3 K+ channel is regulated by the pro-domain of a matrix metalloprotease (Nguyen et al. 2013). Direct binding of caveolin regulates Kv1 channels and allows association with lipid rafts (Pérez-Verdaguer et al. 2016). Addtionally, NavBeta1 interacts with the voltage sensing domain (VSD) of Kv1.3 through W172 in the transmembrane segment to modify the gating process (Kubota et al. 2017). During insertion of Kv1.3, the extended N-terminus of the second α-helix, S2, inside the ribosomal tunnel is converted into a helix in a transition that depends on the nascent peptide sequence at specific tunnel locations (Tu and Deutsch 2017). The microRNA, mmumiR449a, reduced the mRNA expression levels of transient receptor potential cation channel subfamily A member 1 (TRPA1), and calcium activated potassium channel subunit alpha1 (KCNMA1) and increased the level of transmembrane phosphatase with tension homology (TPTE) in the DRG cells (Lu et al. 2017). This channel is regulation by sterols (Balajthy et al. 2017). Loss of function causes atrial fibrillation, a rhythm disorder characterized by chaotic electrical activity of cardiac atria (Olson et al. 2006). The N-terminus and S1 of Kv1.5 can attract and coassemble with the rest of the channel (i.e. Frag(304-613)) to form a functional channel independently of the S1-S2 linkage (Lamothe et al. 2018). This channel may be present in mitochondria (Parrasia et al. 2019). Kv1.3 plays an essential role in the immune response mediated by leukocytes and is functional at both the plasma membrane and the inner mitochondrial membrane. Plasma membrane Kv1.3 mediates cellular activation and proliferation, whereas mitochondrial Kv1.3 participates in cell survival and apoptosis (Capera et al. 2022). Kv1.3 uses the TIM23 complex to translocate to the inner mitochondrial membrane. This mechanism is unconventional because the channel is a multimembrane spanning protein without a defined N-terminal presequence. Transmembrane domains cooperatively mediate Kv1.3 mitochondrial targeting involving the cytosolic HSP70/HSP90 chaperone complex as a key regulator of the process (Capera et al. 2022). While the COOH-terminus of KCNE4 physically interacts with the channel, its transmembrane domain shapes the inactivation properties of the functional complex, fine-tuning the Kv1.3-dependent physiological response in leukocytes (Sastre et al. 2024). |
Eukaryota | Metazoa, Chordata | Kv1.3 homomers and Kv1.3/Kv1.5 heteromers of Homo sapiens (P22001) |
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1.A.1.2.5 | Voltage-gated K+ channel subfamily D, member 2, Kv4.2 or KCND2, in neurons and muscle; forms complexes with auxiliary subunits and scaffolding proteins via its N-terminus, influencing trafficking, temperature-sensitivity and gating (Radicke et al. 2013).These subunits are (1) dipeptidyl-peptidase-like type II transmembrane proteins typified by DPPX-S (e.g., protein 6, P42658; 865 aas, TC#8.A.51), and (2) cytoplasmic Ca2+ binding proteins known as K+ channel interacting proteins (KChIPs; TC#8.A.82.2.2; Q6PIL6) (Seikel and Trimmer 2009). The C-terminus interacts with KChIP2 to influence gating, surface trafficking and gene expression (Han et al., 2006; Schwenk et al., 2008). KChIPs (250 aas for mouse KChIP4a; Q6PHZ8) are homologous to domains in NADPH oxidases (5.B.1). Heteropoda toxin 2 (P58426; PDB 1EMX; TC#8.B.5.2.2) interactions with Kv4.3 and Kv4.1 give rise to differences in gating modifications (DeSimone et al., 2011). Mutations cause autism and seizures due to a slowing of channel inactivation (Lee et al. 2014). The stoichiometry of Kv4.2 and DPP6 is 4:4 (Soh and Goldstein 2008). Neferine, an isoquinoline alkaloid from plants, inhibits Kv4.3 channels, probably by blocking the open state (Wang et al. 2015). SUMOylating (derivatizing with a small ubiquitin-like modifier) at two distinct sites on Kv4.2 increases surface expression and decreases current amplitude (Welch et al. 2019). Modulation of voltage-gated potassium (Kv) channels by auxiliary subunits is central to the physiological function of channels in the brain and heart. Native Kv4 tetrameric channels form macromolecular ternary complexes with two auxiliary beta-subunits-intracellular Kv channel-interacting proteins (KChIPs) and transmembrane dipeptidyl peptidase-related proteins (DPPs)-to evoke rapidly activating and inactivating A-type currents, which prevent the backpropagation of action potentials (see above). Kise et al. 2021 investigated the modulatory mechanisms of Kv4 channel complexes, reporting cryo-EM structures of the Kv4.2-DPP6S-KChIP1 dodecameric complex, the Kv4.2-KChIP1 and Kv4.2-DPP6S octameric complexes, and Kv4.2 alone. The structure of the Kv4.2-KChIP1 complex revealed that the intracellular N terminus of Kv4.2 interacts with its C-terminus that extends from the S6 gating helix of the neighbouring Kv4.2 subunit. KChIP1 captures both the N and the C terminus of Kv4.2. Thus, KChIP1 prevents N-type inactivation and stabilizes the S6 conformation to modulate gating of the S6 helices within the tetramer. Unlike the reported auxiliary subunits of voltage-gated channel complexes, DPP6S interacts with the S1 and S2 helices of the Kv4.2 voltage-sensing domain, which suggests that DPP6S stabilizes the conformation of the S1-S2 helices. DPP6S may therefore accelerate the voltage-dependent movement of the S4 helices. KChIP1 and DPP6S do not directly interact with each other in the Kv4.2-KChIP1-DPP6S ternary complex. Thus, two distinct modes of modulation contribute in an additive manner to evoke A-type currents from the native Kv4 macromolecular complex (Kise et al. 2021). |
Eukaryota | Metazoa, Chordata | Kv4.2 of Homo sapiens (Q9NZV8) |
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1.A.1.2.6 |
Voltage-gated K+ channel, Shaker. Shaker and Shab K+ channels are blocked by quinidine (Gomez-Lagunas, 2010). Also regulated by unsaturated fatty acids (Börjesson and Elinder, 2011). TMSs 3 and 4 comprise the voltage sensor paddle (Xu et al. 2013). Partially responsible for action potential repolarization during synaptic transmission (Ford and Davis 2014). Shaker K+ channels can be mutated in S4 to create an analogous "omega" pore (Held et al. 2018). The NMR structure of the isolated Shaker voltage-sensing domain in LPPG micelles has been reported (Chen et al. 2019). Substituting the first S4 arginine with a smaller amino acid opens a high-conductance pathway for solution cations in the Shaker K+ channel at rest. The cationic current does not flow through the central K+ pore and is influenced by mutation of a conserved residue in S2, suggesting that it flows through a protein pathway within the voltage-sensing domain (Tombola et al. 2005). The current can be carried by guanidinium ions, suggesting that this is the pathway for transmembrane arginine permeation. Tombola et al. 2005 proposed that when S4 moves, it ratchets between conformations in which one arginine after another occupies and occludes to ions in the narrowest part of this pathway. Specific resin acids activate and open voltage-gated channels dependent on its exact binding dynamics (Silverå Ejneby et al. 2021). Charge-voltage curves of a Shaker potassium channel are not hysteretic at steady state (Cowgill and Chanda 2023). shaker is a critical sleep regulator in Drosophila (Cirelli et al. 2005). |
Eukaryota | Metazoa, Arthropoda | Shaker of Drosophila melanogaster (CAA29917) |
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1.A.1.2.7 | Electrically silent lens epithelium K+ channel (Delayed rectifier K+ channel α-subunit, Kv9.1 (Shepard & Rae, 1999)) |
Eukaryota | Metazoa, Chordata | Kv9.1 of Homo sapiens |
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1.A.1.2.8 | Voltage gated K+ channel/MiNK related peptide (MiRP) complex, KVS1(α)/MPS-1/MiRPβ (expressed in chemo- and mechano-sensory neurons. Involved in chemotaxis, mechanotransduction and locomotion (Bianchi et al., 2003)). KVS-1 and KVS-2 are homologous; MPS-1 is member of the MiNK family (8.A.10). KVS-1/MPS-1 association involves hydrophobic forces (Wang and Sesti, 2007). |
Eukaryota | Metazoa, Nematoda | KVS-1 (α)/ MPS-1 (MiRPβ) of Caenorhabditis elegans |
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1.A.1.2.9 | Brain-specific regulatory α-chain homologue that coassembles with other α-subunits to form active heteromultimeric K+ channels of unique kinetic properties, Kv2.3r. The functional expression of this regulatory α-subunit represents a novel mechanism without precedents in voltage-gated channels, which contributes to the functional diversity of K+ channels (Castellano et al., 1997). Beta subunits regulate the response of human Kv4.3 to protein kinae C phosphorylation and provide a potential mechanism for modifying the response of ion conductance to alpha-adrenergic regulation in vivo (Abbott 2017). |
Eukaryota | Metazoa, Chordata | Kv2.3r of Rattus norvegicus (P97557) |
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1.A.1.20.1 | K+ voltage-gated ether-a-go-go-related channel, H-ERG (KCNH2; Erg; HErg; Erg1, Kv11.1) subunit Kv11.1 (long QT syndrome type 2) (Gong et al., 2006; Chartrand et al. 2010; McBride et al. 2013). Selective expression of HERG and Kv2 channels influences proliferation of uterine cancer cells (Suzuki and Takimoto 2004). H-ERG forms a heteromeric K+ channel regulating cardiac repolarization, neuronal firing frequency and neoplastic cell growth (Szabó et al., 2011). Oligomerization is due to N-terminal interactions between two splice variants, hERG1a and hERG1b (Phartiyal et al., 2007). Structure function relationships of ERG channel activation and inhibition have been reviewed (Durdagi et al., 2010). Interactions between the N-terminal domain and the transmembrane core modulate hERG K channel gating (Fernández-Trillo et al., 2011). The marine algal toxin azaspiracid is an open state blocker (Twiner et al., 2012). Verapamil blocks channel activity by binding to Y652 and F656 in TMS S6 (Duan et al. 2007). Hydrophobic interactions between the voltage sensor and the channel domain mediate inactivation (Perry et al. 2013), but voltage sensing by the S4 segment can be transduced to the channel gate in the absence of physical continuity between the two modules (Lörinczi et al. 2015). Mutations give rise to long QT syndrome (Osterbur et al. 2015). Polyphenols such as caffeic acid, phenylethyl ester (CAPE) and curcumin inhibit by modification of gating, not by blocking the pore (Choi et al. 2013). Potassium ions can inhibit tumorigenesis through inducing apoptosis of hepatoma cells by upregulating potassium ion transport channel proteins HERG and VDAC1 (Xia et al. 2016). Incorrectly folded hERG can be degraded by Bag1-stimulated Trc-8-dependent proteolysis (Hantouche et al. 2016). The S1 helix regulates channel activity. Thus, S1 region mutations reduce both the action potential repolarizing current passed by Kv11.1 channels in cardiac myocytes, as well as the current passed in response to premature depolarizations that normally helps protect against the formation of ectopic beats (Phan et al. 2017). Interactions of beta1 integrins with hERG1 channels in cancer cells stimulate distinct signaling pathways that depended on the conformational state of hERG1 (Becchetti et al. 2017). ERG1 is sensitive to the alkaloid, ginsenoside 20(S) Rg3 which alters the gating of hERG1 channels by interacting with and stabilizing the voltage sensor domain in an activated state (Gardner et al. 2017). Channels split at the S4-S5 linker, at the intracellular S2-S3 loop, and at the extracellular S3-S4 loop are fully functional channel proteins (de la Peña et al. 2018). IKr is the rapidly activating component of the delayed rectifier potassium current, the ion current largely responsible for the repolarization of the cardiac action potential. Inherited forms of long QT syndrome (LQTS) in humans are linked to functional modifications in the Kv11.1 (hERG) ion channel and potentially life threatening arrhythmias. hERG1b affects the generation of the cardiac Ikr and plays an important role in cardiac electrophysiology (Perissinotti et al. 2018). X-ray crystallography and cryoEM have revealed features of the "nonswapped" transmembrane architecture, an "intrinsic ligand," and small hydrophobic pockets off a pore cavity. Drug block and inactivation mechanisms are discussed (Robertson and Morais-Cabral 2019). It forms a complex with β-integrin (TC#9.B.87.1.25) and NHE1 (TC# 2.A.36.1.13) (Iorio et al. 2020). Cardiotoxicity is caused mainly by the inhibition of human ether-a-go-go related gene (hERG) channel protein which leads to a life-threatening condition known as cardiac arrhythmia and is due to probable collapse of the pore. (Koulgi et al. 2021). Transmembrane hERG channel currents have been measured based on solvent-free lipid bilayer microarrays (Miyata et al. 2021). A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes has been published (Jæger et al. 2021). Ginsenoside Rg3 may be a promising cardioprotective agent against vandetanib-induced QT interval prolongation through targeting hERG channels (Zhang et al. 2021). Insight has been obtained into the potassium currents of hERG (Guidelli 2023). Two novel KCNH2 mutations contribute to long QT syndrome (Owusu-Mensah et al. 2024). Channel activity is affected by moxifloxacin, terfenadine, arsenic, pentamidine, erythromycin, and sotalol (Goineau et al. 2024). Erg K+ channels containing erg3 subunits mediate a neuronal subthreshold K+ current that plays important roles in the regulation of locomotor behavior in vivo (Schwarz et al. 2024). |
Eukaryota | Metazoa, Chordata | H-ERG of Homo sapiens (Q12809) |
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1.A.1.20.10 | The KCNH1 K+ channel protein of 989 aas and 6 TMSs. Tian et al. 2023 expanded the phenotypic spectrum of KCNH1 and explored the correlations between epilepsy and molecular sub-regional locations. They found two novel missense variants of KCNH1 in three individuals with isolated FS/epilepsy. Variants caused a spectrum of epileptic disorders ranging from a benign form of genetic isolated epilepsy/FS to intractable form of epileptic encephalopathy. The genotypes and variant locations helped explain the phenotypic variation of patients with KCNH1 variants (Tian et al. 2023). |
Eukaryota | Metazoa, Chordata | KCNH1 of Homo sapiens |
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1.A.1.20.2 | Erg2 (Kv11.2; KCNH6) K+ channel with slowly activating delayed rectifier (expressed only in the nervous system) (Shi et al., 1997). The human ortholog of 994 aas and 6 TMSs (Q9H252) is 86% identical to the rat protein. KCNH6 in humans and mice plays a key role in insulin secretion and glucose hemostasis (Yang et al. 2018). GJB2 (TC# 1A.24), KCNH6, and KCNN4 (TC# 1.A.1.16.2) are oncogenic, and GJB2 and KCNN4 were upregulated, while KCNH6 was downregulated in high risk group and glioblastoma (GBM) cells (Huang et al. 2024). The regulatory network showed that KCNH6 was targeted by more miRNAs and transcription factors and KCNN4 interacted with more drugs (Huang et al. 2024). |
Eukaryota | Metazoa, Chordata | Erg2 of Rattus norvegicus |
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1.A.1.20.3 | Erg3, Kv11.3, Eag3, KCNH7, K+ channel with a large transient current at positive potentials (expressed only in the nervous system) (Shi et al., 1997). Erg3-mediated suppression of neuronal intrinsic excitability prevents seizure generation (Xiao et al. 2018). The human ortholog (Q9NS40) is 1196 aas long with 6 TMSs and is 94% identical to the rat protein. |
Eukaryota | Metazoa, Chordata | Erg3 of Rattus norvegicus |
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1.A.1.20.4 | K+ voltage-gated channel, rEAG1; Kv10.1; rat ether a go-go channel 1 (962 aas). Blocked by Cs+, Ba2+ and quinidine (Schwarzer et al., 2008). Cysteines control the N- and C-linker-dependent gating of KCNH1 potassium channels (Sahoo et al., 2012). The 3-d structure has been determined at 3.8 Å resolution using single-particle cryo-EM with calmodulin bound. The structure suggests a novel mechanism of voltage-dependent gating. Calmodulin binding closes the potassium pore (Whicher and MacKinnon 2016). Eag1 has three intracellular domains: PAS, C-linker, and CNBHD. Whicher and MacKinnon 2019 demonstrated that the Eag1 intracellular domains are not required for voltage-dependent gating but likely interact with the VS to modulate gating. Specific interactions between the PAS, CNBHD, and VS domains modulate voltage-dependent gating, and VS movement destabilizes these interactions to promote channel opening. Mutations affecting these interactions render Eag1 insensitive to calmodulin inhibition (Whicher and MacKinnon 2019). The structure of the calmodulin insensitive mutant in a pre-open conformation suggests that channel opening may occur through a rotation of the intracellular domains, and calmodulin may prevent this rotation by stabilizing interactions between the VS and the other intracellular domains. Intracellular domains likely play a similar modulatory role in voltage-dependent gating of the related Kv11-12 channels. The human ortholog, EAG or EAG-1, is 989 aas long and is 95% identical to the rat protein. In ether-a-go-go K+ channels, voltage-dependent activation is modulated by ion binding to a site located in an extracellular-facing crevice between transmembrane segments S2 and S3 in the voltage sensor. Silverman et al. 2004 found that acidic residues, D278 in S2 and D327 in S3, are able to coordinate a variety of divalent cations, including Mg2+, Mn2+, and Ni2+, which have qualitatively similar functional effects, but different half-maximal effective concentrations. EAG (ether-a-go-go) voltage-dependent K+ channels with similarities and differences in the structural organization and gating (Barros et al. 2020). Corydaline binds to a druggable pocket of the hEAG1 channel and inhibits hepatic carcinoma cell viability (Ma et al. 2024). |
Eukaryota | Metazoa, Chordata | EAG1 of Rattus norvegicus (Q63472) |
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1.A.1.20.5 | Potassium voltage-gated channel subfamily H member 3 (Brain-specific eag-like channel 1, BEC1) (Ether-a-go-go-like potassium channel 2) (ELK channel 2, ELK2) (Voltage-gated potassium channel subunit, Kv12.2). Deletion causes hippocampal hyperexcitability and epilepsy (Zhang et al. 2010). A selective inhibitor is ASP2905 (Takahashi et al. 2017). Voltage-sensor movements in the Eag Kv channel under an applied electric field have been measured (Mandala and MacKinnon 2022). |
Eukaryota | Metazoa, Chordata | KCNH3 of Homo sapiens |
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1.A.1.20.6 |
Cyclic nucleotide-binding, voltage-gated, Mg2+-dependent, CaMKII-regulated K+ channel, Eag. Eag recruits CASK (TC# 9.B.106.3.2) to the plasma membrane; forms a heterotetramer (Liu et al. 2010). Phosphorylation is catalyzed by CaMKII (TC# 8.A.104.1.11) |
Eukaryota | Metazoa, Arthropoda | Eag of Drosophila melanogaster |
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1.A.1.20.7 | Cyclic nucleotide-gated K+ channel, CNGC or CNG1 of 894 aas and 6 TMSs (Wheeler and Brownlee 2008). |
Viridiplantae, Chlorophyta | CNG1 of Chlamydomonas reinhardtii |
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1.A.1.20.9 | Potassium voltage-gated channel subfamily H member 5 of 988 aas and 6 TMSs, EAG2 or KCNH5. This pore-forming α-subunit of voltage-gated potassium channel elicits a non-inactivating outward rectifying current. The channel properties may be modulated by cAMP and subunit assembly (Bauer and Schwarz 2018). |
Eukaryota | Metazoa, Chordata | Eag2 of Homo sapiens |
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1.A.1.21.1 | K+- and Na+-conducting NaK channel, NaK2K of 97 aas and 2 TMSs. The 3-D structure has been solved with Na+ and K+bound (Shi et al., 2006). It exhibits tight structural and dynamic coupling between the selectivity filter and the channel scaffold (Brettmann et al. 2015). A hydrophobic residue at the bottom of the selectivity filter, Phe92, appears in dual conformations. One of the two conformations of Phe92 restricts the diameter of the exit pore around the selectivity filter, limiting ion flow through the channel, while the other conformation of Phe92 provides a larger-diameter exit pore from the selectivity filter. Thus, Phe92 acts as a hydrophobic gate (Langan et al. 2020). |
Bacteria | Bacillota | NaK channel of Bacillus cereus (2AHYB) (Q81HW2) |
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1.A.1.21.2 | Two pore domain potassium channel family protein of 122 aas and 2 TMSs. |
Bacteria | Chloroflexota | K+ channel of Anaerolineales bacterium |
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1.A.1.21.3 | Two pore domain potassium channel family protein of 140 aas and 2 TMSs. |
Archaea | Euryarchaeota | K+ channel of Methanosarcina mazei |
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1.A.1.22.1 | The cyclic nucleotide-gated K+ channel, MmaK. (Activated by cyclic AMP and cyclic GMP; inactivated at slightly acidic pH (Kuo et al., 2007)) | Bacteria | Pseudomonadota | MmaK of Magnetospirillum magnetotacticum (Q2W0I8) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.1.23.1 | The pea symbiosis protein, essential for nodulation, mycorrhization, and Nod-factor-induced calcium spiking, SYM8 or DMI1 (Does not make infections 1). (Most similar to 1.A.1.13.2; 894aas; 4 TMSs between residues 136 and 339) (Edwards et al., 2007). |
Eukaryota | Viridiplantae, Streptophyta | SYM8 of Pisum sativum |
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1.A.1.23.2 | Root nuclear envelope CASTOR: homomeric ion channel (preference of cations such as K+ over anions) (Charpentier et al., 2008) (62% identical to 1.A.1.23.1). | Eukaryota | Viridiplantae, Streptophyta | CASTOR of Lotus japonicus (Q5H8A6) |
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1.A.1.23.3 | POLLUX homomeric ion channel (preference for cations over anions) (Charpentier et al., 2008) (81% identical to 1.A.1.23.1). | Eukaryota | Viridiplantae, Streptophyta | POLLUX of Lotus japonicus (Q5H8A5) |
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1.A.1.23.4 | putative ion channel (N-terminal domain) protein with C-terminal TrkA-N domain (DUF1012); NAD-binding lipoprotein. |
Bacteria | Actinomycetota | Ion channel protein of Streptomyces coelicolor |
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1.A.1.24.1 | The cyclic nucleotide regulated K+ channel, CNR-K+ channel (412 aas) | Bacteria | Pseudomonadota | CNR-K+ channel of Rhodopseudomonas palustris (Q02006) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.1.24.2 | K+ channel protein homologue |
Bacteria | Myxococcota | K+ channels protein homologue of Stigmatella aurantiaca (Q08U57) |
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1.A.1.24.3 | Putative 6 TMS potassium channel |
Bacteria | Myxococcota | Potassium ion channel of Myxococcus xanthus |
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1.A.1.24.4 | Putative K+ channel |
Bacteria | Cyanobacteriota | K channel of Cyanotheca (Synechococcus) sp PCC8801 |
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1.A.1.24.5 | Cyclic nucleotide-gated K+ channel of 459 aas. |
Bacteria | Pseudomonadota | Channel of Labenzia aggregata |
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1.A.1.24.6 | Uncharacterized ion channel protein of 276 aas and 6 TMSs |
Bacteria | Bacteroidota | UP of Flavobacterium psychrolimnae |
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1.A.1.25.1 | The 6TMS bacterial cyclic nucleotide-regulated, voltage independent channel, MlotiK1 or MloK1 (Clayton et al., 2008). Gating involves large rearrangements of the cyclic nucleotide-binding domains (Mari et al., 2011). The electron crystalographic structure is available (PDB 4CHW) revealing ligand-induced structural changes (Schünke et al. 2011; Scherer et al. 2014; Kowal et al. 2014). Such changes may be lipid dependent (McCoy et al. 2014). High-speed atomic force microscopy has been used to measure millisecond to microsecond dynamics (Heath and Scheuring 2019). |
Bacteria | Pseudomonadota | MlotiK1 of Mesorhizobium loti (Q98GN8) |
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1.A.1.26.1 | The rodent malaria parasite K+ channel, PfKch1 (929aas) (Ellekvist et al., 2008). | Eukaryota | Apicomplexa | Kch1 of Plasmodium berghei (Q4YNK7) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.1.26.2 | Voltage-gated potassium channel, KCh1, of 1966 aas with about 8 TMSs probably in a 2 (residues 20 - 80) + 6 (residues 550 - 780) TMS arrangement (Wunderlich 2022). |
Eukaryota | Apicomplexa | KCh1 of Plasmodium falciparum |
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1.A.1.26.3 | Uncharacterized protein of 1949 aas and 11 - 13 TMSs in a 2 + 8 - 10 +1 TMS arrangement (Wunderlich 2022). |
Eukaryota | Apicomplexa | UP of Plasmodium falciparum |
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1.A.1.26.4 | K+ channel (K2 gene) of 1461 aas and 8 TMSs with 2 N-terminal TMSs (residues 1 - 80) followed by 6 TMSs (residues 180 - 360). The remainder of the protein is hydrophilic (Desai 2024). |
Eukaryota | Apicomplexa | K2 gene product of Plasmodium falciparum |
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1.A.1.27.1 | Putative 4 TMS ion channel protein. TMSs 1-2 may not be homologous to TMSs 3-4 which probably form the channel. |
Bacteria | Actinomycetota | Hypothetic VIC family member of Streptomyces coelicolor |
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1.A.1.27.2 | Putative 4 TMS potassium ion channel protein. TMSs 1-2 may not be homologous to TMSs 3-4 which probably form the channel. |
Bacteria | Actinomycetota | Putative ion channel of Streptomyces coelicolor |
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1.A.1.27.3 | Uncharacterized protein of 114 aas |
Bacteria | Pseudomonadota | UP of Rhizobium meliloti |
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1.A.1.27.4 | Uncharacterized protein of 148 aas and 3 or 4 TMSs |
Bacteria | Pseudomonadota | UP of Marinobacter hydrocarbonoclasticus |
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1.A.1.28.1 | Putative K+ channel |
Bacteria | Pseudomonadota | Putative K+ channel of Klebsiella varicola (D3RJS6) |
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1.A.1.28.2 | Putative K+ channel |
Bacteria | Pseudomonadota | Putative K+ channel of Pseudomonas fluorescens (C3K1P0) |
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1.A.1.28.3 | Thylakoid membrane 6 TMS voltage-sensitive K+ channel, SnyK; important for photosynthesis (Checchetto et al. 2012). |
Bacteria | Cyanobacteriota | SynK of Synechocystis sp. |
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1.A.1.28.4 | Putative voltage-dependent K+ channel |
Bacteria | Pseudomonadota | K+ channel of Vibrio alginolyticus |
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1.A.1.28.5 | Putative voltage-dependent K+ channel |
Bacteria | Pseudomonadota | K+ channel of E. coli |
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1.A.1.28.6 | Putative voltage-dependent K+ channel |
Bacteria | Pseudomonadota | K+ channel of Acinetobacter baumannii |
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1.A.1.28.7 | Uncharacterized protein of 228 aas and 6 TMSs |
Archaea | Euryarchaeota | UP of Methanoculleus bourgensis (Methanogenium bourgense) |
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1.A.1.28.8 | Two pore domain potassium channel family protein of 246 aas and 6 TMSs. |
Bacteria | Planctomycetota | Putative K+ channel of Planctomycetes bacterium |
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1.A.1.29.1 | The 2 - 4 TMS K+ channel, LctB (Wolters et al. 1999). |
Bacteria | Bacillota | LctB of Bacillus stearothermophilus |
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1.A.1.29.2 | Uncharacterized protein of 481 aas and 2 TMSs. (Pfam CL0030) |
Archaea | Euryarchaeota | UP of Pyrococcus furiosus |
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1.A.1.29.3 | Uncharacterized protein of 326 aas and 2 TMSs |
Bacteria | Pseudomonadota | UP of Pseudoalteromonas luteoviolacea |
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1.A.1.29.4 | C-terminal 2 TMS channel protein of 723 aas with 5 N-terminal pentapeptide repeats in a YjbI domain of unknown function |
Archaea | Euryarchaeota | Channel protein of Natrinema altunense |
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1.A.1.29.5 | Ion transport 2 domain-containing protein of 345 aas and 2 TMSs |
Archaea | Euryarchaeota | Ion transport 2 domain-containing protein of Halococcus salifodinae |
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1.A.1.29.6 | Putative cation transporting channel-2 of 288 aas with 2 N-terminal TMSs (Hug et al. 2016). |
Bacteria | Candidatus Peregrinibacteria | Channel-2 of Candidatus Peribacter riflensis |
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1.A.1.29.7 | Putative K+ channel of 317 aas and 2 TMSs with a central P-loop. |
Archaea | Candidatus Woesearchaeota | K+ channel of Candidatus Woesearchaeota archaeon (marine sediment metagenome) |
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1.A.1.3.1 | Large conductance, voltage- and Ca2+-activated K+ (BK or Slo) channel. Four pairs of RCK1 and RICK2 domains form the Ca2+-sensing apparatus known as the "gating ring" in Big Potassium (BK) channel proteins (Savalli et al., 2012). Gating of BK channels does not seem to require a physical gate. Instead, changes in the pore shape and surface hydrophobicity in the Ca2+-free state allow the channel to readily undergo hydrophobic dewetting transitions, giving rise to a large free energy barrier for K+ permeation (Jia et al. 2018). Voltage-dependent dynamics of the BK channel cytosolic gating ring are coupled to the membrane-embedded voltage sensor (Miranda et al. 2018). Slo channels are targets for insecticides and antiparasitic drugs. Raisch et al. 2021 reported structures of Drosophila Slo in the Ca2+-bound and Ca2+-free forms and in complex with the fungal neurotoxin verruculogen and the anthelmintic drug emodepside. The architecture and gating mechanism of Slo channels are conserved, but potential insect-specific binding pockets are present. Verruculogen inhibits K+ transport by blocking the Ca2+-induced activation signal and precludes K+ from entering the selectivity filter while emodepside decreases the conductance by suboptimal K+ coordination and uncouples ion gating from Ca2+ and voltage sensing (Raisch et al. 2021). In neurosecretion, allosteric communication between voltage sensors and Ca2+ binding in BK channels is crucially involved in damping excitatory stimuli. Carrasquel-Ursulaez et al. 2022 demonstrated that two arginines in the transmembrane segment S4 (R210 and R213) function as the BK gating charges. The energy landscape of the gating particles is electrostatically tuned by a network of salt bridges contained in the voltage sensor domain (VSD). |
Eukaryota | Metazoa, Arthropoda | Ca2+-activated K+ channel of Drosophila melanogaster |
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1.A.1.3.10 | Calcium-, magnesium- and voltage-activated K+ channel, Slo1 (Kcma1; KCNMA, KCNMA1), a BK channel, of 1236 aas and 6 N-terminal TMSs. Its activation dampens the excitatory events that elevate the cytosolic Ca2+ concentration and/or depolarize the cell membrane. It therefore contributes to repolarization of the membrane potential, and it plays a key role in controlling excitability in a number of systems. Ethanol and carbon monoxide-bound heme increase channel activation while heme inhibits channel activation (Tang et al. 2003). The molecular structures of the human Slo1 channel in complex with beta4 has been solved revealing four beta4 subunits, each containing two transmembrane helices, encircling Slo1, contacting it through helical interactions inside the membrane. On the extracellular side, beta4 forms a tetrameric crown over the pore. Structures with high and low Ca2+ concentrations show that identical gating conformations occur in the absence and presence of beta4, implying that beta4 serves to modulate the relative stabilities of 'pre-existing' conformations rather than creating new ones (Tao and MacKinnon 2019). BK channels show increased activities in Angelman syndrome due to genetic defects in the ubiquitin protein ligase E3A (UBE3A) gene (Sun et al. 2019). It is a large-conductance potassium (BK) channel that can be synergistically and independently activated by membrane voltage and intracellular Ca2+. The only covalent connection between the cytosolic Ca2+-sensing domain and the TM pore and voltage sensing domains is a 15-residue 'C-linker' which plays a direct role in mediating allosteric coupling between BK domains (Yazdani et al. 2020). Site specific deacylation by the alpha/beta acyl-hydrolase domain-containing protein 17A, ABHD17a (Q96GS6, 310 aas), controls BK channel splice variant activity (McClafferty et al. 2020). Compared with the structure of isolated hSlo1 Ca2+ sensing gating rings, two opposing subunits in hBK unfurled, resulting in a wider opening towards the transmembrane region of hBK. In the pore gate domain, two opposing subunits moved downwards relative to the two other subunits (Tonggu and Wang 2022). A gating lever, mediated by S4/S5 segment interactions within the transmembrane domain, rotates to engage and stabilize the open conformation of the S6 inner pore helix upon V sensor activation (Sun and Horrigan 2022). An indirect pathway, mediated by the carboxyl-terminal cytosolic domain (CTD) and C-linker connects the CTD to S6, and stabilizes the closed conformation when V sensors are at rest (Sun and Horrigan 2022). Co-dependent regulation of p-BRAF (TC# 8.A.23.1.48) and the potassium channel KCNMA1 levels drives glioma progression (Xie et al. 2023). Potassium channelopathies associated with epilepsy-related syndromes and directions for therapeutic interventionhave been reviewed (Gribkoff and Winquist 2023). The influx of Ca2+, mediated by the hypotonic-induced activation of mechanosensitive channels, is a key step for opening both the BK(Ca) and the IK(Ca) channels. The influx of Ca2+, mediated by the hypotonic-induced activation of mechanosensitive channels, is a key step for opening both the BK(Ca) and the IK(Ca) (TC# 1.A.1.16.2) channels (Michelucci et al. 2023). Disease-associated KCNMA1 variants decrease circadian clock robustness in channelopathy mouse models (Dinsdale et al. 2023). High-resolution structures illuminate key principles underlying voltage and LRRC26 regulation of Slo1 channels (Kallure et al. 2023). Kcnma1 is involved in mitochondrial homeostasis in diabetes-related skeletal muscle atrophy (Gao et al. 2023). Activation of BK channels prevents diabetes-induced osteopenia by regulating mitochondrial Ca2+ and SLC25A5/ANT2-PINK1-PRKN-mediated mitophagy (Jiang et al. 2024). Mammalian Ca2+-dependent Slo K+ channels can stably associate with auxiliary γ subunits which fundamentally alter their behavior. The four γ subunits reduce the need for voltage-dependent activation and, thereby, allow Slo to open independently of an action potential. Using cryo-EM, Redhardt et al. 2024 revealed how the transmembrane helix of γ1/LRRC26 binds and presumably stabilizes the activated voltage-sensor domain of Slo1. Transmembrane determinants of voltage-gating differences between BK (Slo1) and Slo3 channels have been identified (Li et al. 2024). Mutations in the Slo1's TMS5 and TMS6 revealed three residues (I233, L302, and M304) that may play crucial roles in the allosteric coupling between the voltage sensors and the pore gate. Mitochondria are implicated in phenomena such as cytoprotection, cellular senescence, tumor metabolism, and inflammation. The basis for these processes relies on mitochondria such as the synthesis of reactive oxygen species or biophysical properties such as the integrity of the inner mitochondrial membrane. The transport of potassium cations plays a role in these events. K+ influx is mediated by potassium channels present in the inner mitochondrial membrane. Walewska et al. 2018 presented an overview of the properties of mitochondrial large-conductance calcium-activated and mitochondrial ATP-regulated potassium channels. This concerns the role of mitochondrial potassium channels in cellular senescence, and interactions with other mitochondrial proteins or small molecules such as quercetin, hemin, and hydrogen sulfide. Hypoxia and ischemic stroke modify cerebrovascular tone by upregulating endothelial BK(Ca) channels in mammals (Staehr et al. 2025).
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Eukaryota | Metazoa, Chordata | Kcma1 of Homo sapiens |
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1.A.1.3.2 |
Large conductance or L-type Ca2+ and voltage-activated K+ channel (LTCC), α-subunit (subunit α1), BK, BKCa, Kca1.1, Slowpoke, Slo1, KCNMA1 or MaxiK (functions with four β-subunits (TC# 8.A.14) encoded by genes KCNMB1-4 and the γ subunit (TC# 8.A.43) in humans (Toro et al. 2013; Li et al. 2016); the positions of beta2 and beta3 have been determined (Wu et al. 2013). The KB channel is inhibited by 3 scorpion toxins, charybda toxin, iberiotoxin and slotoxin. It forms a ''Ca2+ nanodomain'' complex with Cav1.2 (L-type; 1.A.1.11.4), Cav2.1 (P/Q-type; 1.A.1.11.5) and Cav2.2 (N-type; 1.A.1.11.6) where Ca2+ influx through the Cav channel activates BKCa (Berkefeld et al., 2006; Romanenko et al., 2006). The RCK2 domain is a Ca2+ sensor (Yusifov et al., 2008). Binding of Ca2+ to D367 and E535 changes the conformation around the binding site and turns the side chain of M513 into a hydrophobic core, explaining how Ca2+ binding opens the activation gate of the channel (Zhang et al., 2010). A structural motif in the C-terminal tail of Slo1 confers carbon monoxide sensitivity to human BKCa channels (Williams et al., 2008; Hou et al., 2008). These channels are present in the inner mitochondrial membrane of rat brain (Douglas et al., 2006).The Stress-Axis Regulated Exon (STREX) is responsible for stretch sensitivity. Ca2+ binds to two sites. Ca2+ binding to the RCK1 site is voltage dependent, but Ca2+ binding to the Ca2+ bowl is not (Sweet and Cox et al., 2008). Type 1 IP3 receptors activate BKCa channels via local molecular coupling in arterial smooth muscle cells (Zhao et al., 2010). The open structure is known (Yuan et al., 2012). BKCa is essential for ER calcium uptake in neurons and cardiomyocytes (Kuum et al., 2012) and link Ca2+ signaling to action potential firing and neurotransmitter release via serotonin receptors in many types of neurons (Rothberg 2012). The molecular mechanism of pharmacological activation of BK channels has been discussed by Gessner et al. (2012). The first TMS of the β2-subunit binds to TMS S1 of the α-subunit (Morera et al., 2012). Mutations in Cav1.2 give rise to Timothy syndrome (Dixon et al. 2012). Exhibits low voltage activation by interaction with Cav3 (Rehak et al. 2013) as well as Ca2+-gating (Berkefeld and Fakler 2013). Single-channel kinetics have been reported (Geng and Magleby 2014). The γ-subunit has TC# 8.A.43.1.8. RBK channels regulate myogenesis in vascular smooth muscle cells (Krishnamoorthy-Natarajan and Koide 2016). Latorre et al. 2017 reviewed molecular, physiological and pathological aspects of Slo1. The microRNA, mmumiR449a, reduced the mRNA expression levels of transient receptor potential cation channel subfamily A member 1 (TRPA1), and calcium activated potassium channel subunit alpha1 (KCNMA1) and increased the level of transmembrane phosphatase with tension homology (TPTE) in the DRG cells (Lu et al. 2017), thereby reducing pain. The N-terminal sequence determines its modification by β-subunits (Lorca et al. 2017). Inhibition of BKCa negatively alters cardiovascular function (Patel et al. 2018). BKCa may be the target of verteporfin, a benzoporphyrin photosensitizer that alters membrane ionic currents (Huang et al. 2019). Globotriaosylceramide (Gb3) accumulates due to mutations in the gene encoding alpha-galactosidase A. Gb3 deposition in skin fibroblasts impairs KCa1.1 activity and activate the Notch1 signaling pathway, resulting in an increase in pro-inflammatory mediator expression, and thus, contributing to cutaneous nociceptor sensitization as a potential mechanism of FD-associated pain (Rickert et al. 2019). This channel may be present in mitochondria (Parrasia et al. 2019). The Slo3 (TC# 1.A.1.3.5) cytosolic module confers pH-dependent regulation whereas the Slo1 cytosolic module confers Ca2+-dependent regulation (Xia et al. 2004). Elevated extracellular Ca2+ aggravates iron-induced neurotoxicity because LTCCs mediate iron transport in dopaminergic neurons and this, in turn, results in elevated intracellular Ca2+ and further aggravates iron-induced neurotoxicity (Xu et al. 2020). Agonists include BMS-191011, NS1619, NS11021, epoxyeicosatrienoic acid isoforms, while inhibitors include iberiotoxin and penitrem A which have been used to study the system in megakaryocytes and platelets (Balduini et al. 2021). Medicinal plant products can interact with BKCa (Rajabian et al. 2022). A potent and selective activator of large-conductance Ca2+-activated K+ channels induces preservation of mitochondrial function after hypoxia and reoxygenation by handling of calcium and transmembrane potential (de Souza et al. 2024). Neither the closed channel conformation obtained in the absence of Ca2+ nor an intermediate conformation found in the presence of Ca2+ show density for the N-terminus of the β2 subunit in their pore, likely due to narrower side access portals preventing their entry into the channel pore. Thus, a ball-and-chain inactivation mechanism is proposed (Agarwal et al. 2025). |
Eukaryota | Metazoa, Chordata | BKCa or MaxiK channel of Rattus norvegicus (Q62976) |
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1.A.1.3.3 | Ca2+-activated K+ channel Slo-1 (Maxi K; BK channel) (ethanol-activated; responsible for intoxication) (Davies et al., 2003); tyrosyl phosphorylation regulates BK channels via cortactin (Tian et al. 2008a), but palmitoylation gates phosphorylation-dependent regulation of BK potassium channels (Tian et al., 2008b). Also regulated by Mg2+ which mediates interaction between the voltage sensor and cytosolic domain to activate BK channels (Yang et al., 2007). Modulated by the ss2 subunit (Lee et al., 2010). The structure of the gating ring from the human large-conductance Ca2+-gated K+ channel has been reported (Wu et al., 2010). Four pairs of RCK1 and RICK2 domains form the Ca2+-sensing apparatus known as the "gating ring" in BK channel proteins (Savalli et al., 2012). The dystrophin (Q9TW65) dystrobrevin (Q9Y048) complex controls BK channel localization and muscle activity as well as neurotroansmitter release (Kim et al. 2009, Chen et al. 2011). Syntrophin (Q93646) links various receptors and transporters to the actin cytoskeleton and the dystrophin glycoprotein complex (DGC), and α-catulin (CTN-1; 759 aas, 0 TMSs) facilitates targeting. The BK channel is a tetramer where the pore-forming α-subunit contains seven transmembrane segments (González-Sanabria et al. 2021). It has a modular architecture containing a pore domain with a highly potassium-selective filter, a voltage-sensor domain and two intracellular Ca2+ binding sites at the C-terminus. BK is found in the plasma membrane of different cell types, the inner mitochondrial membrane (mitoBK) and the nuclear envelope's outer membrane (nBK). Like BK channels in the plasma membrane (pmBK), the open probability of mitoBK and nBK channels are regulated by Ca2+ and voltage and modulated by auxiliary subunits. BK channels share common pharmacology to toxins such as iberiotoxin, charybdotoxin, paxilline, and agonists of the benzimidazole family (González-Sanabria et al. 2021).
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Eukaryota | Metazoa, Nematoda | BK K+ channel of Caenorhabditis elegans (Q95V25) |
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1.A.1.3.4 | The one or two component intracellularly Na+ and Cl--activated delayed rectifier K+ channel, rSlo2.2 (Slack; KCNT1)/r Slo2.1 (Slick; KCNT2; TC# 1.A.1.3.6) provides protection against ischemia (Yuan et al., 2003). The N-terminal domain of Slack determines the formation and trafficking of Slick/Slack heteromeric sodium-activated potassium channels (Chen et al., 2009). Slick and Slack can also form separate homooligomeric channels. These channels are widely distributed in the mammalian CNS and they play roles in slow afterhyperpolarization, generation of depolarizing afterpotentials and in setting and stabilizing the resting potential (Rizzi et al. 2015). The small cytoplasmic protein beta-synuclein TC# 1.C.77.1.2) and the transmembrane protein 263 (TMEM 263; TC# 8.A.101.1.1) are interaction partners of both Slick and Slack channels. The inactive dipeptidyl-peptidase (DPP 10) and the synapse associated protein 102 (SAP 102) are constituents of the Slick and Slack channel complexes (Rizzi et al. 2015). KCNT1 reduction could be therapeutically useful in the treatment of KCNT1 epilepsies (Sun et al. 2024). |
Eukaryota | Metazoa, Chordata | Slo2 of Rattus norvegicus (Q9Z258) |
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1.A.1.3.5 | Sperm Slo3 high conductance K+ channel, activated by voltage and intracellular alkalinization. In sperm, it gives rise to pH-dependent outwardly rectifying K+ currents. (required for the ensuing acrosome reaction; activated by phosphatidylinositol 4,5-bisphosphate (PIP(2)) (Tang et al., 2010). The Slo3 cytosolic module confers pH-dependent regulation whereas the Slo1 (TC# 1.A.1.3.2) cytosolic module confers Ca2+-dependent regulation (Xia et al. 2004). When mammalian sperm are released in the female reproductive tract, they are incapable of fertilizing the oocyte. They need a prolonged exposure to the alkaline medium of the female genital tract before their flagellum gets hyperactivated and the acrosome reaction can take place, allowing the sperm to interact with the oocyte (de Prelle et al. 2022). Ionic fluxes across the sperm membrane are involved in two essential aspects of capacitation: the increase in intracellular pH and membrane hyperpolarization. The SLO3 potassium channel and the sNHE sodium-proton exchanger are necessary for the capacitation process to occur. As the SLO3 channel is activated by an increase in intracellular pH and sNHE is activated by hyperpolarization, they act together as a positive feedback system (de Prelle et al. 2022). |
Eukaryota | Metazoa, Chordata | Slo3 of Mus musculus (O54982) |
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1.A.1.3.6 | Human outward rectifying potassium channel, Slo2.1 (also called KCNT2 and Slick) of 1135 aas. Produces rapidly activating outward rectifier K+ currents. Activated by high intracellular sodium and chloride levels. Channel activity is inhibited by ATP and by inhalation of anesthetics such as isoflurane. Inhibited upon stimulation of G-protein coupled receptors such as CHRM1 and GRIA1. Orthologous to 1.A.1.3.4 (Garg et al. 2013) and can form a heteromeric complex with it and several other proteins (see TC# 1.A.1.3.4). Hydrophobic interactions between residues in S5 and the C-terminal end of the pore helix stabilize Slo2.1 channels in a closed state (Suzuki et al. 2016). Despite their apparent high levels of expression, the activities of somatic KNa (Slo2.1 and Slo2.2) channels are tightly regulated by the activity of the Na+/K+ pump (Gray and Johnston 2021). |
Eukaryota | Metazoa, Chordata | Slo2.1 of Homo sapiens |
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1.A.1.3.7 | Slo2.2 sodium-activated potassium channel subfamily T member 1 of 1217 aas and 6 putative N-terminal TMSs plus a P-loop. Cryo electron microscopic structures of the chicken orthologue at 4.5 Å resolution has been solved, revealing a large cytoplasmic gating ring in which resides the Na+-binding site and a transmembrane domain that closely resembles voltage-gated K+ channels (Hite et al. 2015). |
Eukaryota | Metazoa, Chordata | Slo2.2 of Homo sapiens |
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1.A.1.3.8 | SLOwpoke K+ channel, SLO-2 or Slo2, of 1107 aas and 6 TMSs, present in motor neurons. It has six putative TMSs with a K+-selective pore and a large C-terminal cytosolic domain (Lim et al. 1999). Its requirements for both Cl- and Ca2+ are synergistic and associated with the same functional domain (Yuan et al. 2000) which serves to counteract hypoxia stress when cytoplasmic Cl- and Ca2+ concentrations increase (Yuan et al. 2003; Santi et al. 2003). SLO2 protects from hypoxic injury by increasing the permeability of the mitochondrial inner membrane to K+ (Wojtovich et al. 2011). SLO-2 is functionally coupled with CaV1 and regulates neurotransmitter release (Liu et al. 2014). Partially responsible for action potential repolarization during synaptic transmission (Ford and Davis 2014). |
Eukaryota | Metazoa, Nematoda | Slo-2 of Caenorhabditis elegans |
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1.A.1.3.9 | Voltage-gated calcium-activated potassium channel of 862 aas and 6 or 7 TMSs. |
Eukaryota | Evosea | VIC protein of Entamoeba histolytica |
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1.A.1.30.1 | Uncharacterized putative chloride channel protein of 219 aas and 2 TMSs. |
Viruses | Heunggongvirae, Uroviricota | UP of Vibrio phage 1.081.O._10N.286.52.C2 |
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1.A.1.4.1 | K+ channel, AKT1; may form heteromeric channels with KC1 (TC # 1.A.1.4.9) (Geiger et al., 2009). Required for seed development and postgermination growth in low potassium (Pyo et al. 2010). Functions optimally with intermediate potassium concentrations (~1 mM) (Nieves-Cordones et al. 2014). In barley, it may play a role in drought resistance (Cai et al. 2019). HAK/KUP/KT8, GrAKT2.1 and GrAKT1.1 potassium channels may function in response to abiotic stress in Gossypium raimondii (Azeem et al. 2021). Plants obtain nutrients from the soil via transmembrane transporters and channels in their root hairs, from which ions radially transport in toward the xylem for distribution across the plant body. Dickinson et al. 2021 determined structures of the hyperpolarization-activated channel, AKT1, from Arabidopsis thaliana, which mediates K+ uptake from the soil into plant roots. The structures of AtAKT1, embedded in lipid nanodiscs, show that the channel undergoes a reduction of C4 to C2 symmetry, possibly to regulate its electrical activation.
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Eukaryota | Viridiplantae, Streptophyta | AKT1 of Arabidopsis thaliana |
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1.A.1.4.10 | Inward rectifier K+ channel AKT1 (45% identical to 1.A.1.4.1; 944aas) (Garciadeblas et al., 2007). | Eukaryota | Viridiplantae, Streptophyta | Akt1 of Physcomitrella patens (A5PH36) |
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1.A.1.4.11 | Potassium channel, KCN11. The UniProt entry included here is not complete. The correct gene ID is Cre06.g278111 in the Chlamydomonas genome database Phytozome. The complete sequence and description of its function are published by Xu et al. (2016). KCN11 is a 6 TMS organelle K+ channel found exclusively in the contractile vacuole. It is required for osmoregulation under hypotonic conditions (Xu et al. 2016). |
Eukaryota | Viridiplantae, Chlorophyta | KCN11 of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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1.A.1.4.12 | Synthetic light-sensitive K+ channel, BLINK2, of 406 aas and 2 TMSs with a P-loop between the two TMSs (residues 158 - 233). Residues 8 - 142 are derived from residues 403 - 537 of NPH1-1, a light-sensitive ser/thr protein kinase of the oat plant, Avena sativa ( acc # AAC05083); residues 143 - 234 are derived from residues 3 - 94 of the Paramecium bursaria Chlorella virus 1 (PBCV-1) K+ channel, Kcv1 (TC# 1.A.1.12.1); residues 235 - 404 derive from residues 506 - 675 of another K+ channel protein, KAT1 (TC# 1.A.1.12.1). BLINK1 has been used to manipulate stomatal kinetics to improve carbon assimilation, water use, and growth of A. thaliana (Papanatsiou et al. 2019). |
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1.A.1.4.13 | Outwardly rectifying potassium channel, SPORK2, of 843 aas and 6 or 7 TMSs in a 4 +2 + 1 TMS arrangement. The rain tree Samanea saman folds its leaves upon rainfall. Rain perception is in fact a temperature-sensing process, and that Samanea possess an ion channel with a strong temperature sensitivity that is involved in leaf movement (Dreyer and Vergara-Valladares 2023).
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Eukaryota | Viridiplantae, Streptophyta | SPORK2 of Samanea saman |
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1.A.1.4.2 | K+channel, KDC1 (voltage and pH-dependent; inward rectifying). Does not form homomeric channels. The C-terminus functions in the formation of heteromeric complexes with other potassium alpha-subunits such as KAT1 (1.A.1.4.7) (Naso et al., 2009). | Eukaryota | Viridiplantae, Streptophyta | KDC1 of Daucus carota |
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1.A.1.4.3 | Inward rectifying, pH-independent K+ channel, KZM1 (Philippar et al., 2003) | Eukaryota | Viridiplantae, Streptophyta | KZM1 of Zea mays (CAD18901) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.1.4.4 | Guard cell outward rectifying K+ out channel, GORK, controls leaf stomatal pore opening (by increasing solute content) and closing (by decreasing solute content), which in turn controls gas and water loss (Schroeder, 2003). H2S signaling not only activates the ion channel proteins located in the guard cell membrane to induce stomatal closure, but also regulates the transcriptional expression and the activity of RuBisCO, a non-stomatal factor to enhance the photosynthetic efficiency of leaves. There is therefore a beneficial balance between the regulation of H2S signaling on stomatal factors and non-stomatal factors due to drought stress (Zhang et al. 2023). The GORK K+ channel structure reveals gating vital to informing stomatal engineering (Zhang et al. 2025). |
Eukaryota | Viridiplantae, Streptophyta | GORK of Arabidopsis thaliana (CAC17380) |
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1.A.1.4.5 | Root stelar K+ outward rectifying channel, SKOR (involved in K+ release into the xylem sap; part of the plant water stress response) (Gaymard et al., 1998). SKOR is an outwardly rectifying K+ channel that mediates the delivery of K+ from stelar cells to the xylem in the roots, a critical step in the long-distance distribution of K+ from roots to the upper parts of the plant. Liu et al. 2006 and Johansson et al. 2006 reported that SKOR channel activity is strictly dependent on intracellular and extracellular K+ concentrations. Activation by K+ did not affect the kinetics of voltage dependence, indicating that a voltage-independent gating mechanism underlies K+ sensing. The C-terminal non-transmembrane region is required for sensing. The intracellular K+ sensing mechanism couples SKOR activity to the K+ status of the 'source cells', thereby establishing a supply-based unloading system for the regulation of K+ distribution (Liu et al. 2006; Johansson et al. 2006). SKOR may be involved in droght resistance in barley (Cai et al. 2019). |
Eukaryota | Viridiplantae, Streptophyta | SKOR of Arabidopsis thaliana (AAF26975) |
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1.A.1.4.6 | Heterotetrameric K+ channel, KAT2/AKT2/KCT2 (Nieves-Cordones et al. 2014). Forms heteromeric channels (2:2 stoichiometry) with KAT1 (1.A.1.4.7) (Lebaudy et al., 2010) (Properties differ from those of homomeric channels; Xicluna et al., 2007). KAT2 also forms homomeric channels in the plasma membrane (Nieves-Cordones et al. 2014). AKT2 functions in phloem loading and unloading and operates as an inward-rectifying channel that allows H+-ATPase-energized K+ uptake. Through reversible post-translational modifications, it can also function as an open, K+-selective channel, providing energy for transmembrane transport processes. It is present in a complex of several proteins in which it interacts with the receptor-like kinase, MRH1/MDIS2 (Sklodowski et al. 2017). The ortholog in Brassica rapa (Chinese cabbage), KCT2, is induced by stress. It has a TxxTxGYGD motif in the P-domain and a putative cyclic nucleotide-binding-like domain within a long C-terminal region (Zhang et al. 2006). HAK/KUP/KT8, GrAKT2.1 and GrAKT1.1 potassium channels may function in response to abiotic stress in Gossypium raimondii (Azeem et al. 2021).
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Eukaryota | Viridiplantae, Streptophyta | AKT2/KAT2 of Arabidopsis thaliana |
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1.A.1.4.7 | The voltage-sensitive inward rectifying K+ channel, KAT1 (similar to 1.A.1.4.3; activated by protein 14-3-3 (AAF87262)) (Sottocornola et al., 2006). May also transport Na+ and Cs+ (Nakamura and Gaber, 2009). Forms heterotetrameric channels with KAT2 with a stoichiometry of 2:2 (Lebaudy et al., 2010). The pH-sensor is built of a sensory cloud rather than of single key amino acids (Gonzalez et al., 2011). The transmembrane core region of KAT1 is important for its activity in S. cerevisiae, and this involves not only the pore region but also parts of its voltage-sensor domain (Saito et al. 2017). Electromechanical coupling and gating polarity in KAT1 displays a depolarized voltage sensor, which interacts with a closed pore domain directly via two interfaces and indirectly via an intercalated phospholipid. Direct interaction between the sensor and the C-linker hairpin in the adjacent pore subunit is the primary determinant of gating polarity (Clark et al. 2020). Possibly an inward motion of the S4 sensor helix of 5-7 Å underlies a direct-coupling mechanism, driving a conformational reorientation of the C-linker and ultimately opening the activation gate formed by the S6 intracellular bundle. KAT1, and presumably other hyperpolarization-gated plant CNBD channels, can open from an S4-down VSD conformation homologous to the divalent/proton-inhibited conformation of EAG family K+ channels (Zhou et al. 2021). Transmembrane ion transport in plants has been reviewed (Blatt 2024). The Arabidopsis heterotrimeric G protein α subunit binds to and inhibits the inward rectifying potassium channel KAT1 (Guo et al. 2025). |
Eukaryota | Viridiplantae, Streptophyta | KAT1 of Arabidopsis thaliana (Q39128) |
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1.A.1.4.8 | Inward rectifying Shaker K+ channel SPIK (AKT6) (expressed in pollen, and involved in pollen tube development) (Mouline et al., 2002). The shaker potassium Channel family includes 24 members in Gossypium hirsutum L. (cotton) (Wang et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | SPIK of Arabidopsis thaliana |
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1.A.1.4.9 | The KC1 (KAT3) potassium channel-like subunit; regulates other channels such as AKT1 (1.A.1.4.1) and KAT1 (1.A.1.4.7) (Duby et al., 2008); may form heteromeric channels with AKT1 (Geiger et al., 2009). It forms a tripartite SNARE-K+ channel complex which regulates KAT3 channel opening (Honsbein et al., 2009). Tripartite interactions with SNARE (SYP121; SYR1; PEN1) and AKT1 control gating (Grefen et al. 2010). ZKC1 also forms homoleric channels in the endoplasmic reticulum (Nieves-Cordones et al. 2014). |
Eukaryota | Viridiplantae, Streptophyta | KC1 of Arabidopsis thaliana (P92960) |
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1.A.1.5.1 | Cyclic nucleotide-gated (CNG) hyperpolarization-activated nonselective cation HCN channel (PNa+ /PK+ ≈ 1.0) of 682 aas and 6 TMSs. |
Eukaryota | Metazoa, Chordata | CNG channel of Ictalurus punctatus |
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1.A.1.5.10 | Orthologue K+/Na+ pacemaker channel, Hcn4 (Scicchitano et al., 2012). Hyperpolarization-activated cyclic nucleotide-regulated HCN channels underlie the Na+-K+ permeable IH pacemaker current. As with other voltage-gated members of the 6-transmembrane KV channel superfamily, opening of HCN channels involves dilation of a helical bundle formed by the intracellular ends of S6, but this is promoted by inward, not outward, displacement of S4. Direct agonist binding to a ring of cyclic nucleotide-binding sites, one of which lies immediately distal to each S6 helix, imparts cAMP sensitivity to HCN channel opening. At depolarized potentials, HCN channels are further modulated by intracellular Mg2+ which blocks the open channel pore and blunts the inhibitory effect of outward K+ flux. Lyashchenko et al. 2014 showed that cAMP binding to the gating ring enhances not only channel opening but also the kinetics of Mg2+ block. Mutations in HCN4 cause sick sinus and the Brugada syndrome, cardiac abnormalities. HCN4 is associated with famiial sinus bradycardia (Boulton et al. 2017). Activation of Hcn4 by cAMP has been reviewed (Porro et al. 2020). The HCN1-4 channel family is responsible for the hyperpolarization-activated cation current If/Ih that controls automaticity in cardiac and neuronal pacemaker cells. Saponaro et al. 2021 presented cryo-EM structures of HCN4 in the presence or absence of bound cAMP, displaying the pore domain in closed and open conformations. Analysis of cAMP-bound and -unbound structures shed light on how ligand-induced transitions in the channel cytosolic portion mediate the effect of cAMP on channel gating and highlighted the regulatory role of a Mg2+ coordination site formed between the C-linker and the S4-S5 linker. Comparison of open/closed pore states shows that the cytosolic gate opens through concerted movements of the S5 and S6 transmembrane helices. Furthermore, in combination with molecular dynamics analyses, the open pore structures provide insights into the mechanisms of K+/Na+ permeation (Saponaro et al. 2021). |
Eukaryota | Metazoa, Chordata | Hcn4 of Homo sapiens (Q9Y3Q4) |
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1.A.1.5.11 | Hyperpolarization-activated cyclic nucleotide-gated (HCN) inward current-carrying cationic channel, I(f), (HCN2/HCN4) (Ye and Nerbonne, 2009). Functional interactions between the HCN2 TM region and C-terminal region govern multiple CNB fold-mediated mechanisms, implying that the molecular mechanisms of autoinhibition, open-state trapping, and Quick-Activation include participation of TM region structures (Page et al. 2020). Rhythmic activity in pacemaker cells, as in the sino-atrial node in the heart, depends on the activation of HCN channels. As in depolarization-activated K+ channels, the fourth transmembrane segment S4 functions as the voltage sensor in hyperpolarization-activated HCN channels (Wu et al. 2021). S4 in HCN channels moves in two steps in response to hyperpolarizations, and the second S4 step correlates with gate opening (Wu et al. 2021). It is a nuclear hormone receptor that binds estrogens with an affinity similar to that of ESR1/ER-alpha, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (Koyama et al. 2010). It may lack ligand binding ability and has no or only very low ERE binding activity, resulting in the loss of ligand-dependent transactivation ability. Male moujse ejaculation drives sexual satiety and selectively activates Esr2neurons in the BNSTpr of both sexes (Zhou et al. 2023). Changes in binding affinity, rather than changes in cAMP concentration, can modulate HCN channels (Porro et al. 2024). HCN2 deficiency correlates with memory deficits and hyperexcitability of dCA1 pyramidal neurons in Alzheimer's disease (Zhang et al. 2025). |
Eukaryota | Metazoa, Chordata | HCN2/HCN4 channels of Homo sapiens |
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1.A.1.5.12 | Cyclic nucleotide-gated cation channel α3 (CNGA3 or CNG3); photoreceptor cGMP-gated channel α-subunit. Also possibly expressed in inner ear cell cells where it binds to an intracellular C-terminal domain of EMILIN1 (Selvakumar et al., 2012). Elastic network model analysis of the CNGA3 channel supports a modular model of allosteric gating, according to which protein domains are quasi-independent: they can move independently but are coupled to each other allosterically (Gofman et al. 2014). An intact S4 is required for proper protein folding and/or assembly involving two glycosylation sites in the endoplasmic reticulum membrane (Faillace et al. 2004). It may function with CNGB3 (TC# 1.A.1.5.37; Q9NQW8; 809 aas and 6 TMSs). |
Eukaryota | Metazoa, Chordata | CNGA3 of Homo sapiens (Q16281) |
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1.A.1.5.13 | Trout cyclic nucleotide-gated cation channel α3 (CNGA3 or CNG3). Expressed in inner ear cell cells where it binds to an intracellular C-terminus domain of EMILIN1 (Selvakumar et al., 2012). |
Eukaryota | Metazoa, Chordata | CNGA3 of Oncorhynchus mykiss (G9BHJ0) |
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1.A.1.5.14 | Probable cyclic nucleotide-gated ion channel 6 (AtCNGC6) (Cyclic nucleotide- and calmodulin-regulated ion channel 6) | Eukaryota | Viridiplantae, Streptophyta | CNGC6 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.1.5.15 | Cyclic nucleotide gated K+ channel of 650 aas |
Eukaryota | Heterolobosea | Channel of Naegleria gruberi |
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1.A.1.5.16 | Cyanobacterial cyclic nuceotide K+ channel of 454 aas (Brams et al. 2014). |
Bacteria | Cyanobacteriota | Channel of Trichodesmium erythraeum |
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1.A.1.5.17 | Cyclic nucleotide-gated K+channel, SthK, of 430 aas, probably with 6 TMSs in a 2 + 2 + 1 + P-loop + 1 TMS arrangement. The channel is activated by cAMP, not by cGMP, and is highly specific for K+ over Na+. It has a C-terminal hydrophilic cAMP-binding domain linked to the 6 TMS channel domain (Brams et al. 2014). An SthK C-linker domain is essential for coupling cyclic nucleotide binding to channel opening (Evans et al. 2020). An agonist-dependent conformational change in which residues of the B'-helix displayed outward movement with respect to the symmetry axis of the channel in the presence of cAMP was observed, but not with the partial agonist, cGMP. This conformational rearrangement was observed both in detergent-solubilized SthK and in channels reconstituted into lipid nanodiscs. In addition to outward movement of the B'-helix, channel activation involves upward translation of the cytoplasmic domain with formation of state-dependent interactions between the C-linker and the transmembrane domain (Evans et al. 2020). Three-deminsional structures are available (7RSY_A-D). SthK is active in a sparsely tethered lipid bilayer membranes (Andersson et al. 2023). |
Bacteria | Spirochaetota | Channel of Spirochaeta thermophila |
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1.A.1.5.18 | Cyclic nucleotide-gated cation (CNG) channel of 665 aas. |
Eukaryota | Metazoa, Arthropoda | CNG of Drosophila melanogaster |
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1.A.1.5.19 | TAX-2 cyclic nucleotide-gated cation channel-B (CNGB) of 800 aas (Wojtyniak et al. 2013). |
Eukaryota | Metazoa, Nematoda | TAX-2 CNGB of Caenorhabditis elegans |
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1.A.1.5.2 | Hyperpolarization-activated and cyclic nucleotide-gated K+ channel, HCN (bCNG-1) (PNa+/PK+ ≈ 0.3). The human orthologue (O88703) is 863 aas in length and also catalyzes mixed monovalent cation currents K+:Na+= 4:1 (Lyashchenko and Tibbs et al., 2008). Biel et al. (2009) presented a detailed review of hyperpolarization-activated cation-channels. They are inhibited by nicotine and epibatidine which bind to the inner pore (Griguoli et al., 2010). They control cardiac and neuronal rhythmicity. HCN channels contain cyclic nucleotide-binding domains (CNBDs) in their C-terminal regions, linked to the pore-forming transmembrane segment with a C-linker. The C-linker couples the conformational changes caused by the direct binding of cyclic nucleotides to the HCN pore opening. Cyclic dinucleotides antagonize the effect of cyclic nucleotides in HCN4 but not in HCN2 channels. Interaction of the C-linker/CNBD with other parts of the channel appears to be necessary for cyclic-dinucleotide binding in HCN4 channels (Hayoz et al. 2017). A conformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel has been documented (Hu et al. 2023). The voltage-sensor rearrangements, directly influenced by membrane lipid domains, can explain the heightened activity of pacemaker HCN channels when localized in cholesterol-poor, disordered lipid domains, leading to membrane hyperexcitability and diseases (Handlin and Dai 2023). Opioid-induced hyperalgesia and tolerance are driven by HCN ion channels (Han et al. 2024). It acts as a chaperone that facilitates biogenesis and trafficking of functional transporters heterodimers to the plasma membrane. It forms heterodimers with SLC7 family transporters (SLC7A5, SLC7A6, SLC7A7, SLC7A8, SLC7A10 and SLC7A11), a group of amino-acid antiporters (Parker et al. 2021). Heterodimers function as amino acids exchangers, the specificity of the substrate depending on the SLC7A subunit. Heterodimers SLC3A2/SLC7A6 or SLC3A2/SLC7A7 mediate the uptake of dibasic amino acids (Bröer et al. 2000). The intersubunit interface of the C-linker region regulates the gating polarity of voltage-gated ion channels (Lin et al. 2024). Interleukin-6 modulates the expression and function of HCN channels providing a link between inflammation and atrial electrogenesis (Spinelli et al. 2024). |
Eukaryota | Metazoa, Chordata | HCN of Mus musculus |
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1.A.1.5.20 | TAX-4 cyclic nucleotide-gated cation channel A (CNGA) of 733 aas (Wojtyniak et al. 2013). Li et al. 2017 determined the 3.5 Å resolution single-particle electron cryo-microscopy structure in the cyclic guanosine monophosphate (cGMP)-bound open state. The channel has an unusual voltage-sensor-like domain, accounting for its deficient voltage dependence. A carboxy-terminal linker connecting S6 and the cyclic-nucleotide-binding domain interacts directly with both the voltage sensor-like domain and the pore domain, forming a gating ring that couples conformational changes triggered by cyclic nucleotide binding to the gate. The selectivity filter is lined by the carboxylate side chain of a functionally important glutamate and three rings of backbone carbonyls (Li et al. 2017). |
Eukaryota | Metazoa, Nematoda | TAX-4 CNGA of Caenorhabditis elegans |
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1.A.1.5.21 | K+ channel protein, PAK2.1 of 543 aas. Contains a cyclic nucleotide-binding domain (Ling et al. 1998; Jegla and Salkoff 1995). |
Eukaryota | Ciliophora | PAK2.1 of Paramecium tetraurelia |
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1.A.1.5.22 | K+ channel protein, PAK11-MAC of 772 aas. Contains a cyclic nucleotide-binding domain (Ling et al. 1998; Jegla and Salkoff 1995). |
Eukaryota | Ciliophora | PAK11-MAC of Paramecium tetraurleia |
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1.A.1.5.23 | Cyclic nuceotide-gated Na+ channel of 729 aas and 6 putative TMSs, CNGC19. It is constitutively expressed in roots but induced in leaves and shoots under conditions of salt (NaCl) stress (Kugler et al. 2009). CNG19 and CNGC20 self-associate, form heteromeric complexes, and these complexes arei phosphorylated and stabilized by BOTRYTIS INDUCED KINASE1 (BIK1). Tight control of the CNG19/CNGC20 Ca2+ ion channel is important for regulating immunity (Zhao et al. 2021). |
Eukaryota | Viridiplantae, Streptophyta | CNGC19 of Arabidopsis thaliana |
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1.A.1.5.24 | Cyclic nucleotide-gated Na+ channel of 764 aas and 6 putative TMSs, CNGC20. Induced in shoots in response to salt (NaCl) stress (Kugler et al. 2009). CNGC20 self-associates, forms heteromeric complexes with CNGC19, and is phosphorylated and stabilized by BOTRYTIS INDUCED KINASE1 (BIK1). Tight control of the CNGC20 Ca2+ ion channel is important for regulating immunity (Zhao et al. 2021). Spermidine may play a role in salt stress in rice (Saha et al. 2020). |
Eukaryota | Viridiplantae, Streptophyta | CNGC20 of Arabidopsis thaliana |
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1.A.1.5.26 | Cyclic nuceotide gated channel of 706 aas, CNGC18. It is the essential Ca2+ channel for pollen tube guidance (Gao et al. 2016). MLO5 and MLO9 selectively recruit the Ca2+ channel CNGC18-containing vesicles to the plasma membrane through the R-SNARE proteins, VAMP721 and VAMP722 in trans mode. Meng et al. 2020 identified members of the conserved 7 TMS MLO family (expressed in the pollen tube) as tethering factors for Ca2+ channels, revealing a mechanism of molecular integration of extracellular ovular cues and selective exocytosis. This work sheds light on the general regulation of MLO proteins in cell responses to environmental stimuli (Meng et al. 2020). |
Eukaryota | Viridiplantae, Streptophyta | CNGC18 of Arabidopsis thaliana (Mouse-ear cress) |
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1.A.1.5.27 | CNGC15 of 678 aas and 6 TMSs. In Medicago truncatula, three such channels, CNGC15a, b and c, are required for nuclear calcium oscillations, spiking and subsequent symbiotic responses. These three channels form a complex with the potassium permeable channel, DMI1 (TC# 1.A.1.23.1), in the nuclear envelope. They are expressed in flowers and pods, and mutants in these channels have decreased fertilization rates (Charpentier et al. 2016). |
Viridiplantae, Streptophyta | CNG15 of Arabidopsis thaliana |
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1.A.1.5.28 | The cyclic nucleotide-gated cation channel, CNG-1 of 661 aas and 6 TMSs. CNG-1 functions in multiple capacities to link nutritional information with behavioral output (He et al. 2016). |
Eukaryota | Metazoa, Nematoda | CNG-1 of Caenorhabditis elegans |
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1.A.1.5.29 | spHCN1 is a pacemaker hyperpolarization-activated cyclic nucleotide-gated (HCN) non-selective cation channel of 767 aas and 6 TMSs that opens due to inward movement of the positive charges in the fourth TMS (S4). This channel is similar to a COOH-terminal-deleted HCN1 channel, suggesting that the main functional differences between spHCN and HCN1 channels are due to differences in their COOH termini (Vemana et al. 2004). These channels open after only two S4s have moved, and S4 motion is rate limiting during voltage activation of spHCN channels (Bruening-Wright et al. 2007). HCN channels regulate electrical activity in the heart and brain. Distinct from mammalian isoforms, the sea urchin (spHCN) channel exhibits strong voltage-dependent inactivation in the absence of cAMP (Idikuda et al. 2018). The voltage sensor undergoes a large downward motion during hyperpolarization (Dai et al. 2019). Sea urchin HCN1 and 2 (TC# 1.A.1.5.33) (spHCN) channels undergo inactivation with hyperpolarization which occurs only in the absence of cyclic nucleotide (Dai et al. 2021). Removing cAMP produces a largely rigid-body rotation of the C-linker relative to the transmembrane domain, bringing the A' helix of the C-linker in close proximity to the voltage-sensing S4 helix. In addition, rotation of the C-linker is elicited by hyperpolarization minus cAMP. Thus, in contrast to electromechanical coupling for channel activation - the A' helix serves to couple the S4-helix movement for channel inactivation, which is likely a conserved mechanism for CNBD-family channels (Dai et al. 2021). |
Eukaryota | Metazoa, Echinodermata | HPN1 of Strongylocentrotus purpuratus (Purple sea urchin) |
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1.A.1.5.3 |
Heterotetrameric (3A:1B) rod photoreceptor cyclic GMP-gated cation channel, CNGA1 or CNCG or CNCG1 (Zhong et al., 2002) of 686 aas and 6 TMSs. Cyclic nucleotides are required to open the channel. Gating is proposed to be initiated by an anticlockwise rotation of the N-terminal region of the C-linker, which is then, transmitted through the S6 transmembrane helices to the P-helix, and in turn from this to the pore lumen, which opens from 2 to 5 Å, thus allowing for ion permeation (Giorgetti et al. 2005). Defects produce channelopathies (Biel & Michalakis, 2007). A ring of four glutamate residues (Glu363) in the outer vestibule, and a ring of four threonines (Thr360) in the inner vestibule of the pore of CNGA1 channels constitute binding sites for permeating ions (Marchesi et al., 2012). The tetraspanning peripherin-2 (TC# 8.A.40.1.2) links rhodopsin to this cyclic nucleotide-dependent channel in the outer segments of rod photoreceptors. The G266D retinitis pigmentosa mutation in TMS 4 of rhodopsin abolishes binding of peripherin-2 and prevents association with the CNGA1/CNGB1a subunits present in the complex (Becirovic et al. 2014). External protons cause inactivation (Marchesi et al. 2015). CNG transmembrane domains have dynamic structures, undergoing conformational rearrangements (Maity et al. 2015). Moreover, structural heterogeneity of CNGA1 channels has been demonstrated (Maity et al. 2016). The structural basis of calmodulin (CaM) modulation of the rod cyclic nucleotide-gated channel has been elucidated by cryoEM. CaM is a constitutive subunit of the rod channel that ensures high sensitivity in dim light (Barret et al. 2023). |
Eukaryota | Metazoa, Chordata | CNG of Homo sapiens |
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1.A.1.5.30 | Hyperpolarization-activated cyclic nucleotide-modulated cation channel splice variant ABs-II of 682 aas and probably 6 TMSs, Ih channel encoded by the PIIH gene (Ouyang et al. 2007). |
Eukaryota | Metazoa, Arthropoda | Ih channel of Panulirus interruptus (California spiny lobster) (Palinurus interruptus) |
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1.A.1.5.31 | Multi-domain cation channel with a C-terminal cyclic nucleotide-binding domain; of 465 aas and 6 TMS, LliK. Cyclic nucleotide-gated (CNG) and hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels play roles in phototransduction, olfaction, and cardiac pace making. James et al. 2017 used cryoEM to determine the structure of the intact LliK CNG channel. A short S4-S5 linker connects voltage-sensing and pore domains to produce a non-domain-swapped transmembrane architecture. The conformation of the LliK structure may represent a functional state of this channel family not seen before (James et al. 2017). |
Bacteria | Spirochaetota | LliK of Leptospira licerasiae |
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1.A.1.5.32 | HCN1 is a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel of 890 aas and 6 TMSs that opens due to inward movement of the positive charges in the fourth transmembrane domain (S4). These channels open after only two S4s have moved, and S4 motion is rate limiting during voltage activation of spHCN channels (Bruening-Wright et al. 2007). HCN1 exhibits weak selectivity for potassium over sodium ions. It's structure (3.5 Å resolution) is known (Lee and MacKinnon 2017). It contributes to the native pacemaker currents in heart and neurons. It may also mediate responses to sour stimuli. It is inhibited by Cs+, zatebradine, capsazepine and ZD7288 (Gill et al. 2004). HCN1 mutational variants include epileptic encephalopathy and common generalized epilepsy. HCN1 has a pivotal function in brain development and control of neuronal excitability (Marini et al. 2018). The interaction with filamin A seems to contribute to localizing HCN1 channels to specific neuronal areas and to modulating channel activity (Gravante et al. 2004). The HCN domain is required for HCN channel cell-surface expression, and it couples voltage- and cAMP-dependent gating mechanisms (Wang et al. 2020). Changes in the local S4 environment provide a voltage-sensing mechanism for mammalian hyperpolarization-activated HCN channels (Bell et al. 2004). Cation leak is an important pathogenic mechanism in HCN1-mediated developmental and epileptic encephalopathy (DEE), and seizures are exacerbated by sodium channel blockers in patients with HCN1 variants that cause cation leak (McKenzie et al. 2023). HCN1 epilepsy is progressing from genetics and mechanisms to precision therapies (Bleakley and Reid 2023). Opioid-induced hyperalgesia and tolerance are driven by HCN ion channels (Han et al. 2024). A propofol binding site in the voltage sensor domain mediates inhibition of HCN1 channel activity (Burtscher et al. 2025). Propofol rescues voltage-dependent gating of HCN1 channel epilepsy mutants (Kim et al. 2024). |
Eukaryota | Metazoa, Chordata | HCN1 of Homo sapiens |
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1.A.1.5.33 | Hyperpolarization-gated and cyclic nucleotide regulated K+ channel of 638 aas and 6 TMSs, HCN2, present in the flagellum of sea urchin sperm (Galindo et al. 2005). See also TC# 1.A.1.5.29. |
Eukaryota | Metazoa, Echinodermata | HCN2 of Strongylocentrotus purpuratus (Purple sea urchin) |
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1.A.1.5.34 | Cyclic nucleotide-binding domain-containing protein, Cng-3, of 626 aas and 5 - 7 TMSs. It is essential for thermotolerance (Cho et al. 2004). CNG-3 is required in the AWC for adaptation to short (thirty minute) exposures of odor, and contains a candidate PKG phosphorylation site required to tune odor sensitivity (O'Halloran et al. 2017). Cyclic nucleotide-gated channel, CNG-3, determines the timing of transition of temperature preference after a shift in cultivation temperature (Aoki et al. 2018). |
Eukaryota | Metazoa, Nematoda | Cng-3 of Caenorhabditis elegans |
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1.A.1.5.35 | The cyclic ABP-gated K+ channel, SthK of 430 aas and 6 TMSs in a 2 + 2 + 1 + P-loop +1 TMS arrangement. This channel and others have been studied by high-speed atomic force microscopy (HS-AFM) which has made it possible to characterized the conformational dynamics of single unlabeled transmembrane channels and transporters (Heath and Scheuring 2019). The signaling lipid phosphatidylinositol-4,5-bisphosphate (PIP2) regulates many ion channels and inhibits eukaryotic cyclic nucleotide-gated (CNG) channels while activating their relatives, the hyperpolarization-activated and cyclic nucleotide-modulated (HCN) channels. SthK shares features with CNG and HCN channels and is a model for this channel family. Thon et al. 2024 showed that SthK activity is inhibited by PIP2. A cryo-EM structure of SthK in nanodiscs revealed a PIP2-fitting density coordinated by arginine and lysine residues from the S4 helix and the C-linker, located between voltage-sensing and pore domains of adjacent subunits. Mutation of two arginine residues weakened PIP2 inhibition with the double mutant displaying insensitivity to PIP2. |
Bacteria | Spirochaetota | SthK of Spirochaeta thermophila |
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1.A.1.5.36 | Cyclic nucleotide-gated ion channel 17, CNGC17, of 720 aas and 6 TMSs. It forms a functional cation-translocating unit with AHAs that is activated by PSKR1/BAK1 and possibly other BAK1/RLK complexes (Ladwig et al. 2015) and is required for PSK-induced protoplast expansion. |
Eukaryota | Viridiplantae, Streptophyta | CNGC17 of Arabidopsis thaliana (Mouse-ear cress) |
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1.A.1.5.37 | Cyclic GMP-gated ion channel β-subunit of 809 aas and 6 TMSs. It may function with CNGA3 (TC# 1.A.1.5.12), but it does not correct mutational defects in the S4 TMS of the α-subunit, CNGA3 (Faillace et al. 2004). |
Eukaryota | Metazoa, Chordata | CNGB3 of Homo sapiens |
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1.A.1.5.4 | Olfactory heteromeric cyclic nucleotide-gated cation (mainly Na+, Ca2+) channel CNGA2/CNGA4/CNGB1b (present in sensory cilia of olfactory receptor neurons; activated by odorant-induced increases in cAMP concentration) (Michalakis et al., 2006). | Eukaryota | Metazoa, Chordata | CNGA2 complex of Mus musculus CNGA2 (Q62398) CNGA4 (AAI07349) CNGB1b (NP_001288) |
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1.A.1.5.5 | The cyclic nucleotide- and voltage-gated ion (K+, Rb+, Cs+) channel, CNGC1 (inward rectifying). It functions in heavy metal and cation transport, as does CNGC10 (Dreyer and Uozumi, 2011; Zelman et al., 2012). 143 CNGC genes in Glycine max have been identified and classified, and they have been screened for related resistance genes after Fusarium solani infection (Cui et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | CNGC1 of Arabidopsis thaliana (O65717) |
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1.A.1.5.6 | The cyclic nucleotide-gated ion (K+, Rb+, Cs+) channel, CNGC2 (functions in plant defense responses, as does CNGC4) (Zelman et al., 2012). |
Eukaryota | Viridiplantae, Streptophyta | CNGC2 of Arabidopsis thaliana (O65718) |
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1.A.1.5.7 | The cyclic nucleotide-gated ion (K+, Rb+, Cs+) channel, HLM1 (CNGC4) It mediates the hypersensitive response (HR) of plants in programmed cell death. Mutants show abnormal cell death and resistance to infection by Pseudomonas syringae (Balagué et al., 2003; Zelman et al., 2012). |
Eukaryota | Viridiplantae, Streptophyta | HLM1 of Arabidopsis thaliana |
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1.A.1.5.8 | The non-selective cation transporter involved in germination, CNGC3 (Gobert et al., 2006; Zelman et al., 2012). |
Eukaryota | Viridiplantae, Streptophyta | CNG3 of Arabidopsis thaliana (Q9SKD7) |
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1.A.1.5.9 | The cyclic nucleotide-gated K+ channel, Sp-tetraKCNG (2238 aas) (Galindo et al., 2007) | Eukaryota | Metazoa, Echinodermata | Sp-tetraKCNG of Strongylocentrotus purpuratus (ABN14774) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.1.6.1 | K+ channel, MthK or MVP of 209 aas and 6 TMSs. Voltage-gated potassium-selective channel opened by hyperpolarization (Hellmer and Zeilinger 2003). Mediates K+ uptake and sensitivity. The structure and local dynamics of the closed activation gate (lower S6 region) of MVP have been reported (Randich et al. 2014). |
Archaea | Euryarchaeota | MthK channel protein of Methanocaldococcus jannaschii (Methanococcus jannaschii) |
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1.A.1.7.1 | Tok1 twin (dual) barrel outward rectifying K+ channel with exterme assymmetry which includes an extra 4 N-terminal TMSs for a total of 16 TMSs. (Transports K+ and Cs+) (Bertl et al., 2003; Roller et al. 2008). TOKs are outwardly rectifying K+ channels in fungi with two pore-loops and eight transmembrane spans. Lewis et al. 2020 described the TOKs from four fungal pathogens. These TOKs pass large currents only in the outward direction like this ScTOK. ScTOK, AfTOK1 (Aspergillus fumigatus), and H99TOK (Cryptococcus neoformans grubii) are K+-selective and pass current above the K+ reversal potential. CaTOK (Candida albicans) and CnTOK (Cryptococcus neoformans neoformans) pass both K+ and Na+ and conduct above a reversal potential, reflecting the mixed permeability of their selectivity filter. Mutations in CaTOK and ScTOK at sites homologous to those that open the internal gates in classical K+ channels are shown to produce inward TOK currents. Possibly the reversal potential determines ion occupancy, and thus, conductivity, of the selectivity filter gate that is coupled to an imperfectly restrictive internal gate, permitting the filter to sample ion concentrations on both sides of the membrane (Lewis et al. 2020). TOK (tandem-pore outward-rectifying K+) channels consist of eight TMSs and two pore domains per subunit, organized in dimers. They play a role in cellular K+ homeostasis and possibly also in plant-fungus symbioses (Houdinet et al. 2022). |
Eukaryota | Fungi, Ascomycota | Tok1 outward rectifier K+ channel of Saccharomyces cerevisiae |
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1.A.1.7.10 | TOK1 of 741 aas and 8 TMSs in a 6 + 2 TMS arrangement with P-loops between TMSs 5 and 6 as well as 7 and 8. It transports both Na+ and K+, and has been characterized by Lewis et al. 2020. See 1.A.7.1.1 for a more detailed description. |
Eukaryota | Fungi, Ascomycota | TOK1 of Candida albicans (Yeast) |
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1.A.1.7.2 | AtTPK4 two-pore K+ channel 4 (Becker et al., 2004). Asp86 and Asp200 are essential for K+ permeation as well as inward rectification (Marcel et al., 2010). Reviewed by González et al. 2014. |
Eukaryota | Viridiplantae, Streptophyta | AtTPK4 of Arabidopsis thaliana (AAP82009) |
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1.A.1.7.3 | The 2-pore (4TMS) outward rectifying K+ channel, KCO1 or TPK1. Possesses two tandem Ca2+-binding EF-hand motifs, and cytosolic free Ca2+ (~300 nM) activates (Czempinski et al., 1997). Reviewed by González et al. 2014 and Basu and Haswell 2017. |
Eukaryota | Viridiplantae, Streptophyta | KCO1 of Arabidopsis thaliana |
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1.A.1.7.4 | The two pore tonoplast TPK-type K+ channel; maintains K+ homeostasis in plant cells (Hamamoto et al., 2008); activated by 14-3-3 proteins (Latz et al., 2007). This tonoplast-localized TPK-type K+ transporter (TPKa) regulates potassium accumulation in tobacco (Gao et al. 2024). |
Eukaryota | Viridiplantae, Streptophyta | TPK1 of Nicotiniana tobacum (A9QMN9) |
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1.A.1.7.5 | Two-pore potassium channel 5 (AtTPK5) (Calcium-activated outward-rectifying potassium channel 5, chloroplastic) (AtKCO5). Reviewed by González et al. 2014. |
Eukaryota | Viridiplantae, Streptophyta | TPK5 of Arabidopsis thaliana |
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1.A.1.7.6 | Potassium inward rectifier (Kir)-like channel 3 (AtKCO3) | Eukaryota | Viridiplantae, Streptophyta | KCO3 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.1.7.7 | Chloroplast thylakoid two-pore calcium and proton-activated K+ channel, TPK3 of 436 aas and 4 TMSs. Mediates ion counterbalancing, influencing photosynthetic llight utilization (Carraretto et al. 2013). Reviewed by González et al. 2014. This two-pore potassium channel modulates the proton motive force (pmf) necessary to convert photochemical energy into physiological functions. It mediates the potassium efflux from the thylakoid lumen required for the regulation of the transmembrane electrical potential, the enhancement of the pH gradient for ATP synthesis, the regulation of electron flow, and pH-mediated photoprotective responses (Carraretto et al. 2013). It has multiple functions under drought stress (Corti et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | TPK3 of Arabidopsis thaliana |
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1.A.1.7.8 | Putative K+ channel of 96 aas nd 2 TMSs. |
Viruses | Bamfordvirae, Nucleocytoviricota | K+ channel of Yellowstone lake phycodnavirus 2 |
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1.A.1.7.9 | Outward-rectifier potassium channel TOK1 of 699 aas and 8 TMSs in a 6 + 2 TMS arrangement, where a P-loop may exist between TMSs 5 and 6 as well as TMSs 7 and 8. The system has been characterized and compared with other fungal TOK channels by Lewis et al. 2020 |
Eukaryota | Fungi, Ascomycota | TOK1 of Neosartorya fumigata (Aspergillus fumigatus) |
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1.A.1.8.1 | TWIK-1 (KCNK1, HOHO1, KCNO1) inward rectifier K+ channel (Enyedi and Czirják, 2010) expressed in the distal nephron segments (Orias et al. 1997). Lipid tails from both the upper and lower leaflets can partially penetrate into the pore (Aryal et al. 2015). The lipid tails do not sterically occlude the pore, but there is an inverse correlation between the presence of water within the hydrophobic barrier and the number of lipids tails within the lining of the pore (Aryal et al. 2015). |
Eukaryota | Metazoa, Chordata | TWIK-1 of Mus musculus |
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1.A.1.8.2 | TASK-2 (KCNK5) two-pore domain, pH-sensitive, voltage-insensitive, outward rectifying K+ channel (K+ > Rb+ >> Cs+ > NH4+ > Na+ ≈ Li+), present in renal epithelia. Regulated [inhibited] via group 1 metabolotropic glutamate receptors and by inositol phosphates (Chemin et al., 2003). TASK-2 gating is controlled by changes in both extra- and intracellular pH through separate sensors: arginine 224 and lysine 245, located at the extra- and intracellular ends of transmembrane domain 4, respectively. TASK-2 is inhibited by a direct effect of CO2 and is regulated by and interacts with G protein subunits. TASK-2 takes part in regulatory adjustments and is a mediator in the chemoreception process in neurons of the retrotrapezoid nucleus where its pHi sensitivity could be important in regulating excitability and therefore signalling of the O2/CO2 status. Extracellular pH increases, brought about by HCO3- efflux from proximal tubule epithelial cells may couple to TASK-2 activation to maintain electrochemical gradients favourable to HCO3- reabsorption. TASK-2 is expressed at the basolateral membrane of proximal tubule cells (López-Cayuqueo et al. 2014). Mutations are associated with the Balkan Endemic Nephropathy (BEN) chronic tubulointerstitial renal disease (Reed et al. 2016). pH sensing in TASK2 channels is conferred by the combined action of several charged residues in the large extracellular M1-P1 loop (Morton et al. 2005). TASK-2, a member of the TALK subfamily of K2P channels, is opened by intracellular alkalization, leading the deprotonation of the K245 residue at the end of the TM4 helix. This charge neutralization of K245 may be sensitive or coupled to the fenestration state. The most important barrier for ion transport under K245+ and open fenestration conditions is the entrance of the ions into the channel (Bustos et al. 2020).
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Eukaryota | Metazoa, Chordata | TASK-2 of Homo sapiens |
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1.A.1.8.3 | The 2P-domain K+ channel, TWIK 2 (functions in cell electrogenesis (Patel et al., 2000). | Eukaryota | Metazoa, Chordata | TWIK2 of Homo sapiens (Q9Y257) |
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1.A.1.8.4 | Potassium channel subfamily K member 5, Kcnk5a, of 513 aas and 6 TMSs. It is 50% identical with the human ortholog. Genome analysis revealed that its genetic structure in the yellowfin seabream (Acanthopagrus latus) is influenced by a variety of factors including salinity gradients, habitat distance, and ocean currents (Wang et al. 2024) |
Eukaryota | Metazoa, Chordata | KCNK5A of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.A.1.9.1 | TREK-1 (KCNK2) K+ channel subunit (Regulated by group 1 metabotropic glutamate receptors and by diacylglycerols and phosphatidic acids) (Chemin et al., 2003). TREK-1, TREK-2 and TRAAK are all regulated by lysophosphatidic acid, converting these mechano-gated, pH voltage-sensitive channels into leak conductances (Chemin et al., 2005). The mammalian K2P2.1 potassium channel (TREK-1, KCNK2) is highly expressed in excitable tissues, where it plays a key role in the cellular mechanisms of neuroprotection, anaesthesia, pain perception and depression (Cohen et at., 2008). Alternative translation initiation in rat brain yields K2P2.1 potassium channels permeable to sodium (Thomas et al. 2008). The crystal structure of the human 2-pore domain K+ channel, K2P1 has been solved (Miller and Long, 2012). Multiple modalities converge on a common gate to control K2P channel function (Bagriantsev et al., 2011). TREK-1 mediates fast and slow glutamate release in astrocytes upon GPCR activation (Woo et al. 2012). It is a mechanosensitive K+ channel, present in rat bladder myocytes, which is activated by swelling and arachidonic acid (Fukasaku et al. 2016). The M2-hinges of TREK-1 and TREK-2 channels control their macroscopic current, subcellular localization and gating (Zhuo et al. 2017). The human ortholog has acc # O95069 and has an additional N-terminal 15 aas. BL-1249, a compound from the fenamate class of nonsteroidal anti-inflammatory drugs, is known to activate K2P2.1(TREK-1), the founding member of the thermo- and mechanosensitive TREK subfamily (Pope et al. 2018). Spadin and arachidonic acid, are known to suppress and activate TREK-1 channels, respectively (Pappa et al. 2020). Membrane phospholipids control gating of the mechanosensitive potassium leak channel, TREK1 (Schmidpeter et al. 2023). A photoswitchable inhibitor of TREK channels controls pain in wild-type intact freely moving animals (Landra-Willm et al. 2023). TREK-1 is an anesthetic-sensitive K+ channel (Spencer et al. 2023). Covalent chemogenetic K2P channel activators have been developed (Deal et al. 2024). K2P potassium channels regulate excitability by affecting the cellular resting membrane potential in the brain, cardiovascular system, immune cells, and sensory organs. They are important in anesthesia, arrhythmia, pain, hypertension, sleep, and migraine headaches. CATKLAMP (covalent activation of TREK family K+ channels to clamp membrane potential) leverages the discovery of a K2P modulator pocket site that reacts with electrophile-bearing derivatives of a TREK subfamily small-molecule activator, ML335, to activate the channel irreversibly. Deal et al. 2024 showed that CATKLAMP can be used to probe fundamental aspects of K2P function, as a switch to silence neuronal firing, and is applicable to all TREK subfamily members. |
Eukaryota | Metazoa, Chordata | TREK-1 of Mus musculus (P97438)
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1.A.1.9.10 | Potassium channel subfamily K member 16 (2P domain potassium channel Talk-1) (TWIK-related alkaline pH-activated K+ channel 1) (TALK-1 or KCNK16) of 309 aas and 6 TMSs. It is an outward rectifying potassium channel that produces rapidly activating and non-inactivating outward rectifier K+ currents. Allosteric coupling between transmembrane segment 4 and the selectivity filter regulates gating by extracellular pH (Tsai et al. 2022).
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Eukaryota | Metazoa, Chordata | KCNK16 of Homo sapiens |
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1.A.1.9.11 | pH-dependent, voltage-insensitive, background potassium channel protein involved in maintaining the membrane potential, KCNK9, K2P9.1 or TASK3 (TASK-3) of 374 aas (Huang et al. 2011). Terbinafine is a selective activator of TASK3 (Wright et al. 2017). The response of the tandem pore potassium channel TASK-3 to voltage involves gating at the cytoplasmic mouth (Ashmole et al., 2009). TASK-3 is involved in several physiological and pathological processes including sleep/wake control, cognition and epilepsy (Tian et al. 2019). N-(2-((4-nitro-2-(trifluoromethyl)phenyl)amino)ethyl)benzamide (NPBA) is an activator (Tian et al. 2019). KCC2 regulates neuronal excitability and hippocampal activity via interaction with Task-3 channels (Goutierre et al. 2019). A biguanide compound, CHET3, is a highly selective allosteric activator, and TASK-3 is a druggable target for treating pain (Liao et al. 2019). This channel may be present in mitochondria (Parrasia et al. 2019). Differential hydroxymethylation levels in the DNA of patient-derived neural stem cells implicated altered cortical development in bipolar disorder syndrome possibly altering KCNK9 expression (Kumar et al. 2023).
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Eukaryota | Metazoa, Chordata | KCNK9 or TASK3 of Homo sapiens |
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1.A.1.9.12 | Potassium channel subunit of 330 aas. No channel activity was observed in heterologous systems. It probably needs to associate with other proteins (i.e., KCNK3 and KCNK9) to form a functional channel (Huang et al. 2011). | Eukaryota | Metazoa, Chordata | KCNK15 of Homo sapiens |
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1.A.1.9.13 | The Kcnk10a (TREK-2A) K+ channel of 569 aas and 6 TMSs. It localizes in the brain and seems to regulate reproduction (Loganathan et al. 2017). |
Eukaryota | Metazoa, Chordata | TREK-2A of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.A.1.9.14 | Open rectifier K+ channel 1, isoform D of 1001 aas and 6 TMSs, Ork1. |
Eukaryota | Metazoa, Arthropoda | ORK1 of Drosophila melanogaster (Fruit fly) |
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1.A.1.9.2 | KCNK3 K+ channel (TASK1, OAT1, TBAK1) (the K+ leak conductance). TASK1 and 3 may play roles in nontumorigenic primary hyperaldosteronism (Davies et al., 2008). KCNK3/9/15 expression limits membrane depolarization and depolarization-induced secretion at least in part by maintaining intracellular K+ (Huang et al. 2011). TWIK-related acid-sensitive potassium (TASK) channels, members of the two pore domain potassium (K2P) channel family, are found in neurons, cardiomyocytes and vascular smooth muscle cells, where they are involved in the regulation of heart rate, pulmonary artery tone, sleep/wake cycles and responses to volatile anaesthetics (Rödström et al. 2020). K2P channels regulate the resting membrane potential, providing background K+ currents controlled by numerous physiological stimuli. Unlike other K2P channels, TASK channels are able to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. In general, potassium channels have an intramembrane vestibule with a selectivity filter situated above and a gate with four parallel helices located below, but the K2P channels studied so far all lack a lower gate. Rödström et al. 2020 presented the X-ray crystal structure of TASK-1, and showed that it contains a lower gate designated 'X-gate', created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance. This structure is formed by six residues ((243)VLRFMT(248)) that are essential for responses to volatile anaesthetics, neurotransmitters and G-protein-coupled receptors. Mutations within the X-gate and the surrounding regions affect both the channel-open probability and the activation of the channel by anaesthetics. Structures of TASK-1 bound to two high-affinity inhibitors showed that both compounds bind below the selectivity filter and are trapped in the vestibule by the X-gate, which explains their exceptionally low washout rates (Rödström et al. 2020). TWIK-related acid-sensitive K+ channel 2 promotes renal fibrosis by inducing cell-cycle arrest (Zhang et al. 2022). KCNK3 dysfunction plays a role in dasatinib-associated pulmonary arterial hypertension and endothelial cell dysfunction (Ribeuz et al. 2024). TASK-1 (K2P3.1) two-pore-domain potassium channels are atrial-specific and significantly up-regulated in atrial fibrillation (AF) patients, contributing to AF-related electrical remodelling. Treatment of atrial fibrillation with doxapram, a TASK-1 potassium channel inhibitor provides a pharmacological strategy (Wiedmann et al. 2022). |
Eukaryota | Metazoa, Chordata | TASK1 or KCNK3 of Homo sapiens (AAG29340) |
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1.A.1.9.2.3 | K2P channel, TALK-2, KCNK17, TASK4 of 463 aas. Trichome responses to elevated elemental stress in cation exchanger (CAX) mutants have been recorded (Guo et al. 2024). |
Eukaryota | Viridiplantae, Streptophyta | TALK-2 of Arabidopsis thaliana |
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1.A.1.9.3 | Neuronal 2-P (4 TMS) domain K+ membrane tension-gated channel, TRAAK (stimulated by arachidonic acid and polyunsaturated fatty acids (Fink et al., 1998). The crystal structures of conductive and nonconductive human K2P TRAAK K+ channel has been solved (Brohawn et al., 2012; Brohawn et al. 2014). Regulated by mechanical deformation of the membrane and temperature as well as polyunsaturated fatty acids (Brohawn et al., 2012). Multiple modalities converge on a common gate to control K2P channel function (Bagriantsev et al., 2011). In the non-conductive state, a lipid acyl chain accesses the channel cavity through a 5 Å-wide lateral opening in the membrane inner leaflet and physically blocks ion passage. In the conductive state, rotation of transmembrane helix 4 about a central hinge seals the intramembrane opening, preventing lipid block of the cavity and permitting ion entry. Additional rotation of a membrane interacting TM2-TM3 segment, unique to mechanosensitive K2Ps, against TM4 may further stabilize the conductive conformation. Comparison of the structures provodes a biophysical explanation for TRAAK mechanosensitivity--an expansion in cross-sectional area up to 2.7 nm2 in the conductive state is expected to create a membrane-tension-dependent energy difference between conformations that promotes force activation (Brohawn et al. 2014). TM helix straightening and buckling may underlie channel activation (Lolicato et al. 2014). A lipid chain blocks the conducting path in the closed state (Rasmussen 2016). |
Eukaryota | Metazoa, Chordata | TRAAK of Mus musculus (O88454) |
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1.A.1.9.4 | Outward rectifying mechanosensitive 2-P (4 TMS) domain K+ channel, TREK-2 (KCNKA; KCNK10; K2P10). Activated by membrane stretch, acidic pH, arachidonic acid and unsaturated fatty acids. Dong et al. 2015 described crystal structures of the human TREK-2 channel (up to 3.4 angstrom resolution) in two conformations and in complex with norfluoxetine, the active metabolite of fluoxetine (Prozac) and a state-dependent blocker of TREK channels. Norfluoxetine binds within intramembrane fenestrations found in only one of these two conformations. Channel activation by arachidonic acid and mechanical stretch involves conversion between these states through movement of the pore-lining helices. This provides an explanation for TREK channel mechanosensitivity, regulation by diverse stimuli, and possible off-target effects of the serotonin reuptake inhibitor Prozac (Dong et al. 2015). The unique gating properties of TREK-2 and the mechanisms by which extracellular and intracellular stimuli harness pore gating allosterically have been studied (Zhuo et al. 2016). TREK-2 moves from the "down" to the "up" conformation in direct response to membrane stretch. Aryal et al. 2017 showed how state-dependent interactions with lipids affect the movement of TREK-2, and how stretch influences both the inner pore and selectivity filter. They also demonstrated why direct pore block by lipid tails does not represent theprincipal mechanism of mechanogating (Aryal et al. 2017). The M2-hinges of TREK-1 and TREK-2 channels control their macroscopic current, subcellular localization and gating (Zhuo et al. 2017). TREK-2 responds to a diverse range of stimuli. Two states, "up" and "down", are known from x-ray structural crystallographic studies and have been suggested to differ in conductance. Brennecke and de Groot 2018 found that the down state is less conductive than the up state. The introduction of membrane stretch in the simulations shifts the state of the channel toward an up configuration. Membrane pressure changes the conformation of the transmembrane helices directly and consequently also influences the channel conductance (Brennecke and de Groot 2018). 3-d structures are known (PDB 4XDJ_!-D). Phosphatidyl-(3,5)-bisphosphate (PI(3,5)P2) activates (Kirsch et al. 2018). |
Eukaryota | Metazoa, Chordata | TREK-2 of Rattus norvegicus |
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1.A.1.9.5 | The TWiK family muscle K+ channel protein 18 (TWiK or Two-P domain K+ channel family) (controls muscle contraction and organismal movement; Kunkel et al., 2000) | Eukaryota | Metazoa, Nematoda | TWK-18 of Caenorhabditis elegans (Q18120) |
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1.A.1.9.6 | The pH-sensitive 2 pore (4 TMS) K+ channel, TAQLK2, TALK-2 or TASK-4 (Expressed in liver, lung, pancreas and other tissues; Decher et al., 2001). The response of the tandem pore potassium channel TASK-3 (TC# 1.A.1.9.11) (K(2P)9.1) to voltage involves gating at the cytoplasmic mouth (Ashmole et al., 2009). Models have revealed the convergence of amino acid regions that are known to modulate anesthetic activity onto a common three-dimensional cavity that forms a putative anesthetic binding site in tandem pore potassium channels (Bertaccini et al. 2014). Ion occupancy of the selectivity filter controls opening of a cytoplasmic gate in the K2P channel TALK-2 (Neelsen et al. 2024). |
Eukaryota | Metazoa, Chordata | TASK-4 of Homo sapiens |
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1.A.1.9.7 | Sup-9 K+ channel of 329 aas and 6 TMSs. It is involved in coordination of muscle contraction (de la Cruz et al. 2003). Activity is regulated by Sup-18 (de la Cruz et al. 2014) and by Unc-93 (TC# 2.A.1.5.8). It may also be regulated by Sup-10 (Q17374); it may be a suppressor of Unc-93 (de la Cruz et al., 2003). Mutation of a single residue promotes gating of this channel and of several vertebrate and invertebrate two-pore domain potassium channels (Ben Soussia et al. 2019). |
Eukaryota | Metazoa, Nematoda | Sup-9 of Caenorhabditis elegans (O17185) |
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1.A.1.9.8 | TWiK family of potassium channels protein 9 | Eukaryota | Metazoa, Nematoda | twk-9 of Caenorhabditis elegans | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.1.9.9 | TWiK family of potassium channels protein 12 | Eukaryota | Metazoa, Nematoda | Twk-12 of Caenorhabditis elegans |
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1.A.10.1.1 | AMPA-selective glutamate ionotropic channel receptor (GIC; AMPAR), kainate-subtype, GluR-K1; GluR1; GluR-A; GluA1; Gria1 of 906 aas (preferentially monovalent cation selective). A mature complex contains GluR1, TARPs, and PSD-95 (Fukata et al. 2005). The receptor contributes to amygdala-dependent emotional learning and fear conditioning (Humeau et al., 2007). Transmembrane AMPAR regulatory protein (TARP) gamma-7 (TC#8.A.16.2.5) selectively enhances the synaptic expression of Ca2+-permeable (CP-AMPARs) and suppresses calcium-impermeable (CI-AMPAR) activities (Studniarczyk et al. 2013). Thus, TARPs modulate the pharmacology and gating of AMPA-type glutamate receptors (Soto et al. 2014). TARPs interact with the N-terminal domain of the AMPAR and control channel gating; residues in the receptor and the TARP involved in this interaction have been identified (Cais et al. 2014). The auxilary protein, Shisa9 or CKAMP44 (UniProt acc# B4DS77), has a C-terminal PDZ domain that allows interaction with scaffolding proteins and AMPA glutamate receptors (Karataeva et al. 2014). The transmembrane domain alone can tetramerize (Gan et al. 2016). The most potent and well-tolerated AMPA receptor inhibitors, used to treat epilepsy, act via a noncompetitive mechanism. The crystal structures of the rat AMPA-subtype GluA2 receptor in complex with three noncompetitive inhibitors have been solved. The inhibitors bind to a binding site, completely conserved between rat and human, at the interface between the ion channel and linkers connecting it to the ligand-binding domains (Yelshanskaya et al. 2016). The endogenous neuropeptide, cyclopropylglycine, at a physiological concentration of 1 μM, enhances the transmembrane AMPA currents in rat cerebellar Purkinje cells (Gudasheva et al. 2016). The energetics of glutamate binding have been estimated (Yu and Lau 2017). The TMEM108 protein (Q6UXF1 of 575 aas and 2 TMSs, N- and C-terminal, is required for surface expression of AMPA receptors (Jiao et al. 2017). CERC-611 is a selective antagonist of AMPA receptors containing transmembrane AMPA receptor regulatory protein (TARP; TC# 8.A.16) gamma-8 (Witkin et al. 2017). Drug effects, regulatory protein modulators and positive allosteric modulators have been reviewed (Fu et al. 2019). Herguedas et al. 2019 presented a cryo-EM structure of the heteromeric GluA1/2 receptor associated with two transmembrane AMPAR regulatory protein (TARP) gamma8 auxiliary subunits, the principal AMPAR complex at hippocampal synapses. The native heterotetrameric AMPA-R adopts various conformations, which reflect a variable separation of the two dimeric extracellular amino-terminal domains; members of the stargazin/TARP family of transmembrane proteins co-purify with AMPA-Rs and contribute to the density representing the transmembrane region of the complex. Glutamate and cyclothiazide altered the conformational equilibrium of the channel complex, suggesting that desensitization is related to separation of the N-terminal domains (Nakagawa et al. 2005). Positive allosteric modulators (PAMs) of AMPA receptors boost cognitive performance in clinical studies, and mibampator and BIIB104 discriminate between AMPARs complexed with distinct TARPs, and particularly those with lower stargazin/gamma2 efficacy such as BIIB104 (Ishii et al. 2020). Yelshanskaya et al. 2020 identified trans-4-butylcyclohexane carboxylic acid (4-BCCA) binding sites in the transmembrane domain of AMPA receptors, at the lateral portals formed by TMSs M1-M4. At this binding site, 4-BCCA is very dynamic, assumes multiple poses and can enter the ion channel pore. Cannabidiol inhibits febrile seizure by modulating AMPA receptor kinetics through its interaction with the N-terminal domain of GluA1/GluA2 (Yu et al. 2020). Inhibition of AMPA receptors (AMPARs, e.g., TC# 1.A.10.1.1) containing transmembrane AMPAR regulatory protein gamma-8 (TC# 8.A.61.1.10) with JNJ-55511118 (TC#8.A.179.1.1) shows preclinical efficacy in reducing chronic repetitive alcohol self-administration (Hoffman et al. 2021). Mechanisms underlying TARP modulation of the GluA1/2-gamma8 AMPA receptor have been studied (Herguedas et al. 2022). L-Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS). Its associated receptors, localized on neuronal and non-neuronal cells, mediate rapid excitatory synaptic transmission in the CNS and regulate a wide range of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors selective to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) also play an important role in numerous neurological disorders. Golubeva et al. 2022 examined the structural diversity of chemotypes of agonists, competitive AMPA receptor antagonists, positive and negative allosteric modulators, TARP-dependent allosteric modulators, ion channel blockers ans their binding sites. |
Eukaryota | Metazoa, Chordata | GluR-K1 of Rattus norvegicus |
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1.A.10.1.10 | The homo- and heteromeric glutamate receptor, GLR3.3/3.4 (Desensitized in 3 patterns: (1) by Glu alone; (2) by Ala, Cys, Glu or Gly; (3) by Ala, Cys, Glu, Gly, Ser or Asn (Stephens et al., 2008). A regulatory mechanism underlies Ca2+ homeostasis by sorting and activation of AtGLRs by AtCNIHs (see for example, 8.A.61.1.9) (Wudick et al. 2018). May be responsible in part for Cd2+ uptake (Chen et al. 2018). GLR3.3 and GLC3.6 (TC# 1.A.10.1.24) (but not GLR3.4) play different roles in nervous system-like signaling in plant defense by a mechanism that differs substantially from that in animals (Toyota et al. 2018). Members of the banana GLR gene family have been identified, and expression analyses in response to low temperature and abscisic acid/methyl jasmonate concentrations have been reported (Luo et al. 2023). Phosphatidylinositol-specific phospholipase C-associated phospholipid metabolism mediates the DcGLRs channel to promote calcium influx under CaCl2 treatment in shredded carrots during storage (Zhang et al. 2024). |
Eukaryota | Viridiplantae, Streptophyta | GLR3.3/GLR3.4 receptor of Arabidopsis thaliana |
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1.A.10.1.11 |
GriK2; GluK2; GluR6 glutamate receptor, ionotropic kainate 2. The 3-d structure is known (2XXY_A). The domain organization and function have been analyzed by Das et al. (2010). Two auxiliary subunits, Neto1 and Neto2 (Neuropilin and tolloid-like proteins) alter the trafficking, channel kinetics and pharmacology of the receptors (Howe 2014). They reduce inward rectification without altering calcium permeability (Fisher and Mott 2012). Interactions between the pore helix (M2) and adjacent segments of the transmembrane inner (M3) and outer (M1) helices may be involved in gating (Lopez et al. 2013). Mutations in the human GRIK2 (GLUR6) cause moderate-to-severe nonsyndromic autosomal recessive mental retardation (Motazacker et al. 2007). Kainate receptors regulate KCC2 (TC# 1.A.10.1.11) expression in the hippocampus (Pressey et al. 2017). GluR6, carrying the pore loop plus adjacent transmembrane domains of the prokaryotic, glutamate-gated, K+-selective GluR0 (TC# 1.A.10.2.1), adopted several electrophysiological properties of the donor pore upon pore transplantation (Hoffmann et al. 2006). Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders (Stolz et al. 2021). Concanavalin A modulation of kainate receptor function is mediated by a shift in the conformation of the kainate receptor toward a tightly packed extracellular domain (Gonzalez et al. 2021). Partial agonism in heteromeric GLUK2/GLUK5 kainate receptor has been documented, and partial agonism observed with AMPA binding is mediated primarily due to differences in the GluK2 subunit, highlighting the distinct contributions of the subunits towards activation (Paudyal et al. 2023). Kainate receptors (KARs) are a subtype of ionotropic glutamate receptor (iGluR) channels, a superfamily of ligand-gated ion channels which mediate the majority of excitatory neurotransmission in the central nervous system. KARs modulate neuronal circuits and plasticity during development and are implicated in neurological disorders, including epilepsy, depression, schizophrenia, anxiety, and autism (Gangwar et al. 2024). Calcium-permeable KARs undergo ion channel block. Gangwar et al. 2024 presented closed-state structures of GluK2 KAR homotetramers in complex with ion channel blockers NpTx-8, PhTx-74, Kukoamine A, and spermine. Blockers reside inside the GluK2 ion channel pore, intracellular to the closed M3 helix bundle-crossing gate, with their hydrophobic heads filling the central cavity and positively charged polyamine tails spanning the selectivity filter. Molecular dynamics (MD) simulations of our structures illuminate interactions responsible for different affinity and binding poses of the blockers. The structures elucidate the trapping mechanism of KAR channel block and provide a template for designing new blockers that can selectively target calcium-permeable KARs in neuropathologies (Gangwar et al. 2024). |
Eukaryota | Metazoa, Chordata | Grik2 of Rattus norvegicus (P42260) |
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1.A.10.1.12 | The NMDA receptor. The crystal structure of the N-terminal domains (GluN1 and GluN2) have been determined (PDB#3QEL; Talukder and Wollmuth, 2011). The ligand-specific deactivation time courses of GluN1/GluN2D NMDA receptors have been measured (Vance et al., 2011). NMDA receptors are Hebbian-like coincidence detectors, requiring binding of glycine and glutamate in combination with the relief of voltage-dependent magnesium block to open an ion conductive pore. Lee et al. 2014 presented X-ray structures of the Xenopus laevis GluN1-GluN2B NMDA receptor with the allosteric inhibitor, Ro25-6981, partial agonists and the ion channel blocker, MK-801. Receptor subunits are arranged in a 1-2-1-2 fashion, demonstrating extensive interactions between the amino-terminal and ligand-binding domains. The 3-TMS transmembrane domains harbour a closed-blocked ion channel, a pyramidal central vestibule lined by residues implicated in binding ion channel blockers and magnesium, and a approximately twofold symmetric arrangement of ion channel pore loops. GRIN2D mediates developmental and epileptic encephalopathy (XiangWei et al. 2019). |
Eukaryota | Metazoa, Chordata | NMDA receptor of Xenopus laevis (Q91977) |
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1.A.10.1.13 |
Glu2 AMPA receptor (GluR-2; GluR2-flop; CX614; GluA2). The 3-d structure is known at 3.6 Å resolution. It shows a 4-fold axis of symmetry in the transmembrane domain, and a 2-fold axis of symmetry overall, although it is a homotetramer (Sobolevsky et al. 2009). A structure showing an agoniar-bound form of the rat GluA2 receptor revealed conformational changes that occur during gating (Yelshanskaya et al. 2014). GluR2 interacts directly with β3 integrin (Pozo et al., 2012). In general, integrin receptors form macromolelcular complexes with ion channels (Becchetti et al. 2010). TARPS are required for AMP receptor function and trafficking, but seven other auxiliary subunits have also been identified (Sumioka 2013). For example, AMPA receptors are regulated by S-SCAM through TARPs (Danielson et al. 2012). The C-terminal domains of various TARPs (TC#8.A.16.2) play direct roles in the regulation of GluRs (Sager et al. 2011). Whole-genome analyses have linked multiple TARP loci to childhood epilepsy, schizophrenia and bipolar disorders (Kato et al. 2010). Thus, TARPs emerge as vital components of excitatory synapses that participate both in signal transduction and in neuropsychiatric disorders. The architecture of a fully occupied GluR2-TARP complex has been illucidated by cryoEM, showing the homomeric GluA2 AMPA receptor saturated with TARP Υ2 subunits, showing how the TARPs are arranged with four-fold symmetry around the ion channel domain, making extensive interactions with the M1, M2 and M4 TMSs (Zhao et al. 2016). The binding mode and sites for prototypical negative allosteric modulators at the GluA2 AMPA receptor revealing new details of the molecular basis of molulator binding and mechanisms of action (Stenum-Berg et al. 2019). Drug effects, regulatory protein modulators and positive allosteric modulators have been reviewed (Fu et al. 2019). TARP γ2 converts the desensitized state to the high-conductance state which exhibits tighter coupling between subunits in the extracellular parts of the receptor (Carrillo et al. 2020). Sex-dependent differences have been observed in the Ischemia/Reperfusion-induced expression of AMPA receptors (Achzet and Jackson 2024). |
Eukaryota | Metazoa, Chordata | GluR-2 of Homo sapiens (P42262) Drug effects, regulatory protein modulators and positive allosteric modulators have been reviewed (Fu et al. 2019). |
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1.A.10.1.14 | Ionotropic receptor 25a, Ir25a. Not involved in salt sensing (Zhang et al. 2013). It resets the circadian clock in response to temperature (Chen et al. 2015). |
Eukaryota | Metazoa, Arthropoda | Ir25a of Drosophila melanogaster |
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1.A.10.1.15 | Glutamate ionotropic receptor homologue |
Eukaryota | Metazoa, Arthropoda | Glutamate receptor in Daphnia pulex (water flea) |
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1.A.10.1.16 | Olfactory ionotropic receptor, Ir93a of 842 aas |
Eukaryota | Metazoa, Arthropoda | Ir93a of Panulirus argus (spiny lobster) |
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1.A.10.1.17 | Ionotropic sodium channel; attractive, sodium gustatory sensory receptor for positive salt taste. Not involved in salt avoidance which uses a distinct receptor (Zhang et al. 2013). |
Eukaryota | Metazoa, Arthropoda | Ir76b of Drosophila melanogaster |
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1.A.10.1.18 | Calcium channel of 551 aas, Glr1 (Wheeler and Brownlee 2008). |
Viridiplantae, Chlorophyta | Glr1 of Chlamydomonas reinhardtii |
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1.A.10.1.19 | Olfactory glutamate-like ionotropic receptor, kainate 2 isoform X1 of 754 aas and 4 TMSs. Chen et al. 2017 identify 102 putative IR genes, (dubbed AalbIr genes) in the mosquito Aedes albopictus (Skuse), 19 of which showed expression in the female antenna. These putative olfactory AalbIRs share four conservative hydrophobic domains similar to the transmembrane and ion channel pore regions found in conventional iGluRs. To determine their potential functions in host-seeking, Chen et al. 2017 compared their transcript expression levels in the antennae of blood-fed females with that of non-blood-fed females. Three AalbIr genes showed downregulation when the mosquito finished a bloodmeal. |
Eukaryota | Metazoa, Arthropoda | Olfactory receptor of Aedes albopictus (Asian tiger mosquito) (Stegomyia albopicta) |
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1.A.10.1.2 | Glutamate receptor 4, GIC, AMPA-subtype, GluR4, GRIA4 or GluR-D (preferentially monovalent cation selective). Binding of the excitatory neurotransmitter, L-glutamate, induces a conformation change, leading to the opening of the cation channel, thereby converting the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4, CACNG7 or CACNG8, GluR4 shows resensitization characterized by a delayed accumulation of current flux upon continued application of glutamate (Gill et al. 2008; Birdsey-Benson et al. 2010). De novo variants in GRIA4 lead to intellectual disability with or without seizures, gait abnormalities, problems of social behavior, and other variable features (Martin et al. 2017). |
Eukaryota | Metazoa, Chordata | GluR-D of Rattus norvegicus |
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1.A.10.1.20 | Heteromeric ionotropic NMDA receptor (NMDAR) consisting of two subunits, GluN1 (938 aas) and GluN2A (1464 aas). Positions of the Mg2+ and Ca2+ ions in the ion channel divalent cation binding site have been proposed, and differences in the structural and dynamic behavior of the channel proteins in the presence of Mg2+ or Ca2+ have been analyzed (Mesbahi-Vasey et al. 2017). GRIN variants in receptor M2 channel pore-forming loop are associated with neurological diseases (Li et al. 2019). Disease-associated variants have revealed mechanistic aspect of the NMDA receptor (Amin et al. 2021). Cross-subunit interactions that stabilize open states mediate gating in NMDA receptors (Iacobucci et al. 2021). The gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors have been reported (Wang et al. 2021). GluN2A and GluN2B NMDA receptors apparently use distinct allosteric routes (Tian et al. 2021). A negative allosteric modulatory site in the GluN1 M4 determines the efficiency of neurosteroid modulation (Langer et al. 2021). Excitatory signaling mediated by NMDAR is critical for brain development and function, as well as for neurological diseases and disorders. Channel blockers of NMDARs can be used for treating depression, Alzheimer's disease, and epilepsy. Chou et al. 2022 monitored the binding of three clinically important channel blockers: phencyclidine, ketamine, and memantine in GluN1-2B NMDARs at local resolutions of 2.5-3.5 Å around the binding site. The channel blockers form interactions with pore-lining residues, which control mostly off-speeds but not on-speeds (Chou et al. 2022). NMDAR channel blockers include MK-801, phencyclidine, ketamine, and the Alzheimer's disease drug memantine, can bind and unbind only when the NMDAR channel is open. NMDAR channel blockers can enter the channel through two routes: the well-known hydrophilic path from extracellular solution to channel through the open channel gate, and also a hydrophobic path from plasma membrane to channel through a gated fenestration (Wilcox et al. 2022). Pregnane-based steroids are positive NMDA receptor modulators that may compensate for the effect of loss-of-function disease-associated GRIN mutations (Kysilov et al. 2022). The NMDA receptor C-terminal domain signals in development, maturity, and disease (Haddow et al. 2022). Blood tissue Plasminogen Activator (tPA) of liver origin contributes to neurovascular coupling involving brain endothelial N-Methyl-D-Aspartate (NMDA) receptors (Furon et al. 2023). Two gates mediate NMDA receptor activity and are under subunit-specific regulation (Amin et al. 2023). One of the main molecular mechanisms of ketamine action is the blockage of NMDA-activated glutamate receptors (Pochwat 2022). The S1-M1 linker of the NMDA receptor controls channel opening (Xie et al. 2023). Binding and dynamics demonstrated the destabilization of ligand binding for the S688Y mutation in the NMDA receptor GluN1 subunit (Chen et al. 2023). The functional effects of disease-associated NMDA receptor variants have been reviewed (Moody et al. 2023). Co-activation of NMDAR and mGluRs controls protein nanoparticle-induced osmotic pressure in neurotoxic edema (Zheng et al. 2023). Disease-associated nonsense and frame-shift variants resulting in the truncation of the GluN2A or GluN2B C-terminal domain decreases NMDAR surface expression and reduces potentiating effects of neurosteroids (Kysilov et al. 2024). De novo GRIN variants in the M3 helix associated with neurological disorders control channel gating of the NMDA receptor (Xu et al. 2024). Ketamine is a rapid and potent antidepressant. Ketamine injection in depressive-like mice specifically blocks NMDARs in lateral habenular (LHb) neurons, but not in hippocampal pyramidal neurons (Chen et al. 2024). This regional specificity depended on the use-dependent nature of ketamine as a channel blocker, local neural activity, and the extrasynaptic reservoir pool size of NMDARs. Activating hippocampal or inactivating LHb neurons swapped their ketamine sensitivity. Conditional knockout of NMDARs in the LHb occluded ketamine's antidepressant effects and blocked the systemic ketamine-induced elevation of serotonin and brain-derived neurotrophic factor in the hippocampus (Chen et al. 2024). NMDA receptor-modulating treatments for cognitive and plasticity deficits in schizophreniahave been studied (Sehatpour and Kantrowitz 2025). Patient-derived NMDAR mAbs combined with single-particle cryo-EM reveal multiple GluN1 epitopes and distinct functional effects (Spatola and Dalmau 2025). The N-methyl-D-aspartate receptor (NMDAR) is unique among all ligand-gated channels, requiring two ligands, glutamate and glycine, for activation. These receptors function as heterotetrameric ion channels, with the channel opening dependent on the simultaneous binding of glycine and glutamate to the extracellular ligand-binding domains (LBDs) of the GluN1 and GluN2 subunits, respectively (Chou et al. 2024). |
Eukaryota | Metazoa, Chordata | NMDAR of Homo sapiens |
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1.A.10.1.21 | Glutamate receptor 1, GluR1; Glr-1 of 962 aas and 5 TMSs. Plays a role in controlling movement in
response to environmental cues such as food availability and
mechanosensory stimulation such as the nose touch response (Campbell et al. 2016). Regluated by SOL1 (TC# 8.A.47.2.1) (Walker et al. 2006). |
Eukaryota | Metazoa, Nematoda | Glr-1 of Caenorhabditis elegans |
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1.A.10.1.22 | NMDA-like glutamate receptor, NR1, of 964 aas and 4 TMSs. It functions in the organization of feeding, locomotory and defensive behaviors. Two are present, NR1-1 and NR1-2 in nurrons (Ha et al. 2006). |
Eukaryota | Metazoa, Mollusca | NR1 of Aplysia californica (California sea hare) |
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1.A.10.1.23 | Ionotropic glutamate receptor, GluR1 (GluR-1, GluR1-flip; GRIA1; GluH1; CTZ; GluA1) of 906 aas and 4 - 6 TMSs. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter, L-glutamate, induces a conformational change, leading to the opening of the cation-specific channel, thereby converting the chemical signal to an electrical impulse upon entry of Na+ and Ca2+. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, it shows resensitization characterized by a delayed accumulation of current flux upon continued application of glutamate (Kato et al. 2010). The polyamines, spermine, spermidine and putrescine can be drawn into the permeation pathway and get stuck, blocking the movement of other ions. The degree of this polyamine-mediated channel block is highly regulated by processes that control the free cytoplasmic polyamine concentration, the membrane potential, and the iGluR subunit composition (Bowie 2018). (-)-Arctigenin and a series of new analogues have been synthesised and tested for their potential as AMPA and kainate receptor antagonists of human homomeric GluA1 and GluK2 receptors, and thus potential drugs for epilepsy treatment (Rečnik et al. 2021). It may play a role in osteoporosis (Wu et al. 2023).
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Eukaryota | Metazoa, Chordata | GluR-1 of Homo sapiens |
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1.A.10.1.24 | Glutamate-gated receptor 3.6 of 903 aas, GLR3.6. It probably acts as non-selective cation channel, transporting Ca2+ into the cell. It mediates leaf-to-leaf wound signaling. GLR3/6 may be involved in light-signal transduction and calcium homeostasis via the regulation of calcium influx into cells (Mousavi et al. 2013). Together with GLR3.3 (TC# 1.A.10.1.10), it plays a roles in nervous system-like signaling in plant defense. GLR3.3 and GLR3.6 play different roles by a mechanism that differs substantially from that in animals (Toyota et al. 2018). The orthologous channel protein in Dionaea muscipula may play a role in touch-induced hair calcium-electrical signals that excite the Venus flytrap (Scherzer et al. 2022). |
Eukaryota | Viridiplantae, Streptophyta | GLR3.6 of Arabidopsis thaliana |
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1.A.10.1.25 | NMDA receptor subtype 1, NMDAR1, of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. This protein plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. It mediates neuronal functions in glutamate neurotransmission and is involved in cell surface targeting of NMDA receptors. It plays a role in associative learning and in long-term memory consolidation (Xia et al. 2005). F654A and K558Q mutations affect ethanol-induced behaviors in Drosophila.(Troutwine et al. 2019).
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Eukaryota | Metazoa, Arthropoda | NMDAR of Drosophila melanogaster (Fruit fly) |
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1.A.10.1.26 | Ionotropic receptor 21a, Ir21a, of 842 aas and 5 TMSs. Ir21a is a cooling receptor that drives heat seaking in insects to their warm blooded hosts (Greppi et al. 2020). Although Ir21a mediates heat avoidance in Drosophila, it drives heat seeking and heat-stimulated blood feeding in Anopheles. At a cellular level, Ir21a is essential for the detection of cooling, suggesting that during evolution, mosquito heat seeking relied on cooling-mediated repulsion. Thus, the evolution of blood feeding in Anopheles involves repurposing an ancestral thermoreceptor from non-blood-feeding Diptera (Greppi et al. 2020). |
Eukaryota | Metazoa, Arthropoda | Ir21a of Drosophila melanogaster |
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1.A.10.1.27 | Ionotropic receptor precursor, Ir21a, of 948 aas and 5 TMSs. They are found in the sensory endings of neurons in antenna (Greppi et al. 2020). |
Eukaryota | Metazoa, Arthropoda | Ir21a of Aedes aegypti (yellow fever mosquito) |
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1.A.10.1.28 | Glutamate receptor ionotropic, kainate 5, GluK5 or GRIK5, of 980 aas and 4 TMSs. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. This receptor binds kainate > quisqualate > domoate > L-glutamate >> AMPA >> NMDA = 1S,3R-ACPD. The transciption profile (transcriptome) of its gene as well as those of other Ca2+ transporters has been determined as a function of embryonic stage in mice, up until birth (Bouron 2020). Partial agonism in heteromeric GLUK2/GLUK5 kainate receptor has been documented, and partial agonism observed with AMPA binding is mediated primarily due to differences in the GluK2 subunit, highlighting the distinct contributions of the subunits towards activation (Paudyal et al. 2023). |
Eukaryota | Metazoa, Chordata | GRIK5 of Homo sapiens |
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1.A.10.1.29 | Fusion protein with an N-terminal glycine receptor/chloride channel domain (residues 1 - 470) like 1.A.9.3.1 and a C-terminal glutamate receptor/cation channel domain (residues 500 to the end) like 1.A.10.1.13. This fusion protein is from Tupaia chinensis (chinese tree shrew), and the two domains are 93.8% and 97.4% identical to the two proteins (both from Homo sapiens) that they hit in TCDB as noted above. It should be noted that the fusion proteins reported here and in TC#s 1.A.10.1.20 - 23 could reflect the presence of true fusion proteins, or they could be a result of sequencing errors. |
Eukaryota | Metazoa, Chordata | Fusion protein of Tupaia chinensis |
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1.A.10.1.3 | GIC, NMDA-subtype, Grin C2 (highly permeable to Ca2+ and monovalent cations). A single residue in the GluN2 subunit controls NMDA receptor channel properties via intersubunit interactions (Retchless et al., 2012). Memantine (Namenda) is prescribed as a treatment for moderate to severe Alzheimer's Disease.
Memantine functions by blocking the NMDA receptor, and the sites of interaction have been identified (Limapichat et al. 2013). Genetic mutations in multiple NMDAR subunits cause various childhood epilepsy
syndromes (Li et al. 2016). NMDA receptor gating is complex, exhibiting multiple closed, open, and desensitized states, but the structure-energy landscape of gating for the rat homologue has been mapped (Dolino et al. 2017). NMDARs are tetrameric complexes consisting of two glycine-binding GluN1 and two glutamate-binding GluN2 subunits. Four GluN2 subunits encoded by different genes can produce up to ten different di- and triheteromeric receptors. These heteromeric systems have been modeled (Gibb et al. 2018). A conserved glycine associated with diseases permits NMDA receptors to acquire high Ca2+ permeability (Amin et al. 2018). The ND2 protein (see TC# 3.D.1.6.1), a component of the NMDAR complex, enables Src tyrosine protein kinase (TC# 8.A.23.1.12) regulation of NMDA receptors (Scanlon et al. 2017). Drug effects, regulatory protein modulators and positive allosteric modulators have been reviewed (Fu et al. 2019). |
Eukaryota | Metazoa, Chordata | NMDA receptor, Grin C2, of Homo sapiens |
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1.A.10.1.30 | Fusion protein having an N-terminal domain homologous to a glycine receptor (GlyR; residues 1 - 466, 66% identical to TC# 1.A.9.3.1 (GlyR of Homo sapiens)), a central domain homologous to a glutamate receptor (GluR; residues 459 - 1296, 85.5% identical to 1.A.10.1.13, GluR of Homo sapiens)), and a C-terminal domain homologous to a DMT carrier (TC# 2.A.7.8.1, an uncharacerized protein, Yrr6 of Caenorhabditis elegans). |
Eukaryota | Metazoa, Chordata | GlyR-GluR-DMT fusion protein of Bagarius yarrelli |
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1.A.10.1.31 | Fusion protein of 2281 aas and 3 TMSs, two plus a central P-loop at residues 546 - 640 followed by one more TMS (residues 806 - 825) within an N-terminal glutamate receptor domain (residues 1 - 888) similar to that of TC# 1.A.10.1.6 (61% identity) and a C-terminal protein kinase domain (residues 1670 - 2273) homologous to the entirety of TC# 8.A.104.1.4 of 671 aas; 64% identity. The central part of this large fusion protein shows sequence similarity (~40% identity) with a nuclear chromatin condensation inducer (TC#3.A.18.1.1; Q9UKV3). |
Eukaryota | Metazoa, Chordata | Fusion protein of Scophthalmus maximus |
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1.A.10.1.33 | Fusion protein of 1324 aas and 7 putative TMSs in a 1 (N-terminal) + 2 TMSs with a central P-loop + 3 TMSs + 1 C-terminal TMS. The N-terminal ionotropic glutamate receptor , kainate 2-like domain is 43% identical to TC#1.A.10.1.11 while the C-terminal domain is homologous to the N-terminal part of TC# 1.A.9.1.6 (residues 1005 to 1239 in this fusion protein. |
Eukaryota | Metazoa, Arthropoda | Fusion protein of Dermatophagoides pteronyssinus |
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1.A.10.1.34 | Glutamate receptor, ionotropic, delta-1, GRID1or GluD1, of 1009 aas and 5 or 6 TMSs in a 1 or 2 TMSs (N-terminus) + 2 or 3 TMSs + 1 TMS (C-terminus) arrangement. GluD1 is a signal transduction device disguised as an ionotropic receptor (Dai et al. 2021). GABA rather than L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Delta glutamate receptors have been reported to be functional glycine- and serine-gated cation channels in situ (Carrillo et al. 2021). Clinical features, functional consequences, and rescue pharmacology of missense GRID1 and GRID2 human variants have been described (Allen et al. 2023). GluD1 binds GABA and controls inhibitory plasticity (Piot et al. 2023). Fast synaptic neurotransmission in the vertebrate central nervous system relies primarily on ionotropic glutamate receptors (iGluRs), which drive neuronal excitation, and type A γ-aminobutyric acid receptors (GABAARs), which are responsible for neuronal inhibition. The GluD1 receptor, an iGluR family member, is present at both excitatory and inhibitory synapses. GluD1 binds GABA, and activation produces long-lasting enhancement of GABAergic synaptic currents in the adult mouse hippocampus through a non-ionotropic mechanism that is dependent on trans-synaptic anchoring. The identification of GluD1 as a GABA receptor that controls inhibitory synaptic plasticitywas reported by Piot et al. 2023.
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Eukaryota | Metazoa, Chordata | GRID1 of Homo sapiens |
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1.A.10.1.4 |
AMPA glutamate receptor 3 (GluR3, GluA3. GRIA3. LLUR3. GLURC) (non-selective monovalent cation channel and Ca2+ channel) (Ayalon et al., 2005; Midgett et al., 2012). Regulated by AMPA receptor regulatory proteins (TARPs) including stargazin and CNIH auxiliary subunits (Kim et al., 2010; Straub and Tomita, 2011; Jackson and Nicoll, 2011; Bats et al., 2012; Rigby et al. 2015). The domain architecture of a calcium-permeable AMPA receptor in a ligand-free conformation has been solved (Midgett et al., 2012). The TARP, stargazin, is elevated in the somatosensory cortex of Genetic Absence Epilepsy Rats (Kennard et al. 2011). TARPs alter the conformation of pore-forming subunits and thereby affect antagonist interactions (Cokić and Stein 2008). The structural basis of AMPAR regulation by TARP gamma2, or stargazin (STZ) involves variable interaction stoichiometries of the AMPAR-TARP complex, with one or two TARP molecules binding one tetrameric AMPAR (Twomey et al. 2016). The ion channel extracellular collar plays a role in gating and represents a hub for powerful allosteric modulation of AMPA receptor function (Yelshanskaya et al. 2017). The A653T mutation stabilizes the closed configuration of the channel and affects duration of sleep and awake periods in both humans and mice (Davies et al. 2017). The tetramer exhibits 4 distinct conductase leves due to independent subunit activation. Perampanel is an anticonvulsant drug that regulates gating (Yuan et al. 2019). Tetramerization of the AMPA receptor glutamate-gated ion channel is regulated by auxiliary subunits (Certain et al. 2023). A synopsis of multitarget therapeutic effects of anesthetics on depression has been published (Wu and Xu 2023). |
Eukaryota | Metazoa, Chordata | GluR3 of Homo sapiens (P42263) |
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1.A.10.1.5 | The homomeric cation channel/glutamate receptor/kainate 1, GluR5, GluK1, GRIK1 of 918 aas and (weakly responsive to glutamate) (expressed in the developing nervous system) (Bettler et al., 1990). The 3-d structures of the protein have been determined with agonists and antagonists. The agonist, domoic acid, stabilizes the ligand-binding core of the iGluR5 complex in a conformation that is 11 degrees more open than the conformation observed when the full agonist, (S)-glutamate, is bound (Hald et al. 2007). Kainate receptors regulate KCC2 expression in the hippocampus (Pressey et al. 2017). GluR5/ERK signaling is regulated by the phosphorylation and function of the glycine receptor alpha1ins subunit (TC# 9.A.14.3.4) in the spinal dorsal horn of mice (Zhang et al. 2019). The human ortholog is 918 aas long and 97% identical to the rat homolog. (-)-Arctigenin and a series of new analogues are AMPA and kainate receptor antagonists of human homomeric GluA1 and GluK2 receptors (Rečnik et al. 2021). |
Eukaryota | Metazoa, Chordata | GluR5 of Rattus norvegicus |
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1.A.10.1.6 | The heteromeric monovalent cation/Ca2+ channel/glutamate (NMDA) receptor NMDAR1/NMDAR2A/NMDAR2B/NMDAR2C) (Monyer et al., 1992). Note: NR2B is the same as NR3, GluN2A, GRIN2A or subunit epsilon (Schüler et al., 2008). Mediates voltage- and Mg2+-dependent control of Na+ and Ca2+ permeability (Yang et al., 2010). Mutations in the subunit, GRIN1, a 1464 aa protein, identified in patients with early-onset epileptic encephalopathy and profound developmental delay, are located in the transmembrane domain and the linker region between the ligand-binding and transmembrane domains (Yuan et al. 2014; Ohba et al. 2015). Karakas and Furukawa 2014 determined the crystal structure of the heterotetrameric GluN1-GluN2B NMDA receptor ion channel at 4 Å resolution. The receptor is arranged as a dimer of GluN1-GluN2B heterodimers with the twofold symmetry axis running through the entire molecule composed of an amino terminal domain, a ligand-binding domain, and a transmembrane domain. The GluN2 subunit regulates synaptic trafficking of AMPA in the neonatal mouse brain (Hamada et al. 2014). GRIN1 and GRIN2A mutations are associated with severe intellectual disability with cortical visual impairment, epilepsy and oculomotor and movement disorders being discriminating phenotypic features (Lemke et al. 2016; Chen et al. 2017).The cryoEM structure of a triheteromeric receptor including GluN1 (glycine binding), GluN2A and GluN2B (both glutamate binding) has been solved with and without a GluN2B allosteric antagonist, Ro 25-6981 (Lü et al. 2017). Ogden et al. 2017 implicated the pre-M1 region in gating, providing insight into how different subunits contribute to gating, and suggesting that mutations in the pre-M1 helix, such as those that cause epilepsy and developmental delays, can compromise neuronal health. The severity of GRIN2A (Glu2A)-related disorders can be predicted based on the positions of the mutations in the encoding gene (Strehlow et al. 2019). Knock-in mice expressing an ethanol-resistant GluN2A NMDA receptor subunit show altered responses to ethanol (Zamudio et al. 2019). Results of McDaniel et al. 2020 revealed the role of the pre-M1 helix in channel gating, implicated the surrounding amino acid environment in this mechanism, and suggested unique subunit-specific contributions of pre-M1 helices to GluN1 and GluN2 gating. The human ortholog is 998.5% identical. An autism-associated mutation in GluN2B prevents NMDA receptor trafficking and interferes with dendrite growth (Sceniak et al. 2019). The binding of calcium-calmodulin to the C-terminus of GluN1 has long range allosteric effects on the extracellular segments of the receptor that may contribute to the calcium-dependent inactivation (Bhatia et al. 2020). GluN1 interacts with PCDH7 (O60245) to regulate dendritic spine morphology and synaptic function (Wang et al. 2020).Pluripotential GluN1 (NMDA NR1) functions in cellular nuclei in pain/nociception (McNearney and Westlund 2023). |
Eukaryota | Metazoa, Chordata | NR1/NR2A or NR2B or NR2C of Rattus norvegicus |
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1.A.10.1.7 | The glutamate receptor 1.1 precursor (Ligand-gated channel 1.1, AtGLR1 (Kang and Turano, 2003)) | Eukaryota | Viridiplantae, Streptophyta | GLR1 of Arabidopsis thaliana (Q9M8W7) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.10.1.8 | The mouse glutamate receptor δ-2 subunit precursor (GluR δ-2, GluR delta subunit, or GluD2) (Uemura et al., 2004). The 3-d structure in the synaptic junctional complex with presynaptic β-neurexin 1 (β-NRX1 or NRXN1A; Q9ULB1 = the human homologue) and the C1q-like synaptic organizer, cerebellin-1 (Cbln1; 193 aas, 1 or 2 TMSs; Q9R171 = the human homolgue) has been solved (Elegheert et al. 2016). |
Eukaryota | Metazoa, Chordata | GluR δ2 of Mus musculus (Q61625) |
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1.A.10.1.9 | The ionotropic glutamate receptor kainate 4 precursor (Glutamate receptor, KA-1 or EAA1) (Kamboj et al., 1994).Molecular dynamic simulations revealed that water-soluble QTY variants of glutamate transporters, EAA1, EAA2 and EAA3, retain the conformational characteristics of their native transporters (Karagöl et al. 2024). |
Eukaryota | Metazoa, Chordata | KA1 of Homo sapiens (Q16099) |
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1.A.10.2.1 | Glutamate-gated ionotropic K+ channel receptor, GluR0 (5TMSs). X-ray structures are available (PDB: 1IIT) (Lee et al. 2005; Lee et al. 2008) GluR6 (TC# 1.A.10.1.11), carrying the pore loop plus adjacent transmembrane domains of this prokaryotic, glutamate-gated, K+-selective GluR0, adopted several electrophysiological properties of the donor pore upon pore transplantation (Hoffmann et al. 2006). |
Bacteria | Cyanobacteriota | GluR0 of Synechocystis sp. PCC6803 |
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1.A.10.2.2 | Probable Ionotropic glutamate receptor (GluR) |
Bacteria | Bacteroidota | GluR homologue of Algoriphagus sp. PR1 (A3I049) |
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1.A.10.2.3 | Probably Ionotropic glutamate receptor (GluR) |
Bacteria | Chlorobiota | GluR homologue of Chlorobium luteolum (Q3B5G3) |
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1.A.10.2.4 | Probable Ionotropic glutamate receptor (GluR) |
Bacteria | Pseudomonadota | GluR homologue of Vibrio fischeri (B5FDH7) |
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1.A.10.2.5 | Uncharacterized protein of 1003 aas and 5 - 7 TMSs |
Eukaryota | Viridiplantae, Chlorophyta | UP of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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1.A.10.3.1 | Ionotropic ligand (glutamate) receptor of 433 aas and 3 or 4 TMSs (Greiner et al. 2018). |
Viruses | Phycodnaviridae | GluR of Paramecium bursaria Chlorella virus IL-3A |
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1.A.10.3.2 | Ligand-gated ion channel of 448 aas and 4 TMSs in a 3 + 1 TMS arrangement. |
Viruses | Bamfordvirae, Nucleocytoviricota | LIC of Only Syngen Nebraska virus 5 |
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1.A.100.1.1 | The Wongabel virus U5 protein (putative viroporin) of 127 aas and 1 or 2 TMSs. |
Viruses | Mononegavirales | U5 of Wongabel virus |
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1.A.100.1.2 | Putative viroporin of 118 aas and 1 or 2TMSs |
Viruses | Orthornavirae, Negarnaviricota | Putative Viroporin of Joinjakaka virus |
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1.A.100.1.3 | Putative viroporin of 90 aas and 1 TMS |
Viruses | Orthornavirae, Negarnaviricota | Putative viroporin of Kotonkan virus |
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1.A.100.1.4 | Uncharacterized protein of 105 aas and 1 TMS. |
Viruses | Orthornavirae, Negarnaviricota | UP of Parry Creek virus |
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1.A.100.1.5 | alpha1 (α1) protein of 90 aas and 1 TMS |
Viruses | Orthornavirae, Negarnaviricota | alpha1 protein of Koolpinyah virus |
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1.A.101.1.1 | Pex11 of 236 aas and possibly 3 TMSs (Mindthoff et al. 2015). |
Eukaryota | Fungi, Ascomycota | Pex11 of Saccharomyces cerevisiae |
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1.A.101.1.2 | Pex11 of 247 aas. |
Eukaryota | Metazoa, Chordata | Pex11 of Homo sapiens |
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1.A.101.1.3 | Pex11 of 248 aas |
Eukaryota | Viridiplantae, Streptophyta | Pex11 of Arabidopsis thaliana |
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1.A.101.1.4 | Pex11 of 222 aas |
Eukaryota | Euglenozoa | Pex11 of Leishmainia major |
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1.A.101.1.5 | Pex11 of 234 aas |
Eukaryota | Metazoa, Arthropoda | Pex 11 of Drosophila melanogaster (Fruit fly) |
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1.A.101.1.6 | Pex11C-like protein of 199 aas |
Eukaryota | Metazoa, Arthropoda | Pex11C-like protein of Mombyx mori |
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1.A.101.1.7 | Uncharacterized glycosomal protein of 220 aas |
Eukaryota | Euglenozoa | UP of Leishmania major |
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1.A.101.2.1 | Putative Pex11 of 355 aas |
Eukaryota | Fungi, Ascomycota | Pex11 homologue of Aspergillus niger |
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1.A.101.2.2 | Putative Pex11 homologue of 315 aas |
Eukaryota | Fungi, Basidiomycota | Pex11 homologue of Cryptococcus neoformans (Filobasidiella neoformans) |
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1.A.101.2.3 | Uncharacterized protein of 327 aas |
Eukaryota | Fungi, Ascomycota | UP of Bipolaris oryzae |
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1.A.101.2.4 | Pex11 homologue of 290 aas |
Eukaryota | Fungi, Ascomycota | Pex11 homologue of Sphaerulina musiva (Poplar stem canker fungus) (Septoria musiva) |
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1.A.101.2.5 | Uncharacterized protein of 188 aas |
Eukaryota | Oomycota | UP of Aphanomyces astaci |
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1.A.101.3.1 | Uncharacterized protein of 317 aas |
Eukaryota | Fungi, Basidiomycota | UP of Wallemia mellicola (Wallemia sebi |
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1.A.101.3.2 | Uncharacterized protein of 410 aas |
Eukaryota | Fungi, Basidiomycota | UP of Serpula lacrymans (Dry rot fungus) |
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1.A.101.3.3 | Uncharacterized protein of 334 aas |
Eukaryota | Fungi, Basidiomycota | UP of Rhodosporidium toruloides (Yeast) (Rhodotorula gracilis) |
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1.A.101.3.4 | Uncharacterized protein of 228 aas |
Eukaryota | Fungi, Mucoromycota | UP of Mucor circinelloides (Mucormycosis agent) (Calyptromyces circinelloides) |
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1.A.101.4.1 | Uncharacterized glycosomal protein of 225 aas |
Eukaryota | Euglenozoa | UP of Leishmania braziliensis |
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1.A.101.4.2 | Uncharacterized protein of 253 aas |
Eukaryota | Euglenozoa | UP of Leishmania braziliensis |
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1.A.101.4.3 | Uncharacterized protein of 247 aas |
Eukaryota | Euglenozoa | UP of Trypanosoma cruzi |
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1.A.101.5.1 | Uncharacterized protein of 252 aas |
Eukaryota | Haptophyta | UP of Emiliania huxleyi |
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1.A.101.5.2 | Uncharacterized protein of 252 aas |
Eukaryota | Oomycota | UP of Saprolegnia diclina |
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1.A.101.5.3 | Uncharacterized protein of 421 aas |
Eukaryota | Haptophyta | UP of Emiliania huxleyi |
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1.A.101.6.1 | Pex11 of 240 aas |
Eukaryota | Ciliophora | Pex11 of Tetrahymena thermophila |
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1.A.101.6.2 | Uncharacterized protein of 289 aas |
Eukaryota | Ciliophora | UP of Paramecium tetraurelia |
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1.A.101.6.3 | Pex11 domain containing protein of 235 aas |
Eukaryota | Ciliophora | Pex11 of Oxytricha trifallax |
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1.A.101.6.4 | Peroxin Pex11 of 243 aas |
Eukaryota | Viridiplantae, Streptophyta | Pex11 of Physcomitrella patens (Moss) |
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1.A.101.7.1 | Uncharacterized protein of 244 aas |
Eukaryota | Fungi, Ascomycota | UP of Kazachstania africana (Yeast) (Kluyveromyces africanus) |
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1.A.101.7.2 | Pex25 of 294 aas |
Eukaryota | Fungi, Ascomycota | Pex25 of Saccharomyces cerevisiae |
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1.A.101.7.3 | Pex27 of 376 aas and 2 predicted TMSs. |
Eukaryota | Fungi, Ascomycota | Pex27 of Saccharomyces cerevisiae |
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1.A.101.8.1 | Uncharacterized protein of 206 aas |
Eukaryota | Bacillariophyta | UP of Thalassiosira oceanica (Marine diatom) |
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1.A.101.8.2 | Uncharacterized protein of 360 aas |
Eukaryota | Bacillariophyta | UP of Phaeodactylum tricornutum |
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1.A.101.8.3 | Uncharacterized protein of 252 aas |
Eukaryota | Oomycota | UP of Pythium ultimum |
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1.A.102.1.1 | The PB1-F2 protein of 90 aas, and possibly a weakly hydrophobic C-terminal TMS, exhibits viroporin activity, transporting monovalent cations and Ca2+ (Hyser and Estes 2015). |
Viruses | Orthornavirae, Negarnaviricota | PB1-F2 of Influenza virus A |
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1.A.102.1.2 | Influenza A virus PB1-F2 protein of 57 aas |
Viruses | Orthornavirae, Negarnaviricota | PB1-F2 of INfluenza A virus |
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1.A.102.1.3 | PB1-F2 protein of 57 aas and 0 TMSs |
Viruses | Orthornavirae, Negarnaviricota | PB1-F2 of Influenza A virus (A/chicken/Dongguan) |
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1.A.102.1.4 | PB1-F2 viroporin of 90 aas. It is an influenza A virus-encoded proapoptotic mitochondrial protein that creates variably sized pores in planar lipid membranes (Chanturiya et al. 2004). |
Viruses | Orthornavirae, Negarnaviricota | PB1F2 of influenza A virus |
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1.A.103.1.1 | The Parainfluenza Virus 5 (Simian Virus 5) viroporin, SH, of 44 aas and 1 C-terminal TMS. Transports monovalent cations (Hyser and Estes 2015). |
Viruses | Orthornavirae, Negarnaviricota | SH of Parainfluenza Virus 5 (Simian Virus 5) |
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1.A.103.1.2 | SH protein of 44 aas and 1 C-terminal TMS. Transports monovalent cations (Hyser and Estes 2015). |
Viruses | Mononegavirales | SH of Parainfluenza Virus 5 |
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1.A.104.1.1 | The FlhA flagellar biosyththesis energizer Na+ channel of 692 aas and 8 TMSs. Evidence for the Na+ channel activity of FlhA has been presented (Minamino et al. 2016). FlhA and FlhB are transmembrane proteins of the flagellar type III protein export apparatus (TC# 3.A.6), and their C-terminal cytoplasmic domains (FlhAC and FlhBC) coordinate flagellar protein export with assembly. Their (Minamino et al. 2020). FliK-driven conformational rearrangements of FlhA and FlhB are required for export switching of the flagellar protein export apparatus (Minamino et al. 2020). |
Bacteria | Pseudomonadota | FlhA of E. coli |
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1.A.104.1.2 | Flagellar biosynthesis protein FlhA of 728 aas and 8 TMSs in a 4 + 4 TMS arrangement.. |
Bacteria | Verrucomicrobiota | FlhA of Spartobacteria bacterium |
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1.A.104.1.3 | Flagellar biosynthesis protein FlhA of 713 aas and 8 TMSs in a 4 + 4 TMS arrangement. |
Bacteria | Pseudomonadota | FlhA of Lautropia mirabilis |
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1.A.104.1.4 | Flagellar biosynthesis protein FlhA of 729 aas and 8 TMSs in a 4 + 4 TMS arrangement. |
Bacteria | Pseudomonadota | FlhA of Pseudomonas kurunegalensis |
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1.A.105.1.1 | The mixed lineage kinase domain-like (MLKL) protein of 471 aas and 5 TMSs; forms Mg2+-selective channels in the presence of Na+ and K+ (Xia et al. 2016). |
Eukaryota | Metazoa, Chordata | MLKL of Homo sapiens |
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1.A.105.1.2 | Mixed lineage kinase domain-like protein, MLKL, of 711 aas and 4 N-terminal TMSs. |
Eukaryota | Metazoa, Chordata | MLKL of Balaenoptera acutorostrata scammoni (whale) |
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1.A.105.1.3 | Mixed lineage kinase domain-like protein, MLKL, isoform X1 of 503 aas. |
Eukaryota | Metazoa, Echinodermata | MLKL of Acanthaster planci |
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1.A.106.1.1 | The Transmembrane and coiled-coil domains protein 1 (TMCO1, TMCC4, PNAS-10, PNAS-136, UNQ155) of 188 aas and 3 TMSs. It is an ER transmembrane protein that actively prevents Ca2+ stores from overfilling, acting as a "Cacium Load-activated Calcium channel" or ""CLAC"" channel. TMCO1 undergoes reversible homotetramerization in response to ER Ca2+ overloading and disassembly upon Ca2+ depletion to form a Ca2+-selective ion channel as demonstrated in liposomes (Wang et al. 2016). TMCO1 knockout mice reproduce the main clinical features of human cerebrofaciothoracic (CFT) dysplasia spectrum, a developmental disorder linked to TMCO1 dysfunction, and exhibit severe mishandling of ER Ca2+ in cells (Alanay et al. 2014). Thus, TMCO1 provides a protective mechanism to prevent overfilling of ER stores with calcium ions (Wang et al. 2016). It regulates Ca2+ stores in granulosa cells (Sun et al. 2018). TMCO1-mediated Ca2+ leak underlies osteoblast functions via CaMKII signaling (Li et al. 2019). The TMCO1 gene is a tumor suppressor in urinary bladder urothelial carcinomas (UBUC). TMCO1 dysregulates cell-cycle progression via suppression of the AKT pathway, and S60 of the TMCO1 protein is crucial for its tumor-suppressor roles (Li et al. 2017). Batchelor-Regan et al. 2021 published a short review about the clinical and scientific advances made with TMCO1. Ca2+ homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling (Yang et al. 2022). A mechanism of metformin action, restoring cellular ER homeostasis, enabled the development of a nanocarrier-mediated ER targeting strategy for remodeling diabetic periodontal tissue (Zhong et al. 2022). TMCO1 regulates cell proliferation, metastasis and EMT signaling through CALR, promoting ovarian cancer progression and cisplatin resistance (Sun et al. 2024). TMCO1 is a crucial regulator of ovarian cancer progression, influencing VDAC1 through CALR and impacting diverse cellular processes (Sun et al. 2024). |
Eukaryota | Metazoa, Chordata | TMCO1, a CLAC channel of Homo sapiens |
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1.A.106.1.10 | Uncharacterized CLAC channel of 176 aas and 3 TMSs. It appears to be a calcium-selective channel required to prevent calcium stores from overfilling. |
Eukaryota | Evosea | CLAC channel of Entamoeba histolytica |
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1.A.106.1.11 | Calcium load-activated calcium channel homolog, TMCO1, of 186 aas and 3 TMSs. The low resolution 3-dimensional structure of DdTMCO1 has been determined by solution NMR (Zhang et al. 2020). |
Eukaryota | Evosea | TMCO1 of Dictyostelium discoideum (Slime mold) |
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1.A.106.1.12 | Calcium load-activated calcium channel, TMCO1, of 189 aas and 2 or 3 TMSs (Wunderlich 2022). |
Eukaryota | Apicomplexa | TMCO1 of Plasmodium falciparum |
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1.A.106.1.2 | TMCO1 of 183 aas and 3 TMSs |
Eukaryota | Metazoa, Cnidaria | TMCo1 of Hydra vulgaris (Hydra) (Hydra attenuata) |
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1.A.106.1.3 | TMCO1 or Anon-37B-2(TUB2, TuB2, Tu37B2) of 177 aas (Q8IA62) or 183 aas (Q9VJ11) and 3 TMSs. It is a calcium-selective channel required to prevent calcium stores from overfilling. |
Eukaryota | Metazoa, Arthropoda | TMCO1 of Drosophila melanogaster (Fruit fly) |
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1.A.106.1.4 | TMCO1 of 177 aas and 3 TMSs |
Eukaryota | Metazoa, Platyhelminthes | TMCO1 of Schistosoma japonicum (Blood fluke) |
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1.A.106.1.5 | TMCO1 homologue of 201 aas and 3 TMSs |
Eukaryota | Apicomplexa | TMCO1 homologue of Toxoplasma gondii |
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1.A.106.1.6 | Uncharacterized protein of 199 aas and 3 TMSs |
Eukaryota | Viridiplantae, Streptophyta | UP of Zea mays (Maize) |
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1.A.106.1.7 | Uncharacterized protein of 219 aas and 3 TMSs |
Eukaryota | Apicomplexa | UP of Eimeria tenella (Coccidian parasite) |
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1.A.106.1.8 | Uncharacterized protein of 196 aas and 3 TMSs |
Bacteria | Pseudomonadota | UP of Arabidopsis thaliana |
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1.A.106.1.9 | Uncharacterized TMCO1 homologue of 192 aas and 3 TMSs. |
Eukaryota | Viridiplantae, Chlorophyta | UP of Chlamydomonas reinhardtii |
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1.A.106.2.1 | TMCO1 homologue of 167 aas and 3 TMSs |
Archaea | Candidatus Korarchaeota | TMCO1 homologue of Korarchaeum cryptofilum |
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1.A.106.2.2 | Uncharacterized protein of 174 aas and 3 TMSs |
Archaea | Euryarchaeota | UP of Thermococcus nautili |
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1.A.106.2.3 | Uncharacterized protein of 191 aas and 3 TMSs. |
Archaea | Euryarchaeota | UP of Methanobrevibacter smithii |
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1.A.106.2.4 | Uncharacterized protein of 301 aas and 4 TMSs |
Archaea | Euryarchaeota | UP of Halorubrum saccharovorum |
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1.A.106.2.5 | Uncharactized protein of 193 aas and 3 or 4 TMSs |
Archaea | Euryarchaeota | UP of Ferroglobus placidus |
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1.A.107.1.1 | Pore-forming Hemoglobin-α of 142 aas (Morrill and Kostellow 2016). |
Eukaryota | Metazoa, Chordata | Hemoglobin-α of Homo sapiens |
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1.A.107.1.2 | Pore-forming hemoglobin-β of 147 aas (Morrill and Kostellow 2016). |
Eukaryota | Metazoa, Chordata | Hemoglobin-β of Homo sapiens |
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1.A.107.1.3 | Pore-forming myoglobin of 154 aas (Morrill and Kostellow 2016). |
Eukaryota | Metazoa, Chordata | Myoglobin of Homo sapiens |
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1.A.107.1.4 | Pore-forming neuroglobin of 151 aas (Morrill and Kostellow 2016). |
Eukaryota | Metazoa, Chordata | Neuroglobin of Homo sapiens |
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1.A.107.1.5 | Pore-forming cytoglobin of 154 aas (Morrill and Kostellow 2016). |
Eukaryota | Metazoa, Chordata | Cytoglobin of Homo sapiens |
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1.A.108.1.1 | Fibroblast growth factor 2, FGF2, of 288 aas. Forms oligomeric pores in the plasma membrane, and these are involved in its secretion to the external medium where it exerts its action (La Venuta et al. 2016; see family description). The ATP1A1 (TC# 3.A.3.1.1) serves as the receptor for membrane insertion (Zacherl et al. 2015). |
Eukaryota | Metazoa, Chordata | FGF2 of Homo sapiens |
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1.A.108.1.2 | Fibroblast growth factor 23, FGF23 of 251 aas. Functions through FGF receptor 4 to regulate the level of the calcium/inorganic cation channel, TrpC6 or TRP6 (TC# 1.A.4.1.5) (Smith et al. 2017). |
Eukaryota | Metazoa, Chordata | FGF23 of Homo sapiens |
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1.A.108.1.3 | Fibroblast growth factor 14 (Fgf14) of 247 aas and possibly one central TMS. FGF14 is important in regulating the distribution of voltage-gated sodium channels in cerebellar Purkinje and granule cells (Graves et al. 2024). Mutations may be a cause of episodic ataxias (EAs) (Graves et al. 2024). |
Eukaryota | Metazoa, Chordata | Fgf14 of Homo sapiens |
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1.A.109.1.1 | Interleukin-1 alpha, IL1α or IL1A, of 271 aas and 0 TMSs. Regulates gap junctional communication in Sertoli cells, which is critical for sertoli cell barrier/blood-testis barrier (BTB) restructuring (Chojnacka et al. 2016). |
Eukaryota | Metazoa, Chordata | IL1α of Homo sapiens |
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1.A.109.1.2 | Interleukin 1β, IL1β, IL1beta, IL1B, IL1F2, of 269 aas. Its release depends on its insertion into the membrane with the formation of a transmembrane pore (Martín-Sánchez et al. 2016). IL-1beta is generated by macrophages upon activation of intracellular NLRP3 (NOD-like, leucine rich repeat domains, and pyrin domain-containing protein 3), part of the functional NLRP3 inflammasome complex that detects pathogenic microorganisms and stressors, while neutrophils are enhanced by increasing levels of IL-1beta (Yaqinuddin and Kashir 2020). |
Eukaryota | Metazoa, Chordata | IL1beta of Homo sapiens |
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1.A.11.1.1 | Ammonia transporter and regulatory sensor, AmtB (Blauwkamp and Ninfa, 2003; Khademi et al., 2004). It has a cleavable N-terminal signal peptide, and while Amt proteins in Gram-negative bacteria appear to utilize a signal peptide, the homologous proteins in Gram-positive organisms do not (Thornton et al. 2006). |
Bacteria | Pseudomonadota | AmtB of E. coli (P69681) |
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1.A.11.1.10 | AmtB1 of 403 aas and 11 (or 12) TMSs. |
Bacteria | Pseudomonadota | AmtB1 of Stutzerimonas stutzeri (Pseudomonas stutzeri) |
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1.A.11.1.2 | High affinity ammonia/methylammonia uptake carrier, Amt1 or AmtA (Walter et al., 2008) | Bacteria | Actinomycetota | Amt1 of Corynebacterium glutamicum (P54146) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.11.1.3 | Low affinity (KM > 3mM) ammonia uptake carrier, AmtB (Walter et al., 2008) | Bacteria | Actinomycetota | AmtB of Corynebacterium glutamicum (Q79VF1) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.11.1.4 | Ammonia channel protein, AmtB (forms a ternary complex with the trimeric PII protein, GlnZ (AAG10012) and the nitrogenous regulatory glycohydrolase enzyme, DraG, causing DraG sequestration and N2ase regulation (Huergo et al., 2007) | Bacteria | Pseudomonadota | AmtB of Azospirillum brasilense (P70731) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.11.1.5 | Ammonia channel (Ammonia transporter) | Bacteria | Aquificota | Amt of Aquifex aeolicus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.11.1.6 | Trimeric ammonia channel protein, Amt-1 (391 aas) | Archaea | Euryarchaeota | Amt-1 of Archaeoglobus fulgidus (O29285) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.11.1.7 | The ammonium transporter channel, AmtA (regulates NH3 homeostasis during growth and development (Yoshino et al., 2007). | Eukaryota | Evosea | AmtA of Dictyostelium discoideum (Q9BLG4) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.11.1.8 | AMT of 514 aas and 11 TMSs. Trypanosoma cruzi, the etiologic agent of Chagas disease, undergoes drastic metabolic changes when it transits between a vector and mammalian hosts. Amino acid catabolism leads to the production of NH4+, which must be detoxified. Cruz-Bustos et al. 2018 identified an intracellular ammonium transporter of T. cruzi (TcAMT) that localizes to acidic compartments (reservosomes, lysosomes). TcAMT possesses all conserved and functionally important residues that form the pore in other ammonium transporters. Functional expression in Xenopus oocytes followed by a two-electrode voltage clamp showed an inward current that is NH4+ dependent at a resting membrane potential lower than -120 mV and is not pH dependent, suggesting that TcAMT is an NH4+or NH3/H+ transporter. Ablation of TcAMT resulted in defects in epimastigote and amastigote replication, differentiation, and resistance to starvation and osmotic stress (Cruz-Bustos et al. 2018). |
Eukaryota | Euglenozoa | Amt of Trypanosoma cruzi |
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1.A.11.1.9 | Ammonium transporter, NrgA, of 411 aas and 11 TMSs. The nrgA gene is co-transcribed with the glnB gene, and may play a role in molecular export and biofilm formation (Ardin et al. 2014). |
Bacteria | Bacillota | NrgA of Streptococcus mutans |
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1.A.11.2.1 | High-affinity electrogenic ammonia/methylammonia transporter (allosterically activated by the C-terminus (Loqué et al., 2009). NH4+ is stable in the AmtB pore, reaching a binding site from which it can spontaneously transfer a proton to a pore-lining histidine residue (His168). The substrate diffuses down the pore in the form of NH3, while the proton is cotransported through a highly conserved hydrogen-bonded His168-His318 pair (Wang et al. 2012). |
Eukaryota | Viridiplantae, Streptophyta | Amt1 of Arabidopsis thaliana (P54144) |
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1.A.11.2.10 | Putative ammonium transporter 2 | Eukaryota | Metazoa, Nematoda | amt-2 of Caenorhabditis elegans | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.11.2.11 | Ammonium transporter, AmtB or Amt1 of 463 aas and 9 TMSs. Regulated by direct interaction with GlnK (Pedro-Roig et al. 2013). |
Archaea | Euryarchaeota | AmtB of Haloferax mediterranei (Halobacterium mediterranei) |
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1.A.11.2.12 | Ammonium uptake transporter, Amt1 of 458 aas and 11 TMSs. 62% identical to Amt1 of Pyropia yezoensis (Rhodophyta) which is 483 aas long with 11 TMSs and is induced by nitrogen deficiency (Kakinuma et al. 2016). |
Eukaryota | Rhodophyta | Amt1 of Chondrus crispus (Carrageen Irish moss) (Polymorpha crispa) |
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1.A.11.2.13 | High affinity (~50 mμM) ammonium transporter, Amt1.3 of 498 aas and 10 TMSs (Loqué et al. 2006). The tobacco orthologue, of 464 aas and 10 TMSs, NtAMT1.3, is present in roots and leaves and faciltates NH4+ entry. It is up regulated upon nitrogen starvation (Fan et al. 2017). |
Viridiplantae, Streptophyta | Ant1.3 of Arabidopsis thaliana (Mouse-ear cress) |
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1.A.11.2.14 | Putative ammonia/ammonium transporter of 439 aas and 11 TMSs. |
Viruses | Bamfordvirae, Nucleocytoviricota | NH3 transporter of Ostreococcus tauri virus RT-2011 |
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1.A.11.2.15 | Ammonium transporter 3 of 506 aas and 11 TMSs. Symbiotic cnidarians such as corals and anemones form highly productive and biodiverse coral reef ecosystems in nutrient-poor ocean environments, a phenomenon known as Darwin's paradox (Cui et al. 2023). Using the sea anemone Aiptasia, we show that during symbiosis, the increased availability of glucose and the presence of the algae jointly induce the coordinated up-regulation and relocalization of glucose and ammonium transporters. These molecular responses are critical to support symbiont functioning and organism-wide nitrogen assimilation through glutamine synthetase/glutamate synthase-mediated amino acid biosynthesis (Cui et al. 2023). |
Eukaryota | Metazoa, Cnidaria | Amt of Exaiptasia diaphana |
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1.A.11.2.2 | Ammonia-specific uptake carrier, Amt2. For AMT2 from Arabidopsis thaliana NH4+ is the recruited substrate, but the uncharged form NH3 is conducted. AtAMT2 partially co-localizes with electrogenic AMTs and conducts methylamine with low affinity (Neuhäuser et al., 2009). This may explain the different capacities of AMTs to accumulate ammonium in the plant cell. |
Eukaryota | Viridiplantae, Streptophyta | Amt2 of Arabidopsis thaliana |
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1.A.11.2.3 | High-affinity ammonia/methylammonia transporter, Amt1(Paz-Yepes et al., 2007) | Bacteria | Cyanobacteriota | Amt1 of Synechococcus elongatus sp. PCC7942 (Q93IP6) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.11.2.4 | High-affinity ammonia/methylammonia transporter, LeAMT1;1. The ammonium transporter 1 (AMT1) gene family in tomato (Solanum lycopersicum L.) and individual members of the family exhibit different physiological and expression patterns under drought and salt stress conditions (Filiz and Akbudak 2020). |
Eukaryota | Viridiplantae, Streptophyta | LeAMT1;1 of Lycopersicon esculentum (P58905) |
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1.A.11.2.5 | Ammonium/methyl ammonium uptake permease, AmtB (may need AmtB to concentrate [14C]methyl ammonium (Paz-Yepes et al., 2007)) |
Bacteria | Cyanobacteriota | AmtB of Synechococcus sp CC9311 (Q0IDE4) |
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1.A.11.2.6 | Pollen-specific, plasma membrane, high affinity (17μM) ammonium uptake transporter, Amt1;4 (Yuan et al., 2009) (most similar to 1.A.11.2.1). | Eukaryota | Viridiplantae, Streptophyta | Amt1;4 of Arabidopsis thaliana (Q9SVT8) |
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1.A.11.2.7 | Amt2 NH4+/CH3-NH3+ transporter, subject to allosteric activation by a C-terminal region (Loqué et al., 2009). |
Archaea | Euryarchaeota | Amt2 of Archaeoglobus fulgidus (O28528) |
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1.A.11.2.8 | Amt1;1, a proposed NH4+:H+ sumporter (Ortiz-Ramirez et al., 2011) |
Eukaryota | Viridiplantae, Streptophyta | Amt1;1 of Phaseolus vulgaris (E2CWJ2) |
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1.A.11.2.9 | Eukaryota | Evosea | AmtB of Dictyostelium discoideum |
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1.A.11.3.1 | Low-affinity ammonia transporter, Mep1 (Has a pair of conserved his/glu residues; Boeckstaens et al., 2008) | Eukaryota | Fungi, Ascomycota | Mep1 of Saccharomyces cerevisiae (P40260) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.11.3.2 | High-affinity ammonia transporter and sensor, Mep2 (also an NH4+ sensor) (Javelle et al., 2003a; Rutherford et al., 2008) (has a pair of conserved his/his residues; mutation to his/glu as in Mep1 leads to uncoupling of transport and sensor functions (Boeckstaens et al., 2008)) | Eukaryota | Fungi, Ascomycota | Mep2 of Saccharomyces cerevisiae (P41948) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.11.3.3 | High affinity ammonia/methylamine transporter, Amt1 (may also serve as a sensor) (Javelle et al., 2003b) | Eukaryota | Fungi, Basidiomycota | Amt1 of Hebeloma cylindrosporum (Q8NKD5) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.11.3.4 | Low affinity ammonia transporter, Amt2 (Javelle et al., 2001, 2003b) | Eukaryota | Fungi, Basidiomycota | Amt2 of Hebeloma cylindrosporum (Q96UY0) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.11.3.5 | The Mep2 ammonium transporter 60% identical to the S. cerevisiae Mep2 (1.A.11.3.2). (Distinct residues mediate transport and signaling; Dabas et al., 2009). | Eukaryota | Fungi, Ascomycota | Mep2 of Candida albicans (Q59UP8) |
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1.A.11.4.1 | Rhesus (Rh) type C glycoprotein NH3/NH4+ transporter, RhCG (also called tumor-related protein DRC2) (Bakouh et al., 2004; Worrell et al., 2007). Zidi-Yahiaoui et al. (2009) have described characteristics of the pore/vestibule. The structure is known to 2.1 Å resolution (Gruswitz et al., 2010). Each monomer contains 12 transmembrane helices, one more than in the bacterial homologs. Reconstituted into proteoliposomes, RhCG conducts NH3 to raise the internal pH. Models of the erythrocyte Rh complex based on the RhCG structure suggest that the erythrocytic Rh complex is composed of stochastically assembled heterotrimers of RhAG, RhD, and RhCE (Gruswitz et al., 2010). Rh proteins also transport CO2 (Michenkova et al. 2021). |
Eukaryota | Metazoa, Chordata | RhCG of Homo sapiens (Q9UBD6) |
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1.A.11.4.10 | RH (Rhesus) antigen-related protein, Rhr-1 or Rh1, of 463 aas and 12 TMSs. CeRh1 is abundantly expressed in all developmental stages of C. elegans, with highest levels in adults, whereas CeRh2 shows a differential and much lower expression pattern. It is required for passage throung the late stages of C. elegans embryonic development and hypodermal function (Ji et al. 2006). Transports NH3, NH4+ and CO2 (Michenkova et al. 2021).
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Eukaryota | Metazoa, Nematoda | Rhr-1 of Caenorhabditis elegans |
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1.A.11.4.11 | Rh protein of 478 aas and 11 TMSs. It is a primary contributor to ammonia/ammonium ions and CO2 excretion (Michenkova et al. 2021), and poor expression changes the expression levels of many enzymes (Si et al. 2018). |
Eukaryota | Metazoa, Arthropoda | Rh protein of Portunus trituberculatus (the swimming crab) |
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1.A.11.4.12 | The rhesus protein, Rhp1, of 479 aas and 11 TMSs. Reef-building corals maintain an intracellular photosymbiotic association with dinoflagellate algae. As the algae are hosted inside the symbiosome, all metabolic exchanges must take place across the symbiosome membrane. Thies et al. 2022 established that Acropora yongei Rh (ayRhp1) facilitates transmembrane NH3 and CO2 diffusion, and that it is present in the symbiosome membrane. Furthermore, ayRhp1 abundance in the symbiosome membrane was highest around midday and lowest around midnight. Probably ayRhp1 mediates a symbiosomal NH4+-trapping mechanism that promotes nitrogen delivery to algae during the day - necessary to sustain photosynthesis-and restrict nitrogen delivery at night-to keep the algae under nitrogen limitation (Thies et al. 2022). |
Eukaryota | Metazoa, Cnidaria | Rhp1 of Acropora yongei |
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1.A.11.4.2 | Rhesus (Rh) type B glycoprotein NH3/NH4+ transporter, RhBG (~50% identical to type C) (Lopez et al., 2005; Worrell et al., 2008). Electrogenic NH4+ transport is stimulated by alkaline pH(out) but inhibited by acidic pH(out) (Nakhoul et al., 2010). It is regulated by Wnt/β-catenin signalling, a pathway frequently deregulated in many cancers and associated with tumorigenesis (Merhi et al. 2015). Rh proteins also transport CO2 (Michenkova et al. 2021). Rhesus blood group-associated B glycoprotein (RhBG) initiates downstream signaling and functional responses by activating NFκB (Mishra et al. 2024). RhBG interacts with myeloid differentiation primary response-88 (MyD88) to initiate an intracellular signaling cascade that culminates in activation of NFκB (Mishra et al. 2024). The conserved cytosolic J-domain of the RhBG protein interacts with the Toll-interleukin-1 receptor (TIR) domain of MyD88. Decoupling transport and signaling functions apparently occurs. |
Eukaryota | Metazoa, Chordata | RhBG of Homo sapiens (Q9H310) |
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1.A.11.4.3 | Rhesus (Rh) complex (tetramer: RhAG2, RhCE1, RhD1) of 409 aas and 12 TMSs. Exports ammonia from human red blood cells (Conroy et al., 2005). RhAG is also called RH50. RhAG variants (I61R, F65S), associated with overhydrated hereditary stomatocytosis (OHSt), a disease affecting erythrocytes, are alterred for bidirectional ammonium transport (Deschuyteneer et al. 2013). The system transports ammonia, methylammonia, ethylammonia, fluoroethylamine and CO2 Michenkova et al. 2021. 19F-fluoroethylamine has been used to study rapid transport as its NMR spectra are different inside and outside of human red blook cells (Szekely et al. 2006). |
Eukaryota | Metazoa, Chordata | The RhAG/RhCE/RhD, complex of Homo sapiens |
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1.A.11.4.4 | The RH50 NH3 channel (most like human Rh proteins TC# 1.A.11.4.1 and 2; 36-38% identity) (Cherif-Zahar et al., 2007). The Rh CO2 channel protein (3-D structure ± CO2 available) (3B9Z_A; 3B9Y_A) (Li et al., 2007; Lupo et al., 2007) (also transports methyl ammonia) (Weidinger et al., 2007). |
Bacteria | Pseudomonadota | RH50 of Nitrosomonas europaea (Q82X47)
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1.A.11.4.5 | Kidney rhesus glycoprotein p2 (Rhp 2). Transports NH3, methylammonium and CO2 (Nakada et al., 2010; Michenkova et al. 2021). |
Eukaryota | Metazoa, Chordata | Rhp2 of Triakis scyllium (D0VX38) |
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1.A.11.4.6 |
Rhesus-like glycoprotein A (Rh50-like protein RhgA). Transports NH3 and CO2 (Michenkova et al. 2021). |
Eukaryota | Evosea | RhgA of Dictyostelium discoideum |
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1.A.11.4.7 | Ammonium/ammonia/CO2 transporter of 391 aas and 12 TMSs (Michenkova et al. 2021). Shows limited seqences similarity with 9.B.124.1.7 (e-5) (residues 1-5 align with residues 4 - 8 in 9.B.124.1.7). |
Bacteria | Bacillota | Ammonium transporter of [Clostridium] papyrosolvens |
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1.A.11.4.8 | NH3 (NH4+) and CO2 transporting Rhesus glycoprotein, Rhag, of 437 aas and 11 TMSs. Induced by ammonia exposure in the apical membrane of gill epithelia (Chen et al. 2017). |
Eukaryota | Metazoa, Chordata | Rhag of Anabas testudineus (climbing perch) |
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1.A.11.4.9 | NH3 (NH4+)/CO2 transporting Rhesus glycoprotein, Rhcg2, of 482 aas and 11 TMSs. Induced by ammonia exposure in the basolateral membrane of gill epithelia (Chen et al. 2017; Michenkova et al. 2021). |
Bacteria | Metazoa, Chordata | Rhcg2 of Anabas testudineus (climbing perch) |
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1.A.110.1.1 | OTOP1 of 600 aas and 12 TMSs in a 5 + 5 + 2 arrangement. OTOP1 is a pH-sensitive proton-selective ion channel enriched in acid-detecting taste receptor cells and is required for their zinc-sensitive proton conductance (Tu et al. 2018). Two related murine genes, Otop2 and Otop3, and a Drosophila ortholog also encode proton channels. Evolutionary conservation of the gene family and its widespread tissue distribution suggest a broad role for proton channels in physiology and pathophysiology (Tu et al. 2018). Structural motifs for subtype-specific pH-sensitive gating of vertebrate otopetrin proton channels have been analyzed (Teng et al. 2022). Gating elements for carvacrol activation of the OTOP1 proton channel have been examined (Hu et al. 2024). Carvacrol selectively activates mOTOP1, while mOTOP2, mOTOP3, and Chelonia mydas OTOP1 (CmOTOP1) are insensitive to carvacrol activation at neutral pH. Through chimera and point mutation experiments, swapping S134 in transmembrane segment 3 (TMS3) and T247 in the TM56 linker abolished carvacrol activation of mOTOP1 and conferred activation on CmOTOP1. Thus, these two residues are critical for carvacrol sensitivity. Thus, TMS3 and the TMS5-6 linker are pivotal gating residues of OTOP1 channels and potential docking sites for drug design (Hu et al. 2024). |
Eukaryota | Metazoa, Chordata | OTOP1 of Mus musculus |
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1.A.110.1.10 | Otop3 of 600 aas and 12 TMSs in a 5 + 5 + 2 TMS arrangement. The high resolution 3-d structure has been determined by cryoEM (Saotome et al. 2019) (see family description). Applications of solution NMR for studying structure, dynamics, and interactions of polytopic integral membrane proteins have been reviewed (Danmaliki and Hwang 2020). |
Eukaryota | Metazoa, Chordata | Otop3 of Gallus gallus (chicken) |
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1.A.110.1.2 | OTOP1 H+ channel of 612 aas and 10 TMSs in an apparent 4 + 4 + 2 TMS arrangement (Tu et al. 2018). OTOP1 is a protein required for development of gravity-sensing otoconia in the vestibular system. It forms a proton-selective ion channel (Tu et al. 2018). Proton channel activity is only weakly-sensitive to voltage and is probably required in cell types that use changes in intracellular pH for cell signaling or to regulate biochemical or developmental processes (Tu et al. 2018). In the vestibular system of the inner ear, it is required for the formation and function of otoconia, calcium carbonate crystals that sense gravity and acceleration. It regulates purinergic control of intracellular calcium in vestibular supporting cells and may be involved in sour taste perception in sour taste cells by mediating entry of protons within the cytosol. It is also involved in energy metabolism, by reducing adipose tissue inflammation and protecting from obesity-induced metabolic dysfunction. Two extracellular loops in the human Otop1 proton channel function in proton sensing and transport (Li et al. 2022). OTOP1 is N-glycosylated on two asparagine residues in the third extracellular loop. Glycosylation is necessary for OTOP1 to show the maximal degree of H+ current densities at the plasma membrane through promoting its targeting to the plasma membrane. (Sasaki et al. 2024). |
Eukaryota | Metazoa, Chordata | OTOP1 of Homo sapiens |
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1.A.110.1.3 | OTOP2 H+ channel of 562 aas and 10 TMSs in a 5 + 5 + 2 arrangement (Tu et al. 2018). |
Eukaryota | Metazoa, Chordata | OTOP2 of Homo sapiens |
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1.A.110.1.4 | OTOP3 of 596 aas and 10 TMSs in a 5 + 5 + 2 TMS arrangement (Tu et al. 2018). |
Eukaryota | Metazoa, Chordata | OTOP3 of Homo sapiens |
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1.A.110.1.5 | Zinc-sensitive proton channel, OTOP1, of 586 aas and 10 TMSs in a 5 + 5 + 2 TMS arrangement (Tu et al. 2018). It inhibits P2Y purinoceptors and modulates calcium homeostasis and influx of calcium in response to extracellular ATP. It is essential for the formation of otoliths in the inner ear of developing larvae and for the perception of gravity and acceleration (Söllner et al. 2004; Hughes et al. 2004). The 3-d structure has been determined by cryoEM (Saotome et al. 2019) (see family description). Mutations in the Otopetrin 1 gene in mice and fish produce an unusual bilateral vestibular pathology that involves the absence of otoconia without hearing impairment (Hurle et al. 2011). |
Eukaryota | Metazoa, Chordata | OTOP1 of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.A.110.1.6 | OtoPetrin-like (Otpl6) of 581 aas and 12 TMSs. |
Eukaryota | Metazoa, Nematoda | Otpl6 of Caenorhabditis elegans |
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1.A.110.1.7 | OToPetrin-like protein, isoform D, of 647 aas and 12 or 13 TMSs in a 5 +7 or 8 TMS arrangement. |
Eukaryota | Metazoa, Arthropoda | OTOP, isoform D of Drosophila melanogaster (Fruit fly) |
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1.A.110.1.8 | Putative otopetrin of 747 aas and 11 or 12 TMSs in a 1 + 3 + 7 or 8 TMS arrangement. |
Eukaryota | Metazoa, Platyhelminthes | Putative Otop protein of Schistosoma mansoni (Blood fluke) |
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1.A.110.1.9 | The OTOP3 protopn channel protein of 681 aas and 12 TMSs. The cryo-EM structure along with functional characteristics have been described (Chen et al. 2019). XtOTOP3 forms a homodimer with each subunit containing 12 transmembrane helices that can be divided into two structurally homologous halves; each half assembles as an alpha-helical barrel that could serve as a proton conduction pore. |
Eukaryota | Metazoa, Chordata | OTOP3 of Xenopus tropicalis |
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1.A.111.1.1 | The MTGM protein of 79 aas and 2 TMSs, a member of the Romo1 family (Zhao et al. 2009). |
Eukaryota | Metazoa, Chordata | MTGM of Homo sapiens |
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1.A.111.1.2 | MRTM homologue of 108 aas and 2 TMSs. |
Eukaryota | Fungi, Ascomycota | MTGM of Aspergillus niger |
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1.A.111.1.3 | MTGM homologue of 113 aas and 2 TMSs. |
Eukaryota | Fungi, Ascomycota | MTGM homologue of Saccharomyces cerevisiae |
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1.A.111.1.4 | MTGM homologue of 74 aas |
Eukaryota | Viridiplantae, Streptophyta | MTGM of Glycine max |
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1.A.111.1.5 | Reactive oxygen species modulator 1 homologue, Romo1 family member of 128 aas. |
Eukaryota | Evosea | Romo1 of Dictyostelium discoideum |
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1.A.111.1.6 | MTGM protein of 80 aas. |
Eukaryota | Rhodophyta | MTGM of Galdieria sulfuraria |
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1.A.111.1.7 | MTGM homologue of 149 aas |
Eukaryota | Ciliophora | MTGM homologue of Tetrahymena thermophius |
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1.A.111.1.8 | Uncharacterized protein of 165 aas and 2 TMSs. |
Eukaryota | Apicomplexa | UP of Theileria annulata |
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1.A.111.1.9 | Uucharacterized putative reactive oxygen species modulator 1 protein of 168 aas and 2 C-terminal TMSs. |
Eukaryota | Apicomplexa | UP of Plasmodium falciparum |
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1.A.112.1.1 | Kidney metal (Mg2+) transporter, Cyclin (CNN) M2 isoform CRA_b (CNNM2). Defects cause hypomagnesemia. It has an extracellular N-terminus, an N-terminal TMS, a hydrophilic domain followed by 4 TMSs, another hydrophilic domain, and an intracellular C-terminus (de Baaij et al., 2012). CNNM2a forms heterodimers with the smaller isoform CNNM2b. The human splice variant 1 of CNNM2 (ACDP2; Q9H8M5) is a Mg2+ transporter (Brandao et al. 2012). The Bateman module is involved in AMP binding and Mg2+ sensing, and their binding causes a conformational change in the CBS module, transmitted to the transmembrane domain (Corral-Rodríguez et al. 2014). It may be able to transport divalent metal cations, Mg2+, Co2+, Mn2+, Sr2+, Ba2+, Cu2+, Fe2+ and monvalent cation, Na+. In prokaryotes, homologs are CorB/C. |
Eukaryota | Metazoa, Chordata | Cyclin M2, CNNM2, of Mus musculus (Q3TWN3) |
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1.A.112.1.2 | Metal transporter CNNM3 (Ancient conserved domain-containing protein 3) (mACDP3) (Cyclin-M3) of 713 aas and probably 5 TMSs with one N-terminal, and four together in the first half of the protein (Chen et al. 2018). See the family description for the domain order of the CNNM proteins. |
Eukaryota | Metazoa, Chordata | CNNM3 of Mus musculus |
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1.A.112.1.3 | Metal transporter CNNM3 (Ancient conserved domain-containing protein 3) (Cyclin-M3). As of 2018, the function of this protein as a Mg2+ transporter is under debate (Schäffers et al. 2018). |
Eukaryota | Metazoa, Chordata | CNNM3 of Homo sapiens |
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1.A.112.1.4 | Metal transporter CNNM4 (Ancient conserved domain-containing protein 4) (Cyclin-M4). As of 2018, the function of this protein as a Mg2+ transporter was under debate (Schäffers et al. 2018). |
Eukaryota | Metazoa, Chordata | CNNM4 of Homo sapiens |
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1.A.112.1.5 | Mg2+ exporter of 951 aas and 5 TMSs in a 1 + 4 TMS arrangement, CNNM1 (Chen et al. 2018). |
Eukaryota | Metazoa, Chordata | CNNM1 of Homo sapiens |
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1.A.112.1.6 | Putative Mg2+ exporter of 875 aas and 5 TMSs, CNNM2 or ACDP2 (Chen et al. 2018). The bacterial CorC is involved in resistance to antibiotic exposure and to the survival of pathogenic microorganisms in their host environments. CorC possesses a cytoplasmic region containing the (regulatory ?) ATP-binding site (Huang et al. 2021). An inhibitor, IGN95a, targets the ATP-binding site and blocks both ATP binding and Mg2+ export. The cytoplasmic domain structure in complex with IGN95a was determined (Huang et al. 2021). With ATP bound to the cytoplasmic domain, the conformational equilibrium of CorC shifts toward the inward-facing state of the transmembrane domain (Huang et al. 2021). These considerations suggest that CorC may be an ATP-driven Mg2+ efflux porter, and if so, the family belongs in TC sub-class, 3.A. CorC homologs may be able to export Mg2+, Co2+, Mn2+, Sr2+, Ba2+, Cu2+ and Fe2+. |
Eukaryota | Metazoa, Chordata | CNNM2 of Homo sapiens |
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1.A.112.1.7 | Uncharacterized protein of 734 aas and 5 N-terminal TMSs. |
Eukaryota | Euglenozoa | UP of Trypanosoma cruzi |
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1.A.112.1.8 | CNNM Mg2+ transport protein of 494 aas and 5 TMSs in a 1 + 4 TMS arrangement. It has a CNNM domain (residues 1 - 220) and three CBS domains, CBS1, 2, and 3 (residues 230 - 425). |
Eukaryota | Viridiplantae, Streptophyta | CNNM Mg2+ transporter of Arabidopsis thaliana |
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1.A.112.1.9 | CNNM putative Mg2+ transport channel of 527 aas with 5 TMSs. The hydrophobic CNNM domain is N-terminal followed by 3 CBS domains. |
Eukaryota | Viridiplantae, Streptophyta | CNNM of Arabidopsis thaliana |
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1.A.112.2.1 | Uncharacterized protein of 384 aas and 4 TMSs. The region of sequence similarity with established CorC proteins is in a hydrophilic region following the TMSs, putting into question the assignment of this protein to family 9.A.40. The N-terminal domain of 100 aas and 2 TMSs does not show sequence similarity with anything outside of the Candidatus Saccharibacteria bacteria. |
Bacteria | Candidatus Saccharibacteria | UP of Candidatus Saccharibacteria bacterium |
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1.A.112.2.10 | Magnesium and cobalt efflux protein, CorC or MpfA (Magnesium Protection Factor A) of 449 aas and 4 N-terminal TMSs, apparently in a 2 + 2 TMS arrangement. Evidence has been presented that this protein catalyzes active Mg2+ extrusion from the cell (Armitano et al. 2016). If so, It must be an active transporter, either a secondary carrier (TC subclass 2.A) or an ATP hydrolysis-driven exporter (TC subclass 3.A). |
Bacteria | Bacillota | MpfA of Staphylococcus aureus |
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1.A.112.2.11 | PaeA, YtfL, UPF0053 inner membrane protein, Duf21 domain containing protein, HlyC/CorC family transporter, hemolysin homolog of 447 aas and 4 N-terminal TMSs (residues 1 - 200) followed by a large hydrophilic domain (cystathionine beta-synthase, CBS, residues 201 - 447), possibly with a single TMS at about residue 320. It transports cadaverine and putrescine. In fact, Salmonella, Klebsiella pneumoniae (TC# 1.A.112.1.12) and E. coli synthesize, import, and export cadaverine, putrescine, and spermidine to maintain physiological levels of polyamines and provide pH homeostasis. Both low and high intracellular levels of polyamines confer pleiotropic phenotypes or lethality. Iwadate et al. 2021 demonstrated that PaeA (YtfL) is required for reducing cytoplasmic cadaverine and putrescine concentrations. PaeA is involved in stationary phase survival when cells are grown in acidic medium in which they produce cadaverine. The paeA mutant is sensitive to putrescine, but not spermidine or spermine. Sensitivity to external cadaverine in stationary phase is only observed at pH > 8, suggesting that the polyamines need to be deprotonated to passively diffuse into the cell. In the absence of PaeA, intracellular polyamine levels increase and the cells lose viability. Ectopic expression of the known cadaverine exporter, CadB, in stationary phase partially suppresses the paeA mutant phenotype, and overexpression of paeA in exponential phase partially complements a cadB mutant grown in acidic medium. Thus, PaeA is a cadaverine/putrescine exporter, reducing potentially toxic levels under certain stress conditions (Iwadate et al. 2021). |
Bacteria | Pseudomonadota | PaeA of E. coli |
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1.A.112.2.12 | YtfA, DUF21 domain-containing protein, HlyC/CorC family transporter, magnesium and cobalt efflux protein CorC_2 or CorC_3, of 445 aas and 4 N-terminal TMSs plus a large hydrophilic domain as the C-terminal 250 residues. Based on the E. coli ortholog, it probably transports putrescine and canavanine (Iwadate et al. 2021). Klebsiella pneumoniae is a source of widespread contamination of medical equipment, causing pneumonia as well as other multiorgan metastatic infections. During K. pneumoniae infections of lung epithelia, microtubules are severed and then eliminated, and YtfA plays a role, probably by secreting a relevant compound (Chua et al. 2019). |
Bacteria | Pseudomonadota | YtfL of Klebsiella pneumoniae |
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1.A.112.2.13 | CorB (CNNM) has been structurally ellicidated. Chen et al. 2021 determined the crystal structure of an archaeal CorB protein in two conformations (apo and Mg2+-ATP bound). The transmembrane DUF21 domain exists in an inward-facing conformation with a Mg2+ ion coordinated by a conserved pi-helix. In the absence of Mg2+-ATP, the CBS-pair domain adopts an elongated dimeric configuration with previously unobserved domain-domain contacts. A role of the structural rearrangements in mediating Mg2+-ATP sensing was suggested. An in vitro, liposome-based assay was used to demonstrate direct Mg2+ transport by CorB proteins (Chen et al. 2021). CNNM2 and CNNM4 are found abundantly in the basolateral membrane of kidney and colon epithelial cells, where renal/intestinal (re)absorption of Mg2+ occurs. In humans, mutations in CNNM proteins are linked to two genetic diseases: CNNM2 mutations cause hypomagnesemia while mutations in CNNM4 are associated with Jalili syndrome. CNNM2-knockout mice are embryonic lethal, while loss of CNNM4 leads to male infertility and susceptibility to cancer. CNNMs are additionally implicated in hypertension, non-alcoholic steatohepatitis, and schizophrenia (Chen et al. 2021). CorB was proposed to mediate Mg2+ efflux together with CorC and CorD, in which CorC is a soluble protein that shares high sequence similarity to the cytosolic domains of CorB. Subsequently, many other CorB orthologs have been implicated in Mg2+ transport. For example, the Staphylococcus aureus ortholog, MpfA, is thought to function as a Mg2+ exporter as deletion mutants are unable to grow in the presence of high concentrations of magnesium. Disruption of the homologous gene (yhdP) in Bacillus subtilis leads to increased cellular Mg2+ content, again supporting a role in Mg2+ efflux (Chen et al. 2021). MtCorB from a thermophilic archaeon (Methanoculleus thermophilus) has been crystalized and structurally illucidated (Chen et al. 2021). |
Archaea | Methanobacteriati, Methanobacteriota | CorB of Methanoculleus thermophilus |
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1.A.112.2.2 | CNNM (Mg2+ transporter) protein of 434 aas with an N-terminal 4 TMSs, equispaced, large small, large small peaks of hydrophobicity, YrkA (Chen and Gehring 2023). |
Bacteria | Bacillota | YrkA of Bacillus subtilis (Q45494) |
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1.A.112.2.3 | Probable Mg2+ exporter of 452 aas. It does not exhibit hemolysin activity (Sałamaszyńska-Guz and Klimuszko 2008). |
Bacteria | Campylobacterota | TylC-like protein of Campylobacter jejuni |
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1.A.112.2.4 | Uncharacterized protein of 444 aas and 4 TMSs, YhdP. Mutations in yhdP increase the activity of sigmaW (Turner and Helmann 2000). |
Bacteria | Bacillota | YhdP of Bacillus subtilis |
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1.A.112.2.5 | CorC homologue, YfjD or YpjE, of 428 aas and 4 TMSs in a 1 + 3 TMS arrangement at the N-terminus of the protein. This hydrophobic region is followed by a larger hydrophilic domain. It is encoded within a two gene operon with YpjD (CorE), a putative cytochrome c assembly protein of 8 or 9 TMSs (P64432; TC# 9.B.14.3.6) (Huang et al. 2021). |
Bacteria | Pseudomonadota | YfjD of E. coli |
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1.A.112.2.6 | Uncharacterized CorC protein of 327 aas and 3 N-terminal TMSs. The region of sequence similarity with HlyC proteins (TC# 1.C.126) is in a hydrophilic C-terminal region following the TMSs. |
Bacteria | Candidatus Saccharibacteria | UP of Candidatus Saccharibacteria bacterium |
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1.A.112.2.7 | Mg2+ and Co2+ transporter, CorB, of 413 aas and 3 TMSs. It contains DUF21, CBS pair, and CorC-HlyC domainsin succession. |
Bacteria | Pseudomonadota | CorB of Pseudomonas bauzanensis |
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1.A.112.2.8 | HlyC/CorC family transporter of 354 aas and 4 TMSs. |
Bacteria | Actinomycetota | CorC domain protein of Micromonospora peucetia |
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1.A.112.2.9 | Uncharacterized protein of 329 aas and 4 TMSs. |
Bacteria | Verrucomicrobiota | UP of Verrucomicrobia bacterium |
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1.A.113.1.1 | The small integral membrane protein 22 of 81 aas and 1 TM |
Eukaryota | Metazoa, Chordata | Small integral membrane protein 22 of Stegastes partitus |
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1.A.113.1.2 | Small integral membrane protein 5 isoform X1 of 119 aas and 1 TM |
Eukaryota | Metazoa, Chordata | Small integral membrane protein 5 isoform X1 of Anolis carolinensis |
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1.A.113.1.3 | ELN homologue of unknown function with 158 aas and 2 TMSs |
Eukaryota | Metazoa, Chordata | ELN homologue of Alligator mississippiensis (American alligator) |
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1.A.113.1.4 | Small integral membrane DUF4713 protein 22 of 83 aas and 1 TMS |
Eukaryota | Metazoa, Chordata | Small membrane protein-22 of Sorex araneus |
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1.A.113.1.5 | Small integral membrane protein 18 of 111 aas and 1 TMS |
Eukaryota | Metazoa, Chordata | Protein 18 of Phascolarctos cinereus |
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1.A.113.2.1 | Uncharacterized protein of 112 aas and 1 TMS. |
Eukaryota | Metazoa, Chordata | UP of Scleropages formosus (Asian bonytongue) |
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1.A.113.2.2 | Uncharacterized protein of 112 aas and 1 TMS. |
Eukaryota | Metazoa, Chordata | UP of Empidonax traillii |
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1.A.113.2.3 | Uncharacterized protein of 108 aas and 1 TMS. |
Eukaryota | Metazoa, Chordata | UP of Electrophorus electricus (Electric eel) (Gymnotus electricus) |
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1.A.113.3.1 | Uncharacterized protein of 109 aas and 1 TMS. |
Eukaryota | Metazoa, Arthropoda | UP of Apis mellifera |
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1.A.113.3.2 | Uncharacterized protein of 77 aas and 1 TMS. |
Eukaryota | Metazoa, Arthropoda | UP of Anopheles gambiae (African malaria mosquito) |
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1.A.113.3.3 | Uncharacterized protein of 84 aas and 1 TMS. |
Eukaryota | Metazoa, Arthropoda | UP of Harpegnathos saltator (Jerdon's jumping ant) |
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1.A.113.3.4 | Uncharacterized protein of 81 aas and 1 TMS |
Eukaryota | Metazoa, Arthropoda | UP of Helicoverpa armigera |
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1.A.113.3.5 | Uncharacterized protein of 97 aas and 1 TMS |
Eukaryota | Metazoa, Arthropoda | UP of Nasonia vitripennis (Parasitic wasp) |
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1.A.113.3.6 | Uncharacteerized protein of 84 aas and 1 TMS |
Eukaryota | Metazoa, Arthropoda | UP of Nicrophorus vespilloides (Boreal carrion beetle) |
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1.A.113.3.7 | Uncharacterized protein of 87 aas and 1 TMS |
Eukaryota | Metazoa, Arthropoda | UP of Laodelphax striatella (small brown planthopper) |
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1.A.113.3.8 | Uncharacterized protein of 192 aas and 2 putative TMSs. |
Eukaryota | Metazoa, Arthropoda | UP of Folsomia candida (Springtail) |
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1.A.113.5.1 | Endoregulin, ELN, also called small integral membrane protein-6, SMIM6, is of 62 aas and 1 TMS. This protein and the other members of the phospholamban family have been designated "micropeptides". Micropeptides function as regulators of calcium-dependent signaling in muscle. The sarco/endoplasmic reticulum Ca2+ ATPase (SERCA TC# 3.A.3.2.7), is the membrane pump that promotes muscle relaxation by taking up Ca2+ into the sarcoplasmic reticulum. It is directly inhibited by three known muscle-specific micropeptides: myoregulin (MLN), phospholamban (PLN) and sarcolipin (SLN). In non muscle cells, there are two other such micopeptides, endoregulin (ELN) and "another-regulin (ALN) (Anderson et al. 2016). Endoregulin is also known as "small integral membrane protein-6" (SMIM6) while ALN is also known as Protein C4 orf3 (C4orf3). These proteins share key amino acids with their muscle-specific counterparts and function as direct inhibitors of SERCA pump activity. The distribution of transcripts encoding ELN and ALN mirrored that of SERCA isoform-encoding transcripts in nonmuscle cell types. Thus, these two proteins are additional members of the SERCA-inhibitory micropeptide family, revealing a conserved mechanism for the control of intracellular Ca2+ dynamics in both muscle and nonmuscle cell types (Anderson et al. 2016). |
Eukaryota | Metazoa, Chordata | Endoregulin of Homo sapiens |
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1.A.113.5.2 | ELN homologue of 78 aas and 1 TMS. |
Eukaryota | Metazoa, Chordata | ELN homologue of Nothobranchius furzeri |
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1.A.113.5.3 | ELN homologue of 75 aas and 1 TMS. |
Eukaryota | Metazoa, Chordata | ELN of Larimichthys crocea (large yellow croaker) |
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1.A.113.5.4 | Bacterial ELN homologue of unknown function with 101 aas and 1 TMS |
Bacteria | Thermodesulfobacteriota | ELN homologue of Desulfobacteraceae bacterium |
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1.A.113.5.5 | ELN homologue of 85 aas and 1 TMS |
Bacteria | Thermotogota | ELN homologue of Thermotoga sp. |
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1.A.113.5.6 | Small integral membrane protein 6 of 56 aas and 1 TMS, ELN. |
Eukaryota | Metazoa, Chordata | ELN of Mus musculus |
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1.A.114.1.1 | Plasma membrane proton-activated chloride channel, PACC1, or acid-sensitive outwardly-rectifying anion channel PAORAC/ASOR or TMEM206, of 350 aas and 2 TMSs. Ion permeation-changing mutations along the length of TMS2 and at the end of TMS1 suggest that these segments line the pore. TMEM206 probably has orthologs in all vertebrates (Ullrich et al. 2019). Knockout of mouse Pac abolished I Cl,H in neurons and attenuated brain damage after ischemic stroke (Yang et al. 2019). The cryoEM structure (3.1 Å resolution) in active and desensitized states has been determined (Wang et al. 2022). The acid-sensitive site critical for chloral hydrate activation of the proton-activated chloride channel has been identified (Xu et al. 2022). The molecular mechanism underlying desensitization of the proton-activated chloride channel, PAC, has been examined (Osei-Owusu et al. 2022). PACC1 increases endplate porosity and pain in a mouse spine degeneration model (Xue et al. 2024). |
Eukaryota | Metazoa, Chordata | PACC1 of Homo sapiens |
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1.A.114.1.2 | Proton-activated chloride channel of 298 aas and 2 TMSs. It mediates import of chloride ion in response to extracellular acidic pH (Yang et al. 2019) and displays channel activity with kinetic properties distinct from that of the human ortholog. |
Eukaryota | Metazoa, Chordata | TMEM206 of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.A.114.1.3 | TMEM206 of 469 aas and 2 TMSs |
Eukaryota | Metazoa, Porifera | TMEM206 of Amphimedon queenslandica |
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1.A.114.1.4 | TMEM206-like protein of 382 aas and 2 TMSs. |
Eukaryota | Metazoa, Hemichordata | TMEM206 of Saccoglossus kowalevskii |
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1.A.114.1.5 | TMEM206 of 254 aas and 2 TMSs. |
Eukaryota | Metazoa, Chordata | TMEM206 of Callorhinchus milii |
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1.A.114.1.6 | Proton-activated chloride channel of 351 aas and 2 TMSs near the N- and C-termini. TMEM206 is an evolutionarily conserved chloride channel that underlies ubiquitously expressed, proton-activated, outwardly rectifying, anion currents. Deng et al. 2021 reported the cryo-EM structure of pufferfish TMEM206, which forms a trimeric channel, with 6 TMSs, 2 per subunit, each with a large extracellular domain. An ample vestibule in the extracellular region is accessible laterally from the three side portals. The central pore contains multiple constrictions; a conserved lysine residue near the cytoplasmic end of the inner helix forms the presumed chloride ion selectivity filter. The core structure and assembly closely resemble those of the epithelial sodium channel/degenerin family of sodium channels that seem to be unrelated in amino acid sequence and conduct cations instead of anions. Together with electrophysiology, this structure provides insights into ion conduction and gating for these chloride channels (Deng et al. 2021). |
Eukaryota | Metazoa, Chordata | TMEM206 of Tetraodon nigroviridis (Spotted green pufferfish) (Chelonodon nigroviridis) |
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1.A.115.1.1 | The outer mitochondrial membrane pore-forming NADPH-dependent 1-acyldihydroxyacetone phosphate reductase, Ayr1. Unlike most outer membrane porins, Ayr1 consists of α-helicies rather than β-strands (Krüger et al. 2017). |
Eukaryota | Fungi, Ascomycota | Ayr1 of Saccharomyces cerevisiae |
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1.A.115.1.2 | NAD-binding protein of 261 aas and 1 TM |
Archaea | Euryarchaeota | NAD BP of Euryarchaeota archaeon |
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1.A.115.1.3 | SDR family of NAD(P)-dependent oxidoreductases of 287 aas and 0 TM |
Bacteria | Actinomycetota | SDR family protein of Allonocardiopsis opalescens |
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1.A.115.1.4 | Uncharacterized protein of 188 aas and 3 putative TMSs. |
Eukaryota | Fungi, Ascomycota | UP of Botrytis elliptica |
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1.A.115.1.5 | SDR family oxidoreductase of 250 aas and 1 TM |
Bacteria | Pseudomonadota | SDR family protein of Pseudomonas abietaniphila |
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1.A.116.1.1 | Pore-forming envelope viroporin protein, GP2b, of 70 aas and 1 (or 2) TMSs. See family description for deetails (Lee and Yoo 2006). |
Viruses | Orthornavirae, Pisuviricota | Viroporin of Porcine reproductive and respiratory syndrome virus (PRRSV) |
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1.A.116.1.2 | E (envelope) protein of 80 aas and 1 TMS. |
Viruses | Orthornavirae, Pisuviricota | E protein of Kibale red colobus virus 1 |
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1.A.116.1.3 | ORF2b of 70 aas and 1 TMS |
Viruses | Orthornavirae, Pisuviricota | ORF2b of Rodent arterivirus |
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1.A.116.1.4 | E protein of 74 aas and 1 TMS |
Viruses | Orthornavirae, Pisuviricota | E protein of African pouched rat arterivirus |
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1.A.116.1.5 | E protein of 76 aas and 1 TM |
Viruses | Orthornavirae, Pisuviricota | E protein of Mikumi yellow baboon virus 1 |
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1.A.116.1.6 | GP2a protein of 67 aas and 1 TMS. It may function as a viroporin in the virion envelope that facilitates uncoating of the virus in order to release the genomic RNA into the cytoplasm for subsequent replication. |
Viruses | Orthornavirae, Pisuviricota | GP2a protein of Equine arteritis virus (strain Bucyrus) (EAV) |
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1.A.116.1.7 | ORF4a of 79 aas and 1 TMS. |
Viruses | Orthornavirae, Pisuviricota | ORF4a of Simian hemorrhagic fever virus |
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1.A.117.1.1 | Matrix (M)-protein (putative viroporin) of 217 aas with 3 closely spaced TMSs in the N-terminal half of the protein. |
Viruses | Orthornavirae, Pisuviricota | M-protein of Guangdong chinese water skink coronavirus |
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1.A.117.1.2 | Membrane glycoprotein of 222 aas and 3 or 4 TMSs. It is a component of the viral envelope that plays a central role in virus morphogenesis and assembly via its interactions with other viral proteins. However, it may also function a viroporin, Orf3a (Barrantes 2021). Variants of the M protein arise with high frequency, suggesting that these mutants are more biologically fit, perhaps related to glucose uptake during viral replication (Shen et al. 2021). Zhang et al. 2022 reported the cryo-EM structure of the SARS-CoV-2 M protein in two different conformations. M protein forms a mushroom-shaped dimer, composed of two transmembrane domain-swapped three-helix bundles and two intravirion domains. It also assembles into higher-order oligomers. A highly conserved hinge region is key for conformational changes. The M protein dimer is similar to SARS-CoV-2 ORF3a, a viroporin (TC# 1.A.57.1.5). Interaction analyses of M protein with nucleocapsid protein (N) and RNA suggest that the M protein mediates the concerted recruitment of these components through the positively charged intravirion domain (Zhang et al. 2022).
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Viruses | Orthornavirae, Pisuviricota | M-protein of severe acute respiratory syndrome coronavirus 2, SARS CoV2. |
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1.A.117.1.3 | M-protein of 268 aas and 3 N-terminal TMSs |
Viruses | Orthornavirae, Pisuviricota | M protein of Common moorhen coronavirus HKU21 |
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1.A.117.1.4 | Membrane matrix (M) glycoprotein of 261 aas and 3 strongly hydrophobic TMSs in the N-terminal half of the protein, preceded by a single N-terminal TMS (possibly a targetting signal sequence), followed by a relatively hydrophilic C-terminal half that includes 3 weakly hydrophobic peaks that could be transmembrane but probably are not. These properties are characteristic of many but not all of the members of this family, including members of both sub-families, 1.A.57.1 and 1.A. 57.2. |
Viruses | Orthornavirae, Pisuviricota | M-protein of the transmissible gastroenteritis virus (TGEV) |
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1.A.117.1.5 | Matrix (M) protein of 219 aas and 3 N-terminal TMSs. |
Viruses | Orthornavirae, Pisuviricota | M protein (MERS) of betacoronavirus England 1 |
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1.A.117.1.6 | Membrane (M)-protein of 275 aas and 3 (+ 2 or 3 possible) TMSs |
Viruses | Orthornavirae, Pisuviricota | M-protein of Bottlenose dolphin coronavirus |
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1.A.117.1.7 | M-protein, or "M" of 225 aas and 3 TMSs. It is a component of the viral envelope that plays a central role in virus morphogenesis and assembly via its interactions with other viral proteins. |
Eukaryota | Orthornavirae, Pisuviricota | M of Avian infectious bronchitis virus (strain DE072) (IBV) |
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1.A.118.1.1 | Cyclotide, kalata-B1, kB1. Targets membranes in a process that depends on lipid interactions; hemolytic; can disrupt HIV membranes (Henriques et al., 2011). |
Eukaryota | Viridiplantae, Streptophyta | Kalata-B1 of Oldenlandia affinis (P56254) |
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1.A.118.1.2 | Cyclotide, Cycloviolacin O8 |
Eukaryota | Viridiplantae, Streptophyta | Cycloviolacin O8 of Viola odovata (P58440) |
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1.A.118.1.3 | The Varv peptide A/Kalata-B1 |
Eukaryota | Viridiplantae, Streptophyta | Varv of Viola odorata (Q5USN7) |
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1.A.118.1.4 | Cyclotide Oak6 |
Eukaryota | Viridiplantae, Streptophyta | Oak6 of Oldenlandia affinis (D8WS37) |
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1.A.119.1.1 | The drought stress-inducible putative membrane protein, TMPIT1 |
Eukaryota | Viridiplantae, Streptophyta | TMPIT1 of Triticum dicoccoides (G0ZL54) |
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1.A.119.1.10 | Uncharacterized protein of 124 aas and 2 TMSs. This could be a fragment. |
Archaea | UP of an archaeon (phyllosphere metagenome) |
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1.A.119.1.11 | Uncharacterized protein of 409 aas and 7 TMSs. |
Eukaryota | Viridiplantae, Chlorophyta | UP of Chlorella variabilis |
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1.A.119.1.12 | Uncharacterized protein of 325 aas and 5 TMSs in a 2 + 1 + 2 TMS arrangement. |
Eukaryota | Rhizaria | UP of Reticulomyxa filosa |
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1.A.119.1.2 | The TMEM120A or TACAN protein of 343 aas and 7 TMSs. It may function in adipogenesis (Batrakou et al. 2015). TACAN is reported to be a Ca2+-transporting ion channel involved in sensing mechanical pain. It is expressed in a subset of nociceptors in humans, and its heterologous expression increases mechanically evoked currents in cell lines. Purification and reconstitution of TACAN in synthetic lipids generates a functional ion channel that transports Ca2+ (Beaulieu-Laroche et al. 2020). However, Niu et al. 2021 failed to detect the proposed mechanosensitive ion channel activity of TACAN. Using membrane reconstitution methods, they found that TACAN, at high protein concentrations, produces heterogeneous conduction levels that are not mechanosensitive and are most consistent with disruptions of the lipid bilayer. They determined the structure of TACAN using single-particle cryo-EM and observed that it is a symmetrical dimeric transmembrane protein. Each protomer contains an intracellular-facing cleft with a coenzyme A cofactor, confirmed by mass spectrometry. The TACAN protomer is related in three-dimensional structure to a fatty acid elongase, ELOVL7. Thus, TACAN may not be a mechanosensitive ion channel. It may not mediate poking- or stretch-induced channel activities (Rong et al. 2021; Xue et al. 2021). TMEM120A genome organisation functions affect many adipose functions, and its loss may yield adiposity spectrum disorders, including an miRNA-based mechanism that could explain muscle hypertrophy in human lipodystrophy (Czapiewski et al. 2022). TACAN is an ion channel-like protein that may be involved in sensing mechanical pain. Chen et al. 2022 presented the cryo-EM structure of human TACAN (hTACAN). It forms a dimer in which each protomer consists of a transmembrane globular domain (TMD) containing six helices and an intracellular domain (ICD) containing two helices. Molecular dynamic simulations suggest that each protomer contains a putative ion conduction pore. A single-point mutation of the key residue Met207 greatly increases membrane pressure-activated currents, and each hTACAN subunit binds one cholesterol molecule. The wild-type hTACAN may be in a closed state (Chen et al. 2022). TMEM120A can detect mechanical pain stimuli as a mechanosensitive channel, contributes to adipocyte differentiation/functions by regulating genome organization and promotes STING trafficking to active cellular innate immune responses (Qian et al. 2022). These multiple proposed functions of TMEM120A have been reviewed and a molecular mechanism underlying TMEM120A's role in fatty acid metabolism and STING signaling has been proposed (Qian et al. 2022). See also TC# 1.A.5.2.1. TMEM120A/TACAN has been reported to be a regulator of ion channels, mechanosensation, and lipid metabolism (Gabrielle and Rohacs 2023). Its ion transport activity and structure have been examined (Kang and Lee 2024). |
Eukaryota | Metazoa, Chordata | TACAN of Homo sapiens |
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1.A.119.1.3 | TACAN-like protein (homologue) of 199 aas and 7 TMSs |
Eukaryota | Metazoa, Nematoda | TACAN of Arabidopsis thaliana (thale cress) |
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1.A.119.1.4 | Uncharacterized protein of 113 aas and 2 TMSs. This protein corresponds to the last two TMSs in 1.A.119.1.2. It could be a short version of the latter protein, or it could be an incomplete sequence. |
Eukaryota | Metazoa, Platyhelminthes | UP of Schistosoma curassoni |
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1.A.119.1.5 | Uncharacterized protein of 105 aas and 2 TMSs. This protein corresponds to the last two TMSs of the protein listed under TC# 1.A.119.1.2. It could be a short version of the latter protein, or it could be an incomplete sequence. |
Eukaryota | Metazoa, Platyhelminthes | UP of Dibothriocephalus latus |
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1.A.119.1.6 | Uncharacterized protein of 131 aas and 2 TMSs. This protein corresponds to the last two TMSs of the protein with TC# 1.A.119.1.2. It could be a short version of the latter protein, or it could be an incomplete sequence. However, there seem to be multiple versions of this short protein (see TC#s 1.A.119.1.4, 1.5, and 1.6) suggesting that it may be a full-length protein. Also, the two N-terminal TMSs are followed in this protein by a hydrophilic region not present in the other homologues. |
Eukaryota | Metazoa, Nematoda | UP of Nippostrongylus brasiliensis |
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1.A.119.1.7 | Uncharacterized protein of 268 aas with two C-terminal TMSs and a long hydrophilic N-terminal domain. The C-terminus is very similar to that of TC# 1.A.119 .1.5. |
Eukaryota | Metazoa, Platyhelminthes | UP of Schistocephalus solidus |
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1.A.119.1.8 | TMPIT-like protein of 355 aas and 7 TMSs |
Eukaryota | Viridiplantae, Chlorophyta | TMPIT protein of Dunaliella salina |
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1.A.119.1.9 | Transmembrane 120-like protein of 747 aas and 8 probable TMSs in the central part of the protein. |
Eukaryota | Viridiplantae, Chlorophyta | TMEM120 of Chlorella sorokiniana |
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1.A.12.1.1 | Organellar chloride (anion selective) channel, p64 (outwardly rectifying) (437 aas and 1 or 2 TMSs). CLIC5 was the first chloride channel to be identified in the inner mitochondrial membrane, while CLIC4 is located predominantly in the outer mitochondrial membrane. Gururaja Rao et al. 2020 discussed the intracellular chloride channels, their roles in pathologies, such as cardiovascular, cancer, and neurodegenerative diseases, and developments concerning their usage as theraputic targets in humans. The chloride intracellular channel (CLIC) protein family consists of six members in humans (Israeli 2022). CLICs are unique due to their metamorphic property, displaying both soluble and integral membrane forms. The transmembrane conformation has been shown to give rise to ion-channel activity in vitro. CLICs have been implicated in a growing number of physiological processes in various organ systems and associated with distinct disease states. Indeed, the founding member of the family, CLIC5, was shown to be involved in hereditary deafness and various types of cancer. Ligands that inhibit or activate CLIC5 have been identified, and these may provide tools to modulate its activity,possibly ameliorating CLIC5-related pathologies (Israeli 2022). |
Eukaryota | Metazoa, Chordata | CLIC5 or p64 of Bos taurus |
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1.A.12.1.2 | Nuclear chloride channel-27, NCC27 or CLIC1 (Br- > Cl- > I-) (241 aas). CLIC1 has two charged residues, K37 and R29, in its single TMS which are important for the biophysical properties of the channel (Averaimo et al. 2013). A putative Lys37-Trp35 cation-pi interaction stabilizes the active dimeric form of the CLIC1 TMS in membranes (Peter et al. 2013). This channel may play a role in cancer (Peretti et al. 2014). A positively charged motif at the C-terminus of the single TMS enhances membrane partitioning and insertion via electrostatic contacts. It also functions as an electrostatic plug to anchor the TMS in membranes and is involved in orientating the TMS with respect to the cis and trans faces of the membrane (Peter et al. 2014). The CLIC1 protein accumulates in the circulating monocyte membrane during neurodegeneration (Carlini et al. 2020). The involvement of CLIC1 protein functions in physiological and in pathological conditions has been reviewed (Cianci and Verduci 2021). |
Eukaryota | Metazoa, Chordata | CLIC1 or NCC27 of Homo sapiens |
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1.A.12.1.3 | Organellar chloride channel, CLIC-5A (251 aas; 2 TMSs; one of six homologous human genes) (95% identical to 1.A.12.1.1 but lacks the N-terminal 185 residues.) It associates with the cortical actin cytoskeleton (Berryman et al., 2004). | Eukaryota | Metazoa, Chordata | CLIC-5A of Homo sapiens (Q53G01) |
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1.A.12.1.4 | Organellar chloride channel CLIC-6 (CLIC6; 704 aas with two peaks of hydrophobicity between residues 440 and 515). The C-terminal half (residues 400-704) resembles a CLIC channel; the N-terminal half (residues 104-356) resembles a repeated C-terminal region of the bovine Na+/Ca2+,K+ exchanger (TC #2.A.19.4.1) as well as several other bacterial and eukaryotic proteins. This protein inserts into membrane and displays ion conductances with Cl- > Br- > F- > K+. IAA-94 is a CLIC-specific blocker. Channel activity is regulated by pH and redox potential (Loyo-Celis et al. 2023). |
Eukaryota | Metazoa, Chordata | CLIC-6 of Homo sapiens (Q96NY7) |
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1.A.12.1.5 | The Janus protein, CLIC2. The 3-D structure of its water soluble form has been determined at 1.8 Å resolution (Cromer et al., 2007). CLIC2 interacts with the skeletal ryanodine receptor (RyR1) and modulates its channel activity (Meng et al., 2009). |
Eukaryota | Metazoa, Chordata | CLIC2 of Homo sapiens (O15247) |
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1.A.12.1.6 | Chloride intracellular channel protein 4, CLIC4. Regulates the histamine H3 receptor (Maeda et al., 2008)) Discriminates poorly between anions and cations (Singh and Ashley, 2007). 76% identical to CLIC5; it may play a role in cancer (Peretti et al. 2014). CLIC5 was the first mitochondrial chloride channel to be identified in the inner mitochondrial membrane, while CLIC4 is located predominantly in the outer mitochondrial membrane. Gururaja Rao et al. 2020 discussed the intracellular chloride channels, their roles in pathologies, such as cardiovascular, cancer, and neurodegenerative diseases, and developments concerning their usage as theraputic targets in humans. |
Eukaryota | Metazoa, Chordata | CLIC4 of Homo sapiens (Q9Y696) |
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1.A.12.1.7 | Intracellular Cl- channel-3 (CLIC3). The 3-d structure is known (3FY7). This protein is associated with pregnancy disorders (Murthi et al., 2012). |
Eukaryota | Metazoa, Chordata | CLIC3 of Homo sapiens (O95833) |
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1.A.12.2.1 | The plant Cl- intracellular channel protein DHAR1 (glutathione dehydrogenase/dehydroascorbate reductase) (Elter et al., 2007) | Eukaryota | Viridiplantae, Streptophyta | DHAR1 of Arabidopsis thaliana (NP_173387) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.12.2.2 | Putative Glutathione S-transferase. Pore formation has not been demonstrated in prokaryotes. |
Bacteria | Spirochaetota | Probable glutathione S-transferase of Leptospira interrogans |
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1.A.12.3.1 | The bacterial CLIC homologue, stringent starvation protein A, SspA (212 aas; 0 TMSs) [N-terminal Trx domain; C-terminal glutathione S-transferase (GST) domain]. May be involved in acid (Hansen et al. 2005) and sodium ion tolerance (Wu et al. 2014). |
Bacteria | Pseudomonadota | Stringent starvation protein A of E. coli (P0ACA3) |
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1.A.12.3.2 | Glutathione S-transferase, YfcF of 214 aas. Pore formation has not been demostrated. |
Bacteria | Pseudomonadota | YfcF of E. coli |
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1.A.120.1.1 | The coronaviral double membrane-spanning pore complex in the replication organelle (RO) of the viral double membrane vesicle (DMV). The pore consists of a hexameric complex. The primary constituent of each of the six subunits of the pore is the non-structural protein-3, nsp3, of 2309 aas, which may have 5 TMSs, based on a hydrophathy plot of the protein. These are clustered together about two-thrids of the way towards the C-terminus. It is the core constituent of the pore and has both its N-terminal domain of 160 kDa and a smaller C-terminal domain, which contains a ubiquitin domain (Ubi1) of 12.6 kDa, that together form the prongs of the cytoplasmic crown. nsp3 interacts with nsp4, and this complex is believed to drive membrane pairing and participate in DMV biogenesis (Wolff et al. 2020). It may associate with other viral and host proteins. |
Viruses | Orthornavirae, Pisuviricota | nsp3-nsp4 of murine hepatitis virus |
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1.A.120.1.2 | Polyprotein 1a of 4018 aas and ~ 10 TMSs. |
Viruses | Orthornavirae, Pisuviricota | PP 1a of Canine coronavirus |
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1.A.120.1.3 | ORF1a polyprotein, partial of 4345 aas and ~ 7 TMSs. A cell-based system combined with flow cytometry has been used to evaluate antibody responses against SARS-CoV-2 transmembrane proteins in patients with COVID-19 (Martin et al. 2022). |
Viruses | Orthornavirae, Pisuviricota | ORF1a polyprotein of Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2 |
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1.A.121.1.1 | Anterior pharynx-defective 2 (APH-1B) water channel protein of 257 aas and 7 TMSs in a 3 + 1 + 3 TMS arrangement (Dehury and Kepp 2020). |
Eukaryota | Metazoa, Chordata | APH-1B of Homo sapiens |
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1.A.121.1.10 | Uncharacterized protein of 282 aas and 7 TMSs in a 3 + 2 + 2 TMS arrangement. |
Eukaryota | Fungi, Blastocladiomycota | UP of Allomyces macrogynus |
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1.A.121.1.2 | Anterior pharynx-defective 1A (APH-1A) of 265 aas and 7 TMSs in a 3 + 4 TMS arrangement (Dehury and Kepp 2020). See family description for details. |
Eukaryota | Metazoa, Chordata | APH-1A of Homo sapiens |
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1.A.121.1.3 | Gamma-secretase subunit APH1-like of208 aas and 7 TMSs in a 3 + 2 + 2 TMS arrangement. |
Eukaryota | Viridiplantae, Streptophyta | APH1 of Olea europaea subsp. europaea |
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1.A.121.1.4 | Uncharacterized protein of 260 aas and 7 TMSs in a 3 + 4 TMS arrangement. |
Eukaryota | Viridiplantae, Streptophyta | UP of Cannabis sativa |
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1.A.121.1.5 | Uncharacterized protein of 932 aas with a APH domain at the N-terminus with 7 TMSs, a large central hydrophilic domain (or domains) and a C-terminal PE-PGRS domain (TC# 9.B.96). |
Eukaryota | Viridiplantae, Chlorophyta | UP of Gonium pectorale |
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1.A.121.1.6 | Uncharacterized protein of 259 aas and 7 TMSs in a 3 + 4 TMS arrangement. |
Eukaryota | Oomycota | UP of Aphanomyces astaci |
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1.A.121.1.7 | APH1 of 275 aas and 7 TMSs |
Eukaryota | Viridiplantae, Chlorophyta | APH1 of Chlorella sorokiniana |
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1.A.121.1.8 | Uncharacterized protein of 745 aas with a strongly hydrophilic ~500 aas followed by 7 C-terminal TMSs (the APH domain). |
Eukaryota | Oomycota | UP of Nothophytophtyora sp. Chile5 |
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1.A.121.1.9 | Uncharacterized protein of 348 aas with 3 N-terminal TMSs, followed by a hydrophilc region of ~100 aas, followed by 4 TMSs. |
Eukaryota | Evosea | UP of Polysphondylium violaceum |
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1.A.122.1.1 | Putative protein 3A of Tremovirus A of 65 aas and 1 central TMS. It forms a pore in the ER membrane (Liu et al. 2004). |
Viruses | Orthornavirae, Pisuviricota | Protein 3A of Tremovirus A |
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1.A.122.1.2 | Polyprotein of 2134 aas from which protein 3A is derived. |
Viruses | Orthornavirae, Pisuviricota | Polyprotein 2134 of Avian encephalomyelitis virus
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1.A.124.1.7 | Small Mitochondrial Integral Membrane protein 2, SMIM2, of 122 aas and one TMS. |
Eukaryota | Metazoa, Chordata | SMIM2 of Ictidomys tridecemlineatus (thirteen-lined ground squirrel) |
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1.A.124.1.8 | Small mitochondrial integral membrane 2 (SMIM2) protein of 77 aas and 1 TMS near the N-terminus. |
Eukaryota | Metazoa, Chordata | SMIM2 of Lontra canadensis (Northern American river otter) |
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1.A.125.1.1 | Tulane Virus polyprotein of 1447 aas with the first 233 aas corresponding to the viroporin, NS1-2. It has two TMS near the C-terminus of this viroporin (Strtak et al. 2019). See family description for more details. |
Viruses | Orthornavirae, Pisuviricota | NS1-2 of Tulane virus |
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1.A.125.1.2 | Polyprotein of 2037 aas with the viroporin encoded within the ~ first 233 aas. |
Viruses | Polyprotein of Racaecavirus sp., an unclassified Riboviria |
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1.A.125.1.3 | Polyprotein of 1991 aas including an N-terminal viroporin in ~ the first 233 aas, homologous to Ns1-2. |
Viruses | Orthornavirae, Pisuviricota | Polyprotein of marmot norovirus |
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1.A.125.1.4 | Nonstructural polyprotein of 1943 aas and 1 or 2 C-terminal TMSs in the first 233 aas of this polyprotein which probably code for a viroporin (see family description as well as 1.A.125.1.1). |
Viruses | Orthornavirae, Pisuviricota | Polyprotein of Norovirus GVI |
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1.A.125.1.5 | N-terminal leader protein p48 of 398 aas and possibly 1 or 2 C-terminal TMSs. Possible viroporin based on sequence similarity with TC# 1.A.125.1.1. |
Viruses | Orthornavirae, Pisuviricota | p48 of Norovirus GI |
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1.A.125.1.6 | Polyprotein of 2208 aas and at least 4 TMSs, two near the N-terminus of the polyprotein where a viroporin may be present. |
Viruses | Orthornavirae, Pisuviricota | Polyprotein of Guangdong greater green snake calicivirus |
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1.A.125.1.7 | Polyprotein of 2386 aas and 2 probable TMSs at the C-terminal end of the first 260 aas where the viroporin may be. |
Viruses | Orthornavirae, Pisuviricota | Polyprotein of Zhejiang gunthers frog calicivirus 2 |
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1.A.125.2.1 | HRAS-like suppressor 2 of 178 aas and 1 or 2 C-terminal TMSs. |
Eukaryota | Metazoa, Chordata | Suppressor of Cyprinus carpio (common carp) |
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1.A.125.2.2 | Phospholipase A and acyltransferase 3-like of 170 aas and 2 C-terminal TMSs. |
Eukaryota | Metazoa, Chordata | Phospholipase A of Neolamprologus brichardi |
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1.A.125.2.3 | Lecithin retinol acyltransferase family protein of 202 aas with two moderately hydrophobic peaks (N-terminal) and two amphipathic peaks (C-terminal). |
Bacteria | Pseudomonadota | Acyltransferase of Cupriavidus sp. |
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1.A.125.2.4 | Uncharacterized protein of 345 aas and 2 C-terminal TMSs. |
Eukaryota | Metazoa, Chordata | UP of Zonotrichia albicollis (white-throated sparrow) |
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1.A.126.1.10 | Mitogen-activated protein kinase 1 with an N-terminal Mpv17 domain preceding the C-terminal kinase domain of 911 aas and 5 - 7 TMSs in the N-terminal domain. |
Eukaryota | Mpv17- protein kiinase protein of Symbiodinium microadriaticum |
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1.A.126.1.11 | Uncharacterized protein of 287 aas with a 150 aas N-terminal hydrophilic domain and a C-terminal Mpv17 domain with 4 TMSs. |
Eukaryota | Metazoa, Arthropoda | UP of Medioppia subpectinata |
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1.A.126.1.12 | Uncharacterized protein of 268 aas and 5 TMSs, one N-terminal, followed by a 120 residues hydrophilic domain followed by the 4 TMS Mpv17 domain. |
Eukaryota | Haptophyta | UP of Chrysochromulina tobinii |
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1.A.126.1.4 | Mpv17 of 177 aas and 4 TMSs. It is involved in mitochondrial homeostasis, and control of oxidative phosphorylation and mitochondrial DNA (mtDNA) maintenance (Martorano et al. 2019). It is a non-selective cation channel that modulates the membrane potential under normal conditions as well as conditions of oxidative stress (See TC# 1.A.126.1.5). |
Eukaryota | Metazoa, Chordata | Mpv17 of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.A.126.1.5 | Mpv17 of 176 aas and 4 TMSs. It is a non-selective cation channel that modulates the membrane potential under normal conditions as well as conditions of oxidative stress (Antonenkov et al. 2015). It has a pore diameter of 1.8 nm, located the channel's selectivity filter. The channel is weakly cation-selective and shows several subconductance states. Voltage-dependent gating of the channel is regulated by redox conditions and pH and is affected also in mutants mimicking a phosphorylated state. Likewise, the mitochondrial membrane potential (Δψm) and the cellular production of reactive oxygen species were higher in embryonic fibroblasts from Mpv17(-/-) mice. However, despite the elevated Δψm, the Mpv17-deficient mitochondria showed signs of accelerated fission. These observations uncover the role of MPV17 as a Δψm-modulating channel that apparently contributes to mitochondrial homeostasis. |
Eukaryota | Metazoa, Chordata | Mpv17 of Mus musculus |
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1.A.126.1.6 | PXMP2/4 family protein, 4-like of 264 aas and 4 - 6 TMSs. |
Eukaryota | Viridiplantae, Streptophyta | PXMP2/4 protein of Gossypium raimondii |
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1.A.126.1.7 | Glomerulosclerosis Mpv17 of 249 aas and 4 TMSs. |
Eukaryota | Fungi, Ascomycota | Mpv17 of Fusarium mexicanum |
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1.A.126.1.8 | Uncharacterized protein of 314 aas and 4 TMSs. |
Eukaryota | Bacillariophyta | UP of Thalassiosira pseudonana |
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1.A.126.1.9 | Uncharacterized protein of 293 aas and 5 - 7 TMSs, with four distinct hydrophobic peaks in the C-terminal half of the protein plus 1 - 3 TMSs in the N-terminal half. |
Eukaryota | Viridiplantae, Chlorophyta | UP of Chlorella variabilis |
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1.A.129.1.1 | Mitochondrial cyclophilin D (CypD or Cyp3) or peptidyl-prolyl cis-trans isomerase F (PPIF) of 207 aas, possibly with one N-terminal TMS. It regulates formation of the mitochondrial permeable transition pore (mPTP) which consists of several proteins including those of the F-type ATPase and the outer mitochondrial membrane porins (VDACs) as well as other proteins (Dumbali and Wenzel 2022). Cyclophilin D is a mediator of axonal degeneration after intracerebral hemorrhage (Yang et al. 2023). The abnormal opening of mitochondrial permeability transition pore (mPTP) induces the loss of the mitochondrial membrane potential, the impairment of calcium homeostasis and a decrease of ATP production. Cyclophilin D (CypD), localized in the mitochondrial transition pore, and is a mitochondrial chaperone that is a prominent mediator of mPTP (Zhou et al. 2023). |
Eukaryota | Metazoa, Chordata | CypD of Homo sapiens |
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1.A.13.1.1 | Voltage-gated bovine epithelial Cl- channel protein (Ca2+-activated), bEClC. In rats, two possible paralogues (rbCLCA1 and A2) are expressed in the CNS and peripheral organs (Yoon et al., 2006). CLCA1 may play a role in inflammatory airway diseases (Sala-Rabanal et al. 2015). It is called the von Willebrand factor type A, the DUF1973 protein. |
Eukaryota | Metazoa, Chordata | EClC of Bos taurus (NP_001070824) |
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1.A.13.1.10 | Calcium-activated chloride channel, CLCA2 regulator-2 of 943 aas and 2 TMSs, N- and C-terminal. CLCA2 overexpression suppresses epithelial-to-mesenchymal transition in cervical cancer cells through inactivation of ERK/JNK/p38-MAPK signaling pathways (Xin et al. 2022). Transport of CLCA2 to the nucleus by extracellular vesicles controls keratinocyte survival and migration (Seltmann et al. 2024). |
Eukaryota | Metazoa, Chordata | CLCA2 of Homo sapiens |
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1.A.13.1.2 | Ca2+-activated Cl- channel-2, CaCC-2 | Eukaryota | Metazoa, Chordata | CaCC-2 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.13.1.3 | The Ca-activated chloride channel-6 (Lee et al., 2011). |
Eukaryota | Metazoa, Chordata | Ca-CLC-6 of Xenopus laevis (F7IYU6) |
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1.A.13.1.4 | Calcium-activated chloride channel regulator family member 3 (Calcium-activated chloride channel family member 3) (hCLCA3) | Eukaryota | Metazoa, Chordata | CLCA3P of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.13.1.5 | Putative lipoprotein of 1054 aas and 1-3 TMSs. |
Bacteria | Spirochaetota | Putative lipoprotein of Leptospira biflexa |
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1.A.13.1.6 | Ca+2-activated Cl- channel, or Chloride Channel Accessory 1 (CLCA1 or CACC1), of 914 aas. CLCA1 may play a role in inflammatory airway diseases (Sala-Rabanal et al. 2015). It is thought to play a role in Cl- secretion in the intestine (A. Quach, personal communication). Airway mucus hypersecretion is a clinical feature of a number of childhood diseases, including asthma and bronchitis-associated conditions (Rogers 2003). |
Eukaryota | Metazoa, Chordata | CLCA1 of Homo sapiens |
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1.A.13.1.7 | xCLCA3; xCLCA2 of 942 aas and 7 TMSs. xCLCA3 contains a predicted signal sequence, multiple sites of N-linked glycosylation, N-myristoylation, PKA, PKC, and casein kinase II phosphorylation sites, five putative hydrophobic segments, and the HExxH metalloprotease motif. Additionally, the transmembrane prediction server yielded a preserved N-terminal CLCA domain and a von Willebrand factor type A domain with one transmembrane domain in the C-terminal region (Lee and Jeong 2016). xCLCA3 is expressed in a number of tissues, with strong expression in the brain, colon, small intestine, lung, kidney, and spleen, and poor expression in the heart and liver. xCLCA3 may be a candidate CLCA family member as well as a metalloprotease, rather than just an ion channel accessory protein. |
Eukaryota | Metazoa, Chordata | xCLCA3 of Xenopus laevis (African clawed frog) |
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1.A.13.1.8 | VWFA domain-containing protein, CLCA1 of 935 aas and 2 TMSs, N- and C-terminal, and possibly one that is centrally located. The galline CLCA1 displays close genetic distances to mammalian clusters 1, 3 and 4 (Bartenschlager et al. 2022). |
Eukaryota | Metazoa, Chordata | CLCA1 of Gallus gallus (Chicken) |
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1.A.13.1.9 | VWFA domain-containing protein, CLCA2, chloride-transporting anion channel, regulated by calcium ions, of 1005 aas and 2 TMSs, one N-terminal and one C-terminal (Bartenschlager et al. 2022). |
Eukaryota | Metazoa, Chordata | CLCA2 of Gallus gallus (Chicken) |
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1.A.13.2.1 | Hypothetical protein, HP |
Eukaryota | Viridiplantae, Streptophyta | HP of Oryza sativa (B8AFH9) |
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1.A.13.2.2 | Sll0103 |
Bacteria | Cyanobacteriota | Sll0103 of Synechocystis (Q55874) |
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1.A.13.2.3 | The YfbK/CaClC homologue of 575aas and 0 TMSs. YfbK has amyloidogenic regions due to asparagine- and glutamine-rich regions which is a common feature of many known amyloid proteins. This correlates with detergent-induced denaturation resistance (Antonets et al. 2016). |
Bacteria | Pseudomonadota | YfbK of E. coli (P76481) |
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1.A.13.2.4 | Von Willebrand factor type A domain protein of 536 aas and 1 N-terminal TM |
Bacteria | Planctomycetota | Von Willebrand factor of Tuwongella immobilis |
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1.A.13.3.1 | Von Willebrand factor type A protein, vWFA. (905 aas; 2 N-terminal and 1 C-terminal TMSs) |
Bacteria | Chloroflexota | vWFA of Chloroflexus aurantiacus (A9WIT9) |
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1.A.13.4.1 | Bacterial homologue, BatB, of mammalian Ca-CLC channels (N- and C-terminal TMSs) |
Bacteria | Myxococcota | BatB of Myxococcus fulvus (F8CM01) |
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1.A.13.4.2 | von Willebrand factor type A domain protein, BabT, of 340 aas and 3 TMSs, N- and C-terminal as well as at residue 60. |
Bacteria | Pseudomonadati, Bacteroidota | von Willebrand factor type A of Hoylesella ovalis |
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1.A.13.4.3 | von Willebrand factor type A of 346 aas and 3 TMSs, N- and C-terninal and at ~ residue 60. |
Bacteria | Pseudomonadati, Chlorobiota | von Willebrand factor of Chloroherpeton thalassium |
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1.A.13.5.1 | Putative glutamine amidotransferase domain-containing protein of 252 aas and 2-3 TMSs. |
Bacteria | Pseudomonadota | Gln amidotransferase domain protein of E. coli |
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1.A.130.1.1 | Nortia (Nta), the Ca2+ channel protein of 895 aas and ~ 10 TMSs in a 1 + 1 + 2 + 6 [2 + 2 + 2) TMS arrangement (O22752); Feronia (Fer) a receptor-like kinase and constituent of a transmembrane calmodulin-gated calcium (Ca2+) channel protein complexof 542 aas, an MLO-like protein, and Lorleei (Lre, glycosyl PI anchor protein of 165 aas with 2 TMSs, one N-terminal and one C-terminal (B3GS44) (Gao et al. 2022). The channel protein (Nortia) functions in conjunction with these two other proteins, Feronia (Fer), a receptor-like protein kinase, and Lorelei (Lre), a GPI-anchored protein. See the family description, paragraph 1 and Gao et al. 2022 for more details. Two pollen-tube-derived small peptides that belong to the rapid alkalinzation factor (RALF) family seem to be ligands for the FER-LRE co-receptor, which in turn recruits NTA to the plasm membrane. NTA initiates Ca2+ spiking in the synergid cells, for pollen tube reception. Thus, the FER-LRE-NTA complex forms a receptor-channel complex in the female cell to recognize male signals and trigger tertilization. |
Eukaryota | Viridiplantae, Streptophyta | Nta (Nortia) of Arabidopsis thaliana (O22752) |
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1.A.130.1.10 | Uncharacterized protein of 558 aas and possibly 8 TMSs in a 5 + 3 TMS arrangement. |
Eukaryota | Viridiplantae, Streptophyta | UP of Tanacetum cinerariifolium |
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1.A.130.1.11 | Protein MLO of 533 aas with 7 TMSs in a 1 + 1 + 1 + 2 + 2 TMS arrangement. |
Eukaryota | Viridiplantae, Streptophyta | MLO of Hordeum vulgare (Barley |
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1.A.130.1.12 | MLO-like protein 5 of 501 aas and 7 TMSs in a 1 + 1 + 1 + 2 + 2 TMS arrangement. It may be involved in modulation of pathogen defense and leaf cell death. Activity seems to be regulated by Ca2+-dependent calmodulin binding and seems not to require heterotrimeric G proteins. |
Eukaryota | Viridiplantae, Streptophyta | MLO5 of Arabidopsis thaliana |
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1.A.130.1.13 | MLO12 of 1080 aas with 8 TMSs in a 2 + 1 + 4 + 1 TMS arrangement. |
Eukaryota | Viridiplantae, Chlorophyta | MLO12 of Micractinium conductrix |
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1.A.130.1.14 | EF hand domain-containing protein of 465 aas and 7 TMSs in a 1 + 2 + 1 + 2 + 1 TMS arrangement. |
Eukaryota | Apicomplexa | EF hand protein of Besnoitia besnoiti |
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1.A.130.1.15 | Uncharacterized protein of 568 aas and 7 TMSs in a 2 + 1 + 4 TMS arrangement. |
Eukaryota | Viridiplantae, Chlorophyta | UP of Monoraphidium neglectum |
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1.A.130.1.16 | Uncharacterized protein of 716 aas with 8 TMSs in a 4 + 2 + 2 TMS arrangement. |
Eukaryota | Apicomplexa | UP of Toxoplasma gondii |
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1.A.130.1.17 | Calcium binding protein, putative, of 798 aas and 9 TMSs in a 4 + 3 + 2 TMS arrangement. |
Eukaryota | Perkinsozoa | CBP of Perkinsus marinus |
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1.A.130.1.2 | Uncharacteerized protein of 489 aas and possibly 8 TMSs in a 3 + 3 + 2 TMS arrangement. |
Eukaryota | Viridiplantae, Streptophyta | UP of Malus baccata |
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1.A.130.1.3 | Uncharacterized protein of 471 aas and about 8 TMSs, possibly in a 1 + 3 + 1 + 3 TMS arramgement. |
Eukaryota | Viridiplantae, Streptophyta | UP of Zingiber officinale |
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1.A.130.1.4 | Uncharacterized protein of 570 aas and possibly 7 TMSs in a 3 + 4 TMS arrangement. |
Eukaryota | Viridiplantae, Streptophyta | UP of Kingdonia uniflora |
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1.A.130.1.5 | Uncharacterized protein of 1177 aas and possibly 7 TMSs in a 2 + 1 + 2 + 2 TMS arrangement. |
Eukaryota | Viridiplantae, Chlorophyta | UP of Volvox africanus |
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1.A.130.1.6 | Uncharacterized protein of 1346 aas and about 8 TMSs in a 4 + 4 TMS arrangement. |
Eukaryota | Viridiplantae, Streptophyta | UP of Digitaria exilis |
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1.A.130.1.7 | MLO 11 of 762 aas and about 7 TMSs in a 1 + 1 + 2 + 3 TMS arrangement.
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Eukaryota | Viridiplantae, Chlorophyta | MLO11 of Chlorella sorokiniana |
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1.A.130.1.8 | MLO13 of 630 aas and 7 TMSs in a 3 + 2 + 2 TMS arrangement. |
Eukaryota | Viridiplantae, Chlorophyta | MLO13 of Scenedesmus sp. PABB004 |
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1.A.130.1.9 | Uncharacterized protein of 617 aas and 7 or 8 TMSs in a 2 + 1 (+ 1) + 2 + 2 TMS arrangement. |
Eukaryota | Viridiplantae, Streptophyta | UP of Papaver somniferum (opium poppy) |
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1.A.130.2.1 | Uncharacterized protein of 1348 aas and 14 TMSs with a 3 + 2 + 2 + 3 + 2 + 2 TMS arrangement, clearly indicating an internal 7 TMS duplication. This protein and members of subfamily 1.A.130.2 are Stramenopiles of Sar. |
Eukaryota | Oomycota | UP of Bremia lactucae (lettuce downy mildew) |
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1.A.130.2.2 | EF-hand domain pair of 16 probable TMSs in a 3 + 2 + 1 +1 + 1 + 3 + 2 + 2 + 1 TMS arrangement. |
Eukaryota | Oomycota | EF hand protein of Phytophthora cactorum |
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1.A.130.2.3 | EF-hand domain pair of 2457 aas and 18 TMSs in a 2 + 2 + 2 + 3 + 2 + 2 + 2 + 3 TMS arrangement. |
Eukaryota | Oomycota | EF-hand protein of Phytophthora cactorum |
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1.A.130.2.4 | Uncharacterized protein of 639 aas and 7 TMSs in a 1 + 1 + 3 + 2 TMS arrangement. |
Eukaryota | Oomycota | UP of Aphanomyces invadans |
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1.A.130.2.5 | Uncharacterized protein of563 aas and 7 TMSs in a 3 + 2 + 2 TMS arrangement. |
Eukaryota | Oomycota | UP of Aphanomyces stellatus |
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1.A.130.2.6 | Uncharacterized protein of 1034 aas and 7 or 8 TMSs in a 3 + 1 +1 (+1) + 2 + 2 TMS arrangement. |
Eukaryota | UP of Tribonema minus |
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1.A.132.1.1 | Cytochrome c, CycS, of 105 aas. (see family description for details of pore formation. |
Eukaryota | Metazoa, Chordata | Cytochrome c of Homo sapiens |
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1.A.132.1.2 | Cytochrome c of 238 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | Cyt c of Rhodovulum sulfidophilum |
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1.A.132.1.3 | Cytochrome c class I precursor of 123 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | Cyt c of Candidatus Tokpelaia sp. |
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1.A.133.1.1 | The Csx28 pore-forming protein of 177 aas with 1 N-terminal TMS and possibly a second moderately hydrkophhobic region between residues 100 - 140. It transports ions and colapses the inner membrane potential (pmf) by allowing the free flow of ions, possiblly inorganic cations, across the membrane. It has an octomeric structure with a well ordered C-terminal domain (VanderWal et al. 2023). The pore diameter is ~ 10 Å; each protomer is a 4-helix bundle (α1 to α4) where α1 and α2 form the inner lining of the pore and the two C-terminal helices form the outer surface of the pore. Cas13b senses the viral transcript and signals to Csx28. |
Bacteria | Bacteroidota | Csx28 of Prevotella buccae |
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1.A.133.1.2 | Uncharacterized protein of 178 aas with 1 N-terminal TMS. |
Bacteria | Cyanobacteriota | UP of Leptolyngbya sp. |
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1.A.133.1.3 | Uncharacterized protein of 195 aas and 1 N-terminal TMS plus three more moderate peaks of hydrophobicity, where the degree of hydrophobicity is TMS1 > 2 > 3 > 4. |
Bacteria | Bacteroidota | UP of Chitinophagales bacterium (activated sludge metagenome) |
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1.A.133.1.4 | CRISPR-associated protein Csx28 OF 211 aas and kone strongly hydrophobic N-terminal TMS followed by two much less hydrophobic peaks that may be TMSs. |
Bacteria | Bacteroidota | Csx28 of Phaeodactylibacter xiamenensis |
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1.A.133.1.5 | Uncharacterized protein of 181 aas and 1 N-terminal TMS followed by three peaks of low degrees of hydrophobicity. |
Bacteria | Pseudomonadota | UP of Salmonella enterica |
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1.A.133.1.6 | Uncharacterized protein of 172 aas and 1 N-terminal TMS |
Bacteria | Pseudomonadota | UP of Colwellia sp. (invertebrate metagenome) |
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1.A.133.1.7 | Uncharacterized protein of 163 aas and 1 N-terminal TMS. |
Bacteria | Chloroflexota | UP of Anaerolineales bacterium (activated sludge metagenome) |
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1.A.133.1.8 | Uncharacterized protein of 231 aas and 1 N-terminal TMS. |
Bacteria | Actinomycetota | UP of Actinobacteria bacterium OV450 |
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1.A.133.1.9 | Uncharacterized protein of 187 aas and 1 N-terminal TMS. |
Bacteria | Actinomycetota | UP of Kutzneria sp. CA-103260 |
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1.A.134.1.1 | The nutrient sensing ion channel protein, GerAA of 482 aas and 6 -terminal TMSs. These 6 TMSs occur in a 2 + 2 + 2 arrangement (Gao et al. 2023). |
Bacteria | Bacillota | GerAA of Bacillus subtilis |
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1.A.134.1.2 | Germination ion channel protein, GerBA or GerB1, of 483 aas and 6 TMSs. |
Bacteria | Bacillota | GerBA of Bacillus subtilis |
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1.A.134.1.3 | Spore germination protein of 492 aas and 6 TMSs. |
Bacteria | Bacillota | Germination protein of Clostridium aceticum |
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1.A.134.1.4 | Sporulation germination ion channel protein of 571 aas and 6 TMSs. |
Bacteria | Bacillota | Ger protein of Anaerobutyricum hallii |
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1.A.134.1.5 | Protein involved in dipicolinic acid release from spores, SpoVAF, of 493 aas with 6 TMSs. See also TC# 9.A.11.1.1 for the complete complex. |
Bacteria | Bacillota | SpoVAF of Bacillus subtilis |
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1.A.135.1.1 | The ASFV B117L viroporin of 155 aas with 1 TMS near the C-terminus of the protein. |
Viruses | Bamfordvirae, Nucleocytoviricota | B117L viroporin of African swine fever virus (ASFV) |
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1.A.136.1.1 | Type 10 protein secretion system consisting of proteins encoded within a single gene cluster that includes (1) a LysR-type transcriptional regulator (Stm0014; Q8ZS13; 315 aas), (2) a holin (Stm0015; Q8ZS12; 114 aas; see also TC family # 1.E.5), (3) a peptidoglycan hydrolase (a muramidase; Stm0016; Q8ZS11; 177 aas), (4) a second transcriptional regulator, ToxR-like, (Stm17; Q8ZS10), and (5) the secreted exo-chitinase (Stm0018; Q8ZS09; 699 aas). |
Bacteria | Pseudomonadota | Type 10 secretion system of Salmonella enterica (Typhi) LysR-type transcriptional regulator, Q8ZS13 |
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1.A.136.1.2 | Proteins involved in type 10 protein secretion system. These include a holin (ChiW, 108 aas; TC# 1.E.2.1.13; CDG13439), a peptidoglycan hydrolase (phage-related toxin; ChiX; 133 aas; CDG13438), and a spannin belonging to the 1.M.7.1 subfamily of spanins (ChiY; 126 aas; CDG13437). There are three similar Chitinases in S. marcescens, and all of them may be exported via this system (Palmer et al. 2021). |
Bacteria | Pseudomonadota | Type 10 protein secretion system (may be incomplete) of Serratia marcescens subsp. marcescens Db11 |
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1.A.138.1.1 | Unnexin1 (Unx1) of 258 aas and 4 TMSs in a 2 + 2 TMS arrangement (possibly with a transmembrane region at the N-terminus of the protein. See family description for more details (Güiza et al. 2023) |
Eukaryota | Euglenozoa | Unx1 of kinetoplastids of Trypanosoma cruzi |
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1.A.138.1.2 | Unnexin homolog of 254 aas and 4 TMSs |
Eukaryota | Euglenozoa | Unx1 homolog of Diplonema papillatum |
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1.A.138.1.3 | Uncharacterized protein of 235 aas and probably 4 TMSs. |
Eukaryota | Euglenozoa | UP of Bodo saltans |
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1.A.138.1.4 | Uncharacterized protein of 284 aas and 4 probable TMSs. |
Eukaryota | Euglenozoa | UP of Strigomonas culicis |
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1.A.138.1.5 | Uncharacterized protein of 278 aas and possibly 4 or more TMSs. |
Eukaryota | Euglenozoa | UP of Leishmania major |
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1.A.138.2.1 | Uncharacterized protein of 232 aas and 4 TMSs. This protein is a distant member of the subfamily 1.A.138.1 but is more closely related to the proteins in TC family 1.A.101. These two families comprise a superfamily. |
Eukaryota | Euglenozoa | UP of Diplonema papillatum |
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1.A.139.1.1 | Chromogranin B (CHGB), also called secretogranin-1 (SCG1) (677 aas with 1 or 2 N-terminal TMSs), is a large conductance chloride channel present in mammals (Jiang and Yadav 2022). See the family description for details about its enzymatic catalytic activities. |
Eukaryota | Metazoa, Chordata | CHGB of Homo sapiens |
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1.A.139.1.2 | Protein Aster-C or GRAM domain-containing protein 1C of 717 aas and 1 N-terminal TMS. |
Eukaryota | Metazoa, Chordata | Aster-C of Alosa sapidissima (American shad) |
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1.A.139.1.3 | Secretogranin-1 of 676 aas and 1 N-terminal TMS. |
Eukaryota | Metazoa, Chordata | GRAMD1C of Cheilinus undulatus (humphead wrasse) |
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1.A.139.1.4 | Secretogranin-1 of 617 aas and 1 N-terminal TMS. |
Eukaryota | Metazoa, Chordata | Secretogranin of Anguilla anguilla (European eel) |
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1.A.139.1.5 | Chromogranin-A of 617 aas and 1 N-terminal TMS. |
Eukaryota | Metazoa, Chordata | Chromogranin-A of Dromaius novaehollandiae, emu |
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1.A.14.1.1 | The Bax Inhibitor-1, BI-1 of 311 aas (or 237 aas; P55061) and 6 TMSs; it is also called the testis-enhanced gene transcript (TEGT) protein or the transmembrane BAX inhibitor motif-containing protein 6 (TMBIM6). It forms an ER, pH-sensitive, cation-selective, Ca2+-permeable leak channel (Bultynck et al., 2011; Chang et al. 2014). Residues that contribute to the ion-conducting pore and affect apoptosis, cell adhesion and migration independently have been identified (Carrara et al. 2015). The TMBIM6 calcium leak channel activity negatively regulates autophagy and autophagosome formation, influencing cardovascular traits (Swain et al. 2020). It enhances autophagy through regulation of lysosomal calcium (Kim et al. 2020). A TMBIM6 deficiency enhances susceptibility to ER stress due to inhibition of the ER stress sensor IRE1alpha. Its overexpression improves glucose metabolism, and knockout mice develop obesity (Philippaert et al. 2020). TMBIM6 knockout mice feature high glucose-stimulated insulin secretion in vivo. This coincides with profound changes in glucose-mediated Ca2+ regulation in isolated pancreatic beta cells and increases levels of IRE1alpha levels. TMBIM6-mediated metabolic alterations are mainly caused by its role as a Ca2+ release channel in the ER. Thus, TMBIM6(-/-) leads to obesity and hepatic steatosis by blocking Ca2+ transport (Philippaert et al. 2020). The mammalian Transmembrane BAX Inhibitor Motif (TMBIM) protein family in humans consists of six evolutionarily conserved hydrophobic proteins that affect programmed cell death and the regulation of intracellular calcium levels (Zhang et al. 2021). There are seven TMBIM family members in Drosophila melanogaster. Tmbim5 and 6 are essential for fly development and survival but affect cell survival through different mechanisms (Zhang et al. 2021). It prevents VDAC1 multimerization and improves mitochondrial quality control to reduce sepsis-related myocardial injury (Zhou et al. 2023). |
Eukaryota | Metazoa, Chordata | BI-1 or TEGT of Homo sapiens (P55061) |
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1.A.14.1.2 | Uncharacterized protein of 304 aas and 7 TMSs. |
Eukaryota | Euglenozoa | UP of Trypanosoma cruzi marinkellei |
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1.A.14.1.3 | Uncharacterized protein of 238 aas and 7 TMSs |
Eukaryota | Apicomplexa | UP of Babesia microti |
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1.A.14.1.4 | Uncharacterized protein of 317 aas and 7 TMSs |
Eukaryota | Haptophyta | UP of Emiliania huxleyi |
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1.A.14.1.5 | Growth hormone-inducible membrane protein of 345 aas and 8 putative TMSs |
Eukaryota | Metazoa, Chordata | GH-inducible membrahe protein of Anas platyrhynchos (Mallard) (Anas boschas) |
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1.A.14.1.6 | Putative Bax inhibitor of 213 aas and 7 TMSs |
Eukaryota | Evosea | Putative Bax inhibitor of Entamoeba histolytica |
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1.A.14.2.1 | The YccA protein, an inhibitor of FtsH. May share a similar mechanism of action as BI-1 in regulation apoptsis upon prolonged secretion stress (van Stelten et al., 2009). |
Bacteria | Pseudomonadota | YccA of E. coli (P0AAC6) |
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1.A.14.2.2 | The YbhL (AceP) protein. Possibly a pmf-dependent acetate uptake transporter. [14C]Acetate uptake was inhibited by CCCP as well as cold acetate, serine, α-ketoglutarate, lactate, and succinate (M. Inouye, personal communication). |
Bacteria | Pseudomonadota | YbhL of E. coli (P0AAC4) |
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1.A.14.2.3 | The 7 TMS proton-sensitive Ca2+ leak channel, YetJ. The activity and high resolution 3-d structure have been determined (Chang et al. 2014). BsYetJ in lipid nanodiscs is structurally different from those crystallized in detergents. Li et al. 2020 showed that the BsYetJ conformation is pH-sensitive in the apo state (lacking calcium), whereas in a calcium-containing solution, it is stuck in an intermediate state, inert to pH changes. Only when the transmembrane calcium gradient is established can the calcium-release activity of holo-BsYetJ occur and be mediated by pH-dependent conformational changes, suggesting a dual gating mechanism. Conformational substates involved in the process and a key residue, D171, relevant to the gating of calcium were identified. Thus, BsYetJ/TMBIM6 is a pH-dependent, voltage-gated calcium channel (Li et al. 2020). The transmembrane BAX inhibitor-1-containing motif 6 (TMBIM6) protein may modulate apoptosis by regulating calcium homeostasis in the endoplasmic reticulum (ER). Lan et al. 2023 investigated all negatively charged residues in BsYetJ, a bacterial homolog of TMBIM6. They reconstituted BsYetJ in membrane vesicles with a lipid composition similar to that of the ER. The charged residues E49 and R205 work together as a major gate, regulating calcium conductance in these ER-like lipid vesicles. However, these residues become largely inactive when reconstituted in other lipid environments. D195 acts as a minor filter compared to the E49-R205 dyad (Lan et al. 2023). |
Bacteria | Bacillota | YetJ of Bacillus subtilis (O31539) |
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1.A.14.2.4 | Uncharacterized protein, YbhM, of 237 aas and 7 TMSs. The ybhM gene is adjacent to the homologous ybhL gene (TC# 1.A.14.2.2), and another homologous gene is inbetween these two; these two or three genes could function together as a single transporter. |
Bacteria | Pseudomonadota | YbhM of E. coli |
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1.A.14.2.5 | Protein of 234 aas and 7 TMSs encoded by a gene between and homologous to YbhL and YbhM. In the Pfam family Bax1-I. |
Bacteria | Pseudomonadota | Bax1-I protein of E. coli |
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1.A.14.2.6 | Uncharacterized protein of 227 aas and 7 TMSs |
Bacteria | Bacillota | UP of Streptococcus sanguinis |
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1.A.14.2.7 | Bax inhibitor-1, BI1/YccA homologue of 245 aas and 7 TMSs in a 1 + 1 + 2 + 2 + 1 TMS arrangement. BrBI is a bacterial cytoprotective protein involved in membrane homeostasis, cell division, and stress resistance in Brucella suis (Zhang et al. 2021). |
Bacteria | Pseudomonadota | BI-1 of Brucella suis |
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1.A.14.3.1 | The NMDA receptor glutamate binding chain. Also called Protein lifeguard-1, putative MAPK-activating protein PMO2, and transmembrane BAX inhibitor motif-containing protein 3 (TMBIM3, GRINA, LFG1, NMDARA1). The human orthologue is Q7Z429. Stimulation and block by spermine involve separate binding sites and distinct mechanisms (Jin et al. 2008). |
Eukaryota | Metazoa, Chordata | NMDA receptor glutamate binding chain of Rattus sp. (Q63863) |
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1.A.14.3.10 | The Protein Lifeguard 3 (LFG3, RECS1, Tmbim1) of 311 aas and 7 TMSs. LFG3 is a multivesicular body regulator that protects against non-alcoholic fatty liver by targeting the lysosomal degradation of Tlr4 (Zhao et al. 2017). It also protects against pathological cardiac hypertrophy by promoting the lysosomal degradation of activated TLR4 (Deng et al. 2018). RECS1 is a pH-regulated calcium channel, an activity that is essential to trigger cell death (Pihán et al. 2021). |
Eukaryota | Metazoa, Chordata | LFG3 of Homo sapiens |
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1.A.14.3.11 | Uncharacterized protein of 638 aas and 7 N-terminal TMSs |
Eukaryota | Metazoa, Arthropoda | UP of Drosophila eugracilis |
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1.A.14.3.12 | Viroporin, pUS21, of 243 aas and 8 TMSs. It modulates calcium ion homeostasis and protects cells against apoptosis (Luganini et al. 2018). pUS21 of human cytomegalovirus (HCMV) constitutes a TMBIM-derived viroporin that may contribute to HCMV's overall strategy to counteract apoptosis of infected cells (Luganini et al. 2023). US21, one of the 10 US12 genes (US12-US21), is a descendant of a captured cellular transmembrane BAX inhibitor motif-containing gene. It encodes a 7 TMS endoplasmic reticulum (ER)-resident viroporin (pUS21) capable of reducing the Ca2+ content of ER stores, which, in turn, protects cells against apoptosis. The US21 protein is a viral regulator of cell migration and adhesion through mechanisms involving its calcium channel activity (Luganini et al. 2023). US21 viroporin of human cytomegalovirus stimulates cell migration and adhesion (Luganini et al. 2023). |
Viruses | Heunggongvirae, Peploviricota | pUS21 of Human cytomegalovirus (strain Merlin) (HHV-5) (Human herpesvirus 5) |
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1.A.14.3.13 | Lifeguard 2, LFG2, or the Brz-insensitive-long hypocotyl4 mutant ,BIL4, of 239 aas and 7 TMSs. BIL4 regulates cell elongation and Brassinosteroid (BRs; plant steroid hormones) signaling, in part via the regulation of BRI1 localization (Yamagami et al. 2017).
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Eukaryota | Viridiplantae, Streptophyta | BIL4 of Arabidopsis thaliana |
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1.A.14.3.14 | GRINA (Lifguard 1, LFG1, NMDARA1, TMBIM3) has 371 aas and 7 C-terminal TMSs. It is expressed in 218 organ(s) with highest expression in the right hemisphere of the cerebellum. It is involved in ER Ca2+ ion homeostasis and regulates apoptosis. The expression of the pro-apoptotic protein Bax is upregulated, whereas the anti-apoptotic protein Bcl-2 is downregulated in GRINA silenced cells (Xu et al. 2018). Grina/TMBIM3 modulates NMDA receptors and voltage-gated CaV2.2 Ca2+ channels (TC# 1.A.1.11.9) in a G-protein-like manner (Mallmann et al. 2019). GRINA encodes the ionotropic glutamate receptor TMBIM3 (transmembrane BAX inhibitor 1 motif-containing protein family member 3), which regulates cell survival (Rice et al. 2019). |
Eukaryota | Metazoa, Chordata | GRINA of Homo sapiens |
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1.A.14.3.15 | Tmbim3a or Grinaa of 363 aas and 7 C-terminal TMSs. A deficiency in Tmbim3a/Grinaa initiates cold-induced ER stress and cell death by activating an intrinsic apoptotic pathway in zebrafish (Chen et al. 2019). |
Eukaryota | Metazoa, Chordata | Grinaa of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.A.14.3.16 | Protein lifeguard-2 (LFG, LFG2, NMP2, NMP35, TMBIM2), Fas-apoptotic inhibitory molecule 2 (FAIM2) is of 316 aas with 7 TMSs. It is an antiapoptotic protein which protects cells uniquely from Fas-induced apoptosis and regulates Fas-mediated apoptosis in neurons by interfering with caspase-8 activation (Somia et al. 1999; Fernández et al. 2007). It is a member of the transmembrane BAX inhibitor motif-containing (TMBIM) family. The TMBIM family is comprised of six anti-apoptotic proteins that suppress cell death by regulating endoplasmic reticulum Ca2+ homeostasis. It localizes to the lysosome and facilitates autophagosome-lysosome fusion through the LC3 interaction region (Hong et al. 2020). |
Eukaryota | Metazoa, Chordata | LFG2 of Homo sapiens |
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1.A.14.3.2 | Glutamate Receptor Gr2 |
Eukaryota | Gr2 of Capsaspora owczarzaki (E9CCY6) |
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1.A.14.3.3 | Golgi anti-apoptotic protein, GAAP of 237 aas. Forms cation-selective channels; residues that contribute to ion-conduction and affect apoptosis, cell adhesion and migration independently have been identified (Carrara et al. 2015). |
Viruses | Bamfordvirae, Nucleocytoviricota | GAAP of Vaccinia virus, VacV (A2VCJ6) |
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1.A.14.3.4 | Ionotropic glutamate receptor; N-methyl-D-aspartate-associated protein 1 (glutamate-binding). |
Eukaryota | Metazoa, Chordata | Gr1 of Salmo salar (B5X2N0) |
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1.A.14.3.5 | The BH3-only protein, Ynl205c (Büttner et al., 2011) |
Eukaryota | Fungi, Ascomycota | Ynl305c of Saccharomyces cerevisiae (P48558) |
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1.A.14.3.6 | Protein lifeguard 4 (LFG4), also called Golgi anti-apoptotic protein (GAAP), Protein S1R, CGI-119, Transmembrane BAX inhibitor motif-containing protein 4, (TMBIM4) and Z-protein. Forms cation-selective ion channels. Residues that contribute to the ion-conducting pore and affect apoptosis, cell adhesion and migration independently of each other have been identified (Carrara et al. 2015). It's functions have been reviewed (Carrara et al. 2017). The N-methyl-D-aspartate receptor regulates the circadian clock in megakaryocytic cells and impacts cell proliferation through BMAL1 (Hearn et al. 2023). |
Eukaryota | Metazoa, Chordata | TMBIM4 of Homo sapiens |
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1.A.14.3.7 | 7 TMS integral membrane protein |
Bacteria | Planctomycetota | Uncharacterized membrane protein of Rhodopirellula baltica |
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1.A.14.3.8 | Uncharacterized protein of 242 aas and 7 TMSs. |
Bacteria | Cyanobacteriota | UP of Synechococcus elongatus (Anacystis nidulans R2) |
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1.A.14.3.9 | Lifeguard homologue, CG3814 of 244 aas and 7 TMSs. Knockdown of CG3814/LFG in Ddc-Gal4-expressing neurons diminishes its neuroprotective ability, and results in a shortened lifespan and loss of climbing ability, phenotypes that are improved upon overexpression of the pro-survival Buffy (M'Angale and Staveley 2016). |
Eukaryota | Metazoa, Arthropoda | CG3814 of Drosophila melanogaster (Fruit fly) |
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1.A.14.4.1 | Viral protein HWLF3 (342 aas; 7 TMSs) |
Viruses | Heunggongvirae, Peploviricota | HWLF3 of human cytomegalovirus, HHV-5 (Q03307) |
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1.A.14.4.2 | Viral membrane protein US14 of 286 aas and 7 TMSs. |
Viruses | Heunggongvirae, Peploviricota | US14 of Panine herpesvirus 2 (Chimpanzee cytomegalovirus) |
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1.A.14.4.3 | Viral US18 protein of 274 aas and 7 TMSs |
Viruses | Heunggongvirae, Peploviricota | US18 of Human cytomegalovirus (HHV-5) (Human herpesvirus 5) |
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1.A.14.4.4 | Membrane protein US12A of 250 aas and 7 TMSs |
Viruses | Heunggongvirae, Peploviricota | US12A of Simian cytomegalovirus |
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1.A.14.4.5 | Membrane protein US19 of 240 aas and 7 TMSs. |
Viruses | Heunggongvirae, Peploviricota | US19 of Human cytomegalovirus (HHV-5) (Human herpesvirus 5) |
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1.A.141.1.1 | Effector domain protein of 363 aas with two domains, an N-terminal domain of 90 aas and 2 TMSs (residues 24 - 46 and 66 - 88) and the cyclic nucleotide binding domain of the larger C-terminal domain with three moderately hydrophobic peaks that could be TMSs. The N-terminal response domain is a chloride (Cl-) channel domain (Tak et al. 2023). |
Bacteria | Pseudomonadota | Chloride channel protein domain, N-terminus of AOW71412.1 from Enterobacter cloacae |
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1.A.141.1.10 | SAVED domain-containing protein of 370 aas and 2 N-terminal TMSs as well as up to 3 ceontral and C-terminal TMSs. |
Bacteria | Pseudomonadota | SAVAED protein of Pseudomonas citronellolis |
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1.A.141.1.11 | SAVED domain-containing protein of 367 aas and 2 N-terminal TMSs plus up to 3 TMSs in the remainder of the protein. |
Bacteria | Pseudomonadota | SAVED-domain protein of Shewanella xiamenensis |
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1.A.141.1.2 | SAVED domain-containing protein of 355 aas and 2 N-terminal TMSs. The SAVED domain is the cyclic nucleotide binding domain while the N-terminal domain is the chloride (Cl-) channel domain. |
Bacteria | Pseudomonadota | SAVED domain protein of E. coli |
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1.A.141.1.3 | SAVED domain-containing protein of 538 aas and 2 or 3 TMSs, the first two in the N-terminal domain (putative Cl- channel domain) and the C-terminal SAVED domain for binding cyclic nucleotide(s). |
Bacteria | Terrabacteria group | SAVED domain protein of Nostoc sp. 'Peltigera membranacea cyanobiont' N6 |
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1.A.141.1.4 | SAVED domain-containing protein of 338 aas and 2 or 3 TMSs. |
Bacteria | Bacillota | SAVED domain protein of Brevibacillus agri |
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1.A.141.1.5 | Uncharacterized protein of 314 aas and 2 - 4 TMSs, two N-terminal and two more possible TMSs in the C-terminal region of the protein. |
Archaea | Candidatus Heimdallarchaeota | UP of Candidatus Heimdallarchaeota archaeon LC_3 |
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1.A.141.1.6 | SAVED domain-containing protein, BtCap14, of 369 aas and probably 4 N-terminal TMSs followed by a large SAVED hydrophilic domain. It has been shown to transport Cl-, and the channel is activated by cyclic GAMP (Kibby et al. 2023). See family description for more details. |
Bacteria | Bacillota | Cap14 of Bacillus thuringiensis |
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1.A.141.1.7 | SAVED domain-containing protein of 333 aas and 3 or 4 TMSs in a 2 (N-terminal) + 1 or 2 TMSs (C-terninal). |
Bacteria | Bacillota | SAVED domain protein of Otoolea muris |
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1.A.141.1.8 | SAVED domain-containing protein of 649 aas and possibly 4 TMSs, 1 N-terminal and up to 3 TMSs near the C-terminus. |
Bacteria | Myxococcota | SAVED domain protein of Myxococcus sp. CA040A |
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1.A.141.1.9 | SAVED domain-containing protein of 539 aas and several TMSs. |
Bacteria | Chloroflexota | SVAED domain protein of Anaerolineae bacterium |
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1.A.141.2.2 | SAVED domain protein of 343 aas with 2 N-terminal TMSs plus 2 subsequent TMSs at about residues 170 and 300. |
Archaea | Methanobacteriati, Methanobacteriota | SAVED domain protein of Methanosarcina mazei |
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1.A.141.2.3 | SAVED domain-containing protein (plasmid) of 430 aas with 2 N-terminal TMSs and one C-terminal TMS. |
Archaea | Methanobacteriati, Methanobacteriota | Saved domain protein of Haloplanus rubicundus |
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1.A.141.2.4 | SAVED domain protein of 405 aas and 2 N-terminal TMSs (residues 50 - 90) plus 3 C-terminal TMSs (residues 280 - 370) |
Archaea | Methanobacteriati, Methanobacteriota | SAVED domain protein of Halocatena marina |
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1.A.142.1.1 | Monkeypox virus (Mpox virus; Mpkv) viroporin of 49 aas and 1 N-terminal TMS. It forms an oligomeric transmembrane pore that transports ions (Basu et al. 2023). |
Viruses | Bamfordvirae, Nucleocytoviricota | Viroporin of Monkeypox virus |
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1.A.142.1.2 | IMV protein (putatie viroporin) of 49 aas and 1 N-terminal TMS. |
Viruses | Bamfordvirae, Nucleocytoviricota | IMV protein of NY_014 poxvirus |
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1.A.142.1.3 | IMV protein of 49 aas and 1 N-terminal TMS. |
Viruses | Bamfordvirae, Nucleocytoviricota | IMV protein of Raccoonpox virus |
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1.A.143.1.1 | The A15.5L Viroporin of 53 aas and 2 TMSs at residues 7 - 24 and 30 - 50 (Basu et al. 2023). |
Viruses | Bamfordvirae, Nucleocytoviricota | The A15.5L Viroporin of Monkeypox virus |
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1.A.143.1.2 | Uncharacterized protein of 53 aas and 2 TMSs. Putative viroporin. |
Viruses | Bamfordvirae, Nucleocytoviricota | UP (viroporin) of Finch poxvirus |
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1.A.143.1.3 | MC119L viroporin protein homolog of 53 aas and 2 TMSs. |
Viruses | Bamfordvirae, Nucleocytoviricota | MC119L viroporin of Molluscum contagijosum virus, subtype 1 |
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1.A.144.1.1 | The gp063 viroporin IMV membrane protein 12 of 73 aas and 1 TMS encompasing residues 45 - 69, thus being C-terminal. |
Viruses | Bamfordvirae, Nucleocytoviricota | gp063 viroporin protein of Monkeypox virus |
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1.A.144.1.2 | gp063 viroporin Imv membrane protein of 63 aas and 1 C-terminal TMS. |
Viruses | Bamfordvirae, Nucleocytoviricota | gp063 viroporin of Pteropox virus |
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1.A.144.1.3 | Uncharacterized protein of 69 aas with 1 C-terminal TMS. |
Viruses | Bamfordvirae, Nucleocytoviricota | UP of Bovine papular stomatitis virus
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1.A.144.1.4 | Uncharacterized protein of 65 aas with 1 C-terminal TMS. |
Viruses | Bamfordvirae, Nucleocytoviricota | UP of Flamingopox virus FGPVKD09 |
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1.A.145.1.1 | MPXVgp120 viroporin protein of 100 aas and 1 C-terminal TMS.
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Viruses | Bamfordvirae, Nucleocytoviricota | MPXVgp120 viroporin of Monkeypox virus |
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1.A.145.1.2 | Putative viroporin of 65 aas and 2 TMSs, SWPV1-219. |
Viruses | Bamfordvirae, Nucleocytoviricota | SWPV1-219 of Shearwater pox virus |
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1.A.145.1.3 | IMV membrane protein, putative viroporin, of 74 aas and 1 C-terminal TMS. |
Viruses | Bamfordvirae, Nucleocytoviricota | Viroporin of Nile crocodilepox virus |
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1.A.147.1.1 | Cam1 - CRISPR effector, shown to depoloarized the cell when activated, protecting against phage infectiions (Baca et al. 2024). It is 206 aas long with 1 - 3 TMSs. The N-terminal TMS is very hydrophobic while the second and third possible TMSs are less so. See family description for details. |
Eukaryota | Metazoa, Cnidaria | Cam1 of Entacmaea quadricolor (Bubble-tip sanemone) (Parasicyonis actinostolodes)
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1.A.147.1.10 | Uncharacterized TIGR02710 family CRISPR-associated protein of 569 aas and 1 N-terminal TMS. |
Archaea | Candidatus Helarchaeota | UP of Candidatus Helarchaeota archaeon |
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1.A.147.1.2 | Uncharacterized protein of 248 aas and1 N-terminal TMS. |
Bacteria | Nitrospirota | UP of Thermodesulfovibrio islandicus |
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1.A.147.1.3 | DUF6293 family protein of 112 aas and possibly 1 N-terminal TMS. |
Bacteria | Bacillota | DUF6293 family protein of 212 aas and 1 N-terminal TMS. |
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1.A.147.1.4 | DUF1887 family CARF protein of 371 aas and 0 or 1 N-terminal TMS.
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Bacteria | Pseudomonadota | DUF1887 family protein of Neisseria dentiae |
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1.A.147.1.5 | TIGR02710 family CRISPR-associated protein of 478 aas and 1 - 4 TMSs. The region of homology with other members of the family is at the N-terminus of this protein. |
Bacteria | Chloroflexota | TIGR2710 protein of Herpetosiphonaceae bacterium |
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1.A.147.1.6 | Uncharacterized protein of 274 aas and 3 TMSs, 2 near the N-terminus and1 near the C-termnus. |
Bacteria | Pseudomonadota | UP of Thiohalocapsa sp. |
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1.A.147.1.7 | DUF1887 family CARF protein of 386 aas with 1 N-terminal TMS and possibly 1 or 2 more TMSs. |
Bacteria | Pseudomonadota | DUF1887 protein of Dongiaceae bacterium |
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1.A.147.1.8 | Uncharacterized protein VSS75_32315 of 259 aas and 2 N-terminal TMSs plus possibly one more TMS. |
Bacteria | Pseudomonadota | UP of Candidatus Parabeggiatoa sp. |
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1.A.147.1.9 | Uncharacterized CRISPR-associated protein (Cas_Cas02710) of 216 aas with 2 N-terminal TMSs plus one more TMS to the right of the 2 N-terminal TMSs. |
Archaea | UP of uncultured archaeon |
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1.A.148.1.1 | Pore-forming protein after proteolysis to yield peptides. Four such peptides have been released and shown to form pores in the parasitophorous vacuole of T. gonadii (Jastrab and Darwin 2015; Bitew et al. 2024) (see family description). This protein is GRA47 (gene ID TGGT1_254000 = EPR59035.1) and has two TMSs near the N-terminus (residues 50 and 170) separated by a semi hydrophobic sequence that could resemble a P-loop as in members of the VIC (voltage-gated ion channel) (TC# 1.A.1) protein members. The same characteristic is observed for other members of this family. |
Eukaryota | Apicomplexa | PIL98022.1 pore-forming protein (peptide) of Toxoplasm gonadii |
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1.A.148.1.2 | Uncharacterized protein of 544 aas with 2 TMSs and a possibly P-loop between them. |
Eukaryota | Apicomplexa | UP of Neospora caninum Liverpool
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1.A.148.1.3 | Uncharacterized protein of 521 aas and 2 TMSs at residues 50 and 220 with a possible P-loop between them. |
Eukaryota | Apicomplexa | UP of Besnoitia besnoiti |
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1.A.148.1.4 | Uncharacterized protein of 417 aas with possibly 2 TMSs |
Eukaryota | Apicomplexa | UP of Cystoisospora suis |
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1.A.149.1.1 | Hepatitis E ORF3 protein of 114 aas and 2 N-terminal TMSs (Srivastava et al. 2023). See family description for details. |
Viruses | Orthornavirae, Kitrinoviricota | ORF3 of hepatitis E virus |
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1.A.149.1.2 | ORF3 of Paslahepevirus balayani virus of 122 aas and 2 N-terminal TMSs. |
Viruses | Orthornavirae, Kitrinoviricota | ORF3 of Paslahepevirus balayani virus |
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1.A.15.1.1 | Sec62 of 274 aas and 2, 3 or 4 putative TMSs (Lyman and Schekman 1997). |
Eukaryota | Fungi, Ascomycota | Sec62 of Saccharomyces cerevisiae |
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1.A.15.1.2 | Sec62 protein of 348 aas and 4 putative TMSs. |
Eukaryota | Ciliophora | Sec62 of Paramecium tetraurelia |
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1.A.15.1.3 | Translocation protein Sec62 of 276 aas and 3 or 4 putative TMSs. |
Eukaryota | Apicomplexa | Sec62 of Plasmodium vivax |
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1.A.15.1.4 | Translocation protein Sec62 of 264 aas and 4 putative TMSs. |
Eukaryota | Viridiplantae, Streptophyta | Sec62 of Arabidopsis thaliana (Mouse-ear cress) |
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1.A.15.1.5 | Protein translocation protein, Sec62, of 265 aas and 2 - 4 putative TMSs. |
Eukaryota | Viridiplantae, Chlorophyta | Sec62 of Chlorella variabilis (Green alga) |
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1.A.15.1.6 | NS channel protein-1 or Sec62 protein of 399aas and 2 TMSs. Efficient secretion of small proteins in mammalian cells relies on Sec62-dependent posttranslational translocation (Lakkaraju et al. 2012). |
Eukaryota | Metazoa, Chordata | NS channel translocation protein-1 or Sec62 of Homo sapiens |
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1.A.150.1.1 | The Virulence-associated Protein (VAP) of 189 aas with 1 - 4 TMSs in a 1 (N-terminal) plus possibly 3 peaks of low hydrophobicity. See family description (Nehls et al. 2024). |
Bacteria | Actinomycetota | VapA of Prescottella (Rhodococcus) equi |
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1.A.150.1.2 | VapA/VapB family virulence-associated protein of 170 aas and between 1 and 4 TMSs.
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Archaea | Methanobacteriati, Methanobacteriota | Vap Protein of Methanothrix sp. |
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1.A.150.1.3 | VapA/VapB family virulence-associated protein of 146 aas and up to 4 TMSs of low hydrdrophobicity.
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Bacteria | Bacillota | VappA/VapB of Caproicibacter fermentans |
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1.A.150.1.4 | VapA/VapB family virulence-associated protein of 143 aas and 2 or more TMSs. |
Bacteria | Actinomycetota | VapA of Oerskovia sp |
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1.A.151.1.1 | 7 TMS ion channel (7TMIC) of 679 aas and 7 TMSs in a 2 or 3 + 2 + 2 + 1 TMS arrangement (Himmel et al. 2023). |
Eukaryota | Ciliophora | 7TMIC of Tetrahymena thermophila |
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1.A.151.1.2 | Uncharacterized protein of 660 aas and 7 - 10 TMSs in a 2 or 3 + 2 or 3 + 2 or 3 + 1 TMS arrangement. |
Eukaryota | Viridiplantae, Streptophyta | UP of Marchantia polymorpha |
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1.A.151.1.3 | Uncharacterized protein of 704 aas and 7 or 8 TMSs in a 2 or 3 + 2 + 2 + 1 TMS arrangement. |
Eukaryota | Ciliophora | UP of Moneuplotes crassus |
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1.A.151.1.4 | Uncharacterized protein of 646 aas and probably 7 TMSs in a 2 + 2 + 2 + 1 TMS arrangement within residues 380 - 646. |
Eukaryota | Ciliophora | UP of Stylonychia lemnae |
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1.A.151.1.5 | Uncharacterized protein of 549 aas and 7 or 8 TMSs in a 2 or 3 + 2 + 2 + 1 TMS arrangement. |
Eukaryota | Ciliophora | UP of Blepharisma stoltei |
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1.A.151.1.6 | Uncharacterized protein of 648 aas with 8 TMSs in a 3 + 2 + 2 + 1 TMS arrangement. |
Eukaryota | UP of Amoeboaphelidium protococcarum |
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1.A.151.2.2 | Uncharacterized protein of 648 aas and 7 or 8 TMSs in a 3 + 2 + 2 + 1 TMS arrangement. |
Eukaryota | Ciliophora | UP of Paramecium tetraurelia |
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1.A.152.1.1 | The Phtf putative ion channel-receptor protein of 880 aas and about 7 TMSs in a2 or 3 + 2 + 2 + 1 TMS arrangement. |
Eukaryota | Metazoa, Arthropoda | Phtf of Drosophila melanogaster |
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1.A.152.1.2 | Putative Phtf1 ion channel protein of 762 aas and possibly 7 TMSs in a 2 + 2 + 2 + 1 TMS arrangement. |
Eukaryota | Metazoa, Chordata | PHTF of Homo sapiens |
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1.A.152.1.3 | Phtf2 of 785 aas and 7 TMSs in a 2 or 2 + 2 + 2 + 1 TMS arrangement (Himmel et al. 2023). |
Eukaryota | Metazoa, Chordata | Phtf2 of Homo sapiens |
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1.A.152.1.4 | PhtF of 752 aas and 7 TMSs in a 2 + 2 + 2 + 1 TMS arrangement. |
Eukaryota | Metazoa, Chordata | PhtF of Gallus gallus |
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1.A.153.1.1 | Uncharacterized glustatory receptor of 554 aas and 7 TMSs in a 4 + 2 + 1 TMS arrangement (Himmel et al. 2023). |
Eukaryota | Metazoa, Tardigrada | UGR of Remazzottius virieornatus (Water bear) (Tardigrade) |
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1.A.153.1.2 | Uncharacterized protein of 486 aas and 7 TMSs in a 2 + 2 + 2 + 1 TMS arrangement. |
Eukaryota | Metazoa, Tardigrada | UP of Hypsibius exemplaris |
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1.A.153.1.3 | Uncharacterized protein of 491 aas and 8 putative TMSs in a 3 + 2 + 2 + 1 TMS arrangement. |
Eukaryota | Metazoa, Tardigrada | UP of Paramacrobiotus metropolitanus |
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1.A.153.1.4 | Uncharacteried protein of 457 aas and possibly 9 TMSs in a 2 + 3 + 2 + 2 TMS arrangement. |
Eukaryota | Metazoa, Tardigrada | UP of Paramacrobiotus metropolitanus |
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1.A.153.1.5 | Uncharacterized protein of 447 aas with 7 TMSs in a 4 + 2 + 1 TMS arrangement. |
Eukaryota | Metazoa, Tardigrada | UP of Hypsibius exemplaris |
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1.A.154.1.1 | TMEM150c/Tentonin 3 of 249 aas and 6 TMSs. According to Anderson et al. 2018, it reglulates channels such as Piezo 1 and Piezo 2. According to Hong et al. 2016, it has inherent channel activity, but Ojeda-Alonso et al. 2022 could not demonstrate this, Nevertheless, Pak et al. 2024 showed that tentonin 3 is a pore-forming subunit of a slow inactivation mechanosensitive channel. They reported that tentonin 3/TMEM150C (TTN3) confers mechanically activating (MA) currents with slow inactivation kinetics in somato- and barosensory neurons. Thus, purified TTN3 proteins incorporated into the lipid bilayer displayed spontaneous and pressure-sensitive channel currents. These MA currents were conserved across vertebrates and differ from Piezo1 in activation threshold and pharmacological response. Deep neural network structure prediction programs coupled with mutagenetic analysis predicted a rectangular-shaped, tetrameric structure with six transmembrane helices and a pore at the inter-subunit center. The putative pore aligned with two helices of each subunit and had constriction sites whose mutations changed the MA currents. These findings suggest that TTN3 is a pore-forming subunit of a distinct slow inactivation MA channel, potentially possessing a tetrameric structure (Pak et al. 2024). It appears that Tentonin 3 may both modify some channels and be one as well. Kang and Lee 2024 have confirmed the ion channel activity of tentonin and examined its structure. |
Eukaryota | Metazoa, Chordata | Tentonin, TMEM150c, of Homo sapiens |
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1.A.16.1.1 | Formate uptake/efflux permease, FocA. It catalyzes bidirectional transport, has a pentameric aquaporin-like (TC# 1.A.8) structure, and may function by a channel-type mechanism (Falke et al., 2009; Wang et al. 2009). The structure at 2.25 Å resolution has been determined (Wang et al., 2009). The protein is encoded in an operon with pyruvate-formate lyase, PflB. A pyruvate:formate antiport mechanism has been suggested (Moraes and Reithmeier 2012). The C-terminal 6 aas are required for formate transport, but not for homopentamer formation (Hunger et al. 2017). The N-terminus of FocA interacts with PflB, and this interaction is essential for optimal formate translocation (Doberenz et al. 2014). In fact, the GREs, TdcE and PflB, interact with the FNT channel protein, probably to control formate translocation by FocA (Falke et al. 2016). The lipophilic constrictions of FocA mainly act as barriers to isolate the central histidine from the aqueous bulk, preventing protonation via proton wires. Thus, an FNT transport model is supported in which the central histidine is uncharged, and weak acid substrate anion protonation occurs in the vestibule regions of the transporter before passing the constrictions (Schmidt and Beitz 2021). An interplay between the conserved pore residues Thr-91 and His-209 controls formate translocation through the FocA channel (Kammel et al. 2022). T91 is essential for formate permeation in both directions; however, it is particularly important to allow anion efflux. H209 is essential for formate uptake by FocA, strongly suggesting that protonation-deprotonation of this residue plays a role in formate uptake. These observations substantiate the premise that efflux and influx of formate by FocA are mechanistically distinct processes that are controlled by the interplay between T91 and H209 (Kammel et al. 2022). |
Bacteria | Pseudomonadota | FocA of E. coli (P0AC23) |
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1.A.16.1.2 |
Probable formate transporter 2 (Formate channel 2), FocB (Andrews et al. 1997). |
Bacteria | Pseudomonadota | FocB of Escherichia coli |
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1.A.16.1.3 | Formate channel, FocA. Competition of formate by Thr90 from the Ω loop may open the channel (Waight et al., 2010). |
Bacteria | Pseudomonadota | FocA of Vibrio cholerae (F9A868) |
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1.A.16.2.1 | Formate-specific channel protein, FdhC of 280 aas (Nölling and Reeve 1997). |
Archaea | Euryarchaeota | FdhC of Methanobacterium thermoformicium |
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1.A.16.2.2 | Nitrite uptake porter, NitA (Unkles et al., 1991; 2011) |
Eukaryota | Fungi, Ascomycota | NitA of Aspergillus (Emericella) nidulans |
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1.A.16.2.3 | Probable formate uptake permease (Wood et al., 2003). |
Archaea | Euryarchaeota | FdhC of Methanococcus maripaludis |
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1.A.16.2.4 | Nitrite uptake porter of 355 aas, Nar1. |
Eukaryota | Viridiplantae, Chlorophyta | Nar1 of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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1.A.16.2.5 | Nitrite channel transporter, NirC, of 382 aas. Structure/function studies including the x-ray structure of the Salmonella orthologue have been reported (Rycovska-Blume et al. 2015). |
Archaea | Thermoproteota | NirC of Thermofilum pendens |
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1.A.16.2.6 | Nitrite/Nitrate exporter of 476 aas, Nar1 (Cabrera et al. 2014). |
Eukaryota | Fungi, Ascomycota | Nar1 of Pichia angusta (Yeast) (Hansenula polymorpha) |
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1.A.16.2.7 | FNT protein of 313 aas and 6 TMSs that transports L-lactacte (Wiechert et al. 2017). Trophozoites are inhibited by drugs such as MMVOO7839 (Golldack et al. 2017, Hapuarachchi et al. 2017). It seems to transport lactic acid which allows concentrative uptake (Bader and Beitz 2020). However, it exports lactate from inside the parasite to the surrounding parasitophorous vacuole within the erythrocyte cytosol (Lyu et al. 2021). |
Eukaryota | Apicomplexa | PfFNT of Plasmodium falciparum |
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1.A.16.2.8 | Formate/nitrite (FNT) transporter of 356 aas and 6 TMSs. |
Eukaryota | Evosea | FNT of Entamoeba histolytica |
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1.A.16.2.9 | Lactate/formate/nitrate antiporter, or lactate:H+ symporter, FNT, possibly energized by the pmf. It is similar to 1.A.16.2.7, two proteins that are are 74% identical to each other). 3-D structures have been elucidated (PDB# 7E26 and 7E27). It is essential and druggable In vivo (Davies et al. 2023). |
Eukaryota | Apicomplexa | Lactate/formate:H+ symporter (release from the cytoplasm) of Plasmodium falciparum |
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1.A.16.3.1 | Nitrite uptake/efflux channel (Jia et al. 2009). |
Bacteria | Pseudomonadota | NirC of E. coli (P0AC26) |
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1.A.16.3.2 | Uncharacterized transporter YwcJ |
Bacteria | Bacillota | YwcJ of Bacillus subtilis |
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1.A.16.3.3 |
Hydrosulfide (hydrogen sulfide; HS-), Fnt3 (Hsc) channel. Also probably transports chloride, formate and nitrite. The 3-d crystal structure (2.2Å resolution in the closed state) is known (PDB# 3TE2) (Czyzewski and Wang, 2012). The Fnt3 gene is linked to the asrABC operon encoding the sulfite (SO32-) reductase that gives HS- as the product (Czyzewski and Wang 2012). |
Bacteria | Bacillota | Hsc or Fnt3 HS- channel of Clostridium difficile (Q186B7) |
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1.A.16.3.4 | Nitrite transporter, NirC, of 268 aas and 6 TMSs (Park et al. 2008). |
Bacteria | Pseudomonadota | NirC of Klebsiella oxytoca |
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1.A.16.3.5 | Formate channel of 283 aas and 6 TMSs, Fnt or FdhC. Its function has been veritifed (Helmstetter et al. 2019). |
Bacteria | Bacillota | FdhC of Bacillus thuringiensis |
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1.A.16.4.1 | Inner membrane protein, YfdC (310aas; 6 TMSs). May be involved in surfactant resistance (Nakata et al. 2010). |
Bacteria | Pseudomonadota | YfdC of E. coli (P37327) |
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1.A.16.4.2 | Putative FNT transporter of 346 aas |
Bacteria | Pseudomonadota | FNT transporter of Psychrobacter arcticus |
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1.A.16.4.3 | FNT homologue of 313 aas |
Archaea | Euryarchaeota | FNT homologue of Salinarchaeum sp. Harcht-Bsk1 |
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1.A.16.5.1 | FNT homologue of 230 aas |
Bacteria | Mycoplasmatota | FNT homologue of Acholeplasma palmae |
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1.A.16.5.2 | FNT homologue of 213 aas |
Bacteria | Mycoplasmatota | FNT homologue of Acholeplasma laidlawii |
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1.A.17.1.1 | The plasma membrane Ca2 -activated chloride (IClCa) channel, TMEM16A (Anoctamin 1a; ANO1a; ANO1, DOG1, ORAOV2, TAOS2) (Huang et al., 2012; Chen et al. 2011). The mouse orthologue (Q8BHY3), TMEM16A (956aas), is localized to the apical membranes of epithelia as well as intracellular membranes in many cell types. Knockout mice show diminished rhythmic contraction of gastric smooth muscle (Huang et al., 2009). ANO1 is also required for normal tracheal development (Ousingsawat et al., 2009). Expression is upregulated by epidermal growth factor (Mroz and Keely, 2012). Novel 5-substituted benzyloxy-2-arylbenzofuran-3-carboxylic acids are inhibitors (Kumar et al., 2012). TMEM16A channels contribute to the myogenic response in cerebral arteries (Bulley et al., 2012). Membrane stretch activates arterial myocyte TMEM16A channels, leading to membrane depolarization and vasoconstriction. A local Ca2+ signal generated by nonselective cation channels stimulates TMEM16A channels to induce myogenic constriction (Bulley et al., 2012). Ca2+/calmodulin activates bicarbonate (anion) transport (Jung et al. 2012). The protein exists in the membrane as a homodimer where the cytoplasmic N-terminus functions in dimerization (Tien et al. 2013). TMSs 5-6 of the 8 TMSs may comprise parts of the pore-loop that controls Cl- conductance (Adomaviciene et al. 2013). ANO1 confers IClCa in retinal neurons and acts as an intrinsic regulator of the presynaptic membrane potential during synaptic transmission (Jeon et al. 2013). TMEM16A may be a primary driver of the "Grow" (tumor proliferation) or "Go"(metastasis) model for cancer progression, in which TMEM16A expression acts to balance tumor proliferation and metastasis via its promoter methylation (Shiwarski et al. 2014). Regulation of TMEM16A/16B by Ca2+ is mediated by preassociated apo-calmodulin (Yang et al. 2014) as well as CaMKIIδ (Gui et al. 2015). Because the Cl- channel is the only active ion-selective conductance with a reversal potential that lies within the dynamic range of spiral ganglion neurons (SGN) action potentials, developmental alteration of [Cl-], and hence the equilibrium potential for Cl- (ECl), transforms the pre- to the post-hearing phenotype (Zhang et al. 2015). Four basic residues involved in ion selectivity and pore blocker sensitivity have been identified (Peters et al. 2015). Channel activity is required for mucus secretion induced by interleukin-13 (Lin et al. 2015; Zhang et al. 2015). Ano1 may interact cooperatively with TrpV1 (TC# 1.A.4.2.1) to form a thermal sensor (Kanazawa and Matsumoto 2014). Inhibitors have been described (Boedtkjer et al. 2015). The first intracellular loop serves as a Ca2+ binding site and includes D439, E444 and E447 (Pang et al. 2015). It is inhibited by various 4-Aryl-2-amino thiazoles at concentrations as low as 1 mμM (Piechowicz et al. 2016). ANO1 and TRPC6 (1.A.4.1.5) are present in the same macromolecular complex and localize in close spatial proximity in the myocyte plasma membrane. TRPC6 channels probably generate a local intracellular Ca2+ signal that activates nearby ANO1 channels in myocytes to stimulate vasoconstriction (Wang et al. 2016). ANO1 transports bicarbonate which functions in the regulation of pancreatic acinar cell pH (Han et al. 2016). TMEM16A contains two ion conduction pores that are independently activated by Ca2+ binding to sites that are embedded within the transmembrane part of each subunit (Lim et al. 2016). Interactions between the carboxy- terminus and the first intracellular loop in the TMEM16A homo-dimer regulate channel activity (Scudieri et al. 2016). A STAT6-TMEM16A-ERK1/2 signal pathway and TMEM16A channel activity are required for the Interleukin-13 (IL-13)-induced TMEM16A-mediated mucus production (Qin et al. 2016). Angiotensin II elicits a TMEM16A-mediated current, and TMEM16A participates in Ang II-induced basilar constriction via the RhoA/ROCK signaling pathway (Li et al. 2016). 2-acylamino-cycloalkylthiophene-3-carboxylic acid arylamides (AACTs) are inhibitors of TMEM16A, and 48 synthesized analogs (10ab-10bw) of the original AACT compound (10aa) have been synthesized and studied. The most potent compound (10bm), which contains an unusual bromodifluoroacetamide at the thiophene 2-position, had an IC50 ~ 30 nM (Truong et al. 2017). Ano1 plays a role in asthma (Wang et al. 2017). The E143A mutant showed reduced sensitivity to Ca2+ but not to high temperatures, whereas the E705V mutant exhibited reduced sensitivity to both Ca2+ and noxious heat (Choi et al. 2018). Voltage modulation of TMEM16A involves voltage-dependent occupancy of calcium- and anion-binding site(s) within the membrane electric field as well as a voltage-dependent conformational change intrinsic to the channel protein. These gating modalities all critically depend on the sixth transmembrane segment (Peters et al. 2018). TMEM16A in myocytes plays a major functional role in contraction (Mohanakumar et al. 2018). Bile acids activate TMEM16A and thereby increase cholangiocyte fluid secretion (Li et al. 2018). TMEM16A participates in H2O2-induced apoptosis via modulation of mitochondrial membrane permeability (Zeng et al. 2018). Glioma-associate oncogene proteins, Gli1 and Gli2, bind to the promoter and repress ANO1 transcription, dependent on Gli binding to a site close to the ANO1 transcriptional start site (Mazzone et al. 2019). Clarithromycin suppresses IL-13-induced goblet cell metaplasia via the TMEM16A-dependent pathway in guinea pig airway epithelial cells (Hara et al. 2019). TMEM16A is involved in gastric emptying, and TMEM16A inhibition may be effective in treating disorders of accelerated gastric emptying, such as dumping syndrome (Cil et al. 2019). Phosphatidylinositol (4,5)-bisphosphate (PIP2) regulates TMEM16A channel activation and desensitization by binding to a binding site, possibly at the cytosolic interface of TMSs 3-5. The ion-conducting pore of TMEM16A consists of two functionally distinct modules: a Ca2+-binding module formed by TMSs 6-8 and a PIP2-binding regulatory module formed by TMs 3-5, which mediate channel activation and desensitization, respectively (Sui et al. 2020). TMEM16A plays a dual role in LPS-induced intestinal epithelial barrier dysfunction (Sui et al. 2020). Hepatocyte TMEM16A plays a role in nonalcoholic fatty liver disease (NAFLD), and its deletion retards NAFLD progression by ameliorating hepatic glucose metabolic disorder (Guo et al. 2020). Hepatocyte TMEM16A interacts with vesicle-associated membrane protein 3 (VAMP3) to induce its degradation, suppressing the formation of the VAMP3/syntaxin 4 and VAMP3/synaptosome-associated protein 23 complexes (see TC# 1.F.1.1.5). This leads to impairment of hepatic glucose transporter 2 (GLUT2) translocation and glucose uptake (Guo et al. 2020). TMEM16A is a potential biomarker for Lung Cancer (Hu et al. 2019). Allosteric modulation of alternatively spliced Ca2+-activated Cl- channels, TMEM16A by PI(4,5)P2 and CaMKII (TC# 8.A.104.1.11) has been demonstrated (Ko et al. 2020). Signaling through the interleukin-4 and interleukin-13 receptor complexes regulates cholangiocyte TMEM16A expression and biliary secretion (Dutta et al. 2020). A second Ca2+ binding site allosterically controls TMEM16A activation (Le and Yang 2020). A long noncoding RNA (lncRNA), ANO1-AS2, downregulates the ANO1 gene by interacting with the ANO1 gene promoter, which can influence sperm motility and morphology (Saberiyan et al. 2020). Ano1 plays an important role in generating urethral tone (Drumm et al. 2021). Human TMEM16A shows increated expression in many cancers (Chen et al. 2021). TMEM16A is inhibitied by liquiritigenin (Kato et al. 2021) and is activated by the natural product canthaxanthin which promotes gastrointestinal contraction (Ji et al. 2020). TMEM16A ameliorates vascular remodeling by suppressing autophagy via inhibiting Bcl-2-p62 complex formation. It regulates the four-way interaction between p62 (P37198; TC# 1.I.1.1.3), Bcl-2 (TC# 1.A.21.1.10), Beclin-1 (BECN1 or GT197; Q144570; TC# 9.A.15.2.1), and VPS34 (phosphatidylinositol 3-kinase, PI 3-kinase, PIK3C3), and coordinately prevents vascular autophagy and remodeling (Lv et al. 2020). A small molecule inhibitor of TMEM16A (2-bromodifluoroacetylamino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbox ylic acid o-tolylamide) blocks vascular smooth muscle contraction and lowers blood pressure in spontaneously hypertensive rats (Cil et al. 2021). Evodiamine and rutecarpine are TMEM16A inhibitors (Zhao et al. 2021). Cepharanthine is a selective ANO1 inhibitor with potential for lung adenocarcinoma therapy (Zhang et al. 2021). Benzophenanthridine alkaloids suppress lung adenocarcinoma by blocking TMEM16A Ca2+-activated Cl- channels (Zhang et al. 2020). The diverse roles of TMEM16A Ca2+-activated Cl- channels in inflammation have been described (Bai et al. 2021). TMEM16A-mediated breast cancer metastasis has been described in which ROCK1 increases TMEM16A channel activity via moesin phosphorylation. An increase in TMEM16A channel activity promotes cell migration and invasion (Luo et al. 2021). Four Ca2+ sensing sites in TMEM16A have been identfied, and the activation properties of TMEM16A by them has been discussed (Ji et al. 2021). Blockade of TMEM16A protects against renal fibrosis by reducing the intracellular Cl- concentration (Li et al. 2021). The TMEM16A/anoctamin 1 inhibitor T16Ainh-A01 reverses monocrotaline-induced rat pulmonary arterial hypertension (Xie et al. 2020). The role of TMEM16A/ERK/NK-1 signaling in dorsal root ganglia neurons in the development of neuropathic pain induced by spared nerve injury has been studied (Chen et al. 2021). Elevated ANO1 (DOG1) expression is frequent in colorectal cancer and is linked to molecular alterations (Jansen et al. 2022). ANO1 plays a role in the occurrence, development, metastasis, proliferation, and apoptosis of various malignant tumors. Guo et al. 2022 reviewed the mechanism of ANO1 involved in the replication, proliferation, invasion and apoptosis of various malignant tumors. Procyanidin (PC) is an efficacious and selective inhibitor of TMEM16A with an IC50 of 10.6 +/- 0.6 muM. The precise sites (D383, R535, and E624) of electrostatic interactions between PC and TMEM16A are known (Li et al. 2022). TMEM16A is a Ca2+activated Cl- channel that plays critical roles in regulating vascular tone, sensory signal transduction, and mucosal secretion. TMEM16A activation also requires the membrane lipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) (Tembo et al. 2022). TMEM16A may promote angiogenesis of the heart during pressure-overload (Zhang et al. 2022), and it is an immunohistochemical marker of acinic cell carcinoma (Fiorentino et al. 2022). The progress in understanding solute carrier SLC families in nonalcoholic fatty liver disease has been reviewed (Tang et al. 2022). Arctigenin attenuates vascular inflammation induced by high salt through the TMEM16A/ESM1/VCAM-1 pathway (Zeng et al. 2022). Biologics that inactivate Nav1.7 channels have the potential to reduce arthritis pain over a protracted period of time (Reid et al. 2022). Allicin, containing thiosulfinate moieties, inhibits TMEM16A) ion channel activity (Bai et al. 2023). TMEM16A) plays a role in pulmonary hypertension (Yuan et al. 2023). Chloride channels in biliary epithelial cells provide the driving force for biliary secretion. Norursodeoxycholic acid (norUDCA) potently stimulated chloride currents in mouse large cholangiocytes, which was blocked by siRNA silencing and pharmacological inhibition of TMEM16A (Truong et al. 2023). TMEM16A partners with mTOR to influence pathways of cell survival, proliferation, and migration in cholangiocarcinoma (Kulkarni et al. 2023). Analysis of inhibitors of TMEM16A revealed indirect mechanisms involving alterations in calcium signalling (Genovese et al. 2023). Dysregulation of TMEM16A impairs oviductal transport of embryos (Ning et al. 2023). TMEM16A may be a target for cancer treatment (Li et al. 2023). Vasodilators activate TMEM16A in endothelial cells to reduce blood pressure (Mata-Daboin et al. 2023). Tubular TMEM16A promotes tubulointerstitial fibrosis by suppressing PGC-1alpha-mediated mitochondrial homeostasis in diabetic kidney disease (Ji et al. 2023). The TMEM16A channel is a potential therapeutic target for vascular diseases (Al-Hosni et al. 2024). Extracellular glucose and dysfunctional insulin receptor signaling independently upregulate arterial smooth muscle TMEM16A expression (Raghavan et al. 2024). Tamsulosin ameliorates bone loss by inhibiting the release of Cl- through wedging into an allosteric site of TMEM16A (Li et al. 2025). Dysregulation of TMEM16A impairs oviductal transport of embryos (Ning et al. 2023). Salinity and prolactin regulate anoctamin 1 in the model teleost, Fundulus heteroclitus (Breves et al. 2024). Lysis of human erythrocytes due to Piezo1-dependent cytosolic calcium overload provides a mechanism of circulatory removal (Kuck et al. 2024). Hemin has anticancer effects through ANO1 Inhibition in human prostate cancer cells (Park et al. 2024). |
Eukaryota | Metazoa, Chordata | Anoctamin 1a of Homo sapiens (Q5XXA6) |
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1.A.17.1.10 | Anoctamin, Anoh-2. Present in mechanoreceptive neurons and spermatheca (Wang et al. 2013). |
Eukaryota | Metazoa, Nematoda | Anoh-2 of Caenorhabditis elegans |
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1.A.17.1.11 | Anoctamin-like protein At1g73020 | Eukaryota | Viridiplantae, Streptophyta | At1g73020 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.17.1.12 | Ca-ClC Family homologue |
Eukaryota | Ciliophora | Ca-ClC homologue of Paramecium tetraurelia (A0CAP8) |
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1.A.17.1.13 | Ciliate CaClC homologue |
Eukaryota | Ciliophora | CaClC homologue of Paramecium tetraurelia (A0CIB0) |
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1.A.17.1.14 | Water mold Anoctamin-like protein |
Eukaryota | Oomycota | Anoctamin-like protein of Phytophthora infestans (D0NGF4) |
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1.A.17.1.15 | Uncharacterized protein |
Eukaryota | Fungi, Ascomycota | Uncharacterized protein of Schizosaccharomyces japonicus |
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1.A.17.1.16 | Anoctamin-like protein of 701 aas and 8 possible TMSs. |
Eukaryota | Ciliophora | Anoctamin-like protein of Oxytricha trifallax |
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1.A.17.1.17 | TMEM16 (Ist2) ion channel/phospholipid scramblase of 735 aas and 8 - 10 TMSs (Malvezzi et al. 2013). Three high-resolution cryo-EM structures of this scramblase, reconstituted in lipid nanodiscs, revealed that Ca2+-dependent activation of the scramblase entails global rearrangement of the transmembrane and cytosolic domains. Activation of the protein thins the membrane near the transport pathway to facilitate rapid transbilayer lipid movement (Falzone et al. 2019).
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Eukaryota | Fungi, Ascomycota | Ist2 of Aspergillus fumigatus (Neosartorya fumigata) |
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1.A.17.1.18 | TMEM16 of 735 aas and 10 TMSs. Operates as a Ca2+-activated lipid scramblase (Wang et al. 2018). Each subunit of the homodimer contains a hydrophilic membrane-traversing cavity that is exposed to the lipid bilayer as a potential site of catalysis. This cavity harbours a conserved Ca2+-binding site, located within the hydrophobic core of the membrane. Mutations of residues involved in Ca2+ coordination affect both lipid scrambling in N. haematococca TMEM16 and ion conduction in the Cl- channel of TMEM16A. The structure reveals the general architecture of the family and its mode of Ca2+ activation (Brunner et al. 2014). While the cytoplasmic portion of the protein is important for function, it does not appear to regulate scramblase activity via a detectable conformational change (Andra et al. 2018). Dynamic modulation of the lipid translocation groove generates a conductive ion channel in Ca2+-bound nhTMEM16 (Khelashvili et al. 2019) (see family description). Permeation of potassium ions through the lipid scrambling path of nhTMEM16 has been documented (Cheng et al. 2022). Citral amide derivatives possess antifungal activity against Rhizoctonia. solani (Zhang et al. 2024). |
Eukaryota | Fungi, Ascomycota | TMEM16 of Nectria haematococca (Fusarium solani subsp. pisi) |
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1.A.17.1.19 | Increased sodium tolerance protein, Ist2, of 946 aas and 7 TMSs. Ist2 is an endoplasmic reticulum (ER)-resident transmembrane protein that mediates associations between the plasma membrane (PM) and the cortical ER (cER) in baker's yeast (Kralt et al. 2015). |
Eukaryota | Fungi, Ascomycota | Ist2 of Saccharomyces cerevisiae |
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1.A.17.1.2 | Anoctamin 1, isoform b (Gnathodiaphyseal dysplasia 1 protein homologue) (39% identical to Anoctamin 1a) (Planells-Cases and Jentsch, 2009). See also Xu et al. 2015. |
Eukaryota | Metazoa, Chordata | Anoctamin 1b of Homo sapiens (Q75UR0) |
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1.A.17.1.20 | Anoctamin 3, ANO3 or TMEM16C or KCNT1/Slack, of 981 aas and 9 putative TMSs. Has calcium-dependent phospholipid scramblase activity, scrambling phosphatidylcholine and galactosylceramide. Seems to act as a potassium channel regulator and may inhibit pain signaling; can facilitate KCNT1/Slack channel activity by promoting its full single-channel conductance at very low sodium concentrations and by increasing its sodium sensitivity (Scudieri et al. 2012). Mutations cause (i) epilepsy of infancy with migrating focal seizures (EIMFS; also known as migrating partial seizures in infancy), (ii) autosomal dominant nocturnal frontal lobe epilepsy, and (iii) other types of early onset epileptic encephalopathies (EOEEs) (Ohba et al. 2015). TMEM16C/Slack regulation of excitatory synaptic plasticity via GluA1-containing AMPA Receptors is critical for the pathogenesis of remifentanil-induced postoperative hyperalgesia in rats (Li et al. 2021). Specific mutational variants in TMS of ANO3 can be responsible for childhood-onset movement disorders with intellectual disability (Aihara et al. 2022). ANO3 variants have been identified as the cause of craniocervical dystonia (Ousingsawat et al. 2024). ANO3 variants may dysregulate intracellular Ca2+ signalling, as variants in other Ca2+ regulating proteins like hippocalcin (TC# 8.A.82.2.8) were also identified as causes of dystonia. ANO3 is a Ca2+-activated phospholipid scramblase that also conducts ions. Impaired Ca2+ signalling and compromised activation of Ca2+-dependent K+ channels were detected in cells expressing ANO3 variants. The association between ANO3 variants and paroxysmal dystonia, represents a link between these variants and this specific dystonic phenotype (Ousingsawat et al. 2024). |
Eukaryota | Metazoa, Chordata | ANO3 or KCNT1 of Homo sapiens |
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1.A.17.1.21 | Ano5 (GDD1, TMEM16E), of 913 aas and 10 TMSs, is an intracellular calcium-activated chloride channel in the endoplasmic reticulum. It positively modulates bone homeostasis via calcium signaling in GDD (Li et al. 2022), and is associated with bone fragility, limb girdle muscular dystrophy type 2L (LGMD2L), Miyoshi myopathy type 3 (MMD3), and gnathodiaphyseal dysplasia 1 (GDD1) in humans (Jin et al. 2017), but an Ano5 knock-out mutant in mice was not reported to exhibit such symptoms (Xu et al. 2015). The orthologue in mice is TC# 1.A.17.1.2. TMEM16E may function as a phospholipid scramblase in intracellular membranes, promoting sperm motility and function (Gyobu et al. 2016). Dysregulated calcium homeostasis prevents plasma membrane repair in Anoctamin 5/TMEM16E-deficient patient muscle cells (Chandra et al. 2019). Ano5 is involved in familial florid osseous dysplasia (Lv et al. 2019). Pharmacological inhibition of ANO5 or lack of ANO5, prevent Ca2+ uptake into the ER following plasma membrane damage and Ca2+ overload (Chandra et al. 2021). Thus, Cl- uptake into the ER is required to sequester injury-promoted cytosolic Ca2+. Anoctamin 5 regulates the cell cycle and affects the prognosis in gastric cancer (Fukami et al. 2022). Thus, ANO5 may be a key mediator in tumor progression and promises to be a prognostic biomarker for gastric cancer. TMEM16E regulates endothelial cell procoagulant activity and thrombosis (Schmaier et al. 2023). |
Eukaryota | Metazoa, Chordata | Ano5 of Homo sapiens |
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1.A.17.1.22 | Subdued, a calcium-activated chloride channel of 1075 aas. Functions in conjunction with the thermo-TRPs in thermal nociception. Subdued channels may amplify the nociceptive neuronal firing that is initiated by thermo-TRP channels in response to thermal stimuli (Jang et al. 2015). It may also act on phospholipids to transport or hydrolyze them (Le et al. 2019). |
Eukaryota | Metazoa, Arthropoda | Subdued of Drosophila melanogaster |
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1.A.17.1.23 | ANO-like protein of 921 aas and 9 predicted TMSs. |
Eukaryota | Metazoa, Echinodermata | ANO-L family protein of Strongylocentrotus purpuratus (Purple sea urchin) |
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1.A.17.1.24 | Duplicated full length anoctamin of 2084 aas and an etimated 20 TMSs. The protein has two full length repeats, each of about 1000 aas with a ~500 aas hydrophilic domain followed by the first anoctamin domain, and then another 500 aa hydrophilic domain followed by the second anoctamin domain. |
Eukaryota | Oomycota | Dupicated anoctamin of Aphanomyces invadans |
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1.A.17.1.25 | TMem16A or Anoctamin-1 (Ano1) Ca2+-activated anion (Cl-) channel of 960 aas and 10 TMSs. Its structure has been solved by cryoEM (Paulino et al. 2017). The protein shows a similar organization to the fungal nhTMEM16, except for changes at the site of catalysis. There, the conformation of transmembrane helices, constituting a membrane-spanning furrow that provides a path for lipids in scramblases, is replaced to form an enclosed aqueous pore that is largely shielded from the membrane (Paulino et al. 2017). It thus provides a pathway for anions such as Cl-. During activation, the binding of Ca2+ to a site located within the transmembrane domain, in the vicinity of the pore, alters the electrostatic properties of the ion conduction path and triggers a conformational rearrangement of an α-helix that comes into physical contact with the bound ligand, and thereby directly couples ligand binding and pore opening (Paulino et al. 2017). The E143A mutant showed reduced sensitivity to Ca2+ but not to high temperatures, whereas the E705V mutant exhibited reduced sensitivity to both Ca2+ and noxious heat (Choi et al. 2018). Loss of TMEM16A resulted in reduced nephron number and, subsequently, albuminuria and tubular damage (Schenk et al. 2018). mAno1 expression is regulated via alternative promoters, and its transcriptional variation results in variation of the N-terminal sequence of the Ano1 protein due to alternative translation initiation sites (Kamikawa et al. 2018). The Ca2+ gating mechanism of TMEM16A, involving a Ca2+-sensing element close to the anion pore, alters conduction and substrate selection. De Jesús-Pérez et al. 2022 studied the gating-permeant anion relationship using mouse TMEM16A, showing that the apparent Ca2+ sensitivity increases with highly permeant anions and SCN- mole fractions, likely by stabilizing bound Ca2+. Conversely, mutations in crucial gating elements, including the Ca2+-binding site 1,TMS 6, and the hydrophobic gate, impaired anion permeability and selectivity. Thus, there is a reciprocal rationship between gating and selectivity (De Jesús-Pérez et al. 2022). Propagation of pacemaker activity and peristaltic contractions in the mouse renal pelvis rely on Ca2+-activated Cl- Channels such as Ano1 and T-type Ca2+ channels (Grainger et al. 2022). |
Eukaryota | Metazoa, Chordata | Ano1 of Mus musculus |
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1.A.17.1.26 | Anoctamin-10 or TMEM16K of 660 aas and 9 or 10 TMSs. In the presence of Ca2+, TMEM16K directly binds Ca2+ to form a stable complex (Ishihara et al. 2016). In the absence of Ca2+, TMEM16K and TMEM16F (TC# 1.A.17.1.4) aggregate, suggesting that their structures are stabilized by Ca2+. Mutagenesis of acidic residues in TMEM16K's cytoplasmic and transmembrane regions identified five residues that are critical for binding Ca2+. These residues are well conserved between TMEM16F and 16K, and point mutations of these residues in TMEM16F reduced its ability to support Ca2+-dependent phospholipid scrambling (Ishihara et al. 2016). Phosphatidyl serine in the ER of mammalian cells is predominantly localized to the cytoplasmic leaflet, but TMEM16K directly or indirectly mediates Ca2+-dependent phospholipid scrambling (Tsuji et al. 2019). Ano10 plays roles in cell division, migration, apoptosis, cell signalling, and developmental processes (Chrysanthou et al. 2022). There is structural heterogeneity within the ion and lipid channel of TMEM16F (Ye et al. 2024). It coordinates organ morphogenesis in the urochordate notochord (Liang et al. 2024). In fact, anoctamin 10/TMEM16K coordinates organ morphogenesis across scales in the urochordate notochord (Liang et al. 2024). |
Eukaryota | Metazoa, Chordata | TMEM16K of Homo sapiens |
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1.A.17.1.27 | Anoctamin 7, ANO7, or TMEM16G, of 933 aas and 10 TMSs. It has calcium-dependent phospholipid scramblase activity, scrambling phosphatidylserine, phosphatidylcholine and galactosylceramide, but it does not exhibit calcium-activated chloride channel (CaCC) activity. It may play a role in cell-cell interactions (Das et al. 2008). ANO7 is associated with aggressive prostate cancer (Kaikkonen et al. 2018). Insights into the topology and function of Ano7 have been described (Guo et al. 2021). Activation of calcium-activated chloride channels suppresses inherited seizure susceptibility in genetically epilepsy-prone rats (Thomas et al. 2022).
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Eukaryota | Metazoa, Chordata | ANO7 of Homo sapiens |
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1.A.17.1.28 | Anoctamin1, Ano1, TMEM16A of 979 aas and 10 TMSs. It is probably an anion (Cl-) cannel. Fertilization activates TMEM16A channels in X. laevis eggs and induces the earliest known event triggered by fertilization: the fast block to polyspermy (Wozniak et al. 2018). |
Eukaryota | Metazoa, Chordata | Ano1 of Xenopus laivis |
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1.A.17.1.29 | Anoctamin-4, ANO4, TMEM16D, of 955 aas and 10 putative TMSs. 68% identical to ANO3 (TC# 1.A.17.1.20). It has calcium-dependent phospholipid scramblase activity, scrambling phosphatidylserine, phosphatidylcholine and galactosylceramide, and it is a Ca2+-dependent non-selective cation channel (Reichhart et al. 2019). ANO4 is primarily expressed in the CNS and certain endocrine glands, and mutations affecting protein stability have been associated with various neuronal disorders (Reichhart et al. 2021). (E,E)-farnesol is a sesquiterpene acyclic alcohol produced by bacteria, protozoa, fungi, plants, and animals that has vasorelaxant activity (Batista et al. 2023). . |
Eukaryota | Metazoa, Chordata | ANO4 of Homo sapiens |
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1.A.17.1.3 | TMEM16B (Anoctamin-2, ANO2) anion channel. Exists in the membrane as a homodimer where the cytoplasmic N-terminus functions in dimerization (Tien et al. 2013). TMSs 5-6 may comprise parts of the pore-loop that controls Cl- conductance (Adomaviciene et al. 2013). TMEM16A and TMEM16B are differentially expressed during development in the olfactory epithelium of the mouse (Maurya and Menini 2014). |
Eukaryota | Metazoa, Chordata | TMEM16B of Homo sapiens (Q9NQ90) |
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1.A.17.1.30 | Anoctamin-8, Ano8 or TMEM16H, of 1232 aas and 9 TMSs. It tethers the endoplasmic reticulum and plasma membrane for assembly of Ca2+ signaling complexes at the ER/PM compartment (Jha et al. 2019). ANO8 is a key tether in the formation of the ER/PM junctions that are essential for STIM1-STIM1 interaction and STIM1-Orai1 interaction and channel activation at a ER/PM PI(4,5)P2-rich compartment. Moreover, ANO8 assembles all core Ca2+ signaling proteins: Orai1, PMCA, STIM1, IP3 receptors, and SERCA2 at the ER/PM junctions to mediate a novel form of Orai1 channel inactivation by markedly facilitating SERCA2-mediated Ca2+ influx into the ER. This controls the efficiency of receptor-stimulated Ca2+ signaling, Ca2+ oscillations, and the duration of Orai1 activity to prevent Ca2+ toxicity (Jha et al. 2019).
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Eukaryota | Metazoa, Chordata |
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1.A.17.1.31 | Anoctamin 8, Ano8, of 1232 aas and ~ 8 or 9 TMSs. It may not exhibit calcium-activated chloride channel (CaCC) activity, but paclitaxel induces pyroptosis by inhibiting the volume‑sensitive chloride channel leucine‑rich repeat‑containing 8a in ovarian cancer cells (Yang et al. 2023). . |
Eukaryota | Metazoa, Chordata | Ano8 of Homo sapiens |
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1.A.17.1.32 | Anoctamin 1 of 1008 aas and 9 putative TMSs. Salinity and prolactin regulate anoctamin 1 in the model teleost, Fundulus heteroclitus (Breves et al. 2024). |
Eukaryota | Metazoa, Chordata | Anoctamin 1 of Fundulus heteroclitus |
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1.A.17.1.4 | Anoctamin-6 (ANO6: TMEM16F) Ca2+-dependent phospholipid scramblase (flippase) (Suzuki et al., 2010; Chauhan et al. 2016). Defects cause Scott syndrome, and promote assembly of the tenase and prothrombinase complexes involved in blood coagulation (Fujii et al. 2015). It is an essential component of the outwardly rectifying chloride channel (Martins et al., 2011; Keramidas and Lynch 2012). It has also been reported to be an anion channel with delayed Ca2+ activation (Adomaviciene et al. 2013) as well as a Ca2+-activated cation channel with activity that is required for lipid scrambing (Yang et al. 2012). However, Suzuki et al. (2013) showed that TMEM16F is a Ca2+-dependent phospholipid scramblase that exposes phosphatidylserine (PS) to the cell surface but lacks calcium-dependent chloride channel activity (see also Segawa et al. 2011). TMEM16C, 16D, 16G and 16J also have Ca2+-dependent scramblase activities but not channel activity (Suzuki et al. 2013). The pore region suggested to be resonsible for Cl- transport in TMEM16A is also responsible for phospholipid scramblase activity (Suzuki et al. 2014). Anoctamin-6 (Ano6) plays an essential role in C2C12 myoblast proliferation, probably by regulating the ERK/AKT signaling pathway (Zhao et al. 2014). It regulates baeline phosphatidyl serine exposure and cell viability in human embryonic kidney cells (Schenk et al. 2016). A single TMEM16F molecule transports phospholipids nonspecifically between the membrane bilayers dependent on Ca2+. Thermodynamic analyses indicated that TMEM16F transports 4.5 x 104 lipids per second at 25 degrees C, with an activation free energy of 47 kJ/mol, suggesting a channel-dependent, facilitated diffusion,"stepping-stone" mechanism (Watanabe et al. 2018). TMEM16F plays roles in platelet activation during blood clotting, bone formation, and T cell activation. Activation of TMEM16F by Ca2+ ionophores triggers large-scale surface membrane expansion in parallel with phospholipid scrambling (Bricogne et al. 2019). With continued ionophore application,TMEM16F-expressing cells undergo extensive shedding of ectosomes which incorporate The T cell co-receptor PD-1. Cells lacking TMEM16F fail to expand the surface membrane in response to elevated cytoplasmic Ca2+and instead undergo endocytosis with PD-1 internalization. This suggests a new role for TMEM16F as a regulator of Ca2+-activated membrane trafficking (Bricogne et al. 2a019). The inner activation gate consists of three hydrophobic residues, F518, Y563 and I612, in the middle of the phospholipid permeation pathway. Disrupting the inner gate profoundly alters phospholipid permeation. Lysine substitutions of F518 and Y563 lead to constitutively active CaPLSases that bypass Ca2+-dependent activation. An analogous lysine mutation to TMEM16F-F518 in TMEM16A (L543K) is sufficient to confer CaPLSase activity to the Ca2+-activated Cl- channel (CaCC) (Le et al. 2019). ANO6, by virtue of its scramblase activity, may play a role as a regulator of the ADAM-network in the plasma membrane. TMEM16F inhibition limits pain-associated behavior and improves motor function by promoting microglia M2 polarization in mice (Zhao and Gao 2019). Polyphenols do not inhibit the phospholipid scramblase activity of TMEM16F (Le et al. 2020). TMEM16F is a ubiquitously expressed Ca2+-activated phospholipid scramblase that also functions as a largely non-selective ion channel with open, closed and intermediate conformations (Jia et al. 2022). An inner activation gate consists of F518, Y563, and I612, and charged mutations of the inner gate residues leads to constitutively active mammalian (m)TMEM16F scrambling. Lysine substitution of F518 and Y563 leads to spontaneous opening of the permeation pore in the Ca2+-bound state of mTMEM16F. Dilation of the pore exposes hydrophilic patches in the upper pore region, greatly increases the pore hydration level, and enables lipid scrambling (Jia et al. 2022). |
Eukaryota | Metazoa, Chordata | Anoctamin-6 of Homo sapiens (Q4KMQ2) |
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1.A.17.1.5 | Anoctamin-9 (Transmembrane protein 16J) (Tumor protein p53-inducible protein 5) (p53-induced gene 5 protein). It promotes pancreatic tumorigenesis (Jun et al. 2017). |
Eukaryota | Metazoa, Chordata | ANO9 of Homo sapiens |
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1.A.17.1.6 | Uncharacterized protein |
Eukaryota | Fungi, Chytridiomycota | Uncharacterized protein of Batrachochytrium dendrobatidis |
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1.A.17.1.7 | Anoctamin-like protein |
Eukaryota | amoctamin-like protein of Dictyostelium purpureum |
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1.A.17.1.8 | Uncharacterized protein |
Eukaryota | Metazoa, Mollusca | unchacterized protein of Aureococcus anophagefferens |
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1.A.17.1.9 | Anoctamin, Anoh-1 of 822 aas. Functions in a sensory mode-specific manner. Present inamphid sensory neurons to detect external chemical and nociceptive cues (Wang et al. 2013). |
Eukaryota | Metazoa, Nematoda | Anoh-1 of Caenorhabditis elegans |
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1.A.17.2.1 | DUF590 family protein |
Eukaryota | Evosea | DUF590 protein of Dicyostelium discoideum (Q54BH1) |
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1.A.17.2.2 | TMEM16 homologue of 701 aas. |
Eukaryota | Heterolobosea | TMEM16 homologue of Naegleria gruberi (Amoeba) |
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1.A.17.2.3 | Anoctamin homologue of 689 aas |
Eukaryota | Anoctamin of Guillardia theta |
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1.A.17.2.4 | DUF590 homologue of 487 aas |
Eukaryota | Evosea | DUF590 homologue of Entamoeba nuttalli |
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1.A.17.2.5 | DUF590 protein of 914 aas |
Eukaryota | Fungi, Blastocladiomycota | DUF590 protein of Allomyces macrogynus |
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1.A.17.2.6 | Uncharacterized protein of 569 aas and 8 predicted TMSs. |
Eukaryota | Evosea | UP of Dictyostelium fasciculatum (Slime mold) |
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1.A.17.3.1 | Uncharacterized protein of 2464 aas and 11 TMSs. Contains a trypsin-like serine protease domain (residues 100 - 400), a rabaptin (chromosome segregation) domain (residues 900 - 1200), an anoctamin domain (residues 1500 - 2000) and an AAA ATPase-containing von Willebrand factor type A domain (residues 2200 - 2500). |
Eukaryota | Bacillariophyta | UP of Thalassiosira pseudonana (Marine diatom) (Cyclotella nana) |
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1.A.17.3.10 | Uncharacterized protein of 1080 aas |
Eukaryota | Viridiplantae, Chlorophyta | UP of Ostreococcus lucimarinus |
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1.A.17.3.11 | Anoctamin homologue of 1265 aas |
Eukaryota | Ciliophora | Anoctamin homologue of Tetrahymena thermophila |
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1.A.17.3.12 | Uncharacterized protein of 995 aas and 8 TMSs. |
Eukaryota | Ciliophora | UP of Tetrahymena thermophila |
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1.A.17.3.13 | Uncharacterized protein of 10 TMSs in a 3 + 4 +3 arrangement |
Eukaryota | Ciliophora | UP of Paramecium tetraurelia |
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1.A.17.3.14 | Uncharacterized protein of 888 aas and 10 TMSs in a 3 + 4 + 3 arrangement |
Eukaryota | Ciliophora | UP of Paramecium tetraurelia |
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1.A.17.3.15 | Uncharacterized protein of 958 aas and 11 or 12 TMSs in a 3 or 4 + 5 +3 arrangement. |
Eukaryota | Ciliophora | UP of Paramecium tetraurelia |
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1.A.17.3.2 | Uncharacterized protein of 842 aas and 9 TMSs. |
Eukaryota | Bacillariophyta | UP of Thalassiosira pseudonana (Marine diatom) (Cyclotella nana) |
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1.A.17.3.3 | Uncharacterized protein of 835 aas and 9 TMSs. |
Eukaryota | Oomycota | UP of Phytophthora parasitica (Potato buckeye rot agent) |
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1.A.17.3.4 | Uncharacterized protein of 1231 aas and 9 TMSs |
Eukaryota | UP of Aureococcus anophagefferens (Harmful bloom alga) |
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1.A.17.3.5 | Uncharacterized protein of 945 aas and 8 TMSs |
Eukaryota | UP of Ectocarpus siliculosus (Brown alga) |
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1.A.17.3.6 | Uncharacterized protein of 1437 aas |
Eukaryota | Haptophyta | UP of Emiliania huxleyi |
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1.A.17.3.7 | Uncharacterized protein of 1150 aas |
Eukaryota | UP of Capsaspora owczarzaki |
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1.A.17.3.8 | DUF590/putative methyltransferase of 1221 aas and 10 TMSs. |
Eukaryota | Ciliophora | DUF490 homologue of Oxytricha trifallax |
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1.A.17.3.9 | DUF590 homologue of 1026 aas and 10 TMSs |
Eukaryota | Ciliophora | DUF590 homologue of Paramecium tetraurelia (ciliate) |
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1.A.17.4.1 | TMC2, like TMC1, plays a role in hearing and gravity detection (Kawashima et al., 2011). Required for normal function of cochlear hair cells, possibly as a Ca2+ channel (Kim and Fettiplace 2013). TMC1 and TMC2 are both components of hair cell transduction channels and contribute to permeation properties (Pan et al. 2013; Kawashima et al. 2014). Both TMC1 and 2 interact with Protocadherin 15 (Maeda et al. 2014). TMC1 and TMC2 are components of the stereocilia mechanoelectrical transduction channel complex (Kurima et al. 2015). While TMC2 is required for mechanotransduction in mature vestibular hair cells, its expression in the immature cochlea may be an evolutionary remnant (Corns et al. 2017). Transgenic Tmc2 expression preserves inner ear hair cells and vestibular function in mice lacking Tmc1 (Asai et al. 2018). Gentamicin and other antibiotics enter neonatal mouse hair cells predominantly through sensory mechanoelectrical transduction channels, Tmc1 and Tmc2 (Makabe et al. 2020). Human TMC1 and TMC2 are mechanically gated ion channels (Fu et al. 2025).
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Eukaryota | Metazoa, Chordata | TMC2 of Mus musculus (Q8R4P4) |
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1.A.17.4.10 | Transmembrane channel 6, TMC6/EVER1 of 805 aas. Mutations give rise to epidermodysplasia verruciformis (EV), a rare genodermatosis, characterized by increased sensitivity to infection by the beta-subtype of human papillomaviruses (beta-HPVs), causing persistent, tinea versicolor-like dermal lesions (Horton and Stokes 2014). Biallelic mutations in either TMC6 or TMC8 are detected in more than half of the cases of the pre-malignant skin disease epidermodysplasia verruciformis (EV) which together form a complex with CIB1 (TC# 8.A.82.1.9) (Wu et al. 2020). |
Eukaryota | Metazoa, Chordata | TMC6 of Homo sapiens |
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1.A.17.4.11 | Transmembrane channel 8, TMC8/EVER2/EVIN2 of 726 aas. Mutations give rise to epidermodysplasia verruciformis (EV), a rare genodermatosis characterized by increased sensitivity to infection by the beta-subtype of human papillomaviruses (beta-HPVs) as well as increased incidence of cancer, causing persistent, tinea versicolor-like dermal lesions (Horton and Stokes 2014). This is due to release of Zn2+ and Ca2+ from the endoplasmic reticulum (Sirianant et al. 2014). The channel-like domain has been identified (Miyauchi et al. 2016). It plays a role in several aspects of human pathophysiology, such as ion channel permeability, human papillomavirus infection and skin cancer (Lu et al. 2017). Biallelic mutations in either TMC6 or TMC8 are detected in more than half of the cases of the pre-malignant skin disease epidermodysplasia verruciformis (EV), which together form a complex with CIB1 (TC# 8.A.82.1.9) in lymphocytes (Wu et al. 2020). TMC8 is a prognostic immune-associated gene in head and neck squamous cancer (HNSC) cells (Lin et al. 2021).
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Eukaryota | Metazoa, Chordata | TMC8 of Homo sapiens |
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1.A.17.4.12 | Transmembrane channel protein 3, Tmc3 of 1130 aas (Kurima et al. 2003; Beurg et al. 2014). LPS-inducible lncRNA TMC3-antisense-1 (AS1) negatively regulates the expression of IL-10 (Ye et al. 2020). In the brown planthopper, Nilaparvata lugens, TMCs is highly expressed in the female reproductive organ especially in the oviduct (Jia et al. 2020). RNAi-mediated silencing of Nltmc3 substantially decreased the egg-laying number and impaired ovary development. |
Eukaryota | Metazoa, Chordata | Tmc3 of Mus musculus |
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1.A.17.4.13 | Tmc1/Tmc2a or Tmc2b/protocadherin 15a (Pcdh15a). The complex is part of a mechanotransduction system (Maeda et al. 2014). Its trafficing to the plasma membrane depends on the transmembrane O-methyltransferase (TOMT/LRTOMT; 259 aas, 1 N-terminal TMS) (Erickson et al. 2017). Water motion is dependent on this complex (Chou et al. 2017). The role of another protein, Tmie (see TC# 8.A.115), in sensory hair cells is to target and stabilize the Tmc channel subunits to the stereocilia, the site of mechano-electrical transduction (Pacentine and Nicolson 2019). Tmc proteins 1, 2a and 2b are essential for zebrafish hearing although Tmc1 is not, probably because they can (at least partially) substitute for each other (Chen et al. 2020). There are two distinct cell types in inner ear hairs, an upper layer of teardrop shaped cells that rely on Tmc2a, and a lower layer of gourd shaped cells that rely on Tmc1/2b (Smith et al. 2020). Tmc reliance in the ear is dependent on the organ, subtype of hair cell, position within the ear, and axis of best sensitivity (Zhu et al. 2020). |
Eukaryota | Metazoa, Chordata | Tmc1/Tmc2/Pcdh15 complex of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.A.17.4.14 | Tmc4 (MBOAT7) of 712 aas and 10 TMSs (Mancina et al. 2016). It is a calcium-dependent chloride channel that may play a role in nonalcoholic fatty liver disease (NAFLD) (Sookoian et al. 2018) but is not associated with a risk of hepatocellular carcinoma or persistent hepatitis B infection (Wang et al. 2021). Ibuprofen only minimally inhibits the taste response of the ENaC to NaCl, but it significantly inhibits the TMC4 response to NaCl with an IC50 at 1.45 mM. Thus, ibuprofen interferes with detection of salty taste via inhibition of TMC4 (Kasahara et al. 2021). This agrees with the fact that TMC4 is a chloride channel involved in high-concentration salt taste sensation (Kasahara et al. 2021). TMC4 is involved in pH and temperature-dependent modulation of salty taste (Kasahara et al. 2021). Salt-enhancing peptides were identified based on the allosteric sites in TMC4 (Shen et al. 2022). Mechanisms of salt taste reception and the properties of TMC4 as a salt taste-related molecule have been reviewed (Kasahara et al. 2022). Genetic polymorphisms in TMC4 predispose organisms to a higher risk of liver diseases (Rivera-Iñiguez et al. 2022). Umami peptides bind to the TMC4 receptor to enhance saltiness (Xie et al. 2023). Salt-enhancing peptides can effectively reduce sodium consumption from Largemouth bass myosin through virtual hydrolysis, molecular simulation, and sensory evaluation (Bu et al. 2024). Human TMC4 was constructed using Alphafold2. DAF, QIF, RPAL, and IPVM significantly enhanced the saltiness perception, and QIF exhibited the most pronounced effect in enhancing saltiness (P < 0.05). The residues Ala258, Ser546, Ser603, Phe259, Cys265, Glu539, Lys278 and Ser585 were identified as key binding sites (Bu et al. 2024). The saltiness enhancement taste peptides from Jinhua ham and its molecular mechanism of interaction with ENaC/TMC4 receptors has been studied (Ji et al. 2025). |
Eukaryota | Metazoa, Chordata | TMC4 of Homo sapiens |
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1.A.17.4.15 | The mechanoelectric-transduction (MT or MET) complex in auditory hair cells converts the mechanical stimulation of sound waves into neural signals. Tmc1 is of 760 aas and 10 TMSs and is 96% identical to mouse TMC1 (TC# 1.A.17.4.6). Novel TMC1 structural and splice variants are associated with congenital nonsyndromic deafness (Meyer et al. 2005). Variants responsible for hereditary hearing loss have been identified (Wang et al. 2018). There are varying numbers of channels per MET complex, each requiring multiple TMC1 molecules, and together operating in a coordinated, cooperative manner (Beurg et al. 2018). Ballesteros et al. 2018 generated a model of TMC1 based on X-ray and cryo-EM structures of TMEM16 proteins, revealing the presence of a large cavity near the protein-lipid interface that harbors the Beethoven mutation, suggesting that it functions as a permeation pathway. Hair cells are permeable to 3 kDa dextrans, and dextran permeation requires TMC1/2 proteins and functional MET channels (Ballesteros et al. 2018). TMC1 is a pore-forming component of MET channels in auditory and vestibular hair cells (Pan et al. 2018). KCNQ1 rescues TMC1 plasma membrane expression but not mechanosensitive channel activity (Harkcom et al. 2019). A Tmc1 mutation reduces calcium permeability and expression of MET channels in cochlear hair cells (Beurg et al. 2019). Deafness mutation D572N of TMC1 destabilizes TMC1 expression by disrupting LHFPL5 binding (Yu et al. 2020). Homozygous variants in the TMC1 and CDH23 (3354 aas and at least two TMSs, one N-terminal and one near the C-terminus; Q9H251) genes cause autosomal recessive nonsyndromic hearing loss (Zardadi et al. 2020). TMC1 forms a complex with protocadherin 15 (PCDH15, TC# 1.A.82.1.1), lipoma HMGIC fusion partner-like 5 (LHFPL5, TC# 1.A.82.1.1), and transmembrane inner ear protein (TMIE, TC# 8.A.116.1.2). Splicing isoforms of TMC1, LHFPL5, and TMIE have been identified (Zhou et al. 2021). There are four alternative splicing events for the genes encoding these three proteins. The alternative splicing of TMC1 and LHFPL5 is cochlear-specific and occurs in both neonatal and adult (mouse) cochleae (Zhou et al. 2021). Tmc1 deafness mutations impact mechanotransduction in auditory hair cells (Beurg et al. 2021). A TMC1 synonymous substitution is a variant disrupting splicing regulatory elements associated with recessive hearing loss (Vaché et al. 2021). The roles of solute carriers in auditory function have been reviewed (Qian et al. 2022). Autosomal recessive and dominant non-syndromic hearing loss can be due to pathogenic TMC1 variants (Kraatari-Tiri et al. 2022). Mechanical gating of the auditory transduction channel TMC1 involves the fourth and sixth TMSs (Akyuz et al. 2022). Regulation of membrane homeostasis by TMC1 mechanoelectrical transduction channels is essential for hearing (Ballesteros and Swartz 2022). The conductance and organization of the TMC1-containing mechanotransducer channel complex in auditory hair cells has been examined, and it was concluded that each PCDH15 (see 1.A.17.4.13 and 1.A.82.1.1) and LHFPL5 (see 1.A.17.4.15 and 1.A.82.1.1) monomer may contact two channels, irrespective of location (Fettiplace et al. 2022). In addition to mutations in the TMC1 gene, those in MYO3A, PEX6, and KCNQ1 genes can contribute to hearing loss (Elbagoury et al. 2025). . |
Eukaryota | Metazoa, Chordata | TMC1 of Homo sapiens |
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1.A.17.4.16 | Transmembrane Channel-Like Protein 5, TMC5, of 1006 aas and 11 putative TMSs. It promotes prostate cancer cell proliferation through cell cycle regulation and could be a target for treatment (Zhang et al. 2019). Up-regulated TMC5 indicates advanced tumor stage in pancreatic adenocarcinoma (PAAD) patients, and its role in promoting PAAD development may be regulated by STAT3 (Gan et al. 2023). |
Eukaryota | Metazoa, Chordata | TMC5 of Homo sapiens |
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1.A.17.4.17 | Transmembrane channel-like protein 1 of 878 aas and ~ 11 TMSs (Erives and Fritzsch 2019). Mechanosensory transduction (MT) in specialized hair cells of the inner ear may be mediated by TMC1 as the pore component. Other components of the MT complex include protocadherin 15, cadherin 23, lipoma HMGIC fusion partner-like 5, transmembrane inner ear, calcium and integrin-binding family member 2, and ankyrins (Zheng and Holt 2020). |
Eukaryota | Metazoa, Porifera | TMC1 of Amphimedon queenslandica |
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1.A.17.4.18 | Transmembrane channel-like (TMC7) protein, of 723 aas and 11 TMSs. It probably transports Ca2+, and other cations. It is important for oral tongue squamous cell carcinoma (OTSCC), with rapid local invasion and metastasis. The long noncoding (lnc) RNA MIR4713HG is markedly upregulated in OTSCC. Upregulation of MIR4713HG promotes cell proliferation and metastasis (Jia et al. 2021). Micro RNA let7c5p physically binds MIR4713HG, and knockdown of let7c5p counteracts the effect of MIR4713HG on OTSCC. let7c5p exerted this role by affecting the expression level of TMC7 (Jia et al. 2021). TMC7 also affects other types (rectal and panrecatic) of cancer (Watanabe et al. 2014; Cheng et al. 2019), and may be associated with psychosis proneness (Ortega-Alonso et al. 2017). TMC7 deficiency causes acrosome biogenesis defects and male infertility in mice (Wang et al. 2024). TMC7, a non-mechanosensitive TMC, inhibits Piezo2-dependent mechanosensation (West and Schneider 2024). TMC7 functions as a suppressor of Piezo2 in primary sensory neurons blunting peripheral mechanotransduction (Zhang et al. 2024). |
Eukaryota | Metazoa, Chordata | TMC7 of Homo sapiens |
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1.A.17.4.19 | TMC-1 of 1285 aas and 9 TMSs in a 2 + 3 + 4 TMS arrangement. Mutants show strong defects in the avoidance of NaCl concentrations above 100 mM (Chatzigeorgiou et al. 2013). Tmc-1 is a sodium-sensitive channel required for salt chemosensation in C. elegans (Chatzigeorgiou et al. 2013). |
Eukaryota | Metazoa, Nematoda | TMC-1 of Caenorhabditis elegans |
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1.A.17.4.2 | Transmembrane channel-like protein-B, Tmc8 (EVER2). It occurs in the endoplasmic reticulum where it functions to release Ca2+ and Zn2+ and supresses Cl- currents (Sirianant et al. 2014). The functional variant, rs7208422 of the TMC8 gene, has been suggested to have a high impact on susceptibility to beta-papillomaviruses and their oncogenic potential and to also have an influence on alpha-type HPV-related disease (Stoehr et al. 2021). |
Eukaryota | Metazoa, Chordata | Tmc8 of Mus musculus (Q7TN58) |
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1.A.17.4.3 | Hypothetical protein, HP |
Eukaryota | HP of Salpingoeca sp. (F2U2C0) |
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1.A.17.4.4 | Hypothetical protein, HP |
Eukaryota | HP of Capsaspora owczarzaki (E9C7I1) |
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1.A.17.4.5 | Transmembrane channel-like protein 7, TMC7 |
Eukaryota | Metazoa, Arthropoda | TMC7 of Acromyrmex echinatior (F4X8H9) |
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1.A.17.4.6 | Transmembrane channel-like protein-1, Tmc1. Also called Transmembrane cochlear-expressed protein-1, Beethoven protein and deafness protein. Required for normal function of cochlear hair cells, possibly as a Na+/K+/Ca2+ channel (Kim and Fettiplace 2013). TMC1 and TMC2 are both components of hair cell transduction channels and contribute to permeation properties (Pan et al. 2013; Kawashima et al. 2014). Channel activity has been demonstrated for the C. elegans orthologue, and the mouse Tmc1. The C. elegans Tmc1 is probably a Na+-activated Na+-selective mechanosensor. The C. elegans Tmc2 may be a Na+/K+ channel. The mouse Tmc1 is functional and replaces Tmc2 when expressed in C. elegans (WR Schafer, personal communication). Ca2+ currents are blocked by the peptide toxin GsMTx-4 (Beurg et al. 2014). Tmc1 and Tmc2, expressed in cochlear and vestibular hair cells, are required for hair cell mechanoelectric transduction (Nakanishi et al. 2014); mutations disrupt mechanoelectric transduction and are a cause of autosomal dominant and recessive forms of nonsyndromic hearing loss (Gao et al. 2015). Using the mutant mouse model (Tmc1; Beethoven) for progressive hearing loss in humans (DFNA36) this mutation has been shown to affect the MET channel pore, reducing its Ca2+ permeability and its affinity for the permeant blocker, dihydrostreptomycin (Corns et al. 2016). Evidence for TMC1 being the hair cell mechanosensitive channel has been evaluated (Fettiplace 2016). The human orthologue (UniProt acc # Q8TDI8) is 96% identical. Mouse LHFPL5 ((HMGIC fusion partner-like protein 5) co-expresses with TMC1 in auditory hair cells (Li et al. 2019). A region within the N-terminus of mouse TMC1 (residues 138 - 168) precludes trafficking from an intracellular location to the plasma membrane (Soler et al. 2019). TMC1 is an essential component of a leak channel that modulates tonotopy and excitability of mouse auditory hair cells (Liu et al. 2019). VRISPER/Cas has been used to correct defects that result in hereditary hearing loss (Farooq et al. 2020). Repair of Tmc1 via genetic engineering in vivo restored inner hair cell sensory transduction and hair cell morphology and transiently rescued low-frequency hearing (Yeh et al. 2020). TMC1 forms a mechano-electrical transduction channel, which transduces mechanical stimuli into electrical signals at the top of stereocilia of hair cells in the inner ear. Yamaguchi et al. 2023 found that the cytosolic N-terminal region of heterologously-expressed mouse TMC1 (mTMC1) was localized in nuclei of a small population of the transfected HEK293 cells. This raised the possibility that the N-terminal region of heterologously-expressed mTMC1 was cleaved and transported into the nucleus (Yamaguchi et al. 2023). Both Tmc1 and Tmc2 may be mechano-transduction ion channels in ear hair cells (Fu et al. 2025). |
Eukaryota | Metazoa, Chordata | Tmc1 of Mus musculus |
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1.A.17.4.7 | The sodium sensor/cation conductance channel activated by high extracellular Na+, Tmc-1 (Tmc1) (Chatzigeorgiou et al. 2013). It functions in salt taste chemosensation and salt avoidance and is an ionotropic sensory receptor. Wang et al. 2016 showed that C. elegans TMC-1 mediates nociceptor responses to high pH, not sodium, allowing the nematode to avoid strongly alkaline environments in which most animals cannot survive (Spalthoff and Göpfert 2016). TMC-1 and TMC-2 are required for normal egg laying in C. elegans. Mutations in these proteins cause membrane hyperpolarization and disrupt the rhythmic calcium activities in both neurons and muscles involved in egg laying. Mechanistically, TMC proteins enhance membrane depolarization through background leak currents, and ectopic expression of both C. elegans and mammalian TMC proteins results in membrane depolarization (Yue et al. 2018). TMC-1 is necessary for sodium attraction, but not aversion in the nematode. Dao et al. 2020 showed that TMC-1 contributes to the nematode's lithium induced attraction behavior, but not potassium or magnesium attraction, thus clarifying the specificity of the response. In addition, they found that sodium conditioned aversion is dependent on TMC-1 and disrupts both sodium- and lithium-induced attraction (Dao et al. 2020). The C. elegans Tmc-1 is involved in egg-laying inhibition in response to harsh touch (Kaulich et al. 2021). The initial step in the sensory transduction pathway underpinning hearing and balance in mammals involves the conversion of force into the gating of a mechanosensory transduction channel. Jeong et al. 2022 reported the single-particle cryo-EM structure of TMC-1 from C. elegans. The two-fold symmetric complex is composed of two copies each of the pore-forming TMC-1 subunit, the calcium-binding protein CALM-1 and the transmembrane inner ear protein TMIE. CALM-1 (see TC# 8.A.82.1.1) makes contacts with the cytoplasmic face of the TMC-1 subunits, whereas the single-pass TMIE subunits (see TC# 8.A.116) reside on the periphery of the complex, poised like the handles of an accordion. A subset of complexes includes a single arrestin-like protein, arrestin domain protein (ARRD-6; see TC# 8.A.136.1.15), bound to a CALM-1 subunit. Single-particle reconstructions and molecular dynamics simulations showed how the mechanosensory transduction complex deforms the membrane bilayer to suggest roles for lipid-protein interactions in the mechanism by which mechanical force is transduced to ion channel gating (Jeong et al. 2022). |
Eukaryota | Metazoa, Nematoda | TMC-1 of Caenorhabditis elegans |
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1.A.17.4.8 | Tmc2 channel of 1203 aas and 9 - 11 TMSs; functions in touch neurons as a mechanosensitive touch sensor (Chatzigeorgiou et al. 2013; WR Schafer, personal communication). May function as a Na+/K+ channel. TMC-1 and TMC-2 are required for normal egg laying in C. elegans. Mutations in these proteins cause membrane hyperpolarization and disrupt the rhythmic calcium activities in both neurons and muscles involved in egg laying. Mechanistically, TMC proteins enhance membrane depolarization through background leak currents, and ectopic expression of both C. elegans and mammalian TMC proteins results in membrane depolarization (Yue et al. 2018). The structure of the C. elegans TMC-2 complex suggests roles of lipid-mediated subunit contacts in mechanosensory transduction (Clark et al. 2023). The complex is composed of two copies of the pore-forming TMC-2 subunit, the calcium and integrin binding protein CALM-1 and the transmembrane inner ear protein TMIE. Comparison of the TMC-2 complex to the recently published cryo-EM structure of the C. elegans TMC-1 complex highlights conserved protein-lipid interactions, as well as a pi-helical structural motif in the pore-forming helices, that together suggest a mechanism for TMC-mediated mechanosensory transduction (Clark et al. 2024). TMC ion channels are expressed throughout the animal kingdom. Mammals express eight TMCs (mTMC1-8), two of which (mTMC1 and mTMC2) are subunits of mechanotransduction channels (Jiang et al. 2024). C. elegans expresses TMC-1 and TMC-2, which mediate mechanosensation, egg laying, and alkaline sensing. Association with accessory proteins tunes nematode TMC-1 to divergent sensory functions, and distinct TMC-1 domains enable touch and alkaline sensing. These domains are segregated in mammals between mTMC1 and mTMC3. Consistent with these findings, mammalian mTMC1 can mediate mechanosensation in nematodes, while mTMC3 can mediate alkaline sensation. Thus, sequence diversification and association with accessory proteins has led to the emergence of TMC protein complexes with diverse properties and physiological functions (Jiang et al. 2024). The structure of the Caenorhabditis elegans TMC-2 complex suggests roles of lipid-mediated subunit contacts in mechanosensory transduction (Clark et al. 2024). |
Eukaryota | Metazoa, Nematoda | Tmc2 of Caenorhabditis elegans |
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1.A.17.4.9 | Tmc receptor/channel of 1932 aas and about 10 TMSs. Plays a role in Drosophila proprioception and the sensory control of larval locomotion (Guo et al. 2016). These Tmc channels may be activated by membrane curvature in dendrites that are exposed to strain, possibly explaining how different cellular systems rely on a common molecular pathway for mechanosensory responses (He et al. 2019). |
Eukaryota | Metazoa, Arthropoda | Tmc of Drosophila melanogaster |
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1.A.17.5.1 | Uncharacterized protein, DUF221, of 703 aas |
Eukaryota | Viridiplantae, Streptophyta | UP of Zea mays |
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1.A.17.5.10 | The non-rectifying, plasma membrane, calcium-permeable, stress-gated, cation channel 1 (CSC1) of 771 aas (Hou et al. 2014). Activated by hyperosmotic shock. Permeable to Ca2+, K+ and Na+. Inactivation or closure is Ca2+-dependent. The N-terminal region contains 3 TMSs, the first of which may be a cleavable signal peptide., and the C-terminal region contains 6 TMSs corresponding to the DUF221 domain. Arabidopsis contains at least 15 CSCs ((Hou et al. 2014). Some plant homologues are transcriptionally upregulated in response to vaious abiotic and biotic stresses involving mechanical perturbation (Kiyosue et al. 1994). |
Eukaryota | Viridiplantae, Streptophyta | CSC1 of Arabidopsis thaliana |
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1.A.17.5.11 | Osmotically-gated calcium conductance channel of 782 aas. CSC1 (Hou et al. 2014). Activated under hyperosmotic conditions. There are four paralogues in S. cerevisiae. |
Eukaryota | Fungi, Ascomycota | CSC1 of Saccharomyces cerevisiae |
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1.A.17.5.12 | The osmosensitive calcium-permeable cation channel, CSC1 or Tmem63c, of 806 aas and ~10 TMSs. It is activated by hyperosmolarity and Ca2+ (Hou et al. 2014). Tmem63c is a potential pro-survival factor in angiotensin II-treated human podocytes (Eisenreich et al. 2020). It is regulated by microRNA-564 and transforming growth factor beta (TGFβ) in human renal cells, and is therefore a potential target for albuminuria development (Orphal et al. 2020). TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia (Tábara et al. 2022). Mechanosensitivity in OSCA (plants) and TMEM63 (animals) channels is affected by oligomerization and suggest gating mechanisms that may be shared by OSCA/TMEM63, TMEM16, and TMC channels (all in TC family 1.A.17) (Zheng et al. 2023).
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Eukaryota | Metazoa, Chordata | CSC1 of Homo sapiens |
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1.A.17.5.13 | Uncharacterized protein of 901 aas |
Eukaryota | Fornicata | UP of Spironucleus salmonicida |
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1.A.17.5.14 | Uncharacterized protein of 1267 aas and 12 TMSs |
Eukaryota | Evosea | UP of Dictyostelium discoideum (Slime mold) |
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1.A.17.5.15 | Uncharacterized protein of 1548 aas and 12 TMSs. |
Eukaryota | Bacillariophyta | UP of Thalassiosira pseudonana (Marine diatom) (Cyclotella nana) |
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1.A.17.5.16 | Uncharacterized protein of 1172 aas |
Eukaryota | Kinetoplastida | UP of Phytomonas sp. isolate EM1 |
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1.A.17.5.17 | Uncharacterized protein of 1258 aas and 11 TMSs. |
Eukaryota | Fungi, Basidiomycota | UP of Agaricus bisporus (White button mushroom) |
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1.A.17.5.18 | Csc1 homologue of 866 aas and ~ 11 TMSs. Deletioin of this gene causes C. albicans to become senstive to cations and SDS, tolerant to antifungal agents and produce filamentation (Jiang and Yang 2018). |
Eukaryota | Fungi, Ascomycota | Csc1 homologue of Candida albicans |
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1.A.17.5.19 | OSCA1.2 or TMEM63 of 772 aas and 11 TMSs. It is a dimer containing eleven TMSs per subunit, similar to other TMEM16 proteins. Jojoa Cruz et al. 2018 located the ion permeation pathway within each subunit by demonstrating that a conserved acidic residue is a determinant of channel conductance. Molecular dynamics simulations revealed membrane interactions, suggesting a role of lipids in gating. The high resolution structure of this hyperosmolality-gated calcium-permeable channel has been determined (Liu et al. 2018). It contains 11 TMSs and forms a homodimer. The pore-lining residues were clearly identified. Its cytosolic domain contains an RNA recognition motif and two unique long helices. The linker between these two helices forms an anchor in the lipid bilayer and may be essential to osmosensing. Genome-wide analyses of OSCA gene family members in Vigna radiata have revealed their involvement in the osmotic response (Yin et al. 2021). There are 42 OSCA channel proteins in Triticum aestivum, and their diverse roles during development and stress responses have been evaluated (Kaur et al. 2022). Its ion transport activity and structure have been examined (Kang and Lee 2024). |
Eukaryota | Viridiplantae, Streptophyta | OSCA1.2 of Arabidopsis thaliana (Mouse-ear cress) |
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1.A.17.5.2 | Uncharacterized protein of 816 aas containe a DUF221 domain |
Eukaryota | Metazoa, Chordata | UP of Danio rerio |
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1.A.17.5.20 | Dimeric OSCA1.2 of 766 aas and 11 TMSs. The 3-D structure has been determined (K. Maity et al., PNAS, in press). This protein is 69% identical to the A. thaliana ortholog (TC# 1.A.17.5.10). It is a putative early stress-responsive osmolality-sensing ion channel protein. A model has been proposed by which it may mediate hyperosmolality-sensing and consequent gating of ion transport. It has a cytosolic domain structurally related to RNA recognition proteins that includes helical arms paralell to the plane of the membrane. They may sense lateral tension in the inner leaflet, caused by changes in turgor pressure, allowing gating of the channel via coupling of the two domains. |
Eukaryota | Viridiplantae, Streptophyta | OSCA1.2 of Oryza sativa subsp. japonica (Rice) |
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1.A.17.5.21 | TMEM63A or CSC1-like protein of 807 aas and ~10 TMSs. Heterozygous variants in TMEM63A have been identified as the cause of infantile-onset transient hypomyelination. TMEM63A variants are thought to cause transient hypomyelination with favorable developmental progress, but identification of a novel TMEM63A variant showed that the TMEM63A-related clinical spectrum is broad and includes severe developmental delay with seizures (Fukumura et al. 2021). Knowledge has been reviewed about the activation mechanisms and biological functions of TMEM63 channels, and this review provides a concise reference for researchers interested in investigating more physiological and pathogenic roles of this family of proteins with ubiquitous expression in the body (Chen et al. 2023). The protein is a monomer with 11 TMSs (Wu et al. 2024). The mechanosensor that couples breathing to surfactant secretion in the llung is the transmembrane 63 (TMEM63) ion channel (Hook 2024). Single lysine mutations in TMS4 allow non-scrambling Transmembrane Channel/Scramblase (TCS) members to permeate phospholipids (Lowry et al. 2024). Thus, a key role of TMS4 is to control TCS ion and lipid permeation and offers novel insights into the evolution of the TCS superfamily, suggesting that, like TMEM16s, the OSCA/TMEM63 systems maintain a conserved potential to permeate ions and phospholipids. The structure of human TMEM63A in the presence of calcium has been solved by single particle cryo-EM, revealing a distinct monomeric architecture containing eleven transmembrane helices. It has structural similarity to the single subunit of the Arabidopsis thaliana OSCA proteins. Wu et al. 2024 located the ion permeation pathway within the monomeric configuration and observed a nonprotein density resembling lipid. |
Eukaryota | Metazoa, Chordata | TMEM63A of Homo sapiens |
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1.A.17.5.22 | Hyperosmolality-gated Ca2+ permeable channel 2.3, OSCA2.3, of 703 aas and 11 TMSs. The structure of mechanically activated ion channel OSCA2.3 revealed mobile elements in the transmembrane domain (Jojoa-Cruz et al. 2024). |
Eukaryota | Viridiplantae, Streptophyta | OSCA2.3 of Arabidopsis thaliana (thale cress) |
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1.A.17.5.23 | DUF221 domain-containing CSC1 protein (AN2880 gene) of 1033 aas and 11 TMSs. The calF7 mutation in Aspergillus nidulans causes hypersensitivity to the cell wall compromising agents Calcofluor White (CFW) and Congo Red. Hill et al. 2023 demonstrated that the calF7 mutation resides in gene AN2880, encoding a member of the OSCA/TMEM63 family of transmembrane glycoproteins. GFP-tagged wild type CalF localizes principally to the Spitzenkorper and the plasma membrane at growing tips and forming septa. However, both septation and hyphal morphology appear to be normal in calF7 and AN2880 deletion strains, indicating that any role played by CalF in normal hyphal growth and cytokinesis is dispensable (Hill et al. 2023). |
Eukaryota | Fungi, Ascomycota | CalF7 in AN2880 of Aspergillus nidulans |
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1.A.17.5.24 | CSC1-like protein ERD4 of 724 aas and 11 or 10 TMSs in a 3 + 7 or 8 TMS arrangement. It acts as a hyperosmolarity-gated non-selective cation channel that permeates Ca2+ ions, and is a |
Eukaryota | Viridiplantae, Streptophyta | ERD4 of Arabidopsis thaliana (Mouse-ear cress) |
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1.A.17.5.25 | TMEM63 of 463 aas and possibly 8 TMSs in a 4 + 4 TMS arrangement.
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Eukaryota | Metazoa, Arthropoda | TMEM63 of Lepeophtheirus salmonis |
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1.A.17.5.26 | CSC1-like protein, putative of 1039 aas and possibly 9 or 10 TMSs in a 3 (N-terminal) + 6 or 7 TMSs (C-terminal). |
Eukaryota | Apicomplexa | CSC1 protein of Plasmodium falciparum |
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1.A.17.5.3 | Transmembrane protein 63B of 832 aas and about 10 TMSs with a DUF221 domain. It acts as an osmosensitive calcium-permeable cation channel, and is a mechanosensitive ion channel that converts mechanical stimuli into a flow of ions. It is a stretch-activated ion channel that associates with developmental and epileptic encephalopathies as well as progressive neurodegeneration (Vetro et al. 2023). |
Eukaryota | Metazoa, Chordata | TMEM63B of Homo sapiens |
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1.A.17.5.4 | Uncharacterized transmembrane protein 63B of 832 aas with a DUF221 domain. |
Eukaryota | Discosea | UP of Acanthamoeba castellanii |
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1.A.17.5.5 | Uncharacterized protein of 853 aas with a DUF221 domain. |
Eukaryota | Fungi, Ascomycota | UP of Botryotinia fuckeliana |
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1.A.17.5.6 | Phosphate metabolism protein 7, Phm7, of 991 aas and 11 TMSs in a 3 + 4 + 2 + 2 TMS arrangement. It may act as an osmosensitive calcium-permeable cation channel. PHM6 and PHM7 genes are essential for phosphate surplus in the cells of Saccharomyces cerevisiae (Kulakovskaya et al. 2023). PHM6 is not homologous to PHM7 and is a small protein of 104 aas and 1 C-terminal TMS. |
Eukaryota | Fungi, Ascomycota | Phm7 of Saccharomyces cerevisiae |
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1.A.17.5.7 | Sporulation-specific protein 75, Spo75 |
Eukaryota | Fungi, Ascomycota | Spo75 of Saccharomyce cerevisiae |
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1.A.17.5.8 | RSN-1-like protein of 957 aas |
Eukaryota | Fungi, Ascomycota | RSN-1-like protein of Saccharomyces kudriavzevii |
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1.A.17.5.9 | Early response to dehydrate stress protein, ERD4 of 785 aas. The orthologous channel protein in Dionaea muscipula may play a role in touch-induced hair calcium-electrical signals that excite the Venus flytrap (Scherzer et al. 2022). |
Eukaryota | Viridiplantae, Streptophyta | ERD4 of Arabidopsis thaliana |
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1.A.17.6.1 | Uncharacterized protein of 878 aas and 7 putative TMSs. |
Eukaryota | Ciliophora | UP of Oxytricha trifallax |
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1.A.17.6.10 | Uncharacterized protein of 707 aas and 10 TMSs |
Eukaryota | Endomyxa | UP of Plasmodiophora brassicae |
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1.A.17.6.2 | TMC-like protein 8 of 890 aas and 8 TMSs |
Eukaryota | Ciliophora | TMC homologue of Oxytricha trifallax |
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1.A.17.6.3 | Uncharacterized protein of 834 aas and 7 TMSs |
Eukaryota | Ciliophora | UP of Oxytricha trifallax |
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1.A.17.6.4 | Uncharacterized protein of 912 aas and 10 TMSs |
Eukaryota | Oomycota | UP of Phytophthora parasitica (Potato buckeye rot agent) |
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1.A.17.6.5 | Uncharacterized protein of 620 aas and 9 TMSs |
Eukaryota | UP of Ectocarpus siliculosus (Brown alga) |
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1.A.17.6.6 | Uncharacterized protein of 865 aas and 10 TMSs |
Eukaryota | UP of Guillardia theta |
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1.A.17.6.7 | TMC protein of 890 aas and 10 TMSs |
Eukaryota | Ciliophora | TMC protein of Tetrahymena thermophila |
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1.A.17.6.8 | Uncharacterized protein of 1057 aas and 10 TMSs. |
Eukaryota | Ciliophora | UP of Tetrahymena thermophila |
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1.A.17.6.9 | Uncharacterized protein of 867 aas and 10 TMSs. |
Eukaryota | Oomycota | UP of Saprolegnia diclina |
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1.A.17.7.1 | Uncharacterized protein of 836 aas and 12 TMSs. |
Eukaryota | Fornicata | UP of Giardia intestinalis (Giardia lamblia) |
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1.A.17.7.2 | Uncharacterized protein of 637 aas and 8 TMSs. |
Eukaryota | Fornicata | UP of Spironucleus salmonicida |
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1.A.17.7.3 | Distant Anoctamin homologue of 718 aas and 14 TMSs in a 4 + 1+1+1+2+2+2+1 arramgement. |
Eukaryota | Fornicata | Anoctamin homologue of Spironucleus salmonicida |
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1.A.17.7.4 | Uncharacterized Anoctamin homologue of 502 aas and 8 putative TMSs |
Eukaryota | Fornicata | UP of Spironucleus salmonicida |
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1.A.17.7.5 | Uncharacterized anoctamin homologue of 823 aas and 8 predicted TMSs in a 3 + 2 + 3 arrangement. |
Eukaryota | Fornicata | UP of Giardia intestinalis (Giardia lamblia) |
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1.A.18.1.1 | Protein import-related anion-selective channel, Tic110 | Eukaryota | Viridiplantae, Streptophyta | Tic110 of Pisum sativum | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.18.1.2 |
Tic110 channel protein. The x-ray structure (4.2Å resolution) of Tic110B and C from Cyanidioschyzon merolae is known (Tsai et al., 2013). The C-terminal half of Tic110 posesses a rod-shaped helix-repeat structure that is too flattened and elongated to be a channel. The structure is most similar to the HEAT-repeat motif that functions as scaffolds for protein-protein interactions (Tsai et al., 2013). |
Eukaryota | Rhodophyta | Tic110 of Cyanidioschyzon merolae (M1V6H9) |
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1.A.19.1.1 | Matrix protein, M2, an acid activated drug-sensitive proton channel. Transport involves binding to the four His-37s and transfer to water molecules on the inside of the channel (Acharya et al., 2010). Functional properties and structure are known (Hong and Degrado 2012). The cytoplasmic tail facilitates proton conduction (Liao et al. 2015). It is a dimer of dimers (Andreas et al. 2015). The four TMSs flanking the channel lumen alone seem to determine the proton conduction mechanism (Liang et al. 2016). His-37 forms a planar tetrad in the configuration of the bundle accepting and translocating the incoming protons from the N terminal side, exterior of the virus, to the C terminal side, inside the virus (Kalita and Fischer 2017). The cholesterol binding site in M2 that mediates membrane scission in a cholesterol-dependent manner to cause virus budding and release has been identified (Elkins et al. 2017).Transport-related conformational changes coupled to water and H+ movements have been studied (Mandala et al. 2018). The L46P mutant confers a novel allosteric mechanism of resistance towards the influenza A virus M2 S31N proton channel blockers (Musharrafieh et al. 2019). The C-terminal domain of M2 may serve as a sensor that regulates how M2 participates in critical events in the viral infection cycle (Kim et al. 2019). The M2 proton channel protein self-assembles into tetramers that retain the ability to bind to the drug amantadine, and the effects of phospholipid acyl chain length and cholesterol on the peptide association were investigated. Association of the helices depends on the thickness of the bilayer and cholesterol levels present in the phospholipid bilayer. The most favorable folding occurred when there was a good match between the width of the apolar region of the bilayer and the hydrophobic length of the transmembrane helix with tighter association upon inclusion of cholesterol in the lipid bilayer (Cristian et al. 2003). The influenza A M2 homotetrameric channel consists of four transmembrane (TM) and four amphipathic helices (AHs). This viral proton channel is suggested to form clusters in the catenoid budding neck areas in raft-like domains of the plasma membrane, resulting in cell membrane scission and viral release. holesterol-bridged M2 channels can exert a lateral force on the surrounding membrane to induce the necessary negative Gaussian curvature profile, which permits spontaneous scission of the catenoid membrane neck and leads to viral buds and scission (Kolokouris et al. 2025). |
Viruses | Orthornavirae, Negarnaviricota | M2 of influenza virus type A |
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1.A.19.1.2 | Matrix protein M2 of 96 aas and 1 TMS. Forms a proton-selective ion channel that is necessary for the efficient release of the viral genome during virus entry. After attaching to the cell surface, the virion enters the cell by endocytosis. Acidification of the endosome triggers M2 ion channel activity. The influx of protons into the virion interior is believed to disrupt interactions between the viral ribonucleoprotein (RNP), matrix protein 1 (M1), and lipid bilayers, thereby freeing the viral genome from interaction with viral proteins and enabling RNA segments to migrate to the host cell nucleus, where influenza virus RNA transcription and replication occur. Also plays a role in viral proteins secretory pathway. The cytoplasmic tail of Influenza A virus hemagglutinin and membrane lipid composition change the mode of M1 protein association with the lipid bilayer (Kordyukova et al. 2021). Universal scFv antibodies against the influenza M2 protein have been prepaired (Kumar et al. 2023).
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Orthornavirae, Negarnaviricota | M2 of Influenza A virus (A/flat-faced bat/Peru) |
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1.A.19.1.3 | Matrix protein 2, M2, of 80 aas and 1 TMS. The influenza virus ion channel and maturation cofactor M2 is a cholesterol-binding protein and M2 may promote clustering, merger of rafts and the pinching-off (fission) of virus particles (Schroeder et al. 2005). |
Viruses | Orthornavirae, Negarnaviricota | M2 of Influenza A virus (A/swine) |
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1.A.19.1.4 | M2 protein of 95 aas and 1 TMS, AM2. This protein shows 28% identity, 50% similarity and 10% gaps with BM2 (TC# 1.B.58.1.1) with residues 8 - 65 aligning with residues 26 - 81. AM2 forms a range of oligomeric complexes that are strongly influenced by the local chemical environment. Native mass spectrometry of AM2 in nanodiscs with different lipids showed that lipids also affected the oligomeric states of AM2. Finally, nanodiscs uniquely enabled the measurement of amantadine binding stoichiometries to AM2 in the intact lipid bilayer (Townsend et al. 2021). |
Viruses | Orthornavirae, Negarnaviricota |
AM2 of Influenza A virus (A/herring gull/Newfoundland) |
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1.A.19.2.1 | Protein of 489 aas with C-terminal region resembling the M2 protein (33% identity with no gaps). |
Viruses | Protein of Apis mellifera filamentous virus |
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1.A.2.1.1 | ATP-activated inward rectifier K+ channel, IRK1 (also called ROMK (ROMK2) or KIR1.1) (regulated by Sur1, allowing ATP sensitivity; also activated by phosphatidylinositol 4,5-bisphosphate (PIP) with affinity to PIP controlled by protein kinase A phosphorylation (which increases affinity for PIP) and protein kinase C phosphorylation (which decreases affinity for PIP (Zeng et al., 2003). The mechanism of voltage sensitivity of IRK1 inward-rectifier K+ channel block by the polyamine, spermine, has been proposed (Shin and Lu 2005). A putative pH sensor has been identified (Rapedius et al. 2006). Closure of the Kir1.1 pH gate results from steric occlusion of the permeation path by the convergence of four leucines (or phenylalanines) at the cytoplasmic apex of the inner transmembrane helices. In the open state, K+ crosses the pH gate together with its hydration shell (Sackin et al. 2005). Alternariol (AOH), the most important mycotoxin produced by Alternaria species, which are the most common mycoflora infecting small grain cereals worldwide, causes loss of cell viability by inducing apoptosis. AOH-induced apoptosis through a mitochondria-dependent pathway is characterized by p53 activation, an opening of the mitochondrial permeability transition pore (PTP), loss of mitochondrial transmembrane potential (ΔΨm), a downstream generation of O2- and caspase 9 and 3 activation (Bensassi et al., 2012). Pharmacological inhibition of renal ROMK causes diuresis and natriuresis in the absence of kaliuresis (Garcia et al. 2013). Cholesterol binding sites in KIR channels have been identified (Rosenhouse-Dantsker 2019). The ubiquitously expressed family of inward rectifier potassium (KIR) channels, encoded by KCNJ genes, is primarily involved in cell excitability and potassium homeostasis. Disease-associated mutations in KIR proteins have been linked to aberrant inward rectifier channel trafficking (Zangerl-Plessl et al. 2019). Interfacial binding Ssites for cholesterol on Kir, Kv, K2P, and related potassium channels have been identified (Lee 2020). Decreasing pH(in) increases the sensitivity of ROMK2 channels to K+(out) by altering the properties of the selectivity filter (Dahlmann et al. 2004). Interactions of ROMK2 channels with lipid kinases DGKE and AGK may cause channel activation by localized anionic lipid synthesis (Krajewska et al. 2024).
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Eukaryota | Metazoa, Chordata | IRK1 of Homo sapiens (P48048) |
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1.A.2.1.10 |
G-protein-activated inward rectifying K+ channel, Kir3.2, KATP2, KCNJ6, KCNJ7 or GIRK2 of 423 aas and 2 TMSs (Inanobe et al., 2011; Yokogawa et al. 2011). Mutations cause the Keppen-Lubinsky syndrome (Gao et al. 2022). It functions in electrical signaling in neurons and muscle cells (Weng et al. 2021), being important in regulating heart rate and neuronal excitability. It is activated by binding of the βγ-subunit complex to the cytoplasmic pore gate (Yokogawa et al. 2011). Chen et al. 2017 found that GIRK channels are activated by Ivermectin (IVM). Cholesterol binds to and upregulates GIRK channels (GIRK2 and 4), and the binding sites have been determined (Rosenhouse-Dantsker 2018). An inherited gain-of-function mutation in the human GIRK3.4 causes familial human sinus node dysfunction (SND). The increased activity of GIRK channels likely leads to a sustained hyperpolarization of pacemaker cells and thereby reduces heart rate (Kuß et al. 2019). GIRK2 channels are abundantly expressed in the heart and require that phosphatidylinositol bisphosphate (PIP2) is present so that intracellular channel-gating regulators such as Gbetagamma (Gβγ) and Na+ ions maintain the channel-open state. Li et al. 2019 determined how each regulator uses channel domain movements to control gate transitions. Na+ controls the cytosolic gate of the channel through an anti-clockwise rotation, whereas Gβγ stabilizes the transmembrane gate in the open state through a rocking movement of the cytosolic domain. Both effects altered the way by which the channel interacts with PIP2 and thereby stabilizes the open states of the respective gates (Li et al. 2019). The protein plays a role in heart atrial fibrillation-valvular heart disease (VHD) (Zhao et al. 2021). Measurements of ligand binding and channel current have been made (Usher et al. 2021). CryoEM structures of GIRK2 in the presence and absence of the cholesterol analog cholesteryl hemisuccinate (CHS) and phosphatidylinositol 4,5-bisphosphate (PIP2) reveal that CHS binds near PIP2 in lipid-facing hydrophobic pockets of the transmembrane domain, suggesting that CHS stabilizes the PIP2 interaction with the channel to promote engagement of the cytoplasmic domain with the transmembrane region (Mathiharan et al. 2021). It may play a role in Parkinson's Disease (Zhou et al. 2023). The roles of surface and mitochondrial ATP-sensitive potassium channels in cancer have been reviewed (Moon 2024). |
Eukaryota | Metazoa, Chordata | Kir3.2 of Homo sapiens (P48051) |
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1.A.2.1.11 |
Inward rectifying potassium channel 16, Kir5.1 or KCNJ16. (Potassium channel subfamily J member 16). Involved in pH and fluid regulation. It forms heteromers with Kir4.1/KCNJ10 or Kir2.1/KCNJ2. MAGI-1 anchors Kir4.1 channels (Kir4.1 homomer and Kir4.1/Kir5.1 heteromer) and contributes to basolateral K+ recycling. The Kir4.1 A167V mutation is associated with EAST/SeSAME syndrome caused by mistrafficking of the mutant channels and inhibiting their expression on the basolateral surface of tubular cells. These findings suggest that mislocalization of the Kir4.1 channels contributes to renal salt wasting. (Tanemoto et al. 2014). The KCNJ16 gene has been associated with a kidney tubulopathy phenotype, viz. disturbed acid-base homeostasis, hypokalemia and altered renal salt transport. KCNJ16 encodes for Kir5.1, which together with Kir4.1 constitutes a potassium channel located at kidney tubular cell basolateral membranes. Sendino Garví et al. 2024 discovered novel molecular targets for this genetic tubulopathy and identified statins as a potential therapeutic strategy for KCNJ16 defects in the kidney. |
Eukaryota | Metazoa, Chordata | KCNJ16 of Homo sapiens |
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1.A.2.1.12 | G protein-activated inward rectifying K+ channel 1 (Kir3.1; IRK3; KCNJ3; GIRK1). Regulates the heartbeat in humans. Phosphatidylinositol bisphosphate (PIP2) activates by opening the intracelluar G-loop gate (Meng et al., 2012). Along the ion permeation pathway, three relatively narrow regions (the selectivity filter, the inner helix bundle crossing, and the cytosolic G loop) may serve as gates to control ion permeation (Meng et al. 2016). Cholesterol up-regulates neuronal GIRK channel activity (Bukiya et al. 2017). Changes in the levels of cholesterol and PI(4,5)P2 may act in concert to provide fine-tuning of Kir3 channel function (Bukiya et al. 2017). Kir3.1 forms oligomers with Kir3.4 (TC# 1.A.2.1.3) and transporters Rb+ and spermine. It has been suggested that the selectivity filter is responsible for inward rectification and agonist activation as well as permeation and block (Makary et al. 2006). Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification (Pegan et al. 2005). A key basic residue that coordinates PIP2 to stabilize the pre-open and open states of the transmembrane gate flips in the inhibited state to form a direct salt-bridge interaction with the cytosolic gate and destabilize its open state (Gazgalis et al. 2022). |
Eukaryota | Metazoa, Chordata | Kir3.1 (IRK3) of Homo sapiens (P48549) |
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1.A.2.1.13 |
ATP-sensitive inward rectifying K+ channel 8, KCNJ8 or Kir6.1. It acts with Sur2B (3.A.1.208.23). Channel activity is inhibited in oxidative stress via S-glutathionylation (Yang et al., 2011). Oxidative sensitivity is dependent on Cys176 (Yang et al., 2011). These proteins comprise part of a glucose sensing mechanism (Rufino et al. 2013). It may play a role in limb wound repair and regeneration (Zhang et al. 2020). It is inhibited by glibenclamide (glyburide), an antidiabetic sulfonylurea used in the treatment of type II diabetes (Fernandes et al. 2004). Gain-of-function mutations in Kir6.1 and regulatory (SUR1) subunits of KATP channels can cause human neonatal diabetes mellitus by altering insulin secretion (Remedi et al. 2017). Kir6.1, a component of an ATP-sensitive potassium channel, regulates natural killer cell development (Samper et al. 2024). |
Eukaryota | Metazoa, Chordata | Kir6.1 of Homo sapiens (Q15842) |
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1.A.2.1.14 | Inward rectifying potassium (K+) (IRK) channel of 426 aas and 2 TMSs, AgaP. |
Eukaryota | Metazoa, Arthropoda | AgaP of Anopheles gambiae (African malaria mosquito) |
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1.A.2.1.15 | Kir1 (AgaP) K+ channel of 444 aas and 2 TMSs. Kir channels play a role in mosquito fecundity and may be promising molecular targets for the development of a new class of mosquitocides (Raphemot et al. 2014). |
Eukaryota | Metazoa, Arthropoda | Kir1 of Anopheles gambiae (African malaria mosquito) |
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1.A.2.1.16 | Inward rectifying K+ channel, Kir4.1, encoded by the KCNJ10 gene, of 379 aas and 2 TMSs. It is inhibited by chloroethylclonidine and pentamidine which bind in the channel (Rodríguez-Menchaca et al. 2016; Aréchiga-Figueroa et al. 2017). It is also inhibited by chloropuine which inhibits by an open pore blocking mecnanism (Marmolejo-Murillo et al. 2017). Loss-of-function mutations in the pore-forming Kir4.1 subunit cause an autosomal recessive disorder characterized by epilepsy, ataxia, sensorineural deafness and tubulopathy (SeSAME/EST syndrome) Pentamidine potently inhibited Kir4.1 channels when applied to the cytoplasmic side under inside-out patch clamp configuration (IC50 = 97nM). The block was voltage dependent. Molecular modeling predicted the binding of pentamidine to the transmembrane pore region of Kir4.1 at amino acids T127, T128 and E158. Mutation of each of these residues reduced the potency of pentamidine to block Kir4.1 channels (Aréchiga-Figueroa et al. 2017). Mutations in the KCNJ10 gene are associated with a distinctive ataxia, sensorineural hearing loss and a spasticity (Morin et al. 2020). It is regulated by kidins220 (TC# 8.A.28.1.8) (Jaudon et al. 2021). Pentamidine is a potent inhibitor of Kir4.1 (Zhang et al. 2022). Heterozygous KCNJ10 variants affecting the Kir4.1 channel cause Paroxysmal Kinesigenic Dyskinesia (Huang et al. 2024). |
Eukaryota | Metazoa, Chordata | Kir4.1 of Homo sapiens |
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1.A.2.1.17 | KCNJ11 or Kir6.2 or KATP of 390 aas; 96% identical to the rat homologue, TC# 1.A.2.1.7. Congenital hyperinsulinism (CHI) is characterized by persistent insulin secretion despite severe hypoglycemia. Mutations in the pancreatic ATP-sensitive K+ (K(ATP)) channel proteins sulfonylurea receptor 1 (SUR1) and Kir6.2, encoded by ABCC8 and KCNJ11, respectively, is the most common cause of the disease. Many mutations in SUR1 render the channel unable to traffic to the cell surface, thereby reducing channel function. Many studies have shown that for some SUR1 trafficking mutants, the defects could be corrected by treating cells with sulfonylureas or diazoxide (Yan et al. 2007). Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium (Tammaro and Ashcroft 2007). Kir6.2 is an ATP-sensitive potassium (KATP) channel coupling cell metabolism to electrical activity by regulating K+ fluxes across the plasma membrane. Channel closure is facilitated by ATP, which binds to the pore-forming subunit (Kir6.2). Conversely, channel opening is potentiated by phosphoinositol bisphosphate (PIP2), which binds to Kir6.2 and reduces channel inhibition by ATP. The PIP2 binding site has been identified (Haider et al. 2007). KATP channels are metabolic sensors that couple cell energetics to membrane excitability. In pancreatic beta-cells, channels formed by SUR1 and Kir6.2 regulate insulin secretion and are the targets of antidiabetic sulfonylureas. Martin et al. 2017 used cryo-EM to elucidate the structural basis of channel assembly and gating. The structure, determined in the presence of ATP and the sulfonylurea, glibenclamide, at ~6 Å resolution, revealed a closed Kir6.2 tetrameric core with four peripheral SUR1s, each anchored to a Kir6.2 by its N-terminal transmembrane domain (TMD0). Intricate interactions between TMD0, the loop following TMD0, and Kir6.2 near the proposed PIP2 binding site, and where ATP density is observed, suggest that SUR1 may contribute to ATP and PIP2 binding to enhance Kir6.2 sensitivity to both. The SUR1-ABC core is found in an unusual inward-facing conformation whereby the two nucleotide binding domains are misaligned along a two-fold symmetry axis, revealing a possible mechanism by which glibenclamide inhibits channel activity (Martin et al. 2017). a cryo-EM structure of a hamster SUR1/rat Kir6.2 channel bound to a high-affinity sulfonylurea drug glibenclamide and ATP has been solved at 3.63 Å resolution. The structure shows that glibenclamide is lodged in the transmembrane bundle of the SUR1-ABC core connected to the first nucleotide binding domain near the inner leaflet of the lipid bilayer (Martin et al. 2017). The activation of K(ATP) channels contributes to the shortening of action potential duration but is not the primary cause of extracellular K+ accumulation during early myocardial ischemia (Saito et al. 2005). KATP binds nucleotides (Usher et al. 2021). Mitochondrial KATP channels stabilize intracellular Ca2+ during hypoxia in retinal horizontal cells of goldfish (Carassius auratus) (Country and Jonz 2021). Medicinal plant products can interact with KATP (Rajabian et al. 2022). Remodeling of excitation-contraction coupling in transgenic mice expressing ATP-insensitive sarcolemmal KATP channels has been observed (Flagg et al. 2004). Thus, a compensatory increase in I(Ca) counteracts a mild activation of ATP-insensitive K(ATP) channels. Pharmacological inhibitors and ATP enrich a channel conformation in which the Kir6.2 cytoplasmic domain is closely associated with the transmembrane domain, while depleting one where the Kir6.2 cytoplasmic domain is extended away into the cytoplasm. This conformational change remodels a network of intra- and inter-subunit interactions as well as the ATP and PIP2 binding pockets. The structures resolved key contacts between the distal N-terminus of Kir6.2 and SUR1's ABC module involving residues implicated in channel function and showed a SUR1 residue, K134, participates in PIP2 binding. Molecular dynamics simulations revealed two Kir6.2 residues, K39 and R54, that mediate both ATP and PIP2 binding, suggesting a mechanism for competitive gating by ATP and PIP2 (Sung et al. 2022). The natural product, 7-hydroxycoumarin (7-HC), exhibits pharmacological properties linked to antihypertensive mechanisms of action. This relaxant effect induced by 7-HC relies on K+-channels (KATP, BKCa, and, to a lesser extent, Kv) activation and also on Ca2+ influx from sarcolemma and sarcoplasmic reticulum mobilization (inositol 1,4,5-triphosphate (IP3) and ryanodine receptors) (Jesus et al. 2022). Lymphatic contractile dysfunction in mouse models of Cantú Syndrome is oberved with KATP channel gain-of-function mutations (Davis et al. 2023). The structure of an open K (ATP) channel has revealed tandem PIP binding sites mediating the Kir6.2 and SUR1 regulatory interface (Driggers et al. 2023). Insulin secretion is regulated by ATP-sensitive potassium (KATP) channels in pancreatic β-cells. Peroxisome proliferator-activated receptors (PPAR)α ligands are used to treat dyslipidemia. A PPARα ligand, fenofibrate, and PPARγ ligands troglitazone and 15-deoxy-∆12,14-prostaglandin J2 close KATP channels and induce insulin secretion. The PPARα ligand, pemafibrate, is used to treat dyslipidemia and improves glucose intolerance in mice treated with a high fat diet and a novel selective PPARα modulator, it may affect KATP channels or insulin secretion. The effect of fenofibrate and pemafibrate (both at 100 µM) on insulin secretion was measured. Addition of fenofibrate for 10 min increased insulin secretion in low glucose conditions. The KATP channel activity was measured. Although fenofibrate (100 µM) reduced the KATP channel current, it had no effect on insulin mRNA expression (Kitamura et al. 2023). The structure of an open KATP channel revealed tandem PIP2 binding sites mediating the Kir6.2 and SUR1 regulatory interface (Driggers et al. 2024). |
Eukaryota | Metazoa, Chordata | Kir6.2 or KATP of Homo sapiens |
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1.A.2.1.18 | Inward rectifier potassium channel 4, KCNJ4, IRK3 or 4, of 445 aas. Its voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium, and it can be blocked by extracellular barium and cesium. It may play a role in the control of polyamine-mediated channel gating and in the blocking by intracellular magnesium. Overexpression of KCNJ4 correlates with cancer progression and nfavorable prognosis in lung adenocarcinoma (Wu and Yu 2019).
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Eukaryota | Metazoa, Chordata | KMCJ4 of Homo sapiens |
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1.A.2.1.19 | G protein-activated inward rectifier potassium channel 3, GIRK3 or KCNJ9 of 393 aas and 2 TMSs. It is expressed in sensory neurons and spinal cord and has uses both anterograde and retrograde axonal transport (Lyu et al. 2020). |
Eukaryota | Metazoa, Chordata | GIRK3 of Homo sapiens |
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1.A.2.1.2 | G-protein enhanced inward rectifier K channel 2, IRK1, IRK2, KCNJ2, KCNJ5, Kir2.1 (Andersen-Tawil Syndrome (ATS-1) protein; the V302M mutation causing the syndrome, alters the G-loop cytoplasmic K conduction pathway) (Bendahhou et al., 2003; Ma et al., 2007). (Blocked by chloroquine which binds in the cytoplasmic pore domain (Rodriguez-Menchaca et al., 2008)). Forms heteromultimers with Kir3.1 and Kir3.4 (Ishihara et al., 2009). A C-terminal domain is critical for the sensitivity of Kir2.1 to cholesterol (Epshtein et al., 2009). Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification (Caballero et al., 2010). The inhibitory cholesterol binding site has been identified (Fürst et al. 2014). Polyamines and Mg2+ block ion flux synergistically (Huang and Kuo 2016). Long polyamines serve a dual role as both blockers and coactivators (with PIP2) of Kir2.1 channels (Xie et al. 2005). Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification (Pegan et al. 2005). Loss-of-function mutations are a rare cause of long QT syndrome (Fodstad et al. 2004). Fibroblast growth factor 21 ameliorates NaV1.5 and Kir2.1 channel dysregulation in human AC16 cardiomyocytes (Li et al. 2021). The trafficking of Kir2.1 and its role in development have been reviewed (Hager et al. 2021). Cholesterol-induced suppression of Kir2 channels is mediated by decoupling at the inter-subunit interfaces (Barbera et al. 2022). CryoEM studies have revealed a well-connected network of interactions between the PIP2-binding site and the G-loop through residues R312 and H221.Moreover, the intrinsic tendency of the CTD to tether to the TMD and a movement of the secondary anionic binding site to the membrane even without PIP2 was revealed (Fernandes et al. 2022). The results revealed structural features unique to human Kir2.1. Individual protonation events change the electrostatic microenvironment of the pore, resulting in distinct, uncoordinated, and relatively long-lasting conductance states, which depend on levels of ion pooling in the pore and the maintenance of pore wetting (Maksaev et al. 2023). Subunit gating results from individual protonation events in Kir2 channels (Maksaev et al. 2023). |
Eukaryota | Metazoa, Chordata | IRK2 of Homo sapiens (P63252) |
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1.A.2.1.20 | Irk2 of 453 aas and 2 TMSs and a P-loop between them. Small molecule potassium ion channel agonist/antagonist screen reveals seizure suppression via glial Irk2 activation in a Drosophila model of Dup15q syndrome (Geier et al. 2025). |
None | Metazoa, Arthropoda | Irk2 of Drosophila melanogaster |
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1.A.2.1.3 | G-protein activated IRK5 (Kir3.4, KCNJ5, GIRK4) channel. The p75 neurotrophin receptor mediates cell death by activating GIRK channels through phosphatidylinositol 4,5-bisphosphate (Coulson et al., 2008). Cholesterol up-regulates neuronal GIRK channel activity (Bukiya et al. 2017). It forms an oligomeric channel with Kir3.1, transporting K+, Rb+ and spermine. The selectivity filter may be responsible for inward rectification and agonist activation as well as permeation and block by Cs+ (Makary et al. 2006). Ivermictin activates GIRK channels in a PIP2-dependent manner (Chen et al. 2017). GIRK channels function as either homomeric (i.e., GIRK2 and GIRK4) or heteromeric (e.g., GIRK1/2, GIRK1/4, and GIRK2/3) tetramers (Cui et al. 2022). Activators, such as ML297, ivermectin, and GAT1508, activate heteromeric GIRK1/2 channels better than GIRK1/4 channels with varying degrees of selectivity but not homomeric GIRK2 and GIRK4 channels. VU0529331 was the first homomeric GIRK channel activator, but it shows weak selectivity for GIRK2 over GIRK4 homomeric channels. The first highly selective small-molecule activator targeting GIRK4 homomeric channels is 3hi2one-G4 (3-[2-(3,4-dimethoxyphenyl)-2-oxoethyl]-3-hydroxy-1-(1-naphthylmethyl)-1,3-dihydro-2H-indol-2-one). 3hi2one-G4 does not activate GIRK2, GIRK1/2, or GIRK1/4 channels. The binding site of 3hi2one-G4 is formed by TMSs 1 and 2, and slide helix regions of the GIRK4 channel, near the phosphatidylinositol-4,5-bisphosphate binding site; it causes channel activation by strengthening channel-phosphatidylinositol-4,5-bisphosphate interactions. Slide helix residue L77 in GIRK4, corresponding to residue I82 in GIRK2 is a major determinant of isoform-specific selectivity (Cui et al. 2022). Cardiovascular and metabolic characteristics of KCNJ5 somatic mutations are important for primary aldosteronism (Chang et al. 2023). |
Eukaryota | Metazoa, Chordata | IRK5 or GIRK4 of Homo sapiens (P48544) |
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1.A.2.1.4 | Hepatocyte basolateral inwardly rectifying K+ channel, Kir4.2, involved in bile secretion (Hill et al., 2002). This protein is 96% identical to the human KCNJ14 or KCNJ15 of 375 aas (Q99712). |
Eukaryota | Metazoa, Chordata | Kir4.2 of Rattus norvegicus (Q91ZF1) |
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1.A.2.1.5 | Cranial nerve inward rectifying K+ channel, Kir2.4 (IRK4) (Töpert et al., 1998). The human ortholog, of 436 aas, is 94% identical and is called KCMJ14 or IRK4. |
Eukaryota | Metazoa, Chordata | Kir2.4 of Rattus norvegicus (O70596) |
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1.A.2.1.6 | ATP-sensitive K+ channel, Kir6.3 (Zhang et al., 2005) | Eukaryota | Metazoa, Chordata | Kir6.3 of Danio rerio (Q5R205) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.2.1.7 |
Kidney/pancreas/muscle ATP-senstive, ER/Golgi K+ channel, KATP or ROMK (Kir6.2) (Boim et al., 1995) (three alternatively spliced isoforms are called ROMK1-3). Involved in congenital hyperinsulinism (Lin et al., 2008). Regulated by Ankyrin-B (Li et al., 2010). ATP activates ATP-sensitive potassium channels composed of mutant sulfonylurea receptor 1 (SUR1) and Kir6.2 with diminished PIP2 sensitivity (Pratt and Shyng, 2011). This channel protects the myocardium from hypertrophy induced by pressure-overloading (Alvin et al., 2011). Domain organization studies show which domains in Sur and Kir6.2 interact (Wang et al. 2012). KATP channels consisting of Kir6.2 and SUR1 couple cell metabolism to membrane excitability and regulate insulin secretion in pancreatic beta cells, and mutations in the former protein can compensate for mutations in the latter (Zhou et al. 2013). Mutations cause inactivation of channel function by disrupting PIP2-dependent gating (Bushman et al. 2013). Thus, these proteins comprise part of the glucose sensing mechanism (Rufino et al. 2013). A single point mutation can confer voltage sensitivity (Kurata et al. 2010). Its involvement in type II diabetes has been reviewed by Bonfanti et al. 2015. KATP channels (Kir6.2/SUR1) in the brain and endocrine
pancreas couple metabolic status to the membrane potential. In beta-cells, increases in
cytosolic [ATP/ADP] inhibit KATP channel activity, leading to membrane depolarization and
exocytosis of insulin granules. Mutations in ABCC8 (SUR1) or KCNJ11 (Kir6.2) can result in gain or
loss of channel activity and cause neonatal diabetes (ND) or congenital hyperinsulinism (CHI),
respectively. Nucleotide binding without hydrolysis switches SUR1 to stimulatory conformations. Increased affinity for ATP gives rise to ND while decreased affinty gives rise to CHI (Ortiz and Bryan 2015). Kir6.2 can associate with either SUR1 (TC# 3.A.1.208.4) or SUR2A (TC# 3.A.1.208.23) to form heteroctamers, leading to different locations and consequences (Principalli et al. 2015). IATP channels and Ca2+ influx play roles in purinergic vasotoxicity and cell death (Shibata et al. 2018). |
Eukaryota | Metazoa, Chordata | ROMK of Rattus norvegicus (P70673) |
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1.A.2.1.8 | The inward rectifier potassium channel 13, Kir 7.1, Kir1.4, or KCNJ13, of 360 aas and 2 TMSs. A splice variant expressed in mouse tissues shares organisational and functional properties with human leber amaurosis-causing mutations of this channel (Vera et al. 2019). In fact, mutations in KCNJ13 are associated with two retinal disorders; Leber congenital amaurosis (LCA) and snowflake vitreoretinal degeneration (SVD) (Toms et al. 2019). Pinacidil is a channel opener (Sun et al. 2019). It may play a role in the control of polyamine-mediated channel gating and in the blocking by intracellular magnesium. A Kir7.1 disease mutant T153I within the inner pore affects K+ conduction (Beverley et al. 2022). Kir7.1 exhibits small unitary conductance and low dependence on external potassium. Kir7.1 channels also show a phosphatidylinositol 4,5-bisphosphate (PIP(2)) dependence for opening (Hernandez et al. 2023). Retinopathy- associated Kir7.1 mutations map at the binding site for PIP(2), resulting in channel gating defects, leading to channelopathies such as snowflake vitreoretinal degeneration and Leber congenital amaurosis in blind patients. These properties may be due to its unusual structure (Hernandez et al. 2023).
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Eukaryota | Metazoa, Chordata | Kir 7.1 or KCNJ13 of Homo sapiens (O60928) |
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1.A.2.1.9 | The inward-rectifier K+ channel, Kir2.2, KCNJ12, KCNJN1, KCNJ18, IRK2, of 433 aas and 2 TMSs. The 3-d structure at 3.1 Å resolution is available (Tao et al., 2009). (It is 70% identical to Kir2.1 (TC # 1.A.2.1.2)). The structural basis of PIP2 activation of Kir2.2 has been presented (Hansen et al., 2011). Inward rectifier potassium channels (Kir channels) exist in a variety of cells and are involved in maintaining resting membrane potential and signal transduction in most cells, as well as connecting metabolism and membrane excitability of body cells. It is closely related to normal physiological functions of body and the occurrence and development of some diseases. The functional expression of Kir channels in vascular endothelial cells and smooth muscle cells and their changes in disease states were reviewed, especially the recent research progress of Kir channels in stem cells was introduced, in order to have a deeper understanding of Kir channels in vascular tissues and provide new ideas and directions for the treatment of related ion channel diseases (Li and Yang 2023). Cholesterol binding to a conformational state of Kir2.2 channels may destabilize the PI(4,5)P2 interactions with the channels while in the disengaged state, the destabilization occurs where the subunits interact (Beverley et al. 2024). |
Eukaryota | Metazoa, Chordata | Kir2.2 of Homo sapiens (Q14500) |
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1.A.2.2.1 | Prokaryotic K+-selective Kir channel KirBac1.1 (selectivity: K+ = Rb+ = Cs+ >> Li+, Na+ or NMGM) (Enkvetchakul et al., 2004), inward rectifying (Cheng et al., 2009). Closure of the Kir1.1 pH gate results from steric occlusion of the permeation path by the convergence of four leucines (or phenylalanines) at the cytoplasmic apex of the inner transmembrane helices. In the open state, K+ crosses the pH gate together with its hydration shell (Sackin et al. 2005). An inhibitory cholesterol binding site has been identified (Fürst et al. 2014). Conformational changes associated with an open activation gate have been identified, and these suggest an allosteric pathway that ties the selectivity filter to the activation gate through interactions between both transmembrane helices, the turret, the selectivity filter loop, and the pore helix. Specific residues involved in this conformational exchange that are highly conserved among human Kir channels have also been identified (Amani et al. 2020). Anionic lipids, especially cardiolipin, initiate a concerted rotation of the cytoplasmic domain subunits. This action buries ionic side chains away from the bulk water, while allowing water greater access to the K+ conduction pathway (Borcik et al. 2020). Kv1.5 channels are regulated by PKC-mediated endocytic degradation (Du et al. 2021). Pore-forming TMSs control ion selectivity and the selectivity filter conformation in the KirBac1.1 channel (Matamoros and Nichols 2021). Key functional residues involved in gating and lipid allostery of K+ Kir channels have been identified (Yekefallah et al. 2022). |
Bacteria | Pseudomonadota | KirBac1.1 OF Burkholderia pseudomallei (IP7BA; gi33357898) |
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1.A.2.2.2 | The KirBac3.1 K+ channel (a dimer of dimers with gating visualized by atomic force microscopy (Jaroslawski et al., 2007) (regulated by binding lipids, G-proteins, nucleotides, and ions (H+, Ca2+, and Mg2+)). The 3-D structure is available (1XL6_A). The inhibitory cholesterol binding site has been identified (Fürst et al. 2014). The constricted opening in this, and presumably other, Kir channels does not impede potassium conduction (Black et al. 2020). The structural and dynamic properties of a KirBac3.1 mutant revealed the function of a highly conserved tryptophan in the transmembrane domain (Fagnen et al. 2021). |
Bacteria | Pseudomonadota | KirBac3.1 of Magnetospirillum magnetotacticum (D9N164) |
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1.A.2.2.3 |
ATP-sensitive inward rectifying Kir K channel (Choi et al. 2010). |
Bacteria | Pseudomonadota | Kir K+ channel of Chromobacterium violaceum |
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1.A.2.2.4 | Putative K+ channel |
Bacteria | Cyanobacteriota | K+ channel of Synechocystis PCC 6803 |
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1.A.2.2.5 | Inward rectifier potassium channel |
Bacteria | Pseudomonadota | K+ channel of Burkholderia xenovorans |
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1.A.2.2.6 | Uncharacterized algal protein of 886 aas, largely hydrophilic with a VIC-type 2 TMS channel domain near its C-terminus. |
Eukaryota | Viridiplantae, Streptophyta | UP of Klebsormidium nitens |
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1.A.20.1.1 | BNip3 channel-forming protein (Bocharov et al., 2007). It is an apoptosis-inducing protein that can overcome BCL2 suppression and may play a role in repartitioning calcium between the two major intracellular calcium stores in association with BCL2 (Ghavami et al. 2010). It is also involved in mitochondrial quality control via its interaction with SPATA18/MIEAP: in response to mitochondrial damage, it participates in mitochondrial protein catabolic process (also named MALM) leading to the degradation of damaged proteins inside mitochondria. The physical interaction of SPATA18/MIEAP, BNIP3 and BNIP3L/NIX at the mitochondrial outer membrane regulates the opening of a pore in the mitochondrial double membrane in order to mediate the translocation of lysosomal proteins from the cytoplasm to the mitochondrial matrix (Nakamura et al. 2012). Platinum-based combination chemotherapy triggers cancer cell death through induction of BNIP3 and ROS, but not autophagy (Chung et al. 2020).
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Eukaryota | Metazoa, Chordata | BNip3 of Homo sapiens (Q12983) |
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1.A.20.1.2 | NIP3L (NIP3-like protein X; Adenovirus E1B 19kDa-binding protein B5). |
Eukaryota | Metazoa, Chordata | NIP3L of Homo sapiens (O60238) |
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1.A.20.1.3 | BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 homologue of 215 aas and 1 C-terminal TMS. |
Eukaryota | Metazoa, Chordata | BCL2 of Aquila chrysaetos canadensis |
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1.A.20.2.1 | BCL2/Adenovirus E1B interacting protein, NIP3 |
Eukaryota | Metazoa, Nematoda | NIP3 of Caenorhabditis elegans (Q09969) |
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1.A.20.2.2 | NIP2-like protein of 195 aas and 1 C-terminal TMS |
Eukaryota | Metazoa, Nematoda | NIP3 of Trichinella spiralis (Trichina worm) |
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1.A.21.1.1 | Apoptosis regulator Bcl-X(L) of 233 aas. Also called Bcl2-like protein 1, isoform 1. Membrane insertion of the soluble form has been characterized (Vargas-Uribe et al. 2013). The cytosolic domain of Bcl-2 forms small pores in the mitochondrial outer membrane (Peng et al. 2009). The interaction of the C-terminal domain of Vaccinia-Related Kinase 2A (VRK2A) with the B-cell lymphoma-extra Large (Bcl-xL) plays an anti-apoptotic role in cancer (Puja et al. 2023). |
Eukaryota | Metazoa, Chordata | Bcl-X(L) of Homo sapiens |
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1.A.21.1.10 | Bcl-2 apoptosis regulator of 239 aas and 2 TMSs. It suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. It regulates cell death by controlling the mitochondrial membrane permeability and appears to function in a feedback loop system with caspases. It inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1), and it may attenuate inflammation by impairing NLRP1-inflammasome activation, hence CASP1 activation and IL1B release (Bruey et al. 2007). Induction of IFIT1/IFIT3 and inhibition of Bcl-2 orchestrate the treatment of myeloma and leukemia via pyroptosis (He et al. 2024). |
Eukaryota | Metazoa, Chordata | Bcl-2 of Homo sapiens |
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1.A.21.1.11 | Apoptosis regulator BAX-like isoform X2, of 198 aas and 2 or 3 TMSs. |
Eukaryota | Metazoa, Chordata | BAX-like protein of Perca flavescens (yellow perch) |
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1.A.21.1.12 | The Cell Death (CED-9) protein (Siskind et al., 2008) | Eukaryota | Metazoa, Nematoda | CED-9 of Caenorhabditis elegans (P41958) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.21.1.13 | BCL2-associated X protein, BAX, of 204 aas and 1 C-terminal TMS, possibly with a second internal TMS. The expression of the ccBAX gene is down-regulated by the miR-124 miRNA in silver crucian carp upon cyprinid herpesvirus 2 infection (Yu et al. 2021). |
Eukaryota | Metazoa, Chordata | BAX of Carassius gibelio (silver crucian carp) |
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1.A.21.1.2 |
The mitochondrial apoptosis-inducing channel-forming protein, BAX. The C-terminal helix mediates membrane binding and pore formation (Garg et al. 2012). BAX pores are large enough to allow cytochrome c release and it activates the mitochondrial permeabilty transition pore; both play a role in programmed cell death, but the latter is quantitatively more important (Gómez-Crisóstomo et al. 2013). Bax functions like a holin when expressed in bacteria (Pang et al. 2011). Bax (and likely Bak) dimers assemble into oligomers with an even number of molecules that fully or partially delineate pores of different sizes to permeabilize the mitochondrial outer membrane (MOM) during apoptosis (Cosentino and García-Sáez 2016). The membrane domain of Bax interacts with other members of the Bcl-2 family to form hetero-oligomers (Andreu-Fernández et al. 2017). Uren et al. 2017 reviewed how clusters of dimers and their lipid-mediated interactions provide a molecular explanation for the heterogeneous assemblies of Bak and Bax observed during apoptosis. After BAK/BAX activation and cytochrome c loss, the mitochondrial network breaks down, and large BAK/BAX pores appear in the outer membrane. These macropores allow the inner membrane an outlet through which it herniated, carrying with it mitochondrial matrix components including the mitochondrial genome (McArthur et al. 2018). The core/dimerization domain of Bax and Bak is water exposed with only helices 4 and 5 in membrane contact, whereas the piercing/latch domain is in peripheral membrane contact, with helix 9 being transmembrane (Bleicken et al. 2018). The mechanism of the membrane disruption and pore-formation by the BAX C-terminal TMS has been investigated (Jiang and Zhang 2019). Bax membrane permeabilization results from oligomerization of transmembrane monomers (Annis et al. 2005). Bax localization and apoptotic activity are conformationally controled by Pro168 (Schinzel et al. 2004). |
Eukaryota | Metazoa, Chordata | BAX of Homo sapiens (Q07812) |
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1.A.21.1.3 |
The mitochondrial apoptosis-inducing channel-forming protein, BAK. 3-D structures are known (2IMT_A). Functions like a holin when expressed in bacteria (Pang et al. 2011). Formation of the apoptotic pore involves a flexible C-terminal domain (Iyer et al. 2015). Bax (and likely Bak) dimers assemble into oligomers with an even number of molecules that fully or partially delineate pores of different sizes to permeabilize the mitochondrial outer membrane (MOM) during apoptosis (Cosentino and García-Sáez 2016). BAK is a C-tail-anchored mitochondrial outer membrane protein (Setoguchi et al. 2006). BAK plays a role in peroxisomal permeability, similar to mitochondrial outer membrane permeabilization (Hosoi et al. 2017). Uren et al. 2017 reviewed how clusters of dimers and their lipid-mediated interactions provide a molecular explanation for the heterogeneous assemblies of Bak and Bax observed during apoptosis. After BAK/BAX activation and cytochrome c loss, the mitochondrial network breaks down, and large BAK/BAX pores appear in the outer membrane. These macropores allow the inner membrane an outlet through which it herniates, carrying with it mitochondrial matrix components including the mitochondrial genome (McArthur et al. 2018). A high-resolution analysis of the conformational transition of pro-apoptotic Bak at the lipid membrane has been published (Sperl et al. 2021). |
Eukaryota | Metazoa, Chordata | BAK of Homo sapiens (Q16611). |
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1.A.21.1.4 | The BH3-only (Mcl-1) protein (mediates apoptosis). (3-d strucure known) |
Eukaryota | Metazoa, Chordata | BH3-only of Homo sapiens (B4DG83) |
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1.A.21.1.5 |
Pro-survival Bcl-w protein. Binds the BH3-only protein Bop to inhibit Bop-induced apoptosis (Zhang et al. 2012). The structure is known (PDB# 1MK3). |
Eukaryota | Metazoa, Chordata | Bcl-w of Homo sapiens |
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1.A.21.1.6 | Bcl-XL of 289 aas, a C-tail-anchored mitochondrial outer membrane protein (Setoguchi et al. 2006). The BH4 domain of Bcl-XL, but not that of Bcl-2, selectively targets VDAC1 and inhibits apoptosis by decreasing VDAC1-mediated Ca2+ uptake into mitochondria (Monaco et al. 2015). The ER-mitochondrion interface is a critical cell-signaling junction whereby Bcl-xL dynamically interacts with type 3 inositol 1,4,5-trisphosphate receptors (IP3R3) to coordinate mitochondrial Ca2+ transfer and alters cellular metabolism in order to increase the cells' bioenergetic capacity, particularly during periods of stress (Williams et al. 2016). |
Eukaryota | Metazoa, Chordata | Bcl-XL of Xenopus laevis (African clawed frog) |
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1.A.21.1.7 | Pore-forming Bcl-2-related ovarian killer protein, Bok (BokL, Bcl2L9) of 212 aas and 2 or more predicted TMSs. It is an apoptosis regulator that functions through different apoptotic signaling pathways (Einsele-Scholz et al. 2016, Yakovlev et al. 2004, Jääskeläinen et al. 2010). The transmembrane-domain contributes to the pro-apoptotic function and interactions of Bok with other proteins (Stehle et al. 2018). Bok binds to a largely disordered loop in the coupling domain of type 1 inositol 1,4,5-trisphosphate receptors, and high affinity binding is mediated by multivalent interactions (Szczesniak et al. 2021).
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Eukaryota | Metazoa, Chordata | Bok of Homo sapiens |
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1.A.21.1.8 | Bcl-2-like death executioner of 172 aas and 2 TMSs, one in the middle of the protein and one at the C-terminus. |
Eukaryota | Metazoa, Arthropoda | Death executioner of Locusta migratoria (migratory locust) |
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1.A.21.1.9 | Uncharacterized protein of 224 aas and 2 TMSs. |
Eukaryota | Metazoa, Cnidaria | UP of Nematostella vectensis (Starlet sea anemone) |
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1.A.21.2.1 | BH3-interacting domain death agonist of 199 aas and 2 or 3 putative TMSs. |
Eukaryota | Metazoa, Chordata | BH3-interacting agonist of Tachysurus fulvidraco (yellow catfish) |
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1.A.21.2.2 | BH3-interacting domain death agonist-like isoform X3 of 204 aas and 2 or 3 TM |
Eukaryota | Metazoa, Chordata | Death agonists of Boleophthalmus pectinirostris (great blue-spotted mudskipper) |
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1.A.21.2.3 | Uncharacterized protein of 207 aas and 2 or 3 TMSs. |
Eukaryota | Metazoa, Chordata | UP of Lepisosteus oculatus (spotted gar) |
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1.A.21.2.4 | BH3-interacting domain death agonist isoform 2, BID, of 195 aas and 2 or 3 TMSs. BCL-2 family proteins display structural homology to channel-forming bacterial toxins, such as colicins, the transmembrane domain of diphtheria toxin, and the N-terminal domain of delta-endotoxin. By analogy, it has been hypothesized the BCL-2 family proteins would unfold and insert into the lipid bilayer upon membrane association. Oh et al. 2005 showed that helices 6-8 maintain an alpha-helical conformation in membranes with a lipid composition resembling mitochondrial outer membrane contact sites. However, unlike colicins and the transmembrane domain of diphtheria toxin, these helices of BID are bound to the lipid bilayer without adopting a transmembrane orientation. |
Eukaryota | Metazoa, Chordata | BID of Homo sapiens |
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1.A.21.2.5 | BH3-interacting domain death agonist isoform X3 of 241 aas and 2 or 3 TM |
Eukaryota | Metazoa, Chordata | Death agonist of Phocoena sinus |
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1.A.22.1.1 | Large mechanosensitive ion channel: MscL, with a subunit size of 136 aas with 2 TMSs; it catalyzes efflux of ions (slightly cation selective), osmolytes and small proteins. Residues in the putative primary gate are present in the first TMS (Levin and Blount 2004). Protein-lipid interactions are important for gating, dependent on TMS tilting (Iscla et al., 2011b). The carboxyl-terminal cytoplasmic helices assemble into a pentameric bundle that resembles cartilage oligomeric matrix protein, and these are required for the selective formation of the pentamer (Ando et al. 2015). Lysophospholipids can increase the size of particles that can be transported (Foo et al. 2015). 500 - 700 channels are needed for 80% survival follwing a large changes in osmotic pressure, a number of channels similar to that found in wild type E. coli cells (Chure et al. 2018). its activation threshold decreases with membrane thickness; the membrane-thickness-dependent MscL opening mainly arises from structural changes in MscL to match the altered membrane thickness by stretching (Katsuta et al. 2018). MscL can provide a route for antibiotic entry into the E. coli cell, and agonists are available to facilitate their entry (Wray et al. 2020; Zhao et al. 2020). MscL has been used to design a synthetic mechanosensitive signaling pathway in compartmentalized artificial cells (Hindley et al. 2019). Available information at the ultrastructural level on lipids tightly bound to transport proteins and the impact of altered bulk membrane lipid composition has been reviewed (Stieger et al. 2021). Competition between hydrophobic mismatch and tension may result in opening tension for MscL (Wiggins and Phillips 2004). The amphipathic N-terminal helix of MscL acts as a crucial structural element during tension-induced gating, both stabilizing the closed state and coupling the channel to the membrane (Bavi et al. 2016). |
Bacteria | Pseudomonadota | MscL of E. coli (P0A742) |
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1.A.22.1.10 | Osmotic adaptation channel that influences sporulation and secondary metabolite production, Sco3190 (MscL) (Wang et al. 2007). |
Bacteria | Actinomycetota | Sco3190 of Streptomyces coelicolor. |
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1.A.22.1.11 | Large conductance mechanosensitive channel protein, MscL, of 101 aas and 2 TMSs. When the membrane is stretched, MscL responds to the increase of membrane tension and opens a nonselective pore to about 30 A wide, exhibiting a large unitary conductance of approximately 3 nS. The structures of this archaeal MscL, trapped in the closed and expanded intermediate states, has been solved (Li et al. 2015). The comparative analysis of these two new structures reveals significant conformational rearrangements in the different domains of MscL. The large changes observed in the tilt angles of the two transmembrane helices (TMS1 and TMS2) fit well with the helix-pivoting model. Meanwhile, the periplasmic loop region transforms from a folded structure, containing an omega-shaped loop and a short beta-hairpin, to an extended and partly disordered conformation during channel expansion. Moreover, a significant rotating and sliding of the N-terminal helix (N-helix) is coupled to the tilting movements of TMS1 and TMS2. The dynamic relationships between the N-helix and TMS1/TMS2 suggest that the N-helix serves as a membrane-anchored stopper that limits the tilts of TM1 and TM2 in the gating process (Li et al. 2015). Residues I21-T30 in TMS 1 constitute the hydrophobic gate, and the packing of aromatic rings of F23 in each subunit of Ma-MscL is critical to the hydrophobic gate (Zhang et al. 2021). Hydrophilic substitutions of the other functionally important residues, A22 and G26, modulate channel gating by attenuating the hydrophobicity of the F23 constriction. |
Archaea | Euryarchaeota | MscL of Methanosarcina acetivorans |
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1.A.22.1.12 | MscL protein of 171 aas and 2 or 3 TMSs. |
Eukaryota | Rhodophyta | MscL of Chondrus crispus (Carrageen Irish moss) (Polymorpha crispa) |
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1.A.22.1.13 | Putative large-conductance mechanosensitive channel of 101 aas and 2 TMSs. |
Viruses | Bamfordvirae, Nucleocytoviricota | MscL channel of Tetraselmis virus 1 |
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1.A.22.1.14 | MscL homologue of 101 aas and 2 TMSs. |
Viruses | Bamfordvirae, Nucleocytoviricota | MscL of Cafeteria roenbergensis virus BV-PW1]. |
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1.A.22.1.2 | Large mechanosensitive ion channel of 151 aas and 2 TMSs. The 3-D structure is known, and it may reflect a nearly closed rather than fully closed state. Modeling support a clockwise rotation of the pore-forming first TMS promotes gating (Bartlett et al. 2004). |
Bacteria | Actinomycetota | MscL of Mycobacterium tuberculosis (P0A5K8) |
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1.A.22.1.3 | MscL; catalyzes ion and osmolyte release following osmmotic downshift | Bacteria | Bacillota | MscL (YwpC) of Bacillus subtilis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.22.1.4 | MscL (activated by arachidonate (Balleza et al., 2010), 45% identical to MscL of Bacillus subtilis (1.A.22.1.3)). |
Bacteria | Pseudomonadota | MscL of Rhizobium etli (Q2KCQ1) |
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1.A.22.1.5 | The pentameric MscL channel (Iscla et al., 2011). The high resolution structure of a proposed closed but expanded tetrameric intermediate state has been determined (Liu et al. 2009). Adhesive forces to surfaces play an important role, next to other established driving forces, in staphylococcal MscL channel gating (Carniello et al. 2020). Thus, transmembrane antibiotic uptake and solute efflux in infectious staphylococcal biofilms is greatly stimulated when bacteria experience adhesion forces from surfaces as in biofilms. |
Bacteria | Bacillota | MscL of Staphylococcus aureus (P68805) |
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1.A.22.1.6 | MscL; rescues cells form osmotic downshift (Bucarey et al., 2012). |
Bacteria | Actinomycetota | MscL of Micromonospora aurantica (D9T6D3) |
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1.A.22.1.7 | Large-conductance mechanosensitive channel, MscL |
Bacteria | Cyanobacteriota | MscL of Synechococcus sp. |
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1.A.22.1.8 | Bacteria | Bacillota | MscL of Leuconostoc citreum |
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1.A.22.1.9 | Bacteria | Actinomycetota | MscL of Renibacterium salmoninarum |
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1.A.23.1.1 | Minor K+-dependent MscS-type mechanosensitive channel protein, designated KefA, AefA or MscK, (Edwards et al. 2012). |
Bacteria | Pseudomonadota | KefA (AefA) of E. coli |
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1.A.23.1.2 | The putative osmoadaptation receptor, BspA | Bacteria | Pseudomonadota | BspA of Erwinia (Pectobacterium) chrysanthemi | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.23.1.3 | Mini conductance (300 pS) mechanosensitive channel, YjeP or MscM (1107aas; 13 TMSs in a 1 + 12 TMS arrangement). Encoded in an operon with phosphatidyl serine decarboxylase (Moraes and Reithmeier 2012). Protects against hypoosmotic shock (Edwards et al. 2012). |
Bacteria | Pseudomonadota | YjeP of E. coli (P39285) |
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1.A.23.1.4 | Uncharacterized protein of 571 aas and 6 TMSs. |
Bacteria | Bdellovibrionota | UP of Bdellovibrio exovorus |
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1.A.23.1.5 | Mechanosensitive ion channel, MscS, of 952 aas and 10 TMSs. |
Bacteria | Pseudomonadota | MscS of Legionella sp. |
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1.A.23.2.1 | Major MscS channel protein, YggB. Seven residues, mostly hydrophobic, in the first and second transmembrane helices are lipid-sensing residues (Malcolm et al., 2011). X-ray structures are available (Lai et al. 2013). The cytoplasmic cage domain senses macromolecular crowding (Rowe et al. 2014). A gating mechanism has been proposed (Malcolm et al. 2015). The thermodynamics of K+ leak have been studied (Koprowski et al. 2015). In the MscS crystal structure (PDB 2OAU ), a narrow, hydrophobic opening is visible in the crystal structure, and a vapor lock, created by hydrophobic seals consisting of L105 and L109, is the barrier to water and ions (Rasmussen et al. 2015). The voltage dependence of inactivation occurs independently of the positive charges of R46, R54, and R74 (Nomura et al. 2016). The closed-to-open transition may involve rotation and tilt of the pore-lining helices (Edwards et al. 2005). A molecular dynamics study of gating has been published (Sotomayor and Schulten 2004). It suggested that when restraining the backbone of the protein, the channel remained in the open form and the simulation revealed intermittent permeation of water molecules through the channel. Abolishing the restraints under constant pressure conditions led to spontaneous closure of the transmembrane channel, whereas abolishing the restraints when surface tension (20 dyn/cm) was applied led to channel widening. The large balloon-shaped cytoplasmic domain of MscS exhibited spontaneous diffusion of ions through its side openings. Interaction between the transmembrane domain and the cytoplasmic domain of MscS was observed and involved formation of salt bridges between residues Asp62 and Arg128; this interaction may be essential for the gating of MscS. K+ and Cl- ions showed distinctively different distributions in and around the channel (Sotomayor and Schulten 2004). |
Bacteria | Pseudomonadota | YggB or MscS of E. coli (P0C0S1) |
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1.A.23.2.2 | MscS protein. The x-ray structure at 4.2 Å is available (Lai et al. 2013). |
Bacteria | Campylobacterota | MscS of Helicobacter pylori |
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1.A.23.2.3 | MscS mechanosensitive channel of 462 aas and 5 TMSs. |
Bacteria | Candidatus Peregrinibacteria | MscS channel of Candidatus Peribacter riflensis |
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1.A.23.2.4 | Putative small conductance mechanosensetive channel protein of 261 aas and 3 TMSs |
Viruses | Bamfordvirae, Nucleocytoviricota | MscS homologue of Aureococcus anophagefferens virus |
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1.A.23.3.1 | The YkuT osmolyte efflux channel | Bacteria | Bacillota | YkuT of Bacillus subtilis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.23.3.2 | Mechanosensitive NaCl-inducible RpoS-dependent channel (1,000 pS), YbiO (741 aas; 10TMSs). Protects agains hypoosmotic shock (Edwards et al. 2012). |
Bacteria | Pseudomonadota | YbiO of E. coli (P75783) |
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1.A.23.3.3 | Mechanosensitive channel, small conductance, YggB, GluE or MscCG (533 aas; 6-7 TMSs). Mediates glutamate efflux (Becker et al. 2013). The pore domain is in the N-terminus. The C-terminus includes three subdomains, the periplasmic loop, the fourth transmembrane segment, and the cytoplasmic loop, all of which are important for MscCG function, in particular for glutamate excretion (Becker and Krämer 2015). Deletion of the encoding gene results in a 10% increase in lysine production and a decrease in cell mass yield (Xiao et al. 2020).
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Bacteria | Actinomycetota | YggB or MscCG of Corynebacterium glutamicum (P42531) |
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1.A.23.3.4 | MscCG2 of 334 aas and 4 TMSs in a 3 + 1 arrangement. It functions as an L-glutamate exporter and an osmotic safety valve (Wang et al. 2018). It is 23% identical to MscCG (TC# 1.A.23.3.3) in the same organism. MscCG2-mediated L-glutamate excretion was activated by biotin limitation or penicillin treatment, and constitutive L-glutamate excretion was triggered by a gain-of-function mutation (A151V). It was not induced by glutamate producing conditions (Wang et al. 2018). |
Bacteria | Actinomycetota | MscCG2 of Corynebacterium glutamicum |
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1.A.23.3.5 | Small-conductance mechanosensitive channel Msc1 of 533 aas and 5 TMSs in a 4 (N-terminus) + 1 TMS (near the C-terminus) with two smaller peaks of hydrophobicity between these that could be TMSs. This system as well as a second Msc protein, Msc2, are able to export L-glutamate and other metabolites (Kawasaki and Martinac 2020). |
Bacteria | Actinomycetota | Msc1 of Corynebacterium glutamicum |
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1.A.23.4.1 | The MscMJ mechanosensitive channel | Archaea | Euryarchaeota | MscMJ of Methanococcus jannaschii | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.23.4.10 | Uncharacterized MscS homologue |
Bacteria | Campylobacterota | MscS homologue of Helicobacter pylori |
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1.A.23.4.11 | Mitochondrial mechanosensitive ion channel protein 1, MscS-like channel, MSL1, of 497 aas and 5 TMSs. As the sole member of the Arabidopsis MSL family, localized in the mitochondrial inner membrane, MSL1 is essential for maintaining the normal membrane potential of mitochondria. Li et al. 2020 reported a cryoelectron microscopy (cryo-EM) structure of AtMSL1 at 3.3 Å. The overall architecture of AtMSL1 is similar to MscS, but the transmembrane domain of AtMSL1 is larger. Structural differences are observed in both the transmembrane and the matrix domain, and the carboxyl-terminus of AtMSL1 is more flexible while the beta-barrel structure observed in MscS is absent. The side portals in AtMSL1 are significantly smaller, and enlarging the size of the portal by mutagenesis can increase the channel conductance (Li et al. 2020). |
Eukaryota | Viridiplantae, Streptophyta | MSL1 of Arabidopsis thaliana |
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1.A.23.4.12 | Uncharacterized MscS channel of 351 aas and 4 N-terminal TMSs. |
Bacteria | Bdellovibrionota | UP of Bdellovibrio bacteriovorus |
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1.A.23.4.13 | MscS channel of 553 aas and 6 TMSs. |
Eukaryota | Evosea | MscS of Entamoeba histolytica |
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1.A.23.4.14 | Mechanosensitive channel-like 10, Msl10 of 734 aas and 5 or more TMSs. It functions in triggering cell death in a process that is independent of its channel activity (Maksaev et al. 2018). The N-terminus of MSL10 (MSL10(N)) is an exemple of these IDRs. MSL10(N) adopted a predominately helical structure when exposed to the helix-inducing compound, trifluoroethanol (TFE), but in the presence of molecular crowding agents, MSL10(N) underwent structural changes and exhibited alterations to its homotypic interaction favorability. Collective behavior via in vitro imaging of condensates indicated that MSL8(N), MSL9(N), and MSL10(N) have sharply differing propensities for self-assembly into condensates, both inherently and in response to salt, temperature, and molecular crowding. These data establish the N-termini of MSL channels as IDRs with distinct biophysical properties and the potential to respond uniquely to changes in their physiochemical environments (Flynn et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | Mscl10 of Arabidopsis thaliana (Mouse-ear cress) |
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1.A.23.4.15 | Plasma membrane small conductance mechanosensitive channel, MSL4, of 881 aas and 5 putative TMSs (Hamilton et al. 2015). |
Eukaryota | Viridiplantae, Streptophyta | MSL4 of Arabidopsis thaliana |
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1.A.23.4.16 | MscA, a mechanosensitive channel in the ER membranes of filamentous fungi (AN7571). It may have 6 or 7 TMSs in a 4 + 2 or 3 TMS arrangement, but there are also two moderately hydrophobic peaks near the C-terminus of the protein that might be TMSs. Orthologues of MscA and MscB are present in most fungi, including plant and animal pathogens. MscA/MscB and other fungal MscS-like proteins share the three TMSs and the extended C-terminal cytosolic domain that form the structural fingerprint of MscS-like channels (Dionysopoulou et al. 2022). Their overexpression leads to increased CaCl2 toxicity or/and reduction of asexual spore formation. |
Eukaryota | Fungi, Ascomycota | MscA of Emericella nidulans (Aspergillus nidulans) |
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1.A.23.4.17 | MscB (AN6053) of 943 aas, a mechanosensitive channel in the PM membranes of filamentous fungi. It may have 6 or 7 TMSs in a 4 + 2 or 3 TMS arrangement, but there are also two moderately hydrophobic peaks near the C-terminus of the protein that might be TMSs. Orthologues of MscA and MscB are present in most fungi, including plant and animal pathogens. MscA/MscB and other fungal MscS-like proteins share the three TMSs and the extended C-terminal cytosolic domain that form the structural fingerprint of MscS-like channels (Dionysopoulou et al. 2022). Their overexpression leads to increased CaCl2 toxicity or/and reduction of asexual spore formation. |
Eukaryota | Fungi, Ascomycota | MscB of Emericella nidulans (Aspergillus nidulans) |
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1.A.23.4.18 | Msy1 mechanosensitive calcium channel in response to hypo-osmotic shock. The protein is of 1011 aas with 6 or 7 TMSs in a 4 + 2 or 3 TMS arrangement. It regulates intracellular calcium levels and cell volume for survival in response to hypo-osmotic shock. The conductance is about 0.25 nanosiemens (Nakayama et al. 2012). It is involved in maintaining vacuole integrity and protecting the nuclear envelope upon hypo-osmotic shock (Nakayama et al. 2014). |
Eukaryota | Fungi, Ascomycota | Msy1 of Schizosaccharomyces pombe (Fission yeast)
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1.A.23.4.19 | Msy2 of 840 aas and 7 or 8 TMSs in a 4 + 1 + 2 or 3 TMS arrangement. It regulates intracellular calcium levels and cell volume for survival in response to hypo-osmotic shock (Nakayama et al. 2012)., and is involved in maintaining vacuole integrity while protecting the nuclear envelope from hypo-osmotic shock (Nakayama et al. 2014). |
Eukaryota | Fungi, Ascomycota | Msy2 of Schizosaccharomyces pombe |
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1.A.23.4.2 | The MscMJLR mechanosensitive channel | Archaea | Euryarchaeota | MscMJLR of Methanococcus jannaschii | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.23.4.20 | Mechanosensitive ion channel protein, putative, of 1812 aas and 6 TMSs in a 4 (N-terminal) + 2 (central) TMS arrangement (Wunderlich, 2022). |
Eukaryota | Apicomplexa | MscS protein of Plasmodium falciparum
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1.A.23.4.21 | Very small MscS homolog of 109 aas with 1 or 2 TMSs, more similar to bacterial MscS proteins than to eukaryotic homologues. The system has been characterized (Berg et al. 2024). Microsporidian genomes contain mscS genes of both eukaryotic and bacterial origin. Berg et al. 2024 investigated the cryo-electron microscopy structure of the bacterially derived mechanosensitive ion channel of small conductance 2 (MscS2) from Nematocida displodere, an intracellular pathogen of Caenorhabditis elegans. MscS2 is the most compact MscS-like channel known and assembles into a unique superstructure in vitro with six heptameric MscS2 channels. Individual MscS2 channels are oriented in a heterogeneous manner to one another, resembling an asymmetric, flexible six-way cross joint. Microsporidian MscS2 still forms a heptameric membrane channel. |
Eukaryota | Fungi, Microsporidia | MscS2 of Nematocida displodere |
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1.A.23.4.3 | Mechanosensative cation-selective channel with a conductance of 100 pS, YnaI (344aas; 4 - 6 TMSs). Protects against hypoosmotic shock (Edwards et al. 2012). The structure has been solved by cryo-electron microscopy to a resolution of 13 Å (Böttcher et al. 2015). While the cytosolic vestibule is structurally similar to that in MscS, additional density is seen in the transmembrane region, consistent with the presence of two additional TMSs predicted for YnaI. The location of this density suggests that the extra TMSs are tilted, which could induce local membrane curvature extending the tension-sensing paddles seen in MscS. Off-center lipid-accessible cavities are seen that resemble gaps between the sensor paddles in MscS. The conservation of the tapered shape and the cavities in YnaI suggest a mechanism similar to that of MscS (Böttcher et al. 2015). The voltage dependence of inactivation occurs independently of the positive charges of R46, R54, and R74 (Nomura et al. 2016). A 3.8 Å structure by cryoEM revealed a heptamer structural fold similar to previously studied MscS channels. The ion-selective filter is formed by seven hydrophobic methionines (Met158) in the transmembrane pore (Yu et al. 2017). Details of the gating transition for MscS have been predicted (Zhu et al. 2018). YnaI has a gating mechanism based on flexible pore helices (Flegler et al. 2020), and thus, MscS-like channels of different sizes have a common core architecture but show different gating mechanisms and fine-tuned conductive properties. Attempted Cryo-EM structural determination of detergent-free YnaI Using SMA2000 revealed limitations of this method (Catalano et al. 2021). |
Bacteria | Pseudomonadota | YnaI of E. coli (P0AEB5) |
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1.A.23.4.4 | Plant plastid mechanosensitive channel MscS-like-2 (Msl2) (controls plastid organellar morphology, as does Msl3) (Haswell and Meyerowitz, 2006; Haswell et al., 2008). It functions as do the bacterial homologues, but is essential for leaf growth, chloroplast integrity and normal starch accumulation (Jensen and Haswell 2012). msl2 msl3 double mutant seedlings exhibit several hallmarks of drought or environmental osmotic stress, including solute accumulation, elevated levels of the compatible osmolyte proline (Pro), and accumulation of the stress hormone abscisic acid (ABA). Furthermore, msl2 msl3 mutants expressed Pro and ABA metabolism genes in a pattern normally seen under drought or osmotic stress. Pro accumulation in the msl2 msl3 mutant was suppressed by conditions that reduce plastid osmotic stress leading to the conclusion that these channels function like their bacterial homologues (Wilson et al. 2014). |
Eukaryota | Viridiplantae, Streptophyta | Msl2 of Arabidopsis thaliana (Q56X46) |
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1.A.23.4.5 | MscM (YbdG) is a distant member of the MscS family. It displays miniconductance (MscM) activity (Schumann et al., 2010; Edwards et al. 2012). |
Bacteria | Pseudomonadota | MscM (YbdG) of E. coli (P0AAT4) |
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1.A.23.4.6 | Mechanosensitive channel, MscS |
Archaea | Thermoproteota | MscS of Sulfolobus islandicus (C4KE93) |
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1.A.23.4.7 | Mechanosensitive ion channel protein 8 (Mechanosensitive channel of small conductance-like 8) (MscS-like protein 8, Msl8) is a pollen-specific, membrane tension-gated ion channel required for pollen to survive the hypoosmotic shock of rehydration and for full male fertility. It negatively regulates pollen germination but is required for cellular integrity during germination and tube growth. MSL8 thus senses and responds to changes in membrane tension associated with pollen hydration and germination (Hamilton et al. 2015). Mechanosensitive ion channels, MSL8, MSL9, and MSL10, have environmentally sensitive intrinsically disordered regions with distinct biophysical characteristics (Flynn et al. 2023). Intrinsically disordered protein regions (IDRs) are highly dynamic sequences that rapidly sample a collection of conformations over time. In the past several decades, IDRs have emerged as major components of many proteomes, comprising ~30% of all eukaryotic protein sequences. Proteins with IDRs function in a wide range of biological pathways and are notably enriched in signaling cascades that respond to environmental stresses. Flynn et al. 2023 identified and characterized intrinsic disorder in the soluble cytoplasmic N-terminal domains of MSL8, MSL9, and MSL10, three members of the MscS-like (MSL) family of mechanosensitive ion channels. In plants, MSL channels are proposed to mediate cell and organelle osmotic homeostasis. See TC# 1.A.23.4.14 for details of MSL10. |
Eukaryota | Viridiplantae, Streptophyta | MSL8 of Arabidopsis thaliana |
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1.A.23.4.8 | Mechanosensitive ion channel protein 5 (Mechanosensitive channel of small conductance-like 5) (MscS-Like protein 5) | Eukaryota | Viridiplantae, Streptophyta | MSL5 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.23.4.9 | Putative small conductance mechanosensitive channel; Calcium channel, MacS |
Eukaryota | Fungi, Ascomycota | MacS of Mycosphaerella graminicola (Zymoseptoria tritici) |
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1.A.23.5.1 | The cyclic nucleotide-binding MscS homologue, MT2508 (the C-terminal domain is the CAP_ED domain CD00038). It lacks mechanosensitivity but is ligand-gated by cyclic nucleotides (Caldwell et al., 2010). |
Bacteria | Actinomycetota | MscS homologue, MT2508 of Mycobacterium tuberculosis (P71915) |
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1.A.23.6.1 | Chloroplast mechanosensitive channel, Msc1 (anions are preferred over cations) (Nakayama et al., 2007). | Eukaryota | Viridiplantae, Chlorophyta | Msc1 of Chlamydomonas reinhardtii (A3KE12) |
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1.A.23.7.1 | MscS homologue |
Bacteria | Actinomycetota | MscS homologue of Streptomyces coelicolor |
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1.A.23.7.2 | MscS homologue |
Bacteria | Myxococcota | MscS of Myxococcus xanthus |
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1.A.23.8.1 | CmpX of 274 aas and 5 TMSs in a 1 + 4 arrangement. CmpX regulates virulence and controls biofilm formation in P. aeruginosa (Bhagirath et al. 2017). It also modulates intra-cellular c-di-GMP levels. A cmpX knockout showed decreased promoter activity of exoS (PA1362) and increased activity of the small RNA, RsmY. As compared to the wild-type PAO1, the cmpX mutant had elevated intracellular c-di-GMP levels as well as increased expression of wspR (PA3702), a c-di-GMP synthase. Transcription of the major outer membrane porin gene oprF (PA1777) and sigma factor sigX (PA1776) was decreased in the cmpX mutant. The cmpX knockout mutant had increased sensitivity to membrane detergents and antibiotics such as lauryl sulfobetaine, tobramycin, and vancomycin (Bhagirath et al. 2017). Exogenous c-di-GMP inhibits biofilm formation of Vibrio splendidus (Yang et al. 2023). |
Bacteria | Pseudomonadota | CmpX of Pseudomonas aeruginosa |
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1.A.23.8.2 | CmpX protein of 227 aas and 5 TMSs |
Bacteria | Candidatus Wolfebacteria | CmpX of Candidatus Wolfebacteria bacterium |
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1.A.23.8.3 | Uncharacterized protein of 439 aas and 9 TMSs in a 5 + 4 arrangement. |
Bacteria | Pseudomonadota | UP of Brevundimonas viscosa |
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1.A.23.8.4 | Mechanosensitive ion channel protein MscS of 254 aas and 5 TM |
Archaea | Euryarchaeota | MscS of Haloterrigena daqingensis |
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1.A.23.8.5 | Uncharacterized protein of 486 aas and 11 TMSs. |
Bacteria | Pseudomonadota | UP of Hydrogenophaga taeniospiralis |
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1.A.24.1.1 | Connexin 43 (gap junction α-1 protein), CX43 encoded by the GJA1 gene (transports ATP, ADP and AMP better than CX32 does; Goldberg et al., 2002). Hemichannels mediate efflux of glutathione, glutamate and other amino acids as well as ATP (Stridh et al., 2008; Kang et al., 2008). CX43 has a half life of ~3 h due to ubiquitination and lysosomal and proteasomal degradation (Leithe and Rivedal, 2007). Cx43 and Cx46 regulate each other's expression and turnover in a reciprocal manner in addition to their conventional roles as gap junction proteins in lens cells (Banerjee et al., 2011). A mutant form of Connexin 43 causes Oculodentodigital dysplasia (Gabriel et al., 2011). Suppressing the function of Cx43 promotes expression of wound healing-associated genes and hibitits scarring (Tarzemany et al. 2015). Channel conductance and size selectivity are largely determined by pore diameter, whereas charge selectivity results from the amino-terminal domains; transitions between fully open and (multiple) closed states involves global changes in structure of the pore-forming domains (Ek Vitorín et al. 2016). The human Cx43 orthologue is almost identical to the rat protein. It may mediate resistance against the parkinsonian toxin, 1-methyl-4-phenylpyridine (MPP+) which induces apoptosis in neuroblastoma cells by modulating mitochondrial apoptosis (Kim et al. 2016). Dopamine neurons may be the target of MPP+ and play a role in Parkinson's disease. In humans, Cx43 plays roles in the development of the central nervous system and in the progression of glioma (Wang et al. 2017). It interacts with and is regulated by many proteins including NOV (CCN3, IGFBP9; P48745) (Giepmans 2006). Cx43 plays roles in intercellular communication mediated by extracellular vesicles, tunnelling nanotubes and gap junctions (Ribeiro-Rodrigues et al. 2017). Phosphorylation of Cx43 leads to astrocytic coupling and apoptosis, and ultimately, to vascular regeneration in retinal ischemia. Paxillin (Pxn; 591 aas; P49023), a cytoskeletal protein involved in focal adhesion, leads to changes in connexin 43 by direct protein-protein binding, thereby influencing osteocyte gap junction elongation (Zhang et al. 2018). Regulation of Cx43 abundance involves transcriptional/post-transcriptional and translational/post-translational mechanisms that are modulated by an interplay between TGF-beta isoforms and PGE2, IL-1beta, TNF-alpha and IFN-gamma (Cheng et al. 2018). In the developing fetal human kidney, cytoplasmic expression of Cx36 was localized to nephrons in different developmental stages, glomerular vessels and collecting ducts, and of Cx43 was localized to the endothelium of glomerular and peritubular vessels, as well as to the epithelium of the proximal tubules (Ráduly et al. 2019). Mutations in the gap junction protein α1 (GPA1) gene cause oculodentodigital dysplasia (Pace et al. 2019). Expression of connexin 43 is elevated in atypical fibroxanthoma cells (Fernandez-Flores et al. 2020). Astrocytic connexin43 channels are candidate targets in epilepsy treatment (Walrave et al. 2020). Cx43 plays roles in physiological functions such as regulating cell growth, differentiation, and maintaining tissue homeostasis (Sha et al. 2020). Amyloid-beta (TC# 1.C.50) regulates connexin 43 trafficking in cultured primary astrocytes (Maulik et al. 2020). Gap junction protein Cx43 plays a role in regulating cellular function and paracrine effects of smooth muscle progenitor cells (Tien (田婷怡) et al. 2021). A serine residues in the connexin43 carboxyl tail is important for B-cell antigen receptor-mediated spreading of B-lymphocytes (Pournia et al. 2020). Connexin 43 plays an antagonistic role in the development of primary bone tumors as a tumor suppressor and also as a tumor promoter (Talbot et al. 2020). Retinal astrocytes abundantly express Cx43 that forms gap junction (GJ) channels and unopposed hemichannels, and Cx43 is upregulated in retinal injuries. Astrocytic Cx43 plays a role in retinal ganglion cell (RGC) loss associated with injury (Toychiev et al. 2021). Screens for inhibitors of Cx43 hemichannel function have revealed several candidates (Soleilhac et al. 2021). The dodecameric channel is formed by the end-to-end docking of two hexameric connexons, each comprised of 24 transmembrane alpha-helices (Cheng et al. 2019). Cx43 appears to be involved in the tumorigenesis of most pituitary adenomas and have a potential therapeutic value for pituitary tumor therapy (Nunes et al. 2022). Yang et al. 2023 provided an updated understanding of connexin hemichannels and pannexin channels in response to multiple extrinsic stressors and how these activated channels and their permeable messengers participate in toxicological pathways and processes, including inflammation, oxidative damage and intracellular calcium imbalance (Yang et al. 2023). Remodeled connexin 43 hemichannels alter cardiac excitability and promote arrhythmias (Lillo et al. 2023). Insulin docking within the open hemichannel of connexin 43 may reduce risk of amyotrophic lateral sclerosis (Lehrer and Rheinstein 2023). A truncated isoform of Connexin43 caps actin to organize forward delivery of full-length Connexin43 (Baum et al. 2025). Cx43 is abundantly expressed in various types of human cells. Cx43, encoded by the gap junction protein alpha 1 (GJA1) gene, assembles into a hexameric structure in the Golgi apparatus and translocates to the plasma membrane to form hemichannels (Hcs), which pair with those of the cells in contact with each other and form gap junction intercellular communication (GJIC) (Xiong et al. 2024). Cx43 mimetic peptides have been tested for the treatment of different retinal pathologies (Domenech-Bendaña et al. 2025). |
Eukaryota | Metazoa, Chordata | CX43 of Rattus norvegicus |
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1.A.24.1.10 |
Connexin31, Cx31 of 270 aas and 4 TMSs. Also called the gap junction β-3 protein. Mutation Thr202Asn in TMS4 gives rise to erythrokeratodermia (Sugiura et al. 2015). |
Eukaryota | Metazoa, Chordata | Cx31 of Homo sapiens |
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1.A.24.1.11 | Gap junction α-1 protein, GJα-1, Cx43, shf, sof, of 281 aas and 4 TMSs. Can function both as a gap junction and a hemichannel and plays critical diverse roles in zebrafish bone growth (Misu et al. 2016). Cellular communication network factor 2 (ccn2a) acts downstream of Cx43 to influence joint formation during zebrafish fin regeneration (Hyland and Iovine 2025). |
Eukaryota | Metazoa, Chordata | Cx43 of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.A.24.1.12 | Connexin 29 (Cx29, Gjc3, Gje1) of 269 aas and 4 TMSs. The Cx29E269D mutant has a dominant negative effect on the formation and function of gap junctions, explaining the role Cx29 in the development of hearing loss (Hong et al. 2010). Direct axon-to-myelin linkage by abundant KV1 (TC# 1.A.1.2.10 and 12)/Cx29 channel interactions in rodent axons supports the idea of an electrically active role for myelin in increasing both the saltatory conduction velocity and the maximal propagation frequency in mammalian myelinated axons (Rash et al. 2016). |
Eukaryota | Metazoa, Chordata | Cx29 of Mus musculus |
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1.A.24.1.13 | Connexin36, connexin delta2, Cxδ2, GJD2, Cx36 of 321 aas and 4 TMSs. In the developing fetal kidney, cytoplasmic expression of Cx36 is localized to nephrons in different developmental stages, glomerular vessels and collecting ducts. Cx43 is localized to the endothelium of glomerular and peritubular vessels, as well as to the epithelium of the proximal tubules (Ráduly et al. 2019). A reciprocal relationship between Cx36 and seizure-associated neuronal hyperactivityhas been obseerved; thus, Cx36 deficiency contributes to region-specific susceptibility to neuronal hyperactivity, while neuronal hyperactivity-induced downregulation of Cx36 may increase the risk of future epileptic events (Brunal et al. 2020). Cx36 is responsible for signal transmission in electrical synapses by forming interneuronal gap junctions. Lee et al. 2023 determined cryo-electron microscopy structures of Cx36 GJC at 2.2-3.6 Å resolutions, revealing a dynamic equilibrium between its closed and open states. In the closed state, channel pores are obstructed by lipids, while N-terminal TMSs are excluded from the pore. In the open state with pore-lining N-terminal TMSs, the pore is more acidic than those in Cx26 and Cx46/50 GJCs, explaining its strong cation selectivity. The conformational change during channel opening also includes the alpha-to-pi-helix transition of the first transmembrane helix, which weakens the protomer-protomer interaction (Lee et al. 2023). |
Eukaryota | Metazoa, Chordata | Cx36 of Homo sapiens |
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1.A.24.1.14 | Gap junction protein B4, GJB4, or Cx30.3 of 266 aas and 4 TMSs. Small molecules and ions diffuse from one cell to a neighboring cell via the central pore in these dodecameric channels. Mutation can cause a familial form of hypertrophic cardiomyopathy (HCM) and therefore could be a target for the treatment of cardiac hypertrophy and dysfunction (Okamoto et al. 2020). Cx30 and Cx26 hemichannels display similar permeabilities to ATP, but Cx26 gap junctions are six times more permeable than their hemichannels and four times more permeable than Cx30 gap junctions (Xu and Nicholson 2023).
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Eukaryota | Metazoa, Chordata | GJB4 of Homo sapiens |
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1.A.24.1.15 | Gap junction protein alpha 5, GJA5 or CxA5, of 358 aas and 4 TMSs. One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell. GAJ5 is enriched for the function of ion transmembrane transport regulation and is a key atrial fibrillation (AF)-valvular heart disease (VHD) protein (Zhao et al. 2021).
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1.A.24.1.16 | Connexin-43, Cx43, or Gap Junction α-1 protein, GJA1, of 382 aas and 4 TMSs in a 2 + 2 TMS arrangement. Extracellular vesicles enriched in connexin 43 promote a senescent phenotype in bone and synovial cells, contributing to osteoarthritis progression (Varela-Eirín et al. 2022). It is 98% identical to the rat ortholog (TC# 1.A.24.1.1). Cx43 expression is highly sensitive to oxidative distress, leading to reduced expression (Wahl et al. 2022). This effect can be efficiently prevented by the glutathione peroxidase mimetic ebselen. Cx43 expression is tightly regulated by miR-1, which is activated by tachypacing-induced oxidative distress. In light of the high arrhythmogenic potential of altered Cx43 expression, miR-1 may be a target for pharmacological interventions to prevent the maladaptive remodeling processes during chronic distress in the heart (Wahl et al. 2022). Cx43 hemichannels can reversibly transport NAD+ and cyclic ADP-ribose, the latter which acts on cytoplasmic ryanodine receptors (RyRs) (Astigiano et al. 2022). Connexin 43 hemichannels regulate mitochondrial ATP generation, mobilization, and mitochondrial homeostasis against oxidative stress (Zhang et al. 2022). Cx43 and Cx32 catalyze ATP release from cells (Tovar et al. 2023). Jiang et al. 2023 have summarized the association between Cx43 and neuroinflammation, the cornerstones linking inflammation and depression, and Cx43 abnormalities in depression. The orally delivered Connexin43 hemichannel blocker, tonabersat, inhibits vascular breakdown and inflammasome activation in a mouse model of diabetic retinopathy suggesting that tonabersat may be a safe and effective treatment for DR (Mugisho et al. 2023). Conformational changes in the human Cx43/GJA1 gap junction channel have been visualized using cryo-EM (Lee et al. 2023). Simvastatin is an adjuvant in doxorubicin anticancer therapy. Its antioxidant and antiapoptotic activityies showed that Simvastatin interferes with expression and cellular localization of Cx43 that is widely involved in cardioprotection (Pecoraro et al. 2023). CX43 down-regulation promotes cell aggressiveness and 5-fluorouracil-resistance by attenuating cell stiffness in colorectal carcinoma (Han et al. 2023). The structure of a human Cx43 GJC has been solved by cryo-EM and single particle analysis at 2.26 Å resolution. The pore region of Cx43 GJC features several lipid-like densities per Cx43 monomer, located close to a putative lateral access site at the monomer boundary. A previously undescribed conformation on the cytosolic side of the pore, formed by the N-terminal domain and the transmembrane helix 2 of Cx43 are stabilized by a small molecule. Structures of the Cx43 GJC and hemichannels (HCs) in nanodiscs reveal a similar gate arrangement (Qi et al. 2023). Opening of Cx43-formed hemichannels mediates the Ca2+ signaling associated with endothelial cell migration (Espinoza and Figueroa 2023). The roles of Cx43 in disease development from the perspective of subcellular localization have been summarized (Xiong et al. 2023). Opening of Cx43-formed hemichannels mediates the Ca2+ signaling associated with endothelial cell migration (Espinoza and Figueroa 2023). Targeting Cx43 reduces the severity of pressure ulcer progression (Kwek et al. 2023). Multiple sclerosis (MS) is a neurodegenerative disease marked by chronic neuroinflammation thought to be mediated by the inflammasome pathway. Connexin 43 (Cx43) hemichannels contribute to the activation of the inflammasome through the release of adenosine triphosphate (ATP) inflammasome activation signals. Tonabersat significantly reduces disease progression in an experimental mouse model of multiple sclerosis (Kwakowsky et al. 2023). The E3 ubiquitin ligase ITCH negatively regulates intercellular communication via gap junctions by targeting connexin43 for lysosomal degradation (Totland et al. 2024). Cx43 hemichannels and panx1 channels contribute to ethanol-induced astrocyte dysfunction and damage (Gómez et al. 2024). Differential regulation of Cx43 hemichannels and gap junction channels by RhoA GTPase and the actin cytoskeleton has been observed (Jara et al. 2024). |
Eukaryota | Metazoa, Chordata | Cx43 of Homo sapiens |
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1.A.24.1.17 | Gap Junction protein GJD3 (GJA11; GJC1) of 294 aas and 4 TMSs. A rare haplotype of the GJD3 gene segregating in familial Meniere's disease interferes with connexin assembly (Escalera-Balsera et al. 2025). |
Eukaryota | Metazoa, Chordata | GJD3 of Homo sapiens |
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1.A.24.1.2 | Connexin 32 (gap junction β1-protein), CX32 (transports adenosine better than CX43 does; Goldberg et al., 2002). The carboxyl tail regulates gap junction assembly (Katoch et al. 2015). The modeled channel pore-facing regions of TMSs 1 and 2 were highly sensitive to tryptophan substitution while lipid-facing regions of TMSs 3 and 4 were variably tolerant. Residues facing a putative intracellular water pocket (the IC pocket) were also sensitive. Interactions important for voltage gating occurred mainly in the mid-region of the channel in TMS 1. TMS 1 of Cx43 was scanned revealing similar but not identical sensitivities (Brennan et al. 2015). Single point mutations in Cx32, which cause Charcot-Marie-Tooth disease, causes failure in membrane integration, transport defects and rapid degradation. Multiple chaperones detect and remedy this aberrant behavior including the ER-membrane complex (EMC) which helps insert low-hydrophobicity TMSs (Coelho et al. 2019). If they fail to integrate, they are recognized by the ER-lumenal chaperone BiP. Ultimately, the E3 ligase gp78 ubiquitinates Cx32, targeting it for degradation. Thus, cells use a coordinated system of chaperones for membrane protein biogenesis. Dileucine-like motifs in the C-terminal tail of connexin32 control its endocytosis and assembly into gap junctions (Ray et al. 2018). |
Eukaryota | Metazoa, Chordata | CX32 of Rattus norvegicus |
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1.A.24.1.3 | Heteromeric connexin (Cx)32/Cx26; (CxB2, GJβ2, GJB2) (transports cAMP, cGMP and all inositol phosphates with 1-4 esterified phosphate groups (homomeric Cx26(β2) or homomeric Cx32 do not transport the inositol phosphates as well) (Ayad et al., 2006). The GJB2 gene encodes connexin 26, the protein involved in cell-cell attachment in many tissues. GJB2 mutations cause autosomal recessive (DFNB1) and sometimes dominant (DFNA3) non-syndromic sensorineural hearing loss as well as various skin disease phenotypes (Iossa et al., 2011; Tian et al. 2022). TMS1 regulates oligomerization and function (Jara et al., 2012). The carboxyl tail pg Cx32 regulates gap junction assembly (Katoch et al. 2015). In Cx46, neutralization of negative charges or addition of positive charge in the Cx26 equivalent region reduced the slow gate voltage dependence. In Cx50 the addition of a glutamate in the same region decreased the voltage dependence and the neutralization of a negative charge increased it. Thus, the charges at the end of TMS1 are part of the slow gate voltage sensor in Cxs. The fact that Cx42, which has no charge in this region, still presents voltage dependent slow gating suggests that charges still unidentified also contribute to the slow gate voltage sensitivity (Pinto et al. 2016). Syndromic deafness mutations at Asn14 alter the open stability of Cx26 hemichannels (Sanchez et al. 2016). The Leu89Pro substitution in the second TMS of CX32 disrupts the trafficking of the protein, inhibiting the assembly of CX32 gap junctions, which in turn may result in peripheral neuropathy (Da et al. 2016). Cx26 mutants that promote cell death or exert transdominant effects on other connexins in keratinocytes lead to skin diseases and hearing loss, whereas mutants having reduced channel function without aberrant effects on coexpressed connexins cause only hearing loss (Press et al. 2017). When challenged by a field of 0.06 V/nm, the Cx26 hemichannel relaxed toward a novel configuration characterized by a widened pore and an increased bending of the second TMS at the level of the conserved Pro87. A point mutation that inhibited such a transition impeded hemichannel opening in electrophysiology and dye uptake experiments. Thus, the Cx26 hemichannel uses a global degree of freedom to transit between different configuration states, which may be shared among all connexins (Zonta et al. 2018). A group of human mutations within the N-terminal (NT) domain of connexin 26 hemichannels produce aberrant channel activity, which gives rise to deafness and skin disorders, including keratitis-ichthyosis-deafness (KID) syndrome. Structural and functional studies indicate that the NT domain of connexin hemichannels is folded into the pore, where it plays important roles in permeability and gating. The mutation, N14K disrupts cytosolic intersubunit interactions and promotes channel opening (Valdez Capuccino et al. 2018). A missense mutation in the Connexin 26 gene is associated with hereditary autosomal recessive sensorineural deafness (Leshinsky-Silver et al. 2005, Zytsar et al. 2020). Cx26 hemichannels mediate the passage of contents between the cytoplasm and extracellular space. To generate hemichannels, the mutation N176Y was introduced into the second extracellular loop of Cx26. The cryoEM structure of the hexameric hemichannel in lipid bilayer nanodiscs displays an open pore and a 4-helix bundle transmembrane design that is nearly identical to dodecameric GJCs. In contrast to the high resolution of the transmembrane alpha-helices, the extracellular loops are less well resolved. The conformational flexibility of the extracellular loops may be essential to facilitate surveillance of hemichannels in apposed cells to identify compatible Cx isoforms that enable intercellular docking (Khan et al. 2021). A rare variant c.516G>C (p.Trp172Cys) in the GJB2 (connexin 26) gene is associated with nonsyndromic hearing loss (Maslova et al. 2021). Keratitis-ichthyosis-deafness (KID) syndrome is caused by mutations in the GJB2 gene (Asgari et al. 2020). An increase in the partial pressure of carbon dioxide (PCO2) has been shown to cause Cx26 gap junctions to close. Cryo-EM was used to determine the structure of human Cx26 gap junctions under increasing levels of PCO2. Brotherton et al. 2022 showed a correlation between the level of PCO2 and the size of the aperture of the pore, governed by the N-terminal helices that line the pore. Thus, CO2 alone is sufficient to cause conformational changes in the protein. Analysis of the conformational states showed that movements at the N-terminus are linked to both subunit rotation and flexing of the transmembrane helices (Brotherton et al. 2022). Cysteine residues in the C-terminal tail of connexin32 regulate its trafficking (Ray and Mehta 2021). The pathogenesis of common Gjb2 mutations are associated with human hereditary deafness (Li et al. 2023). Pan-cancer analysis of the prognostic and immunological role of GJB2 identifies a potential target for survival and immunotherapy (Jia et al. 2023). The keratitis-ichthyosis-deafness (KID) syndrome is a rare genetic disease caused by pathogenic variants in connexin 26 (gene GJB2), which is a transmembrane channel of the epithelia (López-Sundh et al. 2023). Consequences of pathogenic variants of the GJB2 gene (Cx26) localized in different Cx26 domains have been evaluated (Posukh et al. 2023). A pore locus in E1 of Cx26 and Cx30 impacts hemichannel functionality (Sanchez et al. 2024). An Ala/Glu difference in E1 of Cx26 and Cx30 contributes to their differential anionic permeabilities (Kraujaliene et al. 2024). Differential regulation of Cx26 hemichannels and gap junction channels by RhoA GTPase and the actin cytoskeleton has been observed (Jara et al. 2024). GJB2, KCNH6, and KCNN4 are oncogenic, and GJB2 and KCNN4 were upregulated, while KCNH6 was downregulated in high risk group and glioblastoma (GBM) cells. The regulatory network showed that KCNH6 was targeted by more miRNAs and transcription factors and KCNN4 interacted with more drugs (Huang et al. 2024). |
Eukaryota | Metazoa, Chordata | Cx26/Cx32 of Homo sapiens |
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1.A.24.1.4 | Connexin 35 hemichannels (activated by depolarization; deactivated by hyperpolarization; expressed in retina and brain (Valiunas et al., 2004). | Eukaryota | Metazoa, Chordata | Connexin 35 of Danio rerio (Zebrafish) (Q8JFD6) |
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1.A.24.1.5 | Heteromeric (or homomeric) Connexin46/Connexin50 junction (Cx46/Cx50; Cnx46/Cnx50; GJA8/GJA3) protein. Mutations in CX46 or Cx50 cause cataracts, a cause of visual impairment and blindness (Derosa et al., 2007; Wang and Zhu 2012; Ye et al. 2019), and mutations in Cx46 can cause breast cancer (Grek et al. 2016). Cx43 and Cx46 regulate each other's expression and turnover in a reciprocal manner in addition to their conventional roles as gap junction proteins in lens cells (Banerjee et al., 2011). The N-terminal half of connexin 46 appears to contain the core elements of the pore and voltage gates (Kronengold et al. 2012). In Cx46, neutralization of negative charges or addition of positive charge in the Cx26 equivalent region reduced the slow gate voltage dependence. In Cx50 the addition of a glutamate in the same region decreased the voltage dependence, and the neutralization of a negative charge increased it. Thus, the charges at the end of TMS1 are part of the slow gate voltage sensor in Cxs. The fact that Cx42, which has no charge in this region, still presents voltage dependent slow gating, suggests that charges still unidentified also contribute to the slow gate voltage sensitivity (Pinto et al. 2016). Cx43 is regulated by phosphorylation of Ser-373 (Puebla et al. 2016). A connexin50 mutation in the heterozygous state affects the lipid profile and the oxidative stress parameters in a spontaneously hypertensive rat strain (Šeda et al. 2016). Mutations in Cx50 (N220D and V44M) are responsible for congenital cataracts (Kuo et al. 2017; Zhang et al. 2018) Mutations its gene cause defects in early eye development (Ceroni et al. 2019). Cx50 is important for eye lens transparency, and calmoduin and Ca2+ cooperate in the gating control of Cx50 hemichannels (Zhang et al. 2006). Cx46 hemichannels are modulated by nitric oxide, and the fourth TMS cysteine may be involved in cataract formation (Retamal et al. 2019). Gap19 is a Cx43 hemichannel inhibitor that acts as a gating modifier that decreases main state opening while increasing substate gating (Lissoni et al. 2020). Cx46, almost exclusively expressed in the eye lens, is upregulated in human breast cancer, and correlates with tumor growth (Acuña et al. 2020). EphA2 is required for normal Cx50 localization to the cell membrane, and conductance of lens fiber cells requires normal Eph-ephrin signaling and water channel (Aqp0) localization (Cheng et al. 2021). The Gja8 (Cx50) mutation gives rise to a cataract rat model (Shen et al. 2023). The V219F mutation in Gja8, induced semi-dominant nuclear cataracts. The p.V219F mutation altered Cx50 distribution, inhibited lens epithelial cell proliferation, migration, and adhesion, and disrupted fiber cell differentiation. As a consequence, the nuclear cataract and small lens formed (Shen et al. 2023). León-Fuentes et al. 2023 have reviewed the relationship between Cx46, its role in forming hemichannels and gap junctions, and its connection with cancer and cancer stem cells. Bioelectrical signal propagation involving Cx46 within the developing neuromuscular system is required for appropriate myofiber organization, and disruption leads to defects in behavior (Lukowicz-Bedford et al. 2023). |
Eukaryota | Metazoa, Chordata | Cx46/Cx50 of Homo sapiens: |
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1.A.24.1.6 | Connexin37 (Cx37). The N-terminus contains an α-helix that is required for channel function (Kyle et al., 2009). | Eukaryota | Metazoa, Chordata | Connexin37 of Homo sapiens (P35212) |
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1.A.24.1.7 |
Connexin 30 complex (connexin30.2/connexin31.3 (CX30.2/CX31.3)). Also called connexinΥ3/GJC3/GJε1; 279 aas, encoded by the GJB6 (13q12) gene (Cascella et al. 2016)). ATP is released from cells that stably expressed CX30.2 in a medium with low calcium, suggesting a hemichannel-based function. Liang et al. (2011) suggested that it shares functional properties with pannexin hemichannels rather than gap junction channels. Defects cause nonsyndromic hypoacusia (hearing loss) due to partial loss of channel activity (Su et al. 2012; Su et al. 2013; Cascella et al. 2016). Cx30, but not Cx43, hemichannels close upon protein kinase C activation, showing that connexin hemichannels display not only isoform-specific permeability profiles but also isoform-specific regulation by PKC (Alstrom et al. 2015). The W77S mutant has a dominant negative effect on the formation and function of the gap junction and is probably responsible for hearing loss (Wong et al. 2017). Mutations in Cs30 rescue hearing and reveal roles for gap junctions in cochlear amplification (Lukashkina et al. 2017). The cryo-EM structure of the human Cx31.3/GJC3 connexin hemichannel has been solved (Lee et al. 2020). Cx31.3)/GJC3 hemichannels in the presence and absence of calcium ions and with a hearing-loss mutation R15G were solved at 2.3-, 2.5- and 2.6-Å resolutions, respectively. Compared with available structures of GJICh in the open conformation, the Cx31.3 hemichannel shows substantial structural changes of highly conserved regions in the connexin family, including opening of calcium ion-binding tunnels, reorganization of salt-bridge networks, exposure of lipid-binding sites, and collocation of amino-terminal helices at the cytoplasmic entrance. The hemichannel has a pore with a diameter of ~8 Å and selectively transports chloride ions (Lee et al. 2020). A pore locus in E1 of Cx26 and Cx30 impacts hemichannel functionality (Sanchez et al. 2024). An Ala/Glu difference in E1 of Cx26 and Cx30 contributes to their differential anionic permeabilities (Kraujaliene et al. 2024). |
Eukaryota | Metazoa, Chordata | Cx30.2 of Homo sapiens (Q8NFK1) |
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1.A.24.1.8 | Connexin40 (Cx40; Gap Junction Protein δ4; GJδ4) of 370 aas and 4 TM (Kopanic et al. 2015). A phosphorylatable PDZ-domain-binding motif (PDZbm) at the C-terminus of Cx40 is critical for its trafficking and the ability to form functional GJCs, and is relevant to pulmonary arterial hypertension (PAH) (Wei, L, personal communication).
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Eukaryota | Metazoa, Chordata | Cx40 of Homo sapiens |
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1.A.24.1.9 | Gap junction epsilon-1 protein, Gjf1 of 205 aas and 4 TMSs. Mutations result in variable small eyes and affect lens development (Puk et al. 2008). |
Eukaryota | Metazoa, Chordata | Gjf1 of Mus musculus |
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1.A.24.2.1 | Connexin 47 gap junction (catalyzes intercellular diffusion of neurobiotin, Lucifer yellow and 4',6-diamidino-2-phenylindole; expressed in brain and spinal cord neurons) (Teubner et al., 2001). Possesses sequences between TMSs 2 and 3 and following TMS 4 that differ from these regions in most other connexins. Mutations in the encoding gene can give rise to Pelizaeus-Merzbacher-like disease (Ji et al. 2023). |
Eukaryota | Metazoa, Chordata | Connexin 47 of Mus musculus |
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1.A.24.2.2 | Invertebrate cordate Connexin 47 (White et al., 2004). |
Eukaryota | Metazoa, Chordata | Connexin 47 of Halocynthia pyriformis (Q6U1M0) |
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1.A.24.2.3 | Inverebrate cordate Connexin (Hervé et al., 2005). |
Eukaryota | Metazoa, Chordata | Connexin of Oikopleura dioica (E4YIP4) |
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1.A.24.2.4 | Connexin45 (Cx45; Cx-45; Gap Junction protein γ1; GJγ1; Gjc1; Gja7; CxG1) of 396 aas and 4 TMSs (Kopanic et al. 2015). |
Eukaryota | Metazoa, Chordata | Cx45 of Homo sapiens |
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1.A.25.1.1 | Invertebrate innexin, (gap junction protein), INX3 | Eukaryota | Metazoa, Nematoda | INX3 of C. elegans | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.25.1.10 | Leech innexin, Inx2 (Kandarian et al. 2012; Firme et al. 2012) |
Eukaryota | Metazoa, Annelida | Inx2 of Hirudo verbana |
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1.A.25.1.11 | Duplicated innexin of 801 aas and 8 TMSs. |
Eukaryota | Metazoa, Nematoda | Innexin of Ascaris suum |
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1.A.25.1.12 | Duplicated innexin protein of 813 aas and 8 TMSs. |
Eukaryota | Metazoa, Nematoda | Duplicated innexin of Trichinella spiralis (Trichina worm) |
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1.A.25.1.13 | Innexin2, Inx2 of 359 aas and 4 TMSs. N-terminally elongated domains in innexins may act to plug or manipulate hemichannel closure and provide a mechanism connecting the effect of hemichannel closure directly to apoptotic signaling transduction (Chen et al. 2016). |
Eukaryota | Metazoa, Arthropoda | Inx2 of Spodoptera litura (Asian cotton leafworm) |
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1.A.25.1.14 | Innexin 2, Inx2; Prp33, of 367 aas and 4 TMSs. It is a structural components of gap junctions, and is involved in gap junctional communication between germline and somatic cells which is essential for normal oogenesis (Bohrmann and Zimmermann 2008). In embryonic epidermis, it is required for epithelial morphogenesis as well as for keyhole formation during early stages of proventriculus development in response to wg signaling (Bauer et al. 2004). In follicle cells, it promotes the formation of egg chambers, in part through regulation of shg and baz at the boundary between germ cells and follicle cells. In inner germarial sheath cells, it is required for survival of early germ cells and for cyst formation (Mukai et al. 2011).
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Eukaryota | Metazoa, Arthropoda | Inx2 or Anon-37B-2 of Drosophila melanogaster (Fruit fly) |
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1.A.25.1.15 | Innexin-2 of 358 aas and 6 TMSs. Innexin-2 can participate in many physiological processes during the development of R. americana (Neves et al. 2021). |
Eukaryota | Metazoa, Arthropoda | Innexin-2 of Rhynchosciara americana |
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1.A.25.1.2 | Invertebrate innexin, UNC-7 |
Eukaryota | Metazoa, Nematoda | UNC-7 of Caenorhabditis elegans |
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1.A.25.1.3 | Invertebrate innexin, Ogre | Eukaryota | Metazoa, Arthropoda | Ogre of Drosophila melanogaster | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.25.1.4 | Invertebrate innexin, passover protein (shaking B locus) | Eukaryota | Metazoa, Arthropoda | Passover protein of Drosophila melanogaster | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.25.1.5 | Invertebrate innexin, NSY-5 (INX-19) (Chuang et al., 2007) (establishes left-right neuronal asymmetry) (Oviedo and Levin, 2007) | Eukaryota | Metazoa, Nematoda | NSY-5 (INX-19) of Caenorhabditis elegans (NP_490983) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.25.1.6 | Innexin-14 (Protein Opu-14) |
Eukaryota | Metazoa, Nematoda | Inx-14 of Caenorhabditis elegans |
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1.A.25.1.7 |
Innexin-6 protein, Inx-6 or Opu-6, of 389 aas and 4 TMSs. A single INX-6 gap junction channel consists of 16 subunits, a hexadecamer, in contrast to chordate connexin channels, which consist of 12 subunits. The channel pore diameters at the cytoplasmic entrance and extracellular gap region are larger than those of connexin26 (Oshima et al. 2016). Nevertheless, the arrangements of the transmembrane helices and extracellular loops of the INX-6 monomer are highly similar to those of connexin-26 (Cx26). The INX-6 gap junction channel comprises hexadecameric subunits but reveals an N-terminal pore funnel consistent with Cx26. The helix-rich cytoplasmic loop and C-terminus are intercalated through an octameric hemichannel, forming a dome-like entrance that interacts with N-terminal loops in the pore (Oshima et al. 2016). |
Eukaryota | Metazoa, Nematoda | Inx-6 of Caenorhabditis elegans |
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1.A.25.1.8 | Innexin Inx4 (Innexin-4) (Protein zero population growth) |
Eukaryota | Metazoa, Arthropoda | Zpg of Drosophila melanogaster |
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1.A.25.1.9 |
Leech innexin, Inx6 (Kandarian et al. 2012; Firme et al. 2012) |
Eukaryota | Metazoa, Annelida | Inx6 of Hirudo verbana |
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1.A.25.2.1 | Pannexin-1 (PANX1) has been reported to form functional, single membrane, cell surface channels (Penuela et al., 2007). Pannexin1 is part of the pore forming unit of the P2X(7) receptor death complex (Locovei et al., 2007). It can catalyze ATP release from cells (Huang and Roper, 2010) and promote ATP signalling in mice (Suadicani et al. 2012). It also promotes acetaminophen liver toxicity by allowing it to enter the cell (Maes et al. 2016). Pannexin1 and pannexin2 channels show quaternary similarities to connexons but different oligomerization numbers (Ambrosi et al., 2010). Pannexin 1 constitutes the large conductance cation channel of cardiac myocytes (Kienitz et al., 2011). Pannexin 1 (Px1, Panx1) and pannexin 2 (Px2, Panx2) underlie channel function in neurons and contribute to ischemic brain damage (Bargiotas et al., 2011). Single cysteines in the extracellular and transmembrane regions modulate pannexin 1 channel function (Bunse et al., 2011). Spreading depression triggers migraine headaches by activating neuronal pannexin1 (panx1) channels (Karatas et al. 2013). The channel in the mouse orthologue opens upon apoptosis (Spagnol et al. 2014). Transports ATP out of the cell since L-carbenoxolone (a Panx1 channel blocker) inhibits ATP release from the nasal mucosa, but flufenamic acid (a connexin channel blocker) and gadolinium (a stretch-activated channel blocker) do not (Ohbuchi et al. 2014). CALHM1 (TC#1.N.1.1.1) and PANX1 both play roles in ATP release and downstream ciliary beat frequency modulation following a mechanical stimulus in airway epithelial cells (Workman et al. 2017). Pannexin1 may play a role in the pathogenesis of liver disease (Willebrords et al. 2018). Inhibition of pannexin1 channel opening may provide a novel approach for the treatment of drug (acetaminophen-induced)-induced hepatotoxicity (Maes et al. 2017). Pannexin-1 is necessary for capillary tube formation on Matrigel and for VEGF-C-induced invasion. It is highly expressed in HDLECs and is required for in vitro lymphangiogenesis (Boucher et al. 2018). cryo-EM structure of a pannexin 1 reveals unique motifs for ion selection and inhibition. The cryo-EM structure of a pannexin 1 revealed unique motifs for ion selection and inhibition (Michalski et al. 2020). In another study, Deng et al. 2020 obtained near-atomic-resolution structures of human and frog PANX1 determined by cryo-EM that revealed a heptameric channel architecture. Compatible with ATP permeation, the transmembrane pore and cytoplasmic vestibule were exceptionally wide. An extracellular tryptophan ring located at the outer pore created a constriction site, potentially functioning as a molecular sieve that restricts the sizes of permeable substrates. Pannexin 1 channels in renin-expressing cells influence renin secretion and homeostasis (DeLalio et al. 2020). Structures of human pannexin 1 have revealed ion pathways and mechanism of gating (Ruan et al. 2020). PANX1 is critical for functions such as blood pressure regulation, apoptotic cell clearance and human oocyte development. Ruan et al. 2020 presented several structures of human PANX1 in a heptameric assembly at resolutions of up to 2.8 Å, including an apo state, a caspase-7-cleaved state and a carbenoxolone-bound state. A gating mechanism was revealed that involves two ion-conducting pathways. Under normal cellular conditions, the intracellular entry of the wide main pore is physically plugged by the C-terminal tail. Small anions are conducted through narrow tunnels in the intracellular domain. These tunnels connect to the main pore and are gated by a long linker between the N-terminal helix and the first transmembrane helix. During apoptosis, the C-terminal tail is cleaved by caspase, allowing the release of ATP through the main pore. A carbenoxolone (a channel blocker)-binding site is embraced by W74 in the extracellular entrance. A gap-junction-like structure was observed as expected (Yen and Saier 2007; Chou et al. 2017). Navis et al. 2020 provided a review of the literature on Panx1 structural biology and known pharmacological agents that target it. The R217H mutation perturbs the conformational flexibility of the C-terminus, leading to channel dysfunction (Purohit and Bera 2021). Panx1 plays decisive roles in multiple physiological and pathological settings, including oxygen delivery to tissues, mucociliary clearance in airways, sepsis, neuropathic pain, and epilepsy. It exerts some of these roles in the context of purinergic signaling by providing a transmembrane pathway for ATP, but Panx1 can also act as a highly selective membrane channel for chloride ions without ATP permeability (Mim et al. 2021). Pannexin 1 regulates skeletal muscle regeneration by promoting bleb-based myoblast migration and fusion through a lipid based signaling mechanism (Suarez-Berumen et al. 2021). Pannexin-1 activation by phosphorylation is crucial for platelet aggregation and thrombus formation (Metz and Elvers 2022). Data suggest that in response to hypotonic stress, the intact rat lens is capable of releasing ATP. This seems to be mediated via the opening of pannexin channels in a specific zone of the outer cortex of the lens (Suzuki-Kerr et al. 2022). Expression of pannexin1 in lung cancer brain metastasis and immune microenvironment has been reported (Abdo et al. 2023). Pannexin-1 (Panx1) hemichannels are non-selective transmembrane channels that play roles in intercellular signaling by allowing the permeation of ions and metabolites, such as ATP. Evidence suggests that Panx1 hemichannels control excitatory synaptic transmission. García-Rojas et al. 2023 studied the contribution of Panx1 to the GABAergic synaptic efficacy onto CA1 pyramidal neurons (PyNs) by using patch-clamp recordings and pharmacological approaches in wild-type and Panx1 knock-out (Panx1-KO) mice. Blockage of the Panx1 hemichannel with the mimetic peptide increased the synaptic level of endocannabinoids (eCB) and the activation of cannabinoid receptors type 1 (CB1Rs), which resulted in a decrease in hippocampal GABAergic efficacy, shifting excitation/inhibition (E/I) balance toward excitation and facilitating the induction of long-term potentiation. Thus, Panx1 strongly influences neuronal excitability and plays a key role in shaping synaptic changes affecting the amplitude and direction of plasticity as well as learning and memory processes (García-Rojas et al. 2023). Genetic deletion of PANX1 mitigates kidney tubular cell death, oxidative stress and mitochondrial damage after renal ischemia/reperfusion (I/R) injury through enhanced mitophagy. Mechanistically, PANX1 disrupts mitophagy by influencing the ATP-P2Y-mTOR signal pathway. Thus, PANX1 could be a biomarker for acute kidney injury (AKI) and a therapeutic target to alleviate AKI caused by I/R injury (Su et al. 2023). Blocking pannexin 1 channels alleviates peripheral inflammatory pain but not paclitaxel-induced neuropathy (Lemes et al. 2024). Cx43 hemichannels and panx1 channels contribute to ethanol-induced astrocyte dysfunction and damage (Gómez et al. 2024). Pannexin1 mediates early-life seizure-induced social behavior deficits (Obot et al. 2024). The small molecule raptinal can simultaneously induce apoptosis and inhibit PANX1 activity (Santavanond et al. 2024). A heterozygous missense variant of PANX1 causes human oocyte death and female infertility (Zhou et al. 2024).
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Eukaryota | Metazoa, Chordata | Pannexin-1 of Homo sapiens |
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1.A.25.2.2 | Pannexin1 and pannexin2 (pannexin-2; pannexin 2) channels show quaternary similarities to connexons but different oligomerization numbers (Ambrosi et al., 2010). Pannexin 1 (Px1, Panx1) and pannexin 2 (Px2, Panx2) underlie channel function in neurons and contribute to ischemic brain damage (Bargiotas et al., 2011). PANX2 channels participate in multiple physiological processes including skin homeostasis, neuronal development, and ischemia-induced brain injury. He et al. 2023 presented a cryo-EM structure of human PANX2, which revealed pore properties contrasting with those of the intensely studied paralog, PANX1. The extracellular selectivity filter, defined by a ring of basic residues, more closely resembles that of the distantly related volume-regulated anion channel (VRAC) LRRC8A (TC# 1.A.25.3.1), rather than PANX1. Furthermore, PANX2 displays a similar anion permeability sequence as VRAC, and PANX2 channel activity is inhibited by a commonly used VRAC inhibitor, DCPIB. The shared channel properties between PANX2 and VRAC may complicate dissection of their cellular functions through pharmacological manipulation (He et al. 2023). The cryo-EM structure of the human heptameric PANX2 channel has been solved (Zhang et al. 2023). It is a large-pore ATP-permeable channel with critical roles in various physiological processes, such as the inflammatory response, energy production and apoptosis. Its dysfunction is related to numerous pathological conditions including ischemic brain injury, glioma and glioblastoma multiforme. The structure was solved at a resolution of 3.4 Å. The Panx2 structure assembles as a heptamer, forming an exceptionally wide channel pore across the transmembrane and intracellular domains, compatible with ATP permeation. Comparing Panx2 with Panx1 structures in different states reveals that the Panx2 structure corresponds to an open channel state. A ring of seven arginine residues located at the extracellular entrance forms the narrowest site of the channel, which serves as the critical molecular filter controlling the permeation of substrate molecules. This was further verified by molecular dynamics simulations and ATP release assays. These studies revealed the architecture of the Panx2 channel and provided insights into the molecular mechanism of its channel gating (Zhang et al. 2023). |
Eukaryota | Metazoa, Chordata | Pannexin-2 of Homo sapiens (Q96RD6) |
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1.A.25.2.3 | Pannexin-3, PANX3, of 392 aas and 5 TMSs, is reported to form functional, single membrane, cell surface channels (Penuela et al., 2007)). It functions as an ER Ca2+ channel, hemichannel, and gap junction to promote osteoblast differentiation (Ishikawa et al., 2011). However, Panx3 expression in osteoblasts is not required for postnatal bone remodeling (Yorgan et al. 2019). PANX3 contributes to various developmental and pathophysiological processes by permeating ATP and Ca2+ ions. The cryo-EM structure of human PANX3 has been solved at 2.9-3.2 Å (Tsuyama et al. 2025). The PANX3 channel is heptameric and forms a transmembrane pore along the central symmetric axis. The narrowest constriction of the pore is composed of an isoleucine ring located in the extracellular region, and its size is comparable to that of other pannexins. |
Eukaryota | Metazoa, Chordata | Pannexin-3 of Homo sapiens (gi16418453) |
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1.A.25.2.4 | Pannexin 1a, Panx1a, of 417 aas and 4 TMSs, an ATP channel. Aromatic-aromatic interaction involving Trp123 and Tyr205 in TMSs 2 and 3, respectively are important for the assembly and trafficking of the Zebrafish Panx1a membrane channel (Timonina et al. 2020). |
Eukaryota | Metazoa, Chordata | Panx1a of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.A.25.2.5 | Mouse Pannexin 1 of 426 aas and 4 TMSs. Pannexins are ubiquitously expressed in human and mouse tissues. Pannexin 1 (Panx1), the most thoroughly characterized member of this family, forms plasmalemmal membrane channels permeable to relatively large molecules, such as ATP. Although human and mouse Panx1 amino acid sequences are conserved in the presently known regulatory sites involved in trafficking and modulation of the channel, differences occur in the N- and C-termini of the protein. Cibelli et al. 2023 used a neuroblastoma cell line to study the activation properties of endogenous mPanx1 and exogenously expressed hPanx1. Dye uptake and electrophysiological recordings revealed that in contrast to mouse Panx1, the human ortholog is insensitive to stimulation with high extracellular K+ but responds similarly to activation of the purinergic P2X7 receptor. The two most frequent Panx1 polymorphisms found in the human population, Q5H (rs1138800) and E390D (rs74549886), exogenously expressed in Panx1-null N2a cells revealed that regarding P2X7 receptor mediated Panx1 activation, the Q5H mutant is a gain of function whereas the E390D mutant is a loss of function variant. Collectively, they demonstrated differences in the activation between human and mouse Panx1 orthologs and suggest that these differences may have translational implications for studies where Panx1 has been shown to have a significant impact (Cibelli et al. 2023). |
Eukaryota | Metazoa, Chordata | Pannexin 1 of Mus musculus |
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1.A.25.3.1 | The volume-regulated Anion Channel, VRAC, or volume-sensitive outward rectifying anion channel, VSOR. It is also called the SWELL1 protein. It consists of the leucine-rich repeat-containing protein 8A, with an N-terminal pannexin-like domain, LRRC8A, together with other LRRC8 subunits (B, C, D and E). The first two TMSs of the 4 TMS LRRC8 proteins appear as DUF3733 in CDD (Abascal and Zardoya, 2012). The C-terminal soluble domain shows sequence similarity to the heme-binding protein, Shv, and pollen-specific leucine-rich repeat extension-like proteins (3.A.20.1.1). The volume-regulated anion channel, VRAC, has LRRC8A as a VRAC component. It forms heteromers with other LRRC8 membrane proteins (Voss et al. 2014). Genomic disruption of LRRC8A ablated VRAC currents. Cells with disruption of all five LRRC8 genes required LRRC8A cotransfection with other LRRC8 isoforms to reconstitute VRAC currents. The isoform combination determined the VRAC inactivation kinetics. Taurine flux and regulatory volume decrease also depended on LRRC8 proteins. Thus, VRAC defines a class of anion channels, suggesting that VRAC is identical to the volume-sensitive organic osmolyte/anion channel VSOAC, and explains the heterogeneity of native VRAC currents (Voss et al. 2014). Point mutations in two amino-acyl residues (Lys98 and Asp100 in LRRC8A and equivalent residues in LRRC8C and -E) upon charge reversal, alter the kinetics and voltage-dependence of inactivation (Ullrich et al. 2016). Using cryo-electron microscopy and X-ray crystallography, Deneka et al. 2018 and Kasuya et al. 2018 determined the structures of a homomeric channel of the obligatory subunit LRRC8A. This protein conducts ions and has properties in common with endogenous heteromeric channels. Its modular structure consists of a transmembrane pore domain followed by a cytoplasmic leucine-rich repeat domain. The transmembrane domain, which is structurally related to connexins, is wide towards the cytoplasm but constricted on the outside by a structural unit that acts as a selectivity filter. An excess of basic residues in the filter and throughout the pore attracts anions by electrostatic interaction (Deneka et al. 2018). The structure shows a hexameric assembly, and the transmembrane region features a topology similar to gap junction channels. The LRR region, with 15 leucine-rich repeats, forms a long, twisted arc. The channel pore is located along the central axis and constricted on the extracellular side, where highly conserved polar and charged residues at the tip of the extracellular helix contribute to the permeability to anions and other osmolytes. Two structural populations were identified, corresponding to compact and relaxed conformations. Comparing the two conformations suggests that the LRR region is flexible and mobile with rigid-body motions, which might be implicated in structural transitions on pore opening (Kasuya et al. 2018). VRAC is inhibited by Tamoxifen and Mefloquine (Lee et al. 2017). The intracellular loop connecting TMSs 2 and 3 of LRRC8A and the first extracellular loop connecting transmembrane domains 1 and 2 of LRRC8C, LRRC8D, or LRRC8E are essential for VRAC activity (Yamada and Strange 2018). The N termini of the LRRC8 subunits may line the cytoplasmic portion of the VRAC pore, possibly by folding back into the ion permeation pathway (Zhou et al. 2018). A set of specific modulators of LRRC8 proteins have been discovered, revealing the role of their cytoplasmic domains as regulators of channel activity by allosteric mechanisms (Deneka et al. 2021). On the adipocyte plasma membrane, the SWELL1-/LRRC8 channel complex activates in response to increases in adipocyte volume in the context of obesity. SWELL1 is required for insulin-PI3K-AKT2 signalling to regulate adipocyte growth and systemic glycaemia (Gunasekar et al. 2019). Activation of Swell1 in microglia suppresses neuroinflammation and reduces brain damage in ischemic stroke (Chen et al. 2023). |
Eukaryota | Metazoa, Chordata | The VRAC channel consisting of LRRC8A together with one or two of the subunits, LRRC8B, LRRC8C, LRRC8D and/or LRRC8E of Homo sapiens (Q8IWT6) |
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1.A.25.3.2 | The LRRC8B homologue of 480 aas. Its cytoplasmic domains are regulators of channel activity by allosteric mechanisms (Deneka et al. 2021). |
Eukaryota | Metazoa, Chordata | LRRC8B of Ciona intestinalis (Transparent sea squirt) (Ascidia intestinalis) |
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1.A.25.3.3 | Uncharacterized protein of 467 aas |
Eukaryota | Metazoa, Chordata | UP of Branchiostoma floridae (Florida lancelet) (Amphioxus) |
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1.A.25.3.4 | Uncharacterized ADP-binding protein of 1311 aas and 2 TMSs. May be involved in defense responses. |
Eukaryota | Viridiplantae, Streptophyta | UP of Oryza sativa |
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1.A.25.3.5 | Volume-regulated anion channel subunit LRRC8B-like protein of 666 aas and 4 TMSs. |
Eukaryota | Metazoa, Mollusca | LRRC8B of Mizuhopecten yessoensis |
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1.A.25.3.6 | Uncharacterized protein of 610 aas and 4 TMSs. It is of the Pannexin-like Superfamily. |
Eukaryota | Metazoa, Cnidaria | UP of Thelohanellus kitauei |
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1.A.25.3.7 | Leucine-rich repeat-containing protein 59, LRRC59, of 307 aas and 1 C-terminal TMS. It is a tail-anchored protein that localizes to the ER and the nuclear envelope and is required for nuclear import of FGF1. It might regulate nuclear import by facilitating interaction with the nuclear import machinery and by transporting cytosolic FGF1 to, and possibly through, the nuclear pore (TC# 1.I.1) (Zhen et al. 2012). LRRC59 is post-translationally inserted into ER-derived membranes, possibly by diffusion (Blenski and Kehlenbach 2019). |
Eukaryota | Metazoa, Chordata | LRRC59 of Homo sapiens |
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1.A.25.3.8 | Sr35 of 919 aas with possibly 3 TMSs, one N-terminal, one at about residue 380 and one near the C-terminus of the protein (Förderer et al. 2022). |
Eukaryota | Viridiplantae, Streptophyta | Sr35 of Triticum monococcum |
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1.A.25.3.9 | Zar1 resistosome of 852 aas and possibly about 3 TMSs of low hydrophobicity, is a calcium-permeable channel that triggers plant immune signalling (Bi et al. 2021). It forms a pentameric channel. It is a nucleotide-binding leucine-rich repeat receptor (NLR protein). Homologues in animals are called inflammasomes (Davis et al. 2011). |
Eukaryota | Viridiplantae, Streptophyta | Zar1 of Arabidopsis thaliana
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1.A.26.1.1 | Mg2+, Co2+ transporter, MgtE/SLC41 (Smith et al. 1995). |
Bacteria | Bacillota | MgtE of Bacillus firmus (Q45121) |
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1.A.26.1.2 | The Mg2+ transporter, MgtE. The crystal structure of the N-terminal hydrophilic domain has been determined to 2.3 Å resolution (Hattori et al., 2007) (>50% identical to 9.A.19.1.1), while the C-terminal transmembrane domain has been determined at 2.2 Å resolution (Takeda et al. 2014). The structure reveals a homodimer with the channel at the interface of the two subunits. There is a plug helix connecting the two domains, and the cytoplasmic domain possesses multiple Mg2+ binding sites at the cytoplasmic face that can bind Mg2+, Mn2+ and Ca2+. Dissociation of Mg2+ ions from the cytoplasmic domain induces structural changes in the cytoplasmic domain, leading to channel opening (Wang et al. 2023). Novel crystal structures of the Mg2+-bound MgtE cytoplasmic domains from two different bacterial species, Chryseobacterium hispalense and Clostridiales bacterium allowed identification of multiple Mg2+ binding sites, including ones that were not observed in the previous MgtE structure. These structures reveal the conservation and diversity of the cytoplasmic Mg2+ binding site in MgtE family proteins (Wang et al. 2023). |
Bacteria | Deinococcota | MgtE of Thermus thermophilus (Q5SMG8) |
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1.A.26.1.3 | The MgtE Mg2+ transporter. Its expression can compensate a TrpM7 deficiency in vertebrate B-cells (Sahni et al. 2012). |
Bacteria | Bacillota | MgtE of Bacillus subtilis |
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1.A.26.1.4 | Mg2+, Co2+ transporter, MgtE |
Bacteria | Pseudomonadota | MgtE of Providencia stuartii (Q52398) |
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1.A.26.1.5 | MgtE homologue (function unknown) |
Archaea | Euryarchaeota | MgtE homologue of Methanobacterium thermoautotrophicum (O26717) |
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1.A.26.1.6 | MgtE homologue of 469 AAs and 5 OR 6 TMSs (Pohland and Schneider 2019). |
Bacteria | Cyanobacteriota | MgtE of Prochlorococcus marinus |
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1.A.26.1.7 | Ferrous iron and cobalt importer, FicI, of 454 aas and 5 C-termnal TMSs. FicI may be a secondary, energy-dependent carrier for iron uptake by S. oneidensis under high Fe2+ concentrations, but it can also take up cobalt (Bennett et al. 2018). |
Bacteria | Pseudomonadota | FicI of Shewanella oneidensis |
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1.A.26.2.1 | Mg2+ transporter, SLC41A1 (10 TMSs; N- and C-termini inside) (Wabakken et al., 2003; Schmitz et al., 2007; Kolisek et al., 2008; Sponder et al. 2013). It has been reported to be a Na+:Mg2+ antiporter and therefore a Mg2+ efflux pump (Fleig et al. 2013). Regulated by Mg2+-dependent endosomal recycling through its N-terminal cytoplasmic domain (Mandt et al., 2011). Mutations result in a nephronophthisis (NPHP)-like ciliopathic phenotype (Hurd et al. 2013). Reviewed by Schäffers et al. 2018. SLC41A1 overexpression correlates with immune cell infiltration and acted as an oncogene, predicting poor survival for hepatocellular carcinoma (HCC) patients (Chen et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC41A1 of Homo sapiens |
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1.A.26.2.2 | Mg2+ transporter, SLC41A2 (11 TMSs with the N-terminus out and the C-terminus in) (Sahni et al. 2007). (63% identical to SLC41A1) See also (Wabakken et al., 2003; Schmitz et al., 2007) |
Eukaryota | Metazoa, Chordata | SLC41A2 of Homo sapiens |
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1.A.26.2.3 | Solute carrier protein (SLC) 41A3. The gene is upregulated when mice are given a Mg2+ deficient diet (de Baaij et al. 2013). SLC41A3 knockout mice develop abnormal locomotor coordination. It is an established Mg2+ transporter involved in mitochondrial Mg2+ homeostasis (Schäffers et al. 2018). |
Eukaryota | Metazoa, Chordata | SLC41A3 of Homo sapiens |
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1.A.26.2.4 | MagT or MgtE of 503 aas and 12 TMSs in a 3 + 6 + 3 arrangement. According to CDD, the domain order is: MgtE_N, a CBS pair (two repeats) and an MgtE domain. |
Eukaryota | Metazoa, Nematoda | MagT of Caenorhabditis elegans |
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1.A.26.3.1 | MgtE of 251 aas and 5 TMSs |
Archaea | Euryarchaeota | MgtE of Natrinema gari |
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1.A.27.1.1 | Phospholemman (PLM; FXYD1) forms anion channels and regulates L-type Ca2+ channels as well as several other cation transport systems in cardiac myocytes (Zhang et al. 2015), most importantly the Na+,K+-ATPase (Pavlovic et al. 2013). Palmitoylation of the mammalian Na+ pump's accessory subunit PLM by the cell surface palmitoyl acyl transferase DHHC5 leads to pump inhibition, possibly by altering the relationship between the pump's catalytic α-subunit and specifically bound membrane lipids (Howie et al. 2018). PLM is also regulated by phosphorylation and glutathionylation (Pavlovic et al. 2013). and phosphorylation couteracts the inhibitory effect of palmitoylation (Cheung et al. 2013). The human ortholog has UniProt acc #O00168 and is 89% identical to the dog protein, with all of the difference occurring in the first 20 aas. Palmitoylation affects the regulation of cardiac electrophysiology, by modifying the sodium-calcium exchanger, phospholemman and the cardiac sodium pump, as well as the voltage-gated sodium channel (Essandoh et al. 2020). The conserved FXYD motif is found in this protein as residues 29-32. |
Eukaryota | Metazoa, Chordata | PLM of Canis familiaris |
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1.A.27.1.2 | Cl- conductance inducer protein, Mat-8, of 88 aas and 1 TMS. |
Eukaryota | Metazoa, Chordata | Mat-8 of Mus musculus |
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1.A.27.1.3 | FXYD6 regulator of Na,K-ATPase in the ear and taste buds, phosphohippolin, of 95 aas and 1 TMS (Delprat et al., 2007; Shindo et al., 2011). It is expressed in the central nervous system (Kadowaki et al. 2004) and is the novel biomarker for glioma (Hou et al. 2023). |
Eukaryota | Metazoa, Chordata | FXYD6 of Homo sapiens (Q9H0Q3) |
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1.A.27.1.4 | The sterol (dexamethasone, aldosterone) and low NaCl diet-inducible FXYD domain-containing ion transport regulator 4 precursor (Channel inducing factor, CHIF). It is an IsK-like MinK homologue (Attali et al., 1995). It regulates the Na+,K+-ATPase and the KCNQ1 channel protein as well as other ICNQ channels, opening them at all membrane potentials (Jespersen et al. 2006). CHIF as an indirect modulator of several different ion transport mechanisms, consistent with regulation of the Na+-K+-ATPase as the common denominator (Goldschmidt et al. 2004). |
Eukaryota | Metazoa, Chordata | CHIF of Rattus norvegicus |
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1.A.27.1.5 | FXYD3 (FXYD-3; Mat-8; PLML) with two splice variants, one of 87 aas with 2 TMSs (an N-terminal leader sequence and a central very hydrophobic TMS) and the other of 116 aas and 2 TMSs (Bibert et al. 2006). Both FXYD3 variants co-immunoprecipitate with the Na,K-ATPase. They both associate stably with Na,K-ATPase isozymes but not with the H,K-ATPase or Ca-ATPase. The short human FXYD3 has 72% sequence identity with mouse FXYD3, whereas long human FXYD3 is identical to the short human FXYD3 but has a 26-amino acid insertion after the transmembrane domain. Short and long human FXYD3 RNAs and proteins are differentially expressed during differentiation with long FXYD3 being mainly expressed in nondifferentiated cells while short FXYD3 is expressed in differentiated cells (Bibert et al. 2006). Overexpression of FXYD3, as it occurs in pancreatic cancer, may contribute to the proliferative activity of this malignancy (Kayed et al. 2006). FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters (Li et al. 2023). |
Eukaryota | Metazoa, Chordata | FXYD3 of Homo sapiens |
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1.A.27.1.6 | FXYD4 of 89 aas and 1 TMS. |
Eukaryota | Metazoa, Chordata | FXYD4 of Homo sapiens |
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1.A.27.1.7 | FXYD7 of 80 aas and 1 TMS. The TMS mediates the complex interactions with the Na,K-ATPase (Li et al. 2005). The brain-specific FXYD7 is a member of the FXYD family that associates with the alpha1-beta1 Na,K-ATPase isozyme and induces a 2-fold decrease in its apparent K+ affinity. In contrast to FXYD2 and FXYD4, the conserved FXYD motif in the extracytoplasmic domain is not involved in the association of FXYD7 with the Na,K-ATPase. The conserved Gly40 and Gly29, located on the same face of the TMS, were implicated in the association with and the regulation of Na,K-ATPase (Crambert et al. 2004). The C-terminal valine residue is involved in ER export of FXYD7. FXYDs are a vertebrate innovation and an important site of hormonal action (Pirkmajer and Chibalin 2019). |
Eukaryota | Metazoa, Chordata | FXYD7 of Homo sapiens |
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1.A.27.1.8 | Phospholemman, FXYD1 or PLM of 92 aas and 1 TMS. See 1.A.27.1.1 for details for the dog ortholog. Palmitoylation affects the regulation of cardiac electrophysiology, by modifying the sodium-calcium exchanger, phospholemman and the cardiac sodium pump, as well as the voltage-gated sodium channel (Essandoh et al. 2020). Palmitoylation of PLM inhibits the Na+ K+-ATPase while phosphorylation reverses this inhibition. The conserved FXYD motif is found in this protein at residues 29-32 (Cheung et al. 2013). Dreammist in zebrafish, a neuronal-expressed phospholemman homolog, is important for regulating sleep-wake behaviour (Barlow et al. 2023). |
Eukaryota | Metazoa, Chordata | PLM of Homo sapiens |
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1.A.27.2.1 | γ-subunit (proteolipid) of Na+,K+-ATPase, FXYD2. Also functions as a cation-selective channel (Sha et al. 2008). |
Eukaryota | Metazoa, Chordata | FXYD2 channel and γ-subunit of the Na+,K+-ATPase of Homo sapiens |
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1.A.27.2.2 | Sodium/potassium-transporting ATPase subunit gamma isoform X1of 82 aas and 1 TMS. |
Eukaryota | Metazoa, Chordata | γ-subunit of Pseudopodoces humilis |
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1.A.27.2.3 | Sodium/potassium-transporting ATPase subunit gamma of 61 aas and 1 TMS. |
Eukaryota | Metazoa, Chordata | γ-subunit of Xenopus tropicalis (tropical clawed frog) |
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1.A.27.2.4 | Sodium/potassium-transporting ATPase subunit gamma isoform X1 |
Eukaryota | Metazoa, Chordata | Na+, K+-ATPase regulator of Mus pahari (shrew mouse) |
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1.A.27.2.5 | Sodium/potassium-transporting ATPase subunit gamma isoform X1of 65 aas and 1 TMS. The 3-d structure of a 31 aa peptide including the single TMS is available (PDB# 2N23). |
Eukaryota | Metazoa, Chordata | γ-subunit of Sus scrofa (pig) |
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1.A.27.3.1 | FXYD5 regulator of Na,K+-ATPase and ion channel activities of 178 aas and 1 C-terminal TMS. FXYD5 interacts directly with the Na+,K+-ATPase via their TMSs to affect the Vmax of the latter, and residues involved have been identified (Lubarski et al. 2007). |
Eukaryota | Metazoa, Chordata | FXYD5 of Homo sapiens (178 aas; Q96DB9) |
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1.A.27.3.2 | FXYD domain-containing ion transport regulator 5-like isoform X2 of 89 aas and 2 TMSs. |
Eukaryota | Metazoa, Chordata | FXYD regulator of Ornithorhynchus anatinus (platypus) |
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1.A.27.3.3 | FXYD domain-containing ion transport regulator 5-like isoform X1 of 101 aas and 2 TMSs, N- and C-terminal. TC Blast with this protein retrieves 1.G.12.2.3 with about 90 residues aligning with 29% identity and 45% similarity. These two families may be related. |
Eukaryota | Metazoa, Chordata | FXYD domain protein of Carassius auratus (goldfish) |
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1.A.27.3.4 | FXYD domain-containing ion transport regulator 5-like isoform X2 of 174 aas and 2 TMSs, N- and C-terminal. |
Eukaryota | Metazoa, Chordata | FXYD domain protein of Denticeps clupeoides (denticle herring) |
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1.A.27.3.5 | FXYD domain-containing ion transport regulator 5-like isoform X2 of 170aas and 2 TMSs. |
Eukaryota | Metazoa, Chordata | FXYD domain protein of Rhinatrema bivittatum (two-lined caecilian) |
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1.A.28.1.1 | Kidney vasopressin regulated urea transporter, UT-A2 (splice variant of UT-A1) | Eukaryota | Metazoa, Chordata | UT-A2 of Rattus norvegicus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.28.1.2 | Frog urinary bladder ADH-regulated urea transporter |
Eukaryota | Metazoa | Urea transporter of Rana esculenta (O57609) |
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1.A.28.1.3 | Kidney urea transporter, UT-A1, of 414aas and 11 TMSs in a 5 + 5 + 1 TMS arrangement. It mediates transepithelial urea transport in the inner medullary collecting duct for urinary concentration. Interacts with the C-terminus of Snapin (O95295) and SNARE-associated protein) (Mistry et al., 2007). Also transports formamide, acetamide, methylurea, methylformamide, ammonium carbamate, and acrylamide, and possibly dimethylurea and thiourea as well (Zhao et al., 2007). Mutation of the N-linked glycosylation sites reduces urea flux by reducing the UT-A1 half-life and decreasing its accumulation in the apical plasma membrane. The related erythrocyte urea transporter, UTB (UT-B; TC# 1.A.28.1.5) has been reviewed (Bagnasco, 2006). Mutation of the N-linked glycosylation sites reduces urea flux by reducing the UT-A1 half-life and decreasing its accumulation in the apical plasma membrane (Chen et al. 2006). In vivo, inner medullary collecting duct cells may thus regulate urea uptake by altering UT-A1 glycosylation in response to AVP stimulation. |
Eukaryota | Metazoa, Chordata | UT-A1 of Rattus norvegicus |
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1.A.28.1.4 | THe urea transporter channel protein of 337 aas and 11 TMSs in an apparent 6 + 5 TMS arrangement. The 3-d structure (2.3 Å resolution) is available (Levin et al., 2009). Urea binding and flux as well as dimethylurea (DMU) transport have been modeled (Zhang et al. 2017). |
Bacteria | Thermodesulfobacteriota | Urea channel of Desulfovibrio vulgaris (A1VEP3) |
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1.A.28.1.5 | Urea transporter 1 or UT-B1 (Solute carrier family 14 member 1; Urea transporter of the erythrocyte) (Bagnasco 2006). A phenylphthalazine compound, PU1424, is a potent UT-B inhibitor, inhibiting human and mouse UT-B-mediated urea transport with IC50 values of 0.02 and 0.69 mumol/L, respectively, and exerted 100% UT-B inhibition at high concentrations (Ran et al. 2016). Another potent inhibitor is the thienopyridine, CB-20 (5-ethyl-2-methyl-3-amino-6-methylthieno[2,3-b]pyridine-2,5-dicarboxylate) (Li et al. 2019). UT-B catalyzes transmembrane water transport which can be ued as a reporter system (Schilling et al. 2016). Knocking out both UT1 and UT2 increases urine output 3.5-fold and lowers urine osmolarity (Jiang et al. 2016). The double knockout also lowered blood pressure and promoted maturation of the male reproductive system. Thus, functional deficiency of all UTs causes a urea-selective urine-concentrating defect with few physiological abnormalities in extrarenal organs (Jiang et al. 2016). UT-B may be related to the occurrence of melanoma and play a role in tumor development (Liu et al. 2018). |
Eukaryota | Metazoa, Chordata | SLC14A1 of Homo sapiens |
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1.A.28.1.6 | Urea transporter 2, UT2, HUT2 or UTB (Solute carrier family 14 member 2) (Urea transporter, kidney). Knocking out both UT1 and UT2 increases urine output 3.5-fold and lowers urine osmolarity (Jiang et al. 2016). The double knockout also lowered blood pressure and promoted maturation of the male reproductive system. Thus, functional deficiency of all UTs causes a urea-selective urine-concentrating defect with few physiological abnormalities in extrarenal organs (Jiang et al. 2016). A potent inhibitor of both UT1 and UT2 is the thienopyridine, CB-20 (5-ethyl-2-methyl-3-amino-6-methylthieno[2,3-b]pyridine-2,5-dicarboxylate) (Li et al. 2019). UTB is downregulated in polycythemia vera hematopoietic stem and progenitor cell subpopulations (Tan and Meier-Abt 2021). Urea transporter B downregulates polyamines levels in melanoma B16 cells via p53 activation (Li et al. 2022). |
Eukaryota | Metazoa, Chordata | SLC14A2 of Homo sapiens |
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1.A.28.1.7 | Putative urea transporter of 306 aas and 9 or 10 TMSs |
Bacteria | Pseudomonadota | UT of E. coli |
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1.A.28.2.1 | The dimeric urea transporter, Utp of 300 aas and 9 or probably 10 TMSs. Urea flux is saturable, could be inhibited by phloretin, and was not affected by pH (Raunser et al., 2009) |
Bacteria | Pseudomonadota | Utp of Actinobacillus pleuropneumoniae |
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1.A.29.1.1 | Putative amide transporter (AmiS) (Wilson et al., 1995). |
Bacteria | Pseudomonadota | AmiS of Pseudomonas aeruginosa |
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1.A.29.1.2 | Putative amide transporter (AmiS) | Bacteria | Actinomycetota | AmiS of Rhodococcus erythropolis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.29.1.3 |
Proton-gated urea transport channel (UreI) (pH-sensitive). Allows the transmembrane flow of urea, hydroxyurea and (at a low rate) water. KB for urea is ~150mM (Sachs et al., 2006; Scott et al., 2010). Transport kinetics and selectivity have been defined (Gray et al., 2011). The 3-d structure reveals a hexameric protein with a channel included within the twisted 6 TMS bundle of each protomer. It displays a two helix hairpin structure repeated three times around the central axis of the channel (Strugatsky et al. 2012). |
Bacteria | Campylobacterota | UreI of Helicobacter pylori |
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1.A.29.1.4 | Urea transporter channel (UreI) (pH-insensitive) | Bacteria | Bacillota | UreI of Streptococcus salivarius | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.29.1.5 | Urea transporter channel (UreI) (pH-sensitive) | Bacteria | Campylobacterota | UreI of Helicobacter hepaticus (AAK69200) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.29.1.6 | The hexameric ring urea/acetamide/small amide channel, UreI (7 TMSs) (Huysmans et al., 2012). |
Bacteria | Bacillota | UreI of Bacillus cereus (Q814I5) |
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1.A.3.1.1 | Ryanodine receptor Ca2+ release channel, RyR2. Causes Ca2+ release from the E.R. and consequent cardiac arrhythmia (Chelu and Wehrens, 2007). It associates with FKBP12.6, but phosphorylation by protein kinase A on serine-2030 causes dissociation (Jones et al., 2008). An interaction site for FKBP12.6 may be present at the RyR2 C terminus, proximal to the channel pore, a sterically appropriate location that would enable this protein to play a role in the modulation of this channel (Zissimopoulos and Lai 2005). Enhanced binding of calmodulin corrects arrhythmogenic channel disorder in myocytes (Fukuda et al. 2014). RyR2s can open spontaneously, giving rise to spatially-confined Ca2+ release events known as "sparks." They are organized in a lattice to form clusters in the junctional sarcoplasmic reticulum membrane. The spatial arrangement of RyR2s within clusters strongly influences the frequency of Ca2+ sparks (Walker et al. 2015). Structures of RyR2 from porcine heart in both the open and closed states at near atomic resolutions have been determined using single-particle electron cryomicroscopy (Peng et al. 2016). Structural comparisons revealed breathing motions of the overall cytoplasmic region resulting from the interdomain movements of amino-terminal domains (NTDs), Helical domains, and Handle domains, whereas little intradomain shifts are observed in these armadillo repeat-containing domains. Outward rotations of the central domains, which integrate the conformational changes of the cytoplasmic region, lead to the dilation of the cytoplasmic gate through coupled motions. These observations provide insight into the gating mechanism of RyRs (Peng et al. 2016). RyR2 is subject ot regulation by cytoplasmic Zn2+ (>1nM), and this regulation plays a key role in diastolic SR Ca2+ leakage in cardiac muscle (Reilly-O'Donnell et al. 2017). Ryanodine receptor-mediated SR Ca2+ efflux is apparently balanced by concomitant counterion currents across the SR membrane (Sanchez et al. 2018). Electrical polarity-dependent gating and a unique subconductance of RyR2 is induced by S-adenosyl methionine via the ATP binding site. Thus, SAM may alter the conformation of the RyR2 ion conduction pathway (Kampfer and Balog 2021). Flecainide impacts both Nav1.5 and RyR2 channel functions (Salvage et al. 2022). The brief opening mode of the mitochondrial permeability transition pore (mPTP) serves as a calcium (Ca2+) release valve to prevent mitochondrial Ca2+ (mCa2+) overload. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced arrhythmic syndrome due to mutations in the Ca2+ release channel complex of ryanodine receptor 2 (RyR2). Genetic inhibition of mPTP exacerbates RyR2 dysfunction in CPVT by increasing activation of the CaMKII pathway and subsequent hyperphosphorylation of RyR2 (Deb et al. 2023). Protamine reversibly modulates the calcium release channel/ryanodine receptor 2 (RyR2) and voltage-dependent cardiac RyR2 (Yamada et al. 2023). Calcium release deficiency syndrome (CRDS) is a form of inherited arrhythmia caused by damaging loss-of-function variants in the cardiac ryanodine receptor (RyR2) (Kallas et al. 2023). Cardiomyocyte ryanodine receptor 2 clusters expand and coalesce after application of isoproterenol. Thus, isoproterenol induces rapid, significant, changes in the molecular architecture of excitation-contraction coupling (Scriven et al. 2023). Distinct patterns and length scales of RyR and IP3R1 co-clustering at contact sites between the ER and the surface plasmalemma that encode the positions and the quantity of Ca2+ released at each Ca2+ spark (Hurley et al. 2023). The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic (ER)/sarcoplasmic reticulum (SR) that plays a central role in the excitation-contraction coupling in the heart. Hyperactivity of RyR2 has been linked to ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia and heart failure, where spontaneous Ca2+ release via hyperactivated RyR2 depolarizes diastolic membrane potential to induce triggered activity. In such cases, drugs that suppress RyR2 activity are expected to prevent the arrhythmias. Such inhibitors have been identified (Takenaka et al. 2023). VPS13A disease is associated with histopathological findings implicating abnormal lipid accumulation (Ditzel et al. 2023). Alarin (Claritin; Loratadine) regulates RyR2 and SERCA2 to improve cardiac function in heart failure with preserved ejection fraction (Li et al. 2024). Point mutations in RyR2 Ca2+-binding residues of human cardiomyocytes cause cellular remodelling of cardiac excitation contraction-coupling (Xia et al. 2024). |
Eukaryota | Metazoa, Chordata | Cardiac muscle RyR-CaC of Homo sapiens |
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1.A.3.1.10 | Ryanodine receptor, RyR, of 5139 aas and 6 TMSs. Sensitive to the diamide insecticides, chlorantraniliprole and flubendiamide. It has the conserved C-terminal domain with the consensus calcium-biding EF-hands (calcium-binding motif), the six transmembrane domains, as well as mannosyltransferase, IP3R and RyR (pfam02815) (MIR) domains (Wu et al. 2018). Probably transports monovalent cations and Ca2+. |
Eukaryota | Metazoa, Arthropoda | RyR of Sesamia inferens (pink stem borer) |
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1.A.3.1.11 | The ryanodine receptor of 5140 aas and 6 C-terminal TMSs. It is the targets of diamide insecticides. The mutation I4743M contributes to diamide insecticide resistance (Zuo et al. 2020). The diamide binding site on the Lepidopteran Ryanodine Receptor has been examined (Richardson et al. 2021). Mutations in the ortholog in Spodoptera litura (the common cutworm) (98% identical to this protein) influences diamide resistance (Mei et al. 2025). |
Eukaryota | Metazoa, Arthropoda | RyR of Spodoptera exigua (beet armyworm) (Noctua fulgens) |
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1.A.3.1.2 | The Ryanodine receptor Ca2+/K+ release tetrameric channel, RyR1, present in skeletal muscle, is 5038 aas long. Mutants are linked to core myopathies such as Central Core Disease, Malignant Hyperthermia and Multiple Minicore Disease) (Xu et al., 2008). RyR1 interacts with CLIC2 to modulate its channel activity (Meng et al., 2009). A model pf RyR1 has been constructed encompassing the six transmembrane helices to calculate the RyR1 pore region conductance, to analyze its structural stability, and to hypothesize the mechanism of the Ile4897 CCD-associated mutation. The calculated conductance of the wild-type RyR1 suggests that the pore structure can sustain ion currents measured in single-channel experiments. Shirvanyants et al. 2014 observed a stable pore structure with multiple cations occupying the selectivity filter and cytosolic vestibule, but not the inner chamber. Stability of the selectivity filter depends on interactions between the I4897 residue and several hydrophobic residues of the neighboring subunit. Loss of these interactions in the case of the polar substitution, I4897T, results in destabilization of the selectivity filter, a possible cause of the CCD-specific reduced Ca2+ conductance. A 4.8 Å structure of the rabbit orthologue in the closed state of this 2.3 MDa tetramer (3757 aas/protomer) reveals the pore, the VIC superfamily fold and a potential mechanism of Ca2+ gating (Zalk et al. 2015). A cryo-electron microscopy analysis revealed the structure at 6.1 Å resolution (Efremov et al. 2015). The transmembrane domain represents a chimaera of voltage-gated sodium and pH-activated ion channels. They identified the calcium-binding EF-hand domain and showed that it functions as a conformational switch, allosterically gating the channel. Malignant hyperthermia-associated RyR1 mutations in the S2-S3 loop confer RyR2-type Ca2+- and Mg2+-dependent channel regulation (Gomez et al. 2016). Structural analyses have elucidated a novel channel-gating mechanism and a novel ion selectivity mechanism for RyR1 (Wei et al. 2016). Samsó 2016 reviewed structural determinations of RyR by cryoEM and analyzed the first near-atomic structures, revealing a complex orchestration of domains controlling channel function. The structural basis for gating and activation have been determined (des Georges et al. 2016). Junctin and triadin bind to different sites on RyR1; triadin plays an important role in ensuring rapid Ca2+ release during excitation-contraction coupling in skeletal muscle. RyR1 structure/functioin has been reviewed (Zalk and Marks 2017). Possibly, luminal Ca2+ activates RyR1 by accessing a cytosolic Ca2+ binding site in the open channel as the Ca2+ ions pass through the pore (Xu et al. 2017). The 3-d structures of the native protein in membranes has been determined (Chen and Kudryashev 2020) (see family description). The most common cause of nondystrophic congenital myopathies is mutations in RYR1 (Sorrentino 2022). Targeting ryanodine receptor type 2 can mitigate chemotherapy-induced neurocognitive impairments in mice (Liu et al. 2023). TMS5 plays a dual role in channel gating: the cytoplasmic side interacts with TMS6 to reduce channel activity, whereas the luminal side forms a rigid structural base necessary for S6 displacement in channel opening (Murayama et al. 2024). |
Eukaryota | Metazoa, Chordata | RyR1 of Homo sapiens (P21817) |
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1.A.3.1.3 | The Ryanodine Receptor homologue, RyRi (5,101 aas; 77% identical to the A gambiae RyR) of the aphid, Myzus persicae, is the tartet of diamide insecticides and is made without alternative splicing (Troczka et al. 2015). The almost identical well characterized orthologue from the oriential fruit fly, Bactrocera dorsalis also has its 6 TMSs C-terminal (Yuan et al. 2014). |
Eukaryota | Metazoa, Arthropoda | RyRi of Anopheles gambiae (Q7PMK5) |
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1.A.3.1.4 | Ryanodine receptor (RyR) of 5107 aas. Flubendiamine, a RyR-activating insecticide, induced Ca2+ release in hemocytes (Kato et al. 2009; Wu et al. 2013). |
Eukaryota | Metazoa, Arthropoda | RyR of Pieris rapae (white cabbage butterfly) |
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1.A.3.1.5 | Ryanodine receptor (RyR) of 5127 aas and 6 TMSs. Intracellular calcium channel that is required for proper muscle function during embryonic development and may be essential for excitation-contraction coupling in larval body wall muscles. Mediates general anaesthesia by halothane (Gao et al. 2013) and confers sensitivity to diamide insecticides (Tao et al. 2013). |
Eukaryota | Metazoa, Arthropoda | RyR of Drosophila melanogaster (Fruit fly) |
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1.A.3.1.6 | Ryanodine-sensitive calcium release channel receptor, RyR of 5071 aas and 6 putative TMSs. The tissue lecalization has been described (Hamada et al. 2002). Required for neuronal regeneration (Sun et al. 2014). |
Eukaryota | Metazoa, Nematoda | RyR of Caenorhabditis elegans |
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1.A.3.1.7 | Aphid ryanodine receptor RyR) of 5105 aas and 6 TMSs, a target of insecticides. The sequence of the Acyrthosiphon pisum (Pea aphid) is provided below, but the Toxoptera citricida (98% identiy; Brown citrus aphid; Aphis citricidus) RyR was studied (Wang et al. 2015). |
Metazoa, Arthropoda | Aphid RyR of Acyrthosiphon pisum (Pea aphid) |
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1.A.3.1.8 | Ryanodine receptor, DcRyR shows high sequence identity to RyRs from other insects (76%-95%) and shares many features of insect and vertebrate RyRs, including a MIR domain, two RIH domains, three SPRY domains, four copies of RyR repeat domain, an RIH-associated domain at the N-terminus, two consensus calcium-binding EF-hands and six TMSs at the C-terminus (Yuan et al. 2017). The expression of DcRyR mRNA was the highest in the nymphs and lowest in eggs; it has three alternative splice sites, and the splice variants showed body part-specific expression, being under developmentally regulation (Yuan et al. 2017). |
Eukaryota | Metazoa, Arthropoda | RyR of Dialeurodes citri (Citrus whitefly) (Aleurodes citri) |
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1.A.3.1.9 | Ryanodine-sensitive Ca2+ release channel RyR1 of 5117 aas and 6 TMSs. Diamide insecticides, such as flubendiamide and chlorantraniliprole, selectively activate insect ryanodine receptors of Lepidoptera and Coleoptera pests (Samurkas et al. 2020). They are particularly active against lepidopteran pests of cruciferous vegetable crops, including the diamondback moth, Plutella xylostella. Resistance results from mutation(s) in the ryanodine receptors' transmembrane domain at the C-termini of these proteins (Troczka et al. 2017). Other diamide insecticides, including phthalic and anthranilic diamides, target insect ryanodine receptors (RyRs) and cause misregulation of calcium signaling in insect muscles and neurons. Homology modeling and docking studies with the diamondback moth ryanodine receptor revealed the mechanisms for channel activation, insecticide binding, and resistance (Lin et al. 2019). |
Eukaryota | Metazoa, Arthropoda | RyR1 of Plutella xylostella (Diamondback moth) (Plutella maculipennis) |
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1.A.3.2.1 | Inositol 1,4,5-trisphosphate receptor-2 with 2701 aas and 6 TMSs. Mediates release of intracellular calcium which is regulated by cAMP both dependently and independently of PKA and plays a critical role in cell cycle regulation and cell proliferation. High level expression in humans is an indication of cytogenetically normal acute myeloid leukemia (CN-AML) (Shi et al. 2015). . |
Eukaryota | Metazoa, Chordata | Brain IP3-CaC of Rattus norvegicus |
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1.A.3.2.10 | Calcium release channel III, CRCIII1a of 2598 aas. Associated with recycling vesicles engaged in phagosome formation (Ladenburger and Plattner 2011). |
Eukaryota | Ciliophora | CRCIII1a of Paramecium tetraurelia |
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1.A.3.2.11 | Calcium release channel IV3b, CRCIV3b, of 3127 aas. Display structural and functional properties of ryanodine receptors (Ladenburger et al. 2009). Localized to the alveolar sacs of the cortical subplasmalemmal Ca2+-stores (Plattner et al. 2012). Involved in exocytosis in response to ryanodine receptor agonists (Docampo et al. 2013). |
Eukaryota | Ciliophora | CRCIV3b of Paramecium tetraurelia |
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1.A.3.2.12 | Calcium release channel V-4b, CRCV4b of 2589 aas. Occurs in parasomal (alveolar) sacs (clathrin coated pits) (Docampo et al. 2013). |
Eukaryota | Ciliophora | CRCV4b of Paramecium tetraurelia |
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1.A.3.2.13 | Calcium release channel VI-2b, CRCVI2b. Localized to the contractile vacuole (Docampo et al. 2013). |
Eukaryota | Ciliophora | CRCVI2b of Paramecium tetraurelia |
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1.A.3.2.14 | Endoplasmic reticular inositol triphosphate receptor, IP3R of 3099 aas (Docampo et al. 2013). |
Eukaryota | Kinetoplastida | IP3R of Trypanosoma brucei |
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1.A.3.2.16 | Inositol triphosphate receptor, IP3R, also called Itr-1, Dec-4 and Ife-1, of 2892 aas and 6 TMSs (Baylis and Vázquez-Manrique 2012). Receptor for inositol 1,4,5-trisphosphate, a second messenger that regulates intracellular calcium homeostasis. Binds in vitro to both 1,4,5-InsP3 and 2,4,5-InsP3 with high affinity and does not discriminate between the phosphate at the 1 or 2 position. Can also bind inositol 1,3,4,5-tetrakisphosphate (1,3,4,5-InsP4) and inositol 4,5-bisphosphate (4,5-InsP2), but with lower affinity. Acts as a timekeeper/rhythm generator via calcium signaling, affecting the defecation cycle and pharyngeal pumping (Dal Santo et al. 1999). Affects normal hermaphrodite and male fertility as a participant in intracellular signaling by acting downstream of let-23/lin-3 which regulates ovulation, spermathecal valve dilation and male mating behavior (Walker et al. 2002; Gower et al. 2005). Important for early embryonic development; controls epidermal cell migration and may also regulate filopodial protrusive activity during epithelial morphogenesis (Thomas-Virnig et al. 2004; ). Component of inositol trisphosphate (IP3)-mediated downstream signaling pathways that controls amphid sensory neuronal (ASH)-mediated response to nose touch and benzaldehyde (Walker et al. 2009). |
Eukaryota | Metazoa, Nematoda | IP3 receptor of Caenorhabditis elegans |
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1.A.3.2.17 | IP3R of 3140 aas, RyR1 (Wheeler and Brownlee 2008). |
Viridiplantae, Chlorophyta | IP3R of Chlamydomonas reinhardtii |
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1.A.3.2.2 | The Inositol 1,4,5- triphosphate (InsP3)-like receptor (2838aas). Receptor for inositol 1,4,5-trisphosphate, a
second messenger that mediates the release of intracellular calcium.
May be involved in visual and olfactory transduction as well as myoblast
proliferation. Loss in adult neurons results in obesity in adult flies (Subramanian et al. 2013). |
Eukaryota | Metazoa, Arthropoda | InsP3l receptor Drosophila melanogaster (P29993) |
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1.A.3.2.3 | The cation channel family protein, IsnP3-like protein (2872aas) | Eukaryota | Ciliophora | InsP3-like protein of Tetrahymena themophila (Q23K98) |
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1.A.3.2.4 | The Inositol 1,4,5- triphosphate (InsP3)-like receptor (3036aas) (Ladenburger et al. 2009; Docampo et al. 2013). |
Eukaryota | Ciliophora | InsP3l receptor of Paramecium tetraaurelia (A0CX44) |
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1.A.3.2.5 | The rat inositol trisphosphate receptor (IP3R; IP(3)R1; ITPR3 (human)) is dispensable for rotavirus-induced Ca2+ signaling and replication but critical for paracrine Ca2+ signals that primes uninfected cells for rapid virus spread (Subedi et al., 2012; Perry et al. 2023). The human orthologue, IP3R3 (97.5% identical to the human ortholog), is regulated at the ER-mitochondrion interface by BCL-XL (TC# 1.A.21.1.6) (Williams et al. 2016). Genetic polymorphisms of Ca2+ transport proteins and molecular chaperones in mitochondria-associated endoplasmic reticulum membranes and non-alcoholic fatty liver disease (NAFA5) have been identified. The variant genotypes of Ca2+ transport-associated genes HSPA5 (rs12009 and rs430397) and ITPR2 (rs11048570) probably contribute to the reduction of the NAFLD risk in the Chinese Han population (Tang et al. 2022). Host IP3R channels are dispensable for rotavirus Ca2+ signaling but critical for intercellular Ca2+ waves that prime uninfected cells for rapid virus spread (Perry et al. 2024). A recurrent missense variant in ITPR3 causes demyelinating Charcot-Marie-Tooth with variable severity (Beijer et al. 2025). Mfn2 regulates calcium homeostasis and suppresses PASMCs proliferation via interaction with IP3R3 in humans to mitigate pulmonary arterial hypertension (Wang et al. 2025). |
Eukaryota | Metazoa, Chordata | IP(3)R1 of Rattus norvegicus (Q63269) |
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1.A.3.2.6 | Inositol 1,4,5-trisphosphate receptor type 1 (IP3 receptor isoform 1; ITPR1; IP3R 1; InsP3R1; Itpr1) (Type 1 inositol 1,4,5-trisphosphate receptor) (Type 1 InsP3 receptor) of 2758 aas and 6 TMSs near the C-terminus. An intronic variant in ITPR1 causes Gillespie syndrome, characterized by bilateral symmetric partial aplasia of the iris presenting as a fixed and large pupil, cerebellar hypoplasia with ataxia, congenital hypotonia, and varying levels of intellectual disability (Keehan et al. 2021). The cryoEM structure has been determined (Baker et al. 2021). Binding of the erlin1/2 complex (TC# 8.A.195) to the third intralumenal loop of IP3R1 triggers its ubiquitin-proteasomal degradation (Gao et al. 2022). IP3R channels participate in the reticular Ca2+ leak towards mitochondria (Gouriou et al. 2023). It is a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia (Tolonen et al. 2023). Aberrant Ca2+ signaling is a key link between human pathogenic PSEN1 (Presenilin-1 variants (PSEN1 p.A246E, p.L286V, and p.M146L)) and cell-intrinsic hyperactivity prior to deposition of abnormal Aß (Hori et al. 2024). |
Eukaryota | Metazoa, Chordata | ITPR1 of Homo sapiens |
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1.A.3.2.7 | Contractile vacuole complex calcium release channel (CRC)II; IP3Rn (Ladenburger et al. 2006). Functions in osmoregulation by promoting expulsion of water and some ions including Ca2+. Also functions in calcium homeostasis (Ladenburger et al. 2006; Docampo et al. 2013). |
Eukaryota | Ciliophora | IP3Rn or CRCII of Paramecium trtraurelia |
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1.A.3.2.8 | Putative IP3R calcium-release channel VI-3 of 2021 aas (Docampo et al., 2013). |
Eukaryota | Ciliophora | Calcium-release channel VI-3 of Paramecium tetraurelia |
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1.A.3.2.9 | CRCI-1a; IP3R. Functions similarly to TC# 1.A.3.2.7 (Docampo et al. 2013). Cortical Ca2+ stores (alveolar sacs) are activated during stimulated trichocyst exocytosis, mediating store-operated Ca2+ entry (SOCE). Ca2+ release channels (CRCs) localise to alveoli and are Ryanodine receptor-like proteins (RyR-LPs) as well as inositol 1,4,5-trisphosphate receptors (IP3Rs), members of the CRC family with 6 subfamilies (Plattner 2014). |
Eukaryota | Ciliophora | CRCI-1a of Paramecium tetraurelia |
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1.A.30.1.1 | The flagellar motor (pmf-dependent) (MotA-MotB). TMSs 3 and 4 of MotA and the single TMS of MotB comprise the proton channel, which is inactive until the complex assembles into a motor. Hosking et al. 2006 identify a periplasmic segment of the MotB protein that acts as a plug to prevent premature proton flow. The plug is in the periplasm just C-terminal to the MotB TMS flanked by Pro52 and Pro65. The Pro residues and Ile58, Tyr61, and Phe62 are essential for plug function (Hosking et al. 2006). The mechanism of proton passage and coupling to flagellar rotation has been proposed (Nishihara and Kitao 2015). About a dozen MotA/B complexes are anchored to the peptidoglycan layer around the motor through the C-terminal peptidoglycan-binding domain of MotB (Castillo et al. 2013). Dynamic permeation by hydronium ions, sodium ions, and water molecules has been observed using steered molecular dynamics simulations, and free energy profiles for ion/water permeation were calculated (Kitao and Nishihara 2017). They also examined the possible ratchet motion of the cytoplasmic domain induced by the protonation/deprotonation cycle of the MotB proton binding site, Asp32. The motor (MotAB) consists of a dynamic population of mechanosensitive stators that are embedded in the inner membrane and activate in response to external load. This entails assembly around the rotor, anchoring to the peptidoglycan layer to counteract torque from the rotor and opening of a cation channel to facilitate an influx of cations, which is converted into mechanical rotation. Stator complexes are comprised of four copies of an integral membrane A subunit and two copies of a B subunit. Each B subunit includes a C-terminal OmpA-like peptidoglycan-binding (PGB) domain. This is thought to be linked to a single N-terminal transmembrane helix by a long unstructured peptide, which allows the PGB domain to bind to the peptidoglycan layer during stator anchoring. The high-resolution crystal structures of flagellar motor PGB domains from Salmonella enterica have been solved (Liew et al. 2017). Change in the C ring conformation for switching and rotation involve loose and tight intersubunit interactions (Sakai et al. 2019). |
Bacteria | Pseudomonadota | MotA and MotB of E. coli |
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1.A.30.1.2 | The flagellar motor (smf-dependent) (PomAB; MotXY) (Okabe et al., 2005). PomB interacts with the third TMS of PomA in the Na+-driven polar flagellum (Yakushi et al. 2004). Sodium-powered stators of the flagellar motor can generate torque in the presence of the sodium channel blocker, phenamil, with mutations near the peptidoglycan-binding region of PomB (Ishida et al. 2019). FliL associates with the flagellar stator in the sodium-driven Vibrio motor (Lin et al. 2018). When the ion channel is closed, PomA and PomB interact strongly. When the ion channel opens, PomA interacts less tightly with PomB. The plug and loop between TMSs 1 and 2 regulate activation of the stator, which depends on the binding of sodium ion to the D24 residue of PomB (Nishikino et al. 2019). The PomA helices parallel to the inner membrane play roles in the hoop-like function in securing the stability of the stator complex and the ion conduction pathway (Nishikino et al. 2022). Na+-binding sites are formed by critical aspartic acid and threonine residues located in the TMSs of PomAB (Kojima et al. 2023). Vibrio alginolyticus forms a single flagellum at its cell pole. FlhF and FlhG are the main proteins responsible for the polar formation of the single flagellum. MS-ring formation in the flagellar basal body appears to be an initiation step for flagellar assembly. The MS-ring is formed by a single protein, FliF, which has two transmembrane (TM) segments and a large periplasmic region. FlhF is required for the polar localization of Vibrio FliF, and FlhF facilitated MS-ring formation when FliF was overexpressed in E. coli cells. These results suggest that FlhF interacts with FliF to facilitate MS-ring formation. Fukushima et al. 2023 detected this interaction using Vibrio FliF fragments fused to a tag of Glutathione S-transferase (GST) in E. coli. The N-terminal 108 residues of FliF, including the first TMS and the periplasmic region, could pull FlhF down. In the first step, Signal Recognition Particle (SRP) and its receptor are involved in the transport of membrane proteins to target them, which delivers them to the translocon. FlhF may have a similar or enhanced function as SRP, which binds to a region rich in hydrophobic residues (Fukushima et al. 2023). |
Bacteria | Pseudomonadota | PomAB/MotXY of Vibrio alginolyticus |
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1.A.30.1.3 | The flagellar motor (pmf-dependent) (MotAB) (Ito et al., 2004) |
Bacteria | Bacillota | MotAB of Bacillus subtilis |
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1.A.30.1.4 | The flagellar motor (smf-dependent) (MotPS) (Ito et al., 2004) |
Bacteria | Bacillota | MotPS (YtxDE) of Bacillus subtilis |
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1.A.30.1.5 | The H+-driven flagellar motor complex, MotABXY (MotXY are required for systems 1.A.30.1.5 and 1.A.30.1.6; Koerdt et al., 2009). |
Bacteria | Pseudomonadota | The H+-driven flagellar motor complex of Shewanella oneidensis |
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1.A.30.1.6 | The Na+-driven flagellar motor complex, PomAB MotXY (MotXY are required for systems 1.A.30.1.5 and 1.A.30.1.6; Koerdt et al., 2009) |
Bacteria | Pseudomonadota | The Na+-driven flagellar motor complex of Shewanella oneidensis |
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1.A.30.1.7 | The motor complex of the bacterial flagellum, MotAB. MotA is 295 aas long with about 5 putative TMSs in a 2 + 1 + 2 TMS arrangement, possibly with a C-terminal additional TMS. MotB is 309 aas long with a single N-terminal TMS. They comprise the stator element of the flagellar motor
complex and are required for rotation of the flagellar motor. Together they form the transmembrane proton channel. These two proteins are 94 and 91% identical to the E. coli complex (TC# 1.A.30.1.1) (Morimoto and Minamino 2014). |
Bacteria | Pseudomonadota | MotAB of Salmonella enterica, subspecies Typhimurium |
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1.A.30.2.1 | The TonB energy-transducing system. ExbB/D (the putative H+ channel) are listed here; TonB is listed under TC# 2.C.1.1.1. Deletion of the cytoplasmic loop gives rise to immediate growth arrest (Bulathsinghala et al. 2013). The rotational surveillance and energy transfer (ROSET) model of TonB action postulates a mechanism for the transfer of energy from the IM to the OM, triggering iron uptake and concentration in the periplasm (Klebba 2016). |
Bacteria | Pseudomonadota | The TonB system of E. coli |
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1.A.30.2.10 | Putative biopolymer transport proteins ExbB/ExbD-like 3 (Sll1404/Sll1405). Involved in the TonB-dependent energy-dependent transport of iron-siderophores via FhuA (Sll1406; TC# 1.B.14.2.9) using TonB (TC# 2.C.1.3.1) (Qiu et al. 2018). ExbB may protect ExbD from proteolytic degradation and functionally stabilizes TonB. |
Bacteria | Cyanobacteriota | ExbBD of Synechocystis sp. (strain PCC 6803 / Kazusa) |
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1.A.30.2.11 | ExbB/ExbD/ExbD' of 254 aas, 150 aas, and 147 aas, respectively, with 3, 1 and 1 TMSs, respectively. The genes encoding these three proteins are adjacent to each other. ExbD and TonB (TC# 2.C.1.3.1) interact directly (Qiu et al. 2018). |
Bacteria | Cyanobacteriota | ExbB/ExbD/ExbD' of Synechocystis sp. (strain PCC 6803 / Kazusa) |
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1.A.30.2.2 | The TolA energy-transducing system. TolQ/R (the putative H+ channel) are listed here; TolA is listed under TC# 2.C.1.2.1, together with its auxiliary proteins. The channel is lined by TolR-Asp23, TolQ-Thr145 and TolQ-Thr178. The Tol-Pal complex, energized by TolQRA, and using the outer membrane proteins, BtuB and OmpF as receptors, is responsible for the uptake of colicin ColE9 and other bacteriocins; in this process, the complex in the outer membrane bridges and immobilizes the complex components in the inner membrane (Rassam et al. 2018). Salmonella Tol-Pal reduces outer membrane glycerophospholipid levels for envelope Hhomeostasis and survival during bacteremia in a process dependent on the TolQR channel (Masilamani et al. 2018). |
Bacteria | Pseudomonadota | The TolA system of E. coli |
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1.A.30.2.3 |
Putative TolA Energizer, TolQ1/TolR1 |
Bacteria | Myxococcota | TolQ1/R1 of Myxococcus xanthus |
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1.A.30.2.4 |
Putative TolA Energizer, TolQ2/TolR2 |
Bacteria | Myxococcota | TolQ2/R2 of Myxococcus xanthus |
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1.A.30.2.5 |
Putative TolA Energizer, TolQ3/TolR3 |
Bacteria | Myxococcota | TolQ3/R3 of Myxococcus xanthus |
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1.A.30.2.6 |
Putative TolA Energizer, TolQ4/TolR4 |
Bacteria | Myxococcota | TolQ4/R4 of Myxococcus xanthus |
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1.A.30.2.7 |
Putative TolA-dependent Energizer, TolQ5/TolR5 or AglX/AglV. Identified as an essential motor for adventurous gliding motility (Nan et al. 2011). |
Bacteria | Myxococcota | TolQ5/R5 or AglX/AglV of Myxococcus xanthus |
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1.A.30.2.8 | The putative ExbBD energizer (H+-channel). |
Bacteria | Spirochaetota | ExbBD of Leptospira interrogans |
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1.A.30.2.9 | TolQ/TolR |
Bacteria | Spirochaetota | TolQ/R of Leptospira interrogans |
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1.A.30.3.1 | TolQ (DUF2149)/TolR |
Bacteria | Thermodesulfobacteriota | TolQ/TolR of Geobacter sp. M18 |
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1.A.30.3.2 |
Motor for adventurous motility, AglR (a TolQ homologue)/AglS (a TolR homologue) (Nan et al. 2011). The mechanism by which the AglRS proteins energize adventurous gliding motility has been proposed (Jakobczak et al. 2015; Mignot and Nöllmann 2017). |
Bacteria | Myxococcota | AglQ/AglR of Myxococcus xanthus |
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1.A.30.3.3 | Adventurous gliding motility proteins AglR, AglS and AglV. These three proteins presumably function in gliding motility but are homologues of MotA/ExbB, MotB/ExbD and MotB/ExbD, respectively. |
Bacteria | Bdellovibrionota | AglRSV of Bdellovibrio bacteriovorus |
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1.A.30.3.4 | Putative gliding motility energizing system, AglR/AglS/AglS'. Similar to the three components of another system in the same organism with TC# 1.A.30.3.3. |
Bacteria | Bdellovibrionota | AglR/S/S' of Bdellovibrio bacteriovorus |
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1.A.30.4.1 | SiiAB putative energizer of giant adhesin, SiiE (repetitive 5,559 aa protein) export (Wille et al. 2013). |
Bacteria | Pseudomonadota | SiiAB of Salmonella enterica |
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1.A.30.4.2 | SiiA/B (MotB/A) homologues of 236 and 362 aas with 1 and 4 putative TMSs, respectively. |
Bacteria | Campylobacterota | SiiA/B of Sulfurimonas denitrificans (Thiomicrospira denitrificans) |
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1.A.30.4.3 | SiiA/B (MotB/A) homologues of 315 and 350 aas with 1 and 4 putative TMSs, respectively. Functions with the Type I (ABC) protein secretion exporter of TC# 3.A.1.109.6). |
Bacteria | Thermodesulfobacteriota | SiiA/B homologues of Desulfovibrio salexigens |
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1.A.30.5.1 | Uncharacterized MotA homologue of 301 aas and 3 to 5 TMSs. If 5, TMSs 1, 4 and 5 are strongly hydrophobic while TMSs2 and 3 are quite hydrophilic. The gene encoding this protein is flanked by genes encoding two large proteins, one anotated as a microtubule binding protein but showing limited sequence similarity to TolA (522 aas and one N-terminal TMS; Q6MNS1) and the other a large Ala/Glu-rich protein (794 aas with an N-terminal phosphopeptide binding motif (FHA), two ATP synthase domains (B and E), and one TMS near the C-terminus; Q6MNS3). |
Bacteria | Bdellovibrionota | UP of Bdellovibrio bacteriovorus |
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1.A.30.6.1 | ZorA/ZorB forming a putative proton channel. ZorA (704 aas; 4 TMSs; ABS66238; a putative methyl chemotaxis protein) is a very distant MotA homologue showing most sequence similarity to TC# 1.A.30.5.1) while ZorB is a clear MotB homologue (254 aas with 1 N-terminal TMS; ABS66239; hits 1.A.30.1.4 with a score of e-09). This system is proposed to function as an anti-phage defense system. ZorAB are only two such components, suggested to have proton channel activity (Doron et al. 2018). |
Bacteria | Pseudomonadota | ZorAB of Xanthobacter autotrophicus Py2 |
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1.A.30.6.2 | ZorA/ZorB (MotAB homologues) of 704 aas with 3 TMSs and 254 aas with 1 N-terminal TMS. |
Bacteria | Pseudomonadota | ZorAB of Pseudomonas aeruginosa |
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1.A.30.6.3 | ZorA/ZorB components of an anti-phage defense system (Doron et al. 2018). |
Bacteria | Pseudomonadota | ZorAB of Acinetobacter baumannii |
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1.A.30.6.4 | ZorAB, putative H+ channel proteins, MotAB homologues, functioning in defense against phage attack (Doron et al. 2018). |
Bacteria | Pseudomonadota | ZorAB of E. coli PA10 |
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1.A.30.6.5 | ZorAB, putative proton channel proteins, homologues of MotAB, possibly involved in resistance to phage invasion (Doron et al. 2018). |
Bacteria | Bacillota | ZorAB of Acidaminococcus fermentans DSM 20731 |
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1.A.30.6.6 | ZorA (673 aas amd 3 - 4 TMSs)/ZorB (248 aas and 1 N-terminal TMS) |
Bacteria | Cyanobacteriota | ZorAB of Prochlorothrix hollandica PCC 9006 |
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1.A.30.6.7 | ZorAB |
Bacteria | Thermotogota | ZorAB of Thermosipho africanus |
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1.A.30.6.8 | ZorA (472 aas and 3 TMSs)/ZorB (222 aas and 1 N-terminal TMS. |
Bacteria | Bacteroidota | ZorAB of Spirosoma linguale |
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1.A.31.1.1 | Annexin X | Eukaryota | Metazoa, Arthropoda | Annexin X of Drosophila melanogaster | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.31.1.2 | Annexin VI | Eukaryota | Metazoa, Chordata | Annexin VI of Homo sapiens (673 aas; P08133) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.31.1.3 | Annexin A1 (McNeil et al., 2006) |
Eukaryota | Metazoa, Chordata | Annexin A1 of Homo sapiens (346 aas; P04083) |
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1.A.31.1.4 | Annexin 2 or Annexin A2 (ANXA2) of 339 aas. Forms a tetrameric complex with the S100A10 protein and binds the C-terminus of the AHNAK protein via the N-terminus of annexin 2 (De Seranno et al., 2006). Direct translocation of Annexin 2 to the cell surface occurs by pore-formation. External annexin A2 acts as a plasminogen receptor, able to stimulate fibrinolysis and cell migration (Pompa et al. 2017). Ahnak (of 5890 aas; Q09666) regulates calcium homeostasis in several organs, plays a pivotal role in kidney and ureter development, and maintains the function of the urinary system (Lee et al. 2023). This huge protein consists of > 50 repeat sequences. |
Eukaryota | Metazoa, Chordata | Annexin 2 of Homo sapiens |
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1.A.31.1.5 | Non-selective cation channel-forming annexin 1 of 313 aas, Ann1 (Kodavali et al. 2013). |
Eukaryota | Viridiplantae, Streptophyta | Ann1 of Medicago truncatula |
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1.A.31.1.6 | Annexxin of 369 aas. Schistosomiasis, a major parasitic disease of humans, is second only to malaria in its global impact. The disease is caused by digenean trematodes that infest the vasculature of their human hosts. These flukes are limited externally by a body wall composed of a syncytial epithelium, the apical surface membrane, a parasitism-adapted dual membrane complex. Annexins are important for the stability of this apical membrane system. Leow et al. 2013 presented the first structural and immunobiochemical characterization of an annexin from Schistosoma mansoni. The crystal structures of annexin B22 (4MDV and 4MDU) in the apo and Ca2+ bound forms confirmed the presence of the previously predicted α-helical segment in the II/III linker and revealed a covalently linked head-to-head dimer. The dimeric arrangement revealed a non-canonical membrane binding site and a probable binding groove opposite the binding site. Annexin B22 expression correlated with life stages of the parasite that possess the syncytial tegument layer, and ultrastructural localization by immuno-electron microscopy confirmed the occurrence of annexins in the tegument of S. mansoni. |
Eukaryota | Metazoa, Platyhelminthes | Annexin B22 of Schistosoma mansoni |
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1.A.31.1.7 | Annexin A5 of 320 aas. Annexin A5 (ANXA5), a Ca2+ and phospholipid binding protein, interacts with the N-terminal leucine-rich repeats of polycystin-1 (TC# 1.A.5.1.2). This interaction is direct and specific, and involves a conserved sequence of the ANXA5 N-terminal domain (Markoff et al. 2007). |
Eukaryota | Metazoa, Chordata | Annexin A5 of Homo sapiens |
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1.A.31.1.8 | Annexin D1 (Anx23; Ann1; AnnAT1; AtoxY; Oxy5) of 317 aas. It has a peroxidase activity and may act to
counteract oxidative stress (Gorecka et al. 2005). May also mediate regulated, targeted
secretion of Golgi-derived vesicles during seedling development (Clark et al. 2005). Can transport Ca2+ (Demidchik et al. 2018). |
Eukaryota | Viridiplantae, Streptophyta | Annexin 1D of Arabidopsis thaliana (Mouse-ear cress) |
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1.A.31.1.9 | Annexin XII, Annexin 12, Annexin-12, AnnexinB12 of 316 aas. It is a calcium- and phospholipid-binding protein, phosphorylated by PKC. The x-ray structure of the heximer has been solved (Luecke et al. 1995). A reversible transition occurs between the surface trimer and membrane-inserted monomer (Ladokhin and Haigler 2005). |
Eukaryota | Metazoa, Cnidaria | Annexin-12 of Hydra vulgaris |
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1.A.32.1.1 | NB glycopeptide | Viruses | Orthornavirae, Negarnaviricota | NB of influenza virus type B | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.32.1.2 | Uncharacterized protein of 83 aas and 1 TMS. |
Viruses | Orthornavirae, Negarnaviricota | UP of Influenza B virus (B/Shanghai) |
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1.A.32.1.3 | Neuraminidase, NB-NA, of 468 aas and possibly two TMSs. The first is N-terminal and forms a large hydrophobic peak, while the second is C-terminal and forms a small hydrophobic peak. 1.A.32.1.1 corresponds in sequence to the N-terminal 41 aas of this protein. |
Viruses | Orthornavirae, Negarnaviricota | Neuraminidase of Influenza B virus |
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1.A.33.1.1 | Heat shock cognate 70 kDa protein, Hsc70 | Eukaryota | Viridiplantae, Streptophyta | Hsc70 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.33.1.2 | Heat shock protein-70 homologue, DnaK. Although DnaK homologues are ubiquitous, a transport function in eukaryotes, but not in prokaryotes has been demonstrated. |
Bacteria | Pseudomonadota | DnaK of E. coli |
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1.A.33.1.3 | Heat shock protein 70(1B) | Eukaryota | Metazoa, Chordata | Hsp70(1B) of Homo sapiens (AAH57397) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.33.1.4 | DnaK of 611 aas |
Bacteria | Bacillota | DnaK of Bacillus subtiiis |
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1.A.33.1.5 | Glucose regulated protein, GRP78 of 654 aas. GRP78, a member of the ER stress protein family. It can relocate to the surface of cancer cells, playing a role in promoting cell proliferation and metastasis. GRP78 consists of two major functional domains: the ATPase and protein/peptide-binding domains. The protein/peptide-binding domain of cell-surface GRP78 has served as a novel functional receptor for delivering cytotoxic agents (e.g., a apoptosis-inducing peptide or taxol) across the cell membrane. The ATPase domain of GRP78 (GRP78ATPase) has potential as a transmembrane delivery system of cytotoxic agents including nucleotides (e.g., ATP-based nucleotide triphosphate analogs) (Hughes et al. 2016). It may also play a role in facilitating the assembly of multimeric protein complexes inside the ER (Evensen et al. 2013). It is involved in the correct folding of proteins and degradation of misfolded proteins via its interaction with DNAJC10, probably to facilitate the release of DNAJC10 from its substrate (Evensen et al. 2013). Grp78 as a critical factor in Kras-mutated adenomagenesis. This can be attributed to a critical role for Grp78 in GLUT1 expression and localization, targeting glycolysis and the Warburg effect (Spaan et al. 2023). ). |
Eukaryota | Metazoa, Chordata | GRP78 of Homo sapiens |
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1.A.33.1.6 | Lhs1, Hsp70 homolog of 881 aas and 1 N-terminal TMS. It is a chaperone required for protein translocation and folding in the endoplasmic reticulum via the ERAD pathway ( TC# 3.A.25) (Steel et al. 2004). The Lhs1-dependent ERAD pathway is influenced by the transmembrane domain context (Sukhoplyasova et al. 2023). |
Eukaryota | Fungi, Ascomycota | Lhs1 of Saccharomyces cerevisiae |
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1.A.33.2.1 | MMAR_0617 MOMP (Hsp70 homologue) (van der Woude et al. 2013). |
Bacteria | Actinomycetota | MMAR_0617 of Mycobcterium marinum |
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1.A.33.2.2 | Hsp70 homologue of 581 aas. |
Bacteria | Actinomycetota | Hsp70 homologue of Mycobacterium tuberculosis |
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1.A.33.2.3 | Hsp70 homologue of 455 aas |
Bacteria | Actinomycetota | Hsp70 of Nocardia farcinica |
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1.A.34.1.1 | The Bacillus SpoIIQ/SpoIIIAH transcompartment channel interconnects the forespore and the mother cell. The activity of sigmaG requires this channel apparatus through which the adjacent mother cell provides substrates that generally support gene expression in the forespore. Flanagan et al. 2016 reported that SpoIIQ is bifunctional, specifically maximizing sigmaG activity as part of a regulatory circuit that prevents sigmaG from activating transcription of the gene encoding its own inhibitor, the anti-sigma factor CsfB. |
Bacteria | Bacillota | The SpoIIQ/SpoIIIAH complex of Bacillus subtilis |
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1.A.34.1.2 | SpoIIQ homologue of one of the two components (SpoIIQ and SpoIIIAH) of the gap junction-like channel-forming complex of B. subtilis. Several SpoIIQ homologues in various E. coli strains were identified, but no homologue of the SpoIIAH component was found. Therefore, pore formation can not be inferred. |
Bacteria | Pseudomonadota | SpoIIQ homologue of E. coli |
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1.A.34.1.3 | Uncharacterized metaloprotease family M23 of 245 aas. Shows sequence similarity to SpoIIQ in an 80 residue region, residues 140 - 220 in both proteins. |
Bacteria | Pseudomonadota | UP of E. coli |
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1.A.34.1.4 | SpoIIQ-SpoIIIAH complex spanning the two membranes of the mother cell and the prespore. Inhibiting SpoIIQ, SpoIIIAA, or SpoIIIAH function apparently prevents the formation of infectious C. difficile spores and thus disease transmission (Fimlaid et al. 2015). spoIIQ or spoIIIAH mutants that complete engulfment are impaired in post-engulfment, forespore and mother cell-specific gene expression, in agreement with a channel-like function (Serrano et al. 2016). |
Bacteria | Bacillota | SpoIIQ-SpoIIIAH of Clostridium difficile |
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1.A.35.1.1 | Divalent cation (Mg2+, Co2+ and Ni2+) transport system, CorA. Helical tilting and rotation in TM1 generates an iris-like motion that increases the diameter of the permeation pathway, triggering ion conduction, thus defining the gating mechanism (Dalmas et al. 2014). The expression of corA is regulated by the 5' upstream region that senses variations of intracellular magnesium ions (Vézina Bédard et al. 2024). |
Bacteria | Pseudomonadota | CorA of E. coli (P0ABI4) |
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1.A.35.1.2 | Divalent cation (Mg2+, Co2+ and Ni2+) transport system, CorA |
Bacteria | Pseudomonadota | CorA of Salmonella typhimurium (P0A2R8) |
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1.A.35.1.3 | Magnesium transport protein CorA |
Bacteria | Bacillota | CorA of Bacillus subtilis |
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1.A.35.2.1 | Aluminum resistance protein AlR1p; Alr1; ALR1, LLR1; MNR1 (Mg2+ homeostasis transporter [Mg2+ regulated]) AlR1p and AlR2p (P43553; a close paralogue) both catalyze uptake of Mg2+ and a variety of heavy metals (da Costa et al., 2007). Truncation of Alr1 showed that the N-terminal 239 amino acids and the C-terminal 53 amino acids are not essential for magnesium uptake (Lee and Gardner 2006). Mutations in the C-terminal part of ALR1 that is homologous to bacterial CorA magnesium transporters that gave severe phenotypes had amino acid changes in the small region containing the TMSs. Eighteen single amino acid mutants in this region were classified into three categories for magnesium uptake: no, low and moderate activity. Conservative mutations that reduced or inactivated uptake led to the identification of Ser(729), Ile(746) and Met(762) (part of the conserved GMN motif) as critical residues. High expression of inactive mutants inhibited the capability of wild-type Alr1 to transport magnesium, consistent with Alr1 forming homo-oligomers (Lee and Gardner 2006). Alr1 may play a role in cadmium resistance (Kern et al. 2005). |
Eukaryota | Fungi, Ascomycota | Al1Rp of Saccharomyces cerevisiae |
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1.A.35.2.2 | Inner mitochondrial membrane manganese channel protein MnR2p or MRS2-11. The regulatory domain of Mrs2 from the yeast inner mitochondrial membrane is similar to the E. coli regulatory domain of CorA with Met309 serving the same function as Met291 in CorA (Khan et al. 2013). |
Eukaryota | Fungi, Ascomycota | MnR2p of Saccharomyces cerevisiae |
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1.A.35.2.3 | Eukaryota | Fungi, Ascomycota | C27B12.12c of Schizosaccharomyces pombe |
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1.A.35.3.1 | Divalent metal ion (Mg2+, Ca2+, Ni2+, etc.) transporter of 317 aas and 3 TMSs. The cryo-EM structure shows a pentameric channel with an asymmetric domain structure and featuring differential separations between the trans-segments, probably reflecting mechanical coupling of the cytoplasmic domain to the transmembrane domain and suggesting a gating mechanism (Cleverley et al. 2015). |
Archaea | Euryarchaeota | CorA of Methanocaldococcus jannaschii (Methanococcus jannaschii) |
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1.A.35.3.2 | Magnesium transport protein, CorA. The structure at 2.7 Å resolution is known. The CorA monomer has a C-terminal membrane domain containing two transmembrane segments and a large N-terminal cytoplasmic soluble domain. In the membrane, CorA forms a homopentamer shaped like a funnel which binds fully hydrated Mg2+ in the periplasm (Maguire 2006). A ring of positive charges are external to the ion-conduction pathway at the cytosolic membrane interface, and highly negatively charged helices in the cytosolic domain appear to interact with the ring of positive charge to facilitate Mg2+ entry. Mg2+ ions are present in the cytosolic domain that are well placed to control the interaction of the ring of positive charge and the negatively charged helices, and thus, control Mg2+ entry (Maguire 2006). Gating is achieved by helical rotation upon the binding of a metal ion substrate to the regulatory binding sites. The preference for Co2+ over Mg2+ has been reported to be determined by the presence of threonine side chains in the channel (Nordin et al. 2013), but more recently, Kowatz and Maguire 2018 showed that Co2+ is not a substrate, and that the intersubunit bound Mg2+ is not required for function and does not control the open versus closed states. |
Bacteria | Thermotogota | CorA of Thermotoga maritima |
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1.A.35.3.3 | Putative metal ion transporter YfjQ | Bacteria | Bacillota | YfjQ of Bacillus subtilis |
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1.A.35.3.4 | Putative CorA protein of 302 aas |
Bacteria | Bacillota | CorA of Streptococcus sanguinis |
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1.A.35.3.5 | MIP family protein of 366 aas. Mg2+,Co2+ and the CorA-specific inhibitor (Co(III) hexamine chloride) bind in the loop at the same binding site. This site includes the glutamic acid residue from the conserved "MPEL" motif (Hu et al. 2009). |
Bacteria | Actinomycetota | CorA of Mycobacterium tuberculosis |
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1.A.35.3.6 | The CorA-homologous magnesium ion transporter of 831 aas, Mgt1. Is critical for parasite development and virulence (Zhu et al. 2009). |
Eukaryota | Euglenozoa | Mgt1 of Leishmania major |
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1.A.35.3.7 | Putative Mg2+ transporter of 322 aas and 2 or 3 TMSs. |
Viruses | Heunggongvirae, Uroviricota | CorA protein of Lactobacillus phage LfeInf |
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1.A.35.3.8 | Uncharacterized CorA homologue of 373 aas and 3 TMSs (Pohland and Schneider 2019). |
Bacteria | Cyanobacteriota | CorA of Acaryochloris marina |
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1.A.35.3.9 | Divalent metal ion CorA channel of 325 aas and 2 large C-terminal peaks of hydrophobicity that are likely to be TMSs, plus four moderately hydrophobic peaks equally spaced in residues 10 - 200. It may transport Mg2+, Zn2+, Cd2+, Co2+, Cu2+ and Mn2+ as well as other di-valent and tri-valent metal cations. This suggestion is based on homology with other members of the MIT family. |
Archaea | Asgard | CorA of the Asgard group archaea |
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1.A.35.4.1 | Zn2+/Cd2+ efflux system, ZntB. Mg2+ is not transported. Wan et al. 2011 reported crystal structures in dimeric and physiologically relevant homopentameric forms at 2.3 Å and 3.1 Å resolutions, respectively. The funnel-like structure is similar to that of the homologous Thermotoga maritima CorA Mg2+ channel and a Vibrio parahaemolyticus ZntB (VpZntB). However, the central α7 helix forming the inner wall of the StZntB funnel is oriented perpendicular to the membrane instead of the marked angle seen in CorA or VpZntB. Consequently, the StZntB funnel pore is cylindrical, not tapered, which may represent an "open" form of the ZntB soluble domain. There are three Zn2+ binding sites in the full-length ZntB, two of which could be involved in Zn2+ transport. |
Bacteria | Pseudomonadota | ZntB of Salmonella enterica serovar Typhimurium |
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1.A.35.4.2 | The ZntB Zn2+/Cd2+ transporter. The 1.9Å structure of the N-terminal cytoplasmic domain of ZntB has been solved (Tan et al., 2009). |
Bacteria | Pseudomonadota | ZntB of Vibrio parahaemolyticus (Q87M69) |
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1.A.35.5.1 | Mitochondrial inner membrane Mg2+ channel protein, Mrs2 (Schindl et al., 2007). Mutational analyses have been carried out, suggesting that internal Mg2+ affects intron splicing (Weghuber et al. 2006). MRS2 is involved in mitochondrial Mg2+ homeostasis (Schäffers et al. 2018). The G-M-N motif determines the ion selectivity, likely together with the negatively charged loop at the entrance of the channel, thereby forming the Mrs2p selectivity filter (Sponder et al. 2013). |
Eukaryota | Fungi, Ascomycota | Mrs2 of Saccharomyces cerevisiae (Q01926) |
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1.A.35.5.10 | Mg2+ transporter, MIT3, of 478 aas with 2 C-terminal TMSs (Wunderlich 2022) |
Eukaryota | Apicomplexa | MIT3 of Plasmodium falciparum |
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1.A.35.5.11 | Magnesium transporter 9, Mgt9, of 378 aas and possibly 2 TMSs, one at residue 160 and one C-terminal. In cassava (Manihot esculenta) This protein associates with aquaporin PIP2;7 (B2M0U5) interact synergistically to promote water and Mg2+ uptake (Ma et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | Mgt9 of Arabidopsis thaliana |
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1.A.35.5.2 | High affinity root Mg2+ transporter, Mrs2/MGT1/MRS2-10. Plants have at least 11 Mrs2 homologues, and they can form homo as well as heterooligomeric channels (Schmitz et al. 2013). Expression in an E. coli triple mutant, corA mgtA yhiD, which required high (>10 mM) Mg2+ for growth, allowed growth on >1 mM Mg2+ and resulted in Al3+ sensitivity (Ishijima et al. . 2015). It therefore appears that MRS2-10 catalyzes Mg2+ and Al 3+ uptake. |
Eukaryota | Viridiplantae, Streptophyta | Mrs2-10 of Arabidposis thaliana (Q9SAH0) |
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1.A.35.5.3 | Magnesium transporter MRS2-11, MRS2B, chloroplastic (Magnesium Transporter 10) (AtMGT10). Expression in an E. coli triple mutant, corA mgtA yhiD, which required high (>10 mM) Mg2+ for growth, allowed growth on >1 mM Mg2+ and resulted in Al3+ sensitivity (Ishijima et al. 2015). |
Eukaryota | Viridiplantae, Streptophyta | MGT10 of Arabidopsis thaliana |
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1.A.35.5.4 | Magnesium transporter MRS2-4 (Magnesium Transporter 6) (AtMGT6) | Eukaryota | Viridiplantae, Streptophyta | MRS2-4 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.35.5.5 | Mitochondrial inner membrane magnesium transporter MFM1; LPE10 (MRS2 function modulating factor 1) |
Eukaryota | Fungi, Ascomycota | MFM1 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.35.5.6 | Magnesium transporter MRS2-5 (Magnesium Transporter 3) (AtMGT3) | Eukaryota | Viridiplantae, Streptophyta | MRS2-5 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.35.5.7 | MRS2 (HPTm MRS2L) of 443 aas and 2 C-terminal TMSs. Implicated in mitochondrial Mg2+ homeostasis (Schäffers et al. 2018). The human MRS2 magnesium-binding domain is a regulatory feedback switch for channel activity (Uthayabalan et al. 2023). It is a magnesium (Mg2+) entry protein channel in mitochondria. Whereas MRS2 contains two transmembrane domains constituting a pore in the inner mitochondrial membrane, most of the protein resides within the matrix. This research exposes a mechanism for human MRS2 autoregulation by negative feedback from the NTD and identifies a novel gain of function mutant (Uthayabalan et al. 2023). |
Eukaryota | Metazoa, Chordata | MRS2 of Homo sapiens |
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1.A.35.5.8 | MIT1 of 529 aas and 2 C-terminal TMSs. It is a Mg2+/Co2+/Ni2+ ion channel (Wunderlich 2022). |
Eukaryota | Apicomplexa | MIT1 of Plasmodium falciparum |
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1.A.35.5.9 | Magnesium transport channel, MIT2, of 468 aas with 2 C-terminal TMSs. |
Eukaryota | Apicomplexa | MIT2 of Plasmodium falciparum |
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1.A.36.1.1 | The intracellular chloride channel, CLIC-like, Clcc1 (Mid1-related chloride [anion] channel, MCLC), of 551 aas. Its loss results in endoplasmic reticular (ER) stress, misfolded protein accumulation, and neurodegeneration (Jia et al. 2015). |
Eukaryota | Metazoa, Chordata | MCLC of Homo sapiens |
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1.A.36.1.2 | CLIC- homologue |
Eukaryota | Metazoa, Cnidaria | CLIC homologue of Nematostella vectensis |
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1.A.36.1.3 | Clic-like Chloride channel protein 1 |
Eukaryota | Metazoa, Arthropoda | Clic-like protein of Acromyrmex echinatior (Panamanian leafcutter ant) (Acromyrmex octospinosus echinatior) |
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1.A.36.1.4 | Putative chloride channel |
Viruses | Heunggongvirae, Peploviricota | Chloride channel of Abalone herpesvirus Victorial |
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1.A.36.1.5 | Chloride channel, CLIC-like protein 1 of 508 aas. |
Eukaryota | Metazoa, Chordata | CLIC of Xenopus laevis (African clawed frog) |
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1.A.36.2.1 | OOC-3 protein, isoform B. Required for establishment of cortical domains in C. elegans embryos (Basham and Rose 1999; Pichler et al. 2000). |
Eukaryota | Metazoa, Nematoda | OOC-3 of Caenorhabditis elegans |
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1.A.36.2.2 | Uncharacterized protein |
Eukaryota | Metazoa, Nematoda | Uncharacterized protein of Loa loa |
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1.A.37.1.1 | The CD20 (Cluster of differentiation-20) protein (297 aas and 4 TMSs) is a putative cation channel (B-lymphocyte CD20 antigen) or an indirect regulator of calcium release. The 3-d structure has been determined (Rougé et al. 2020). It is targeted by monoclonal antibodies for the treatment of malignancies and autoimmune disorders. Rituximab (RTX) activates complement to kill B cells. Rougé et al. 2020 obtained a structure of CD20 in complex with RTX, revealing a compact double-barrel dimer bound by two RTX antigen-binding fragments (Fabs), each of which engages a composite epitope. RTX cross-links CD20 into circular assemblies which leads to a structural model for complement recruitment. Transport of Cd2+ and its complexes (mainly Cd2+ bound to glutathione) occurs by the ABC transporters ABCB1 (P-glycoprotein, MDR1), ABCB6, ABCC1 (multidrug resistance related protein 1, MRP1), ABCC7 (cystic fibrosis transmembrane regulator, CFTR), and ABCG2 (breast cancer related protein, BCRP). Potential detoxification strategies underlying ABC transporter-mediated efflux of Cd2+ and Cd2+ complexes are discussed (Thévenod and Lee 2024). |
Eukaryota | Metazoa, Chordata | CD20 of Homo sapiens |
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1.A.37.1.5 | Uncharacterized protein of 247 aas and 4 TMSs in a 3 + 1 TMS arrangement. |
Eukaryota | Metazoa, Chordata | UP of Xiphophorus couchianus (Monterrey platyfish) |
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1.A.37.2.1 | Membrane-spanning 4 TMS subfamily A member 10 (MS4A superfamily), HTm4 |
Eukaryota | Metazoa, Chordata | HTm4 of Homo sapiens (Q96PG2) |
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1.A.37.3.1 | 4 TMS testes development-related NYD-SP21 protein |
Eukaryota | Metazoa, Chordata | NYD-SP21 of Homo sapiens (Q96JA4) |
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1.A.37.3.2 | MS4A2 of 244 aas and 4 TMSs. High affinity receptor that binds to the Fc region of immunoglobulins epsilon. Aggregation of Fc epsilon receptor (FCERI) by multivalent antigens is required for the full mast cell response, including the release of preformed mediators (such as histamine) by degranulation and de novo production of lipid mediators and cytokines (Penhallow et al. 1995). Also mediates the secretion of important lymphokines. Binding of allergen to receptor-bound IgE leads to cell activation and the release of mediators responsible for the manifestations of allergy. |
Metazoa, Chordata | MS412 of Homo sapiens |
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1.A.37.3.3 | Uncharacterized membrane-spanning 4-domain subfamily A member 4A-like protein of 261 aas and 4 or 5 TMSs in a 3 or 4 + 1 TMS arrangement. |
Eukaryota | Metazoa, Chordata | UP of Cyprinus carpio |
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1.A.37.4.1 | Fam189A1 or CD20 family with 539 aas and 4 TMSs. |
Eukaryota | Metazoa, Chordata | CD20 family protein of Homo sapiens |
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1.A.37.4.2 | Uncharacterized protein of 1323 aas and 4 TMSs in a 3 + 1 TMS arrangement at the N-terminus of this protein followed by a long hydrophilic region of ~1000 aas. The hydrophobic region of this protein shows significan sequence similarity with members of family TC# 9.B.200. |
Eukaryota | Metazoa, Cnidaria | UP of Actinia tenebrosa (Australian red waratah sea anemone) |
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1.A.37.5.1 | Sarcospan, SSPN, of 242 aas and 4 TMSs. Part of the smooth muscle sarcoglycan-sarcospan complex which in involved in idiopathic cardiomyopathy associated with myocardial ischemia (Cohn et al. 2001). Regulated by astroglial connexin 30 channels (TC# 1.A.24.1.7; Boulay et al. 2015). Analysis of sarcospan overexpression in mdx skeletal muscle reveals compensatory remodeling of cytoskeleton-matrix interactions that promote mechanotransduction pathways (McCourt et al. 2023). |
Eukaryota | Metazoa, Chordata | Sarcospan of Bos taurus |
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1.A.37.6.1 | TMem196 of 185 aas and 4 TMSs, Acts as a tumor suppressor (Liu et al. 2015). |
Eukaryota | Metazoa, Chordata | TMem196 protein of Canis lupus familiaris (Dog) (Canis familiaris) |
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1.A.37.7.1 | Transmembrane protein 212, TMEM212, of 194 aas and 4 or 5 TMSs (Brown et al. 2012). |
Eukaryota | Metazoa, Chordata | TMEM212 of Homo sapiens |
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1.A.37.8.1 | TMEM176B cation channel of 270 aas and 4 TMSs in a 3 + 1 TMS arrangement. It is upregulated in Meniere's disease (Sun et al. 2018). Phylogenetic analyses of the MS4A and TMEM176 gene families have been reported (Zuccolo et al. 2010). Pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers (Segovia et al. 2019). Inflammasome activation may reinforce anti-tumor immunity by boosting CD8(+) T cell priming as well as by enhancing T helper type 17 (Th17) responses. Modulation of TMEM176B provides one such mechanism, and this protein provides a potential target to unleash inflammasome activation, leading to reinforced anti-tumor immunity and improved efficacy of immune checkpoint blockers (Segovia et al. 2020). TMEM176B regulates AKT/mTOR signaling and tumor growth in triple-negative breast cancer (Kang et al. 2021). A subpopulation of CD146(+) macrophages enhances antitumor immunity by activating the NLRP3 inflammasome, and this involves TMEM176B. |
Eukaryota | Metazoa, Chordata | TMEM176B of Homo sapiens |
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1.A.37.8.2 | TMEM176A of 235 aas and 4 to 6 TMSs in a 3 or 4 TMS cluster followed by a 1 or 2 TMS cluster. Epigenetic silencing of TMEM176A activates ERK signaling in human hepatocellular carcinoma due to promoter methylation (Li et al. 2018). |
Eukaryota | Metazoa, Chordata | TMEM176A of Homo sapiens |
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1.A.37.8.3 | Uncharacterized protein of 244 aas and 5 TMSs in a 4 + 1 TMS arrangement. |
Eukaryota | Metazoa, Chordata | UP of Carassius auratus |
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1.A.37.8.4 | Uncharacterized TMEM176 homologue of 326 aas and an apparent 4 TMSs in a 3 + 1 TMS arrangement with a C-terminal annexin domain (see TC# 1.A.31). |
Eukaryota | Metazoa, Chordata | UP of Branchiostoma floridae (Florida lancelet) (Amphioxus) |
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1.A.38.1.1 | The Golgi pH regulator, GPHR, of 455 aas and 9 TMSs in a 5 + 4 TMS arrangement. |
Eukaryota | Metazoa, Chordata | GPHR of Cricetulus griseus (B2ZXD5) |
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1.A.38.1.2 | Uncharacterized protein of 367 aas and 8 TMSs. |
Eukaryota | Evosea | UP of Entamoeba histolytica |
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1.A.38.1.3 | The GPCR-type G protein, COLD1, of 455 aas and 9 TMSs in a 5 + 4 TMS arrangement. In cold tolerant cultivars (AC Q7X7S8)
Met-187 is replaced by Lys-187. This polymorphism is associated with
divergence in chilling tolerance of rice cultivars. COLD1 confers
adaptation of japonica rice to chilling and originated from the Chinese
wild populations of Oryza rufipogon (Ma et al. 2015). |
Eukaryota | Viridiplantae, Streptophyta | COLD1 of Oryza sativa subsp. indica (Rice) |
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1.A.38.2.1 | 10 TMS homologue (826 aas) |
Eukaryota | Euglenozoa | 10 TMS homologue of Leishmania mexicana (E9AL43) |
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1.A.38.3.1 | 4-5 TMS homologue (398 aas) |
Eukaryota | Apicomplexa | 4-5 TMS homologue of Plasmodium yoelii (Q7RQA4) |
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1.A.39.1.1 | The Type C influenza M2-like protein, CM2, of 374 aas and 2 TMSs near the C-terninus of the protein (Stewart and Pekosz 2012). |
Viruses | Orthornavirae, Negarnaviricota | CM2 of Type C influenza virus |
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1.A.39.1.2 | P42 protein of 387 aas and 2 TMSs. |
Viruses | Orthornavirae, Negarnaviricota | P42 of Influenza D virus (D/swine/Oklahoma) |
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1.A.39.1.3 | CM2 protein of 105 aas and 2 TMSs. A processed version of 1.A.39.1.1. |
Viruses | Orthornavirae, Negarnaviricota | CM2 of Influenza virus type C |
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1.A.4.1.1 | Transient receptor potential (TRP) protein. Assembles in vivo as a homomultimeric channel, not as a heteromeric channel with TrpL as the subunit (Katz et al. 2013). It is a light-sensitive calcium channel that is required for inositide-mediated Ca2+ entry in the retina during phospholipase C (PLC)-mediated phototransduction. Ca2+ influx may then feed back and inhibit PLC, thereby facilitating phosphatidylinositol 4,5 bisphosphate (PIP2) recycling. Trp and trpl act together in the light response, though it is unclear whether as heteromultimers or as distinct units, and are activated by fatty acids and metabolic stress. It is also required for olfactory adaptation and may be involved in olfactory system development (Störtkuhl et al. 1999). Mechanical force activates the light-dependent channels TRP and TRPL in excised patches from the rhabdomere of Drosophila photoreceptors (Delgado et al. 2024). |
Eukaryota | Metazoa, Arthropoda | TRP protein of Drosophila melanogaster (P19334) |
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1.A.4.1.10 | Trp-2 channel; controls nicotine-dependent behavior (Xiao and Xu 2009). The TRPC orthologues TRP-1 and -2 genetically complement the loss of syndecan by suppressing neuronal guidance and locomotory defects related to increases in neuronal calcium levels. The widespread and conserved syndecan-TRPC axis therefore fine tunes cytoskeletal organization and cell behavior (Gopal et al. 2015). |
Eukaryota | Metazoa, Nematoda | Trp-2 of Caenorhabditis elegans |
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1.A.4.1.11 | TRP channel homologue, Trp1, of 766 aas and 6 - 9 TMSs. Contains Ankyrin - PKD1 - TrpC channel domains. Exhibits properties of mammalian signal transduction Trp channels (Arias-Darraz et al. 2015). Photoswitchable reagents are used for investigating various types of TRPC channels, including TRPC2, TRPC3, TRPC5, and TRPC6, to gain new insights into the gating mechanisms and functions of these channels (Ojha et al. 2023). |
Eukaryota | Viridiplantae, Chlorophyta | TRP channel homologue of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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1.A.4.1.12 | TrpC4 of 977aas. In epidermal keratinocytes, a syndecan-TRPC4 complex controls adhesion, adherens junction composition, and early differentiation in vivo and in vitro (Gopal et al. 2015). Constitutively active TRPC1/C4-dependent background Ca2+ entry fine-tunes Ca2+ cycling in beating adult cardiomyocytes. Double TRPC1/C4-gene inactivation protects against development of maladaptive cardiac remodelling without altering cardiac or extracardiac functions contributing to this pathogenesis (Camacho Londoño et al. 2015). A cryo-EM structure of TRPC4 in its unliganded (apo) state has beeen solved to an overall resolution of 3.3 A. It reveals a unique architecture with a long pore loop stabilized by a disulfide bond. Beyond the shared tetrameric six-transmembrane fold, the TRPC4 structure deviates from other TRP channels with a unique N-terminal cytosolic domain which forms extensive aromatic contacts with the TRP and the C-terminal domains (Duan et al. 2018). |
Eukaryota | Metazoa, Chordata | TrpC4 of Homo sapiens |
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1.A.4.1.13 | Transient receptor potential ion channel protein, TRP6, of 2341 aas and 6 - 9 TMSs. |
Eukaryota | Viridiplantae, Chlorophyta | TRP6 OF Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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1.A.4.1.14 | Flagellar associated calcium channel protein of 1,729 aas, FAP148 (Wheeler and Brownlee 2008). |
Eukaryota | Viridiplantae, Chlorophyta | FAP148 of Chlamydomonas reinhardtii |
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1.A.4.1.15 | Transient potential protein-gamma, Trpγ, of 1128 aas and 10 TMSs. A light-sensitive cation/calcium channel that is required for inositide-mediated Ca2+ entry in the retina during phospholipase C (PLC)-mediated phototransduction. It forms a regulated cation channel when heteromultimerized with TrpL (Xu et al. 2000). |
Eukaryota | Metazoa, Arthropoda | TrpL of Drosophila melanogaster (Fruit fly) |
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1.A.4.1.16 | Short transient receptor potential channel 7 of 722 aas and 7 or 8 TMSs plus the P-loop. TRPC3.6, TRPC3.7, and TRPV4.7 are important for thermal regulation in oysters (Fu et al. 2021). |
Eukaryota | Metazoa, Mollusca | TRP channel 7 of Crassostrea gigas (Pacific oyster) (Crassostrea angulata) |
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1.A.4.1.2 | TRP7 receptor-activated capacitative Ca2+ entry channel |
Eukaryota | Metazoa, Chordata | TRP7 of Mus musculus (Q9WVC5) |
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1.A.4.1.3 | TRPC1 store-operated Ca2+ channel (Liu et al., 2003) (activated by the metabotropic [G- protein-dependent] glutamate receptor, mGluR1) (Kim et al., 2003) (controls salivary gland fluid secretion in mice (Liu et al., 2007a). Constitutively active TRPC1/C4-dependent background Ca2+ entry fine-tunes Ca2+ cycling in beating adult cardiomyocytes. Double TRPC1/C4-gene inactivation protects against development of maladaptive cardiac remodelling without altering cardiac or extracardiac functions contributing to this pathogenesis (Camacho Londoño et al. 2015). Regulated by drebrin (DBN1; 649 aas; Q16643) (Pabon et al. 2017). TRPC1 null mutations exacerbate memory loss and apoptosis induced by amyloid-beta (Li et al. 2018). Pulsed focused ultrasound (pFUS) acoustic radiation forces mechanically activate a Na+-containing TRPC1 (TC# 1.A.4..1.3) channel generating current upstream of voltage-gated Ca2+ channels (VGCC) rather than directly opening VGCC (Burks et al. 2019). |
Eukaryota | Metazoa, Chordata | TRPC1 of Homo sapiens (P48995) |
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1.A.4.1.4 | TRPC3 store-operated non-selective cation channel (activated by thapsigargin and 2 acyl glycerol; forms a heteromeric channel with TrpC1, TC #1.A.4.1.3) (Liu et al., 2005). A structural model of the TRPC3 permeation pathway based on a sodium channel (TC# 1.A.1.14.5) with a localized selectivity filter and an occluding gate with evidence for allosteric coupling between the gate and the selectivity filter has been proposed (Ko et al. 2009; Lichtenegger et al. 2013). The channel may have a large internal chamber surrounded by signal sensing antennas (Mio et al. 2007). TRPC channels are involved in store-operated calcium entry and calcium homeostasis, and they are implicated in human diseases such as neurodegenerative disease, cardiac hypertrophy, and spinocerebellar ataxia (Fan et al. 2018). The structure in a lipid-occupied, closed state has been solved at 3.3 Å resolution. TRPC3 has four elbow-like membrane reentrant helices prior to the first transmembrane helix. The TRP helix is perpendicular to, and thus disengaged from, the pore-lining S6, suggesting a different gating mechanism from other TRP subfamily channels. The third transmembrane helix S3 is remarkably long, shaping a unique transmembrane domain, and constituting an extracellular domain that may serve as a sensor of external stimuli. Fan et al. 2018 identified two lipid binding sites, one being sandwiched between the pre-S1 elbow and the S4-S5 linker, and the other being close to the ion-conducting pore, where the conserved LWF motif of the TRPC family is located. The cytoplasmic domain allosterically modulates channel gating (Sierra-Valdez et al. 2018). This channel may be present in mitochondria (Parrasia et al. 2019). TRPC3 and TRPC6 channels are calcium-permeable non-selective cation channels. The gain-of-function (GOF) mutations of TRPC6 lead to familial focal segmental glomerulosclerosis (FSGS) in humans. Guo et al. 2022 reported the cryo-EM structures of human TRPC3 in both high-calcium and low-calcium conditions. They identified both inhibitory and activating calcium-binding sites in TRPC3 that couple intracellular calcium concentrations to the basal channel activity. These calcium sensors are structurally and functionally conserved in TRPC6. The GOF mutations of TRPC6 activate the channel by allosterically abolishing the inhibitory effects of intracellular calcium. Structures of human TRPC6 in complex with two chemically distinct inhibitors bound at different ligand-binding pockets revealed different conformations of the transmembrane domain (Guo et al. 2022). TRPC3 is primarily gated by lipids, and its surface expression is dependent on cholesterol (Clarke et al. 2022). Regulating the activity of the SOCE response via SARAF activity may allow therapeutic strategies for triple-negative breast cancer (Saldías et al. 2023). |
Eukaryota | Metazoa, Chordata | TRPC3 of Homo sapiens (Q13507) |
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1.A.4.1.5 | Transient receptor potential canonical-6, TRPC6, a non-selective cation channel that is directly activated by diacylglycerol (DAG (Szabó et al. 2015). Mutation causes a particularly aggressive form of familial focal segmental glomerulosclerosis (Winn et al., 2005; Mukerji et al., 2007). Tang et al. 2018 presented the structure of the human TRPC6 homotetramer in complex with a high-affinity inhibitor, BTDM, solved by single-particle cryo-EM to 3.8 Å resolution. The structure shows a two-layer architecture in which the bell-shaped cytosolic layer holds the transmembrane layer. Extensive inter-subunit interactions of cytosolic domains, including the N-terminal ankyrin repeats and the C-terminal coiled-coil, contribute to the tetramer assembly. The high-affinity inhibitor BTDM wedges between the S5-S6 pore domain and voltage sensor-like domain to inhibit channel opening (Tang et al. 2018). TRPC6 may regulate the glomerular filtration rate by modulating mesangial cell contractile function through multiple Ca2+ signaling pathways (Li et al. 2017). Several proteins including podocin (8.A.21.1.2), nephrin (8.A.23.1.33), CD2AP (8.A.34.1.5) and TRPC6 form a macromolecular assembly that constitutes the slit-diaphragm in podocytes that resembles tight junctions (Mulukala et al. 2020). Two small molecules, GSK1702934A and M085, directly activate TRPC6 via a mechanism involving stimulation of the extracellular cavity formed by the pore helix and transmembrane helix S6 (Yang et al. 2021). Na+/Ca2+ exchanger, NCX1, and canonical transient receptor potential channel 6 (TRPC6) are recruited by STIM1 to mediate Store-Operated Calcium Entry in primary cortical neurons (Tedeschi et al. 2022). Guo et al. 2022 reported the cryo-EM structures of human TRPC3 in both high-calcium and low-calcium conditions. They identified both inhibitory and activating calcium-binding sites in TRPC3 that couple intracellular calcium concentrations to the basal channel activity. These calcium sensors are structurally and functionally conserved in TRPC6. The GOF mutations of TRPC6 activate the channel by allosterically abolishing the inhibitory effects of intracellular calcium. Structures of human TRPC6 in complex with two chemically distinct inhibitors bound at different ligand-binding pockets revealed different conformations of the transmembrane domain (Guo et al. 2022). The selective TRPC6 agonist, 3-(3-,4-Dihydro-6,7-dimethoxy-3,3-dimethyl-1-isoquinolinyl)-2H-1-benzopyran-2-one (C20) binds to the extracellular agonist binding site of TRPC6, protects hippocampal mushroom spines from amyloid toxicity in vitro, efficiently recovers synaptic plasticity in 5xFAD brain slices, penetrates the blood-brain barrier and recovers cognitive deficits in 5xFAD mice. Thus, C20 is the novel TRPC6-selective drug suitable to treat synaptic deficiency in Alzheimer's disease-affected hippocampal neurons (Zernov et al. 2022). Paraoxonase 2 (PON2) deficiency reproduces lipid alterations of diabetic and inflammatory glomerular disease while affecting TRPC6 signaling (Hagmann et al. 2022). Capsazepine (CPZ) inhibits TRPC6 conductance and is protective in adriamycin-induced nephropathy and diabetic glomerulopathy (Hagmann et al. 2023). The mammalian TRPC subfamily comprises seven transmembrane proteins (TRPC1-7) forming cation channels in the plasma membrane of mammalian cells. TRPC channels mediate Ca2+ and Na+ influx into cells. Amongst TRPCs, TRPC6 deficiency or increased activity due to gain-of-function mutations has been associated with multiple diseases, such as kidney, pulmonary, and neurological diseases. Indeed, the TRPC6 protein is expressed in various organs and is involved in diverse signalling pathways. The last decade saw a surge in studies concerning the physiological roles of TRPC6 and describing the development of new pharmacological tools modulating TRPC6 activity (Saqib et al. 2023). One defective TRPC6 gene copy is not sufficient to cause focal segmental glomerulosclerosis (FSGS), which is inherited as an autosomal dominant disease. Increased rather than reduced calcium influx through TRPC6 is required for podocyte cell death (Batool et al. 2023). Pharmacological activation of the TRPC6 channel prevents colitis progression (Nishiyama et al. 2024). Steroid-resistant nephrotic syndrome is due to variants of the TRPC6 gene (Zhao et al. 2024). The discovery of TRPC6 in glandular tissues indicates a role in salivary gland function and calcium homeostasis (Carl et al. 2024). Selective knockdown of TRPC6 channels in the ventral tegmental area (VTA) dopaminergic (DA) neurons confers mice with depression-like behavior (Wang et al. 2024). |
Eukaryota | Metazoa, Chordata | TRPC6 of Homo sapiens (Q9Y210) |
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1.A.4.1.6 | Sperm TRP-3 (SPE-41) Ca2+-permeable channel. Translocated from vesicles to the plasma membrane upon sperm activation in a process dependent on the 4TMS SPE-38 protein (8.A.36.1.1) (Singaravelu et al., 2012) during sperm-egg interactions leading to fertilization (Xu et al., 2003). |
Eukaryota | Metazoa, Nematoda | TRP-3 of Caenorhabditis elegans (AAQ22724) |
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1.A.4.1.7 | Short transient receptor channel 5 (TrpC5 or Htrp5) (transports Ca2+ and Sr2+ in the presence of Orai1 and STIM1 (TC# 1.A.52.1.1) (Ma et al., 2008). It is a cold-transducer in the peripheral nervous system (Zimmermann et al., 2011). A small-molecule inhibitor suppresses progressive kidney disease in rats (Zhou et al. 2017). ORAI and TRP, and the transmembrane Ca2+ sensors, stromal interaction molecules (STIMs), are involved in thrombosis and thrombo-inflammation in platelets and immune cells. Disregulated store-operated Ca2+ (SOCE) fluxes in platelets and immune cells are responsible, and the potential of SOCE inhibition as a therapeutic option to prevent or treat arterial thrombosis as well as thrombo-inflammatory disease states such as ischemic stroke have been considered (Mammadova-Bach et al. 2019). The molecular architecture of the Galpha(i)-bound TRPC5 ion channel has been solved (Won et al. 2023). G-protein coupled receptors (GPCRs) and ion channels serve as key molecular switches through which extracellular stimuli are transformed into intracellular effects, and it has long been postulated that ion channels are direct effector molecules of the alpha subunit of G-proteins (Galpha; see TC family 8.A.43). Won et al. 2023 presented cryo-EM structures of the human TRPC5-Galpha(i3) complexes with a 4:4 stoichiometry in lipid nanodiscs. Galpha(i3) binds to the ankyrin repeat edge of TRPC5 ~ 50 Å away from the cell membrane. Electrophysiological analyses showed that Galpha(i3) increases the sensitivity of TRPC5 to phosphatidylinositol 4,5-bisphosphate (PIP(2)), thereby rendering TRPC5 more easily opened in the cell membrane, where the concentration of PIP(2) is physiologically regulated. These observations show that ion channels are one of the direct effector molecules of Galpha proteins triggered by GPCR activation-providing a structural framework for unraveling the crosstalk between two major classes of transmembrane proteins: GPCRs and ion channels (Won et al. 2023). |
Eukaryota | Metazoa, Chordata | TrpC5 of Homo sapiens (Q9UL62) |
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1.A.4.1.8 | TrpL (Trp-like), isoform A (1124 aas). A light-sensitive calcium channel that is required for inositide-mediated Ca2+ entry in the retina during phospholipase C (PLC)-mediated phototransduction (Lan et al. 1998; Chyb et al. 1999). It is required for vision in the dark and in dim light. and binds calmodulin. Trp and TrpL act together in the light response (Bähner et al. 2002). TrpL assembles in vivo as a homo-multimeric channe, not as a hetero-meric channels as reported previously (Katz et al. 2013). Mechanical force activates the light-dependent channels TRP TC# 1.A.4.1.1) and TRPL in excised patches from the rhabdomere of Drosophila photoreceptors (Delgado et al. 2024). |
Eukaryota | Metazoa, Arthropoda | TrpL of Drosophila melanogaster (P48994) |
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1.A.4.1.9 | Trp-1 isoform channel; controls nicotne-dependent behavior (Xiao and Xu 2009). TRPC orthologues TRP-1 and -2 genetically complement the loss of syndecan by suppressing neuronal guidance and locomotory defects related to increases in neuronal calcium levels. The widespread and conserved syndecan-TRPC axis therefore fine tunes cytoskeletal organization and cell behavior (Gopal et al. 2015). |
Eukaryota | Metazoa, Nematoda | Trp-1 of Caenorhabditis elegans |
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1.A.4.10.1 | TRP cation-slective channel homologue of 1177 aas |
Eukaryota | Viridiplantae, Chlorophyta | TRP channel homologue of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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1.A.4.10.2 | TRP channel homologue of 962 aas |
Eukaryota | Ciliophora | TRP channel homologue of Oxytricha trifallax |
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1.A.4.10.3 | TRP channel homologue of 1486 aas |
Eukaryota | Viridiplantae, Chlorophyta | TRP channel homologue of Volvox carteri |
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1.A.4.2.1 | Vanilloid receptor subtype 1 (VR1 or TRPV1) (noxious, heat-sensitive [opens with increasing temperatures; e.g., >42°C]; also sensitive to acidic pH and voltage and inflamation; serves as the receptor for the alkaloid irritant, capsaicin, for resiniferatoxin and for endo-cannabinoids (Murillo-Rodriguez et al. 2017). Resiniferatoxin binds to the capsaicin receptor (TRPV1) near the extracellular side of the S4 transmembrane domain (Chou et al. 2004). It is regulated by bradykinin and prostaglandin E2) (contains a C-terminal region, adjacent to the channel gate, that determines the coupling of stimulus sensing and channel opening) (Garcia-Sanz et al., 2007; Matta and Ahern, 2007). It is activated and sensitized by local anesthetics in sensory neurons (Leffler et al., 2008). A bivalent tarantula toxin activates the capsaicin receptor (TRPV1) by targeting the outer pore domain (Bohlen et al., 2010). Single-channel properties of TRPV1 are modulated by phosphorylation (Studer and McNaughton, 2010). TRPV1 mediates an itch associated response (Kim et al., 2011). The thermosensitive TRP channel pore turret is part of the temperature activation apparatus (Yang et al., 2010). Modular thermal sensors in temperature-gated transient receptor potential (TRP) channels have been identified (Yao et al., 2011). TRPV1 opening is associated with major structural rearrangements in the outer pore, including the pore helix and selectivity filter, as well as pronounced dilation of a hydrophobic constriction at the lower gate, suggesting a dual gating mechanism (Cao et al. 2013). Allosteric coupling between upper and lower gates may account for modulation exhibited by TRPV1 and other TRP channels (Liao et al. 2013). TRPV1 regulates longevity and metabolism by neuropeptides in mice (Riera et al. 2014). The pore of TRPV1 contains the structural elements sufficient for activation by noxious heat (Zhang et al. 2017). In bull sperm, TRPV1 functions in the regulation of motility and the acrosome reaction (Kumar et al. 2019). The dynamics of water in the transmembrane pore of TRPV1 have been studied (Trofimov et al. 2019). TRPV1 - 6 channel subunits do not combine arbitrarily. With the exception of TRPV5 and TRPV6, TRPV channel subunits preferentially assemble into homomeric complexes (Hellwig et al. 2005). TrpV1-gated ion channels have been used as sensors for imaging applications (Zhu et al. 2021). Capsaicin and protons differently modulate the activation kinetics of the mouse TrpV1 channel induced by depolarization (Takahashi et al. 2021). The impact of TRPV1 on cancer pathogenesis and therapy has been reviewed (Li et al. 2021). TRPV1 may be an analgesic target for patients experiencing pain after oral irradiation (Lai et al. 2021). The vanilloid (capsaicin) receptor TRPV1 functions in blood pressure regulation and may be a therapeutic target in hypertension (Szallasi 2023). Chu et al. 2023 elucidated the redox state of C387-C391 mediated long-range allostery of TRPV1, which provided new insights into the activation mechanism of TRPV1. TRPV1 channels are players in the reticulum-mitochondria Ca2+ coupling in a rat cardiomyoblast cell line (Tessier et al. 2023). TRPV1 is a target for recovery from chronic pain, producing analgesic effects after its inhibition. The study of TrpV1 channel antagonists revealed possible drug design purposes (Gianibbi et al. 2024). Galangin improves ethanol-induced gastric mucosal injuryby targetting TrpV1 (Lin et al. 2024). Magnetic fields can activate transient receptor potential vanilloid (TRPV) channels when coupled with ferritin (Hernández-Morales et al. 2024). |
Eukaryota | Metazoa, Chordata | TrpV1 or VR1 of Rattus norvegicus |
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1.A.4.2.10 | TRPV5 epithelial Ca2+ channel (ECaC1) (forms homo- and heterotetrameric channels with TRPV6; requires the S100A10-annexin 2 complex for routing to the plasma membrane) (Hoenderop et al., 2003; van de Graaf et al., 2003). The kidney maintains whole body calcium homoeostasis due to the reabsorption of Ca2+ filtered by the kidney glomerulus. TRPV5 regulates urinary Ca2+ excretion by mediating active Ca2+ reabsorption in the distal convoluted tubule of the kidney. The histidine kinase, nucleoside diphosphate kinase B (NDPK-B), activates TRPV5 channel activity and Ca2+ flux, and this activation requires histidine 711 in the carboxy terminal tail of TRPV5. In addition, the histidine phosphatase, protein histidine phosphatase 1 (PHPT1), inhibits NDPK-B activated TRPV5 (Cai et al. 2014). TRPV5 also transports cadmium (Cd2+). The L530R mutation is associated with recurrent kidney stones (Wang et al. 2017). May be stabilized by Mucin-1 (Muc1; P15941) (Al-Bataineh et al. 2017). TRPV5 inhibitors have been identified (Hughes et al. 2019). A modular and reusable model of epithelial transport in the proximal convoluted tubule of the kidney has appeared (Noroozbabaee et al. 2022). Only TrpV5 and TrpV6 are calcium selective, while others are general for inorganic cations, and an explanatory mechanism has been proposed (Ives et al. 2023). The structural basis for the activation of TRPV5 channels by long-chain acyl-Coenzyme-Ahas been elucidated (Lee et al. 2023). |
Eukaryota | Metazoa, Chordata | TRPV5 of Homo sapiens (NP_062815) |
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1.A.4.2.11 | TRPV6 epithelial Ca2+ channel (ECaC2) (forms homo- and heterotetrameric channels with TRPV5; requires the S100A10-annexin 2 complex for routing to the plasma membrane) (Hoenderop et al., 2003; van de Graaf et al., 2003). Epithelial TrpV6, but not TrpV5, is inhibited by the regulator of G-protein signaling 2 (RGS2; Q9JHX0; 211 aas) by direct binding (Schoeber et al., 2006). Calmodulin (CaM) positively affects TRPV6 activity upon Ca2+ binding to EF-hands 3 and 4, located in the high Ca2+ affinity CaM C-terminus (Lambers et al. 2004). Cyclophilin B is an accessory activating protein (Stumpf et al., 2008). The crystal structure of rat TRPV6 at 3.25 A resolution revealed shared and unique features compared with other TRP channels (Saotome et al. 2016). Intracellular domains engage in extensive interactions to form an intracellular 'skirt' involved in allosteric modulation. In the K+ channel-like transmembrane domain, Ca2+ selectivity is determined by direct coordination of Ca2+ by a ring of aspartate side chains in the selectivity filter (Saotome et al. 2016). Replacing Gly-516 within the cytosolic S4-S5 linker (conserved in all TRP channel proteins) by ser forces the channels into an open conformation, thereby enhancing constitutive Ca2+ entry and preventing inactivation (Hofmann et al. 2016). Tetrameric ion channels have either swapped or non-swapped arrangements of the S1-S4 and pore domains. Singh et al. 2017 showed that mutations in the transmembrane domain can result in conversion from a domain-swapped to the non-swapped fold. These results raise the possibility that a single ion channel subtype can fold into either arrangement in vivo, affecting its function in normal or disease states. Cryo-EM structures of human TRPV6 in the open and closed states shows that the channel selectivity filter adopts similar conformations in both states, consistent with its explicit role in ion permeation. The iris-like channel opening is accompanied by an alpha-to-pi-helical transition in the pore-lining transmembrane helix S6 at an alanine hinge just below the selectivity filter. As a result of this transition, the S6 helices bend and rotate, exposing different residues to the ion channel pore in the open and closed states (McGoldrick et al. 2017). TRPV6 is an epithelial Ca2+-selective channel associated with transient neonatal hyperparathyroidism (TNHP), an autosomal-recessive disease caused by TRPV6 mutations that affect maternal-fetal calcium transport (Suzuki et al. 2018). TRPV6 mediates calcium uptake in epithelia, and its expression increases in numerous types of cancer while inhibitors suppress tumor growth. Singh et al. 2018 presented crystal and cryo-EM structures of human and rat TRPV6 bound to 2-aminoethoxydiphenyl borate (2-APB), a TRPV6 inhibitor and modulator of numerous TRP channels. 2-APB binds to TRPV6 in a pocket formed by the cytoplasmic half of the S1-S4 transmembrane helix bundle. 2-APB induces TRPV6 channel closure by modulating protein-lipid interactions. The 2-APB binding site may be present in other members of vanilloid subfamily TRP channels. The crystal structure has been determined (see 30299652 and Yelshanskaya et al. 2020). Novel mutations in TRPV6 give rise to the spectrum of transient neonatal hyperparathyroidism (Suzuki et al. 2020). TRPV6) plays roles in calcium absorption in epithelia and bone and is involved in human diseases including vitamin-D deficiency, osteoporosis, and cancer. Cai et al. 2020 showed that the TRPV6 intramolecular S4-S5 linker to the C-terminal TRP helix (L/C) and N-terminal pre-S1 helix to TRP helix (N/C) interactions, mediated by Arg470:Trp593 and Trp321:Ile597 bonding, respectively, are autoinhibitory and are required for maintaining TRPV6 at basal states. Disruption of either interaction by mutations or blocking peptides activates TRPV6. The N/C interaction depends on the L/C interaction but not inversely. Three cationic residues in S5 or the C terminus are involved in binding PIP2 to suppress both interactions, thereby activating TRPV6 (Cai et al. 2020). The biochemistry and pathophysiology of TRPV6 calcium channels have been reviewed (Walker and Vuister 2023). The structure of human TRPV6 in complex with the plant-derived phytoestrogen genistein, extracted from Styphnolobium japonicum, inhibits cell invasion and metastasis of cancer cells. Cryo-EM combined with other techniques revealed that genistein binds in the intracellular half of the TRPV6 pore and acts as an ion channel blocker and gating modifier. Genistein binding to the open channel causes pore closure and a two-fold symmetrical conformational rearrangement in the S4-S5 and S6-TRP helix regions (Neuberger et al. 2023). TRPV6 is also inhibited by the phytocannabinoid tetrahydrocannabivarin (Neuberger et al. 2023). |
Eukaryota | Metazoa, Chordata | TRPV6 of Homo sapiens (NP_071858) |
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1.A.4.2.12 | Epithelial calcium channel, ECaC (Liao et al., 2007). | Eukaryota | Metazoa, Chordata | ECaC of Danio rerio (Q6JQN0) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.4.2.13 | TrpV1 of 839 aas and ~ 6 TMSs. Molecular determinants of vanilloid sensitivity have been examined (Gavva et al. 2004). Ligand-activated non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli. TRPV1 channels are present in odontoblasts, suggesting that odontoblasts may directly respond to noxious stimuli such as a thermal-heat stimulus (Okumura et al. 2005). It may mediate proton influx and be involved in intracellular acidosis in nociceptive neurons. It is also involved in mediating inflammatory pain and hyperalgesia (Benemei et al. 2015). The 3.4 Å resolution structure shows that the overall fold is the same as for voltage-gated ion channels (TC# 1.A.1) (Liao et al. 2013). Capsaicin-induced apoptosis in glioma cells is mediated by TRPV1 (Amantini et al. 2007). Capsaicin binds to a pocket formed by the channel's TMSs, where it takes a ""tail-up, head-down"" configuration. Binding is mediated by both hydrogen bonds and van der Waals interactions. Upon binding, capsaicin stabilizes the open state of TRPV1 by ""pull-and-contact"" with the S4-S5 linker (Yang and Zheng 2017). Several protein kinases, including PKD1 (protein kinase D1), Cdk5 (cyclin-dependent kinase 5) and LIMK (LIM- motif containing kinase) regulate TRPV1 and inflammatory thermal hyperalgesia (Zhang and Wang 2017). TrpV1 and TrpA1 are inflammatory mediators causing cutaneous chronic itch in several diseases (Xie and Li 2018). The locations and characteristics of volatile general anesthetic binding sites in the transmembrane domain of TRPV1 have been examined (Jorgensen and Domene 2018). The TRPV1 ion channel is a neuronal sensor that plays an important role in nociception and neuropathic as well as inflammatory pain. In clinical trials, hyperthermia and thermo-hypoaesthesia are major side effects of TRPV1 antagonists (Damann et al. 2020). The TRPV1 ion channel is a polymodal sensor integrating stimuli from molecular modulators with temperature, pH and transmembrane potential. Temperature-dependent gating may constitute the molecular basis for its role in heat sensation and body temperature regulation. Damann et al. 2020 characterized the prototypic small molecule TRPV1 inhibitors GRT12360V and GRTE16523. The oxidizing reagent copper-o-phenanthroline is an open channel blocker of TRPV1 (Tousova et al. 2004). Lack of TRPV1 aggravates obesity-associated hypertension through the disturbance of mitochondrial Ca2+ homeostasis in brown adipose tissue (Li et al. 2022). Lipoic/Capsaicin-related amides are TRPV1 agonists endowed with protective properties against oxidative stress (Brizzi et al. 2022). Agonistic/antagonistic properties of lactones in food flavors on the sensory ion channels, TRPV1 and TRPA1 have been reviewed (Ogawa et al. 2022). TRPV1 channel modulators provide a prospective therapy for diabetic neuropathic pain (Liu et al. 2023). Drosophila appear to possess intricate pain sensitization and modulation mechanisms similar to those in mammals (Jang et al. 2023). Barbamide enhances the effect of the TRPV1 agonist capsaicin and enhanced store-operated calcium entry (SOCE) responses in mice after depletion of intracellular calcium (Hough et al. 2023). The safety and efficacy of topical ocular SAF312 (Libvatrep) in post-photorefractive keratectomy (PRK) pain, an inhibitor of TRPV1, has been evaluated (Thompson et al. 2023). Modulation of membrane trafficking of AQP5 in the lens in response to changes in zonular tension is mediated by TRPV1 (Petrova et al. 2023). The TRPV1 channel, in addition to being associated with pain, plays a role in immune regulation, and their dysregulation frequently affects the development of rheumatoid arthritis (Qu et al. 2023). Irreversible protein unfolding, which is generally thought to be destructive to physiological function, is essential to TRPV1 thermal transduction and, possibly, to other strongly temperature-dependent processes in biology (Mugo et al. 2023). Strong pathogenetic associations of TRPV1 with neurodegenerative diseases (NDs), in particular Alzheimer's disease (AD), Parkinson's disease (PD) and multiple sclerosis (MS) via regulating neuroinflammation have been forthcming. Therapeutic effects of TRPV1 agonists and antagoniststs on the treatment of AD and PD in animal models are emerging. Mugo et al. 2023 summarized the current understanding of TRPV1's effects and its agonists and antagonists as a therapeutic means in neurodegenerative diseases, and highlight future treatment strategies using natural TRPV1 agonists. Increased response in TrpV1(V527M) channels to protons and enhanced sensitization by arachidonic acid metabolite 12-hydroxyeicosatetraenoic acid (12-HETE), two inflammatory mediators released in the cornea after tissue damage, may contribute to the pathogenesis of corneal neuralgia after refractive surgery (Gualdani et al. 2024). TRPV1 alleviates APOE4-dependent microglial antigen presentation and T cell infiltration in Alzheimer's disease (Lu et al. 2024). Indole-2-carboxamide is an effective scaffold for the design of new TRPV1 agonists (Maramai et al. 2025). ST-6631, a novel TRPV1 agonist, ameliorates the swallowing reflex comparable to capsaicin in a dysphagia model (Miyauchi 2024). Licorice extract isoliquiritigenin increases cytosol calcium and induces apoptosis in colon cancer cells via TrpV1 (Wang et al. 2025). |
Eukaryota | Metazoa, Chordata | TrpV1 of Homo sapiens |
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1.A.4.2.14 | Epithelial calcium channel 2, ECaC2; TrpV6 of 719 aas and 6 TMSs. It displays all structural features typical for mammalian ECaCs including three ankyrin repeats, six transmembrane domains, and a putative pore region between TM V and TM VI (Qiu and Hogstrand 2004). |
Eukaryota | Metazoa, Chordata | ECaC2 of Takifugu rubripes (Japanese pufferfish) (Fugu rubripes) |
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1.A.4.2.2 | Stretch-inhibitable non-selective cation channel, SIC |
Eukaryota | Metazoa, Chordata | SIC of Rattus norvegicus |
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1.A.4.2.3 | Vitamin D-responsive, apical, epithelial Ca2+ channel, ECaC |
Eukaryota | Metazoa, Chordata | ECaC of Oryctolagus cuniculus |
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1.A.4.2.4 | Insulin-like growth factor I-regulated Ca2+ channel |
Eukaryota | Metazoa, Chordata | IGF-regulated Ca2+ channel of Mus musculus |
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1.A.4.2.5 | Vanilloid receptor-related, osmotically activated channel, VR-OAC (also called TRPV4, VRL2, VROAC and Trp12); required for bladder voiding in mice (Gevaert et al., 2007). Regulated by Pacsin3 via its SH3 domain which affects its subcellular localization and inhibits its activity in a stimulus-specific fashion (D'hoedt et al., 2008). Responsible for autosomal dominant brachyolmia (Rock et al., 2008). Multiple gating mechanisms have been demonstrated for TRPV4 (Loukin et al., 2010). TRPV4 Ca2+ signalling regulates endothelial vascular function (Sonkusare et al., 2012) and adipose oxidative metabolism, inflammation and energy homeostasis (Ye et al. 2012). H2O2 induces Ca2+ influx into microvascular endothelial cells via TrpV4 (Suresh et al. 2015). TrpV4 orthologs are volume-sensors, rather than osmo-sensors (Toft-Bertelsen et al. 2017) that mediate fluid secretion by the ciliary body. They are important for vertebrate vision by providing nutritive support to the cornea and lens, and by maintaining intraocular pressure (Jo et al. 2016). Interacts with the A-kinase anchor protein 5 (AKAP5 or AKAP79 of 427 aas; TC# 8.A.28.1.6; P24588) (Mack and Fischer 2017). Mutations in TRPV4 are associated with accelerated chondrogenic differentiation of dental pulp stem cells (Nonaka et al. 2019). The homolog in Cynops pyrrhogaster (85% identical) is inhibited by RN1734 and may play a role in the sperm acrosome reaction (Kon et al. 2019). TRPV4 antagonism attenuates aortic inflammation and remodeling via decreased smooth muscle cell activation and neutrophil transendothelial migration (Shannon et al. 2020). It forms a tight complex with CD98hc (TC# 8.A.9.2.2) and beta1 integrin (TC# 9.B.87.1.8) in focal adhesions where mechanochemical conversion takes place. CD98hc knock down inhibits TRPV4-mediated calcium influx induced by mechanical forces, but not by chemical activators, thus confirming the mechanospecificity of this signaling response. Molecular analysis revealed that forces applied to beta1 integrin must be transmitted from its cytoplasmic C-terminus via the CD98hc cytoplasmic tail to the ankyrin repeat domain of TRPV4 in order to produce ultra-rapid, force-induced, channel activation within the focal adhesion (Potla et al. 2020). TRPV4 mutations, resulting in severe gain of function, cause mixed neuropathy and skeletal phenotypes in humans (Taga et al. 2022). Cell swelling, heat, and chemical agonists use distinct pathways for the activation of TRPV4 (Vriens et al. 2004). Human TRPV4 is involved in immune activation, and because of its diverse engagement in the neuronal and immune systems, it is a potential therapeutic target for several immune-related disorders (Acharya et al. 2022). It is one of the major non-selective cation channel proteins that plays a crucial role in sensing biotic and abiotic stresses, such as pathogen infection, temperature, mechanical pressure and osmotic pressure changes by regulating Ca2+ homeostasis (He et al. 2022). The structure of human TRPV4 in complex with GTPase RhoAhas been determined, providing a template for the design of future therapeutics for treatment of TRPV4-related diseases (Nadezhdin et al. 2023). AQP4-independent TRPV4 modulation of plasma membrane water permeability has been documented (Barile et al. 2023). The possibility to tune plasma membrane water permeability more finely through TRPV4 might represent a protective mechanism in cells constantly facing severe osmotic challenges to avoid the potential deleterious effects of the rapid cell swelling occurring via AQP channels (Barile et al. 2023). Hydrophobic gating and bundle-crossing mechanisms co-exist and complement one and another in the human TRPV4 channel. In particular, a single hydrophilic mutation in the lower pore can increase pore hydration and reduce the ion permeation free energy barrier by about half without affecting the bundle crossing (Huang and Chen 2023). TRPV4 plays a role in programmed cell death (Ma et al. 2024). TRPV4 regulates collagen remodeling and could pave the way for new approaches to manage fibrotic lesions (Wang et al. 2024). Inflammation-induced TRPV4 channels exacerbate blood-brain barrier dysfunction in multiple sclerosis (Hansen et al. 2024). TRPV4 may promote hepatitis B virus (HBV) replication and capsid assembly via methylation modification (Zhang et al. 2024). Calcium-activated potassium channels function as amplifiers of TRPV4-mediated pulmonary edema formation in male mice (Li et al. 2024). The human ortholog is 95% identical, and TRPV4 in human corneal epithelial cells, stabilizes the tear film, enhances natural cytokine communication, and suppresses detrimental immune responses (Harrell and Volarevic 2024), A deficiency of endothelial TRPV4 cation channels ameliorates experimental abdominal aortic aneurysm (Qian et al. 2025). Combined clinical, structural and cellular studies discriminated pathogenic and benign TRPV4 variants (Berth et al. 2025).
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Eukaryota | Metazoa, Chordata | VR-OAC (TrpV4) of Rattus norvegicus |
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1.A.4.2.6 | Osmosensitive transient receptor potential channel 3, O-TRP3 | Eukaryota | Metazoa, Chordata | O-TRP3 of Mus musculus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.4.2.7 | Intestinal endocyte Ca2+ (Sr2+; Ba2+) entry channel, CaT1. Excision of the Trpv6 gene leads to severe defects in epididymal Ca2+ absorption and male fertility as does the single D541A pore mutation (Weissgerber et al., 2012). |
Eukaryota | Metazoa, Chordata | CaT1 of Rattus norvegicus |
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1.A.4.2.8 | The noxious heat (>52°C)-sensitive vanilloid-like receptor cation selective channel, TRPV2. Ca2+-dependent desensitization of TRPV2 channels is mediated by hydrolysis of phosphatidylinositol 4,5-bisphosphate (Mercado et al., 2010). Deleting the first N-terminal 74 residues preceding the ankyrin repeat domain (ARD) shows a key role for this region in targeting the protein to the membrane. Co-translational insertion of the membrane-embedded region occurs with the TM1-TM4 and TM5-TM6 regions assembling as independent folding domains. ARD is not required for TM domain insertion into the membrane (Doñate-Macian et al. 2015). The TRPV2 structure has been solved at 4 Å resolution by cryoEM (Zubcevic et al. 2016). Formation of a physical complex between mouse TRPV2 (GRC) and the mouse RGA protein promotes cell surface expression of TRPV2 (Stokes et al. 2005). The role of Ca2+ infllux via TRPV1 in cell death and survival related to cancer has been evaluated (Zhai et al. 2020). A helix-turn-helix motif for high temperature dependence of TRPV2 has been identified (Liu and Qin 2021). As noted above, TRPV2 is a ligand-operated temperature sensor. Zhang et al. 2022 combined calcium imaging and patch-clamp electrophysiology with cryo-EM to explore how TRPV2 activity is modulated by the phytocannabinoid Δ9-tetrahydrocannabiorcol (C16) and by probenecid. C16 and probenecid act in concert to stimulate TRPV2 responses including histamine release from mast cells. Each ligand causes distinct conformational changes in TRPV2. Although the binding for probenecid remains elusive, C16 associates within the vanilloid pocket. As such, the C16 binding location is distinct from that of cannabidiol, partially overlapping with the binding site of the TRPV2 inhibitor piperlongumine (Zhang et al. 2022). The cation-permeable TRPV2 channel is important for cardiac and immune cell function (Gochman et al. 2023). Cannabidiol (CBD), a non-psychoactive cannabinoid of clinical relevance, is one of the few molecules known to activate TRPV2. Using the patch-clamp technique, Gochman et al. 2023 discovered that CBD can sensitize current responses of the rat TRPV2 channel to the synthetic agonist 2-aminoethoxydiphenyl borate (2-APB) by over two orders of magnitude, without sensitizing channels to activation by moderate (40°C) heat. Using cryo-EM, Gochman et al. 2023 uncovered a new small-molecule binding site in the pore domain of rTRPV2 in addition to a nearby CBD site. Intrinsically disordered regions in TRPV2 mediate protein-protein interactions (Sanganna Gari et al. 2023). Sitagliptin eye drops prevent the impairment of retinal neurovascular unit in a Trpv2+/- rat model (Ramos et al. 2024). Plumbagin is a novel TRPV2 inhibitor that ameliorates microglia activation and brain injury (Ding et al. 2025). |
Eukaryota | Metazoa, Chordata | TRPV2 of Homo sapiens |
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1.A.4.2.9 | The temperature (heat; >39°C)-sensitive, capsaicin-insensitive receptor cation-selective channel, TRPV3 or TRL3 (may form heterooligomers with VR1 (TRPV1; TC #1.A.4.2.1)). Incensole acetate, an incense component, elicits psychoactivity by activating TRPV3 channels in the brain (Moussaieff et al., 2008). TRPV3 is activated by synthetic small-molecule chemicals and natural compounds from plants as well as warm temperatures. Its function is regulated by a variety of physiological factors including extracellular divalent cations and acidic pH, intracellular ATP, membrane voltage, and arachidonic acid. It shows a broad expression pattern in both neuronal and non-neuronal tissues including epidermal keratinocytes, epithelial cells in the gut, endothelial cells in blood vessels, and neurons in dorsal root ganglia and the CNS. TRPV3 null mice exhibit abnormal hair morphogenesis and compromised skin barrier function, and it may play critical roles in inflammatory skin disorders, itch, and pain sensation (Luo and Hu 2014). TRPV3 gating involves large rearrangements at the cytoplasmic inter-protomer interface, and this motion triggers coupling between cytoplasmic and transmembrane domains, priming the channel for opening (Zubcevic et al. 2019). Mutations in TRPV3 cause painful focal plantar keratoderma (Peters et al. 2020). TRPV3 is a temperature-sensitive, nonselective cation channel expressed prominently in skin keratinocytes that plays important roles in hair morphogenesis and maintenance of epidermal barrier function. Mechanisms of proton inhibition and sensitization have been discussed (Wang et al. 2021). Mechanisms of proton inhibition and sensitization of TRPV3 have been considered (Wang et al. 2021). TRPV3 is predominantly expressed in skin keratinocytes and has been implicated in cutaneous sensation and associated with numerous skin pathologies and cancers. TRPV3 is inhibited by the natural coumarin derivative osthole, an active ingredient of Cnidium monnieri, which has been used in traditional Chinese medicine for the treatment of various human diseases. Neuberger et al. 2021 presented cryo-EM structures of TRPV3 in complex with osthole, revealing two types of osthole binding sites in the transmembrane region of TRPV3 that coincide with the binding sites of agonist 2-APB. Osthole binding converts the channel pore into a previously unidentified conformation with a widely open selectivity filter and closed intracellular gate. The structures provide insight into competitive inhibition of TRPV3 by osthole (Neuberger et al. 2021). Scutellarein attenuates atopic dermatitis by selectively inhibiting TRP Vanilloid 3 (Wang et al. 2022). TRPV3 involvement in itching, heat pain, hair development, and TRPV3-related skin diseases has been reviewed (Guo et al. 2023). Temperature-sensitive contact modes allosterically gate TRPV3 (Burns et al. 2023). More than 210 structures from more than 20 different TRP channels have been determined, and all are tetramers. TrpV3 exhibits the pore-dilation phenomenon, whereby prolonged activation leads to increased conductance, permeability to large ions and loss of rectification (Lansky et al. 2023). TRPV3 can exist in a pentameric state which is in dynamic equilibrium with the canonical tetramer through membrane diffusive protomer exchange. The pentamer population increased upon diphenylboronic anhydride (DPBA) addition, an agonist that has been shown to induce TRPV3 pore dilation with a larger pore size (Lansky et al. 2023). TRPV3 is a candidate gene for the suri phenotype in the alpaca (Pallotti et al. 2024). Insights into thermosensation, channel modulation, and skin homeostasis involving TRPV3 have been reported (Lei and Tominaga 2024). |
Eukaryota | Metazoa, Chordata | TRPV3 of Homo sapiens |
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1.A.4.3.1 | Olfactory, mechanosensitive channel. Forms a complex with Stim1 and Orai1 (TC# 1.A.52.1.1) which is required for SOC currents (Cheng et al., 2008) (most similar to 1.A.4.8.1, but both are most closely related to 1.A.4.2). Serves as a chemo-, osmo- and touch sensation receptor (Xiao and Xu 2009). |
Eukaryota | Metazoa, Nematoda | Olfactory channel of Caenorhabditis elegans |
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1.A.4.3.2 | The Nanchung (Nan) hearing ion channel; mediates hypo-osmotically activated Ca2+ influx in chordotonal neurons of insects (Kim et al., 2003). Nanchung is the "dry" humidity receptor, one of two hygrosensation receptors. These two transient receptor potential channels are needed for sensing humidity. The other is Water witch (Wtrw), involved in detecting moist air. Neurons associated with specialized sensory hairs in the third segment of the antenna express these channels, and neurons expressing Wtrw and Nan project to central nervous system regions associated with mechanosensation. Construction of the hygrosensing system with opposing receptors may allow an organism to very sensitively detect changes in environmental humidity (Liu et al. 2007). Two commercial insecticides, pymetrozine and pyrifluquinazon, target the heteromeric TRPV ion channel complex which is specifically expressed in the chordotonal organ neurons in Drosophila species and may play roles in male-specific behavior (Mao et al. 2018). |
Eukaryota | Metazoa, Arthropoda | Nan of Drosophila melanogaster (833 aas; Q9VUD5) |
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1.A.4.3.3 | TrpV-type Osm-2 (OSM2) chemo-, osmo- and touch sensation receptor channel (Xiao and Xu 2009). It is also called OCR-2. To survive, C. elegans depends on sensing soluble chemicals with transmembrane proteins (TPs) in the cilia of its chemosensory neurons. Cilia rely on intraflagellar transport (IFT) to facilitate the distribution of cargo, such as TPs, along the ciliary axoneme (van Krugten et al. 2022). IFT and diffusion in ciliary dynamics contribute to ciliary signal transduction and chemosensing. |
Eukaryota | Metazoa, Nematoda | Osm-2 of Caenorhabditis elegans |
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1.A.4.3.4 | TRP channel homologue of 1240 aas |
Eukaryota | TRP channel homologue of Ectocarpus siliculosus |
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1.A.4.3.5 | TRP channel homologue of 1724 aas |
Eukaryota | TRP channel homologue of Ectocarpus siliculosus (Brown alga) |
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1.A.4.3.6 | INACTIVE of 1123 aas and 6 probable TMSs between residues 380 and 660. The sensory ciliary function underlying hearing in the adult fly requires an active maintenance program which involves DmIFT88 and at least two of its signalling transmembrane cargoes, DmGucy2d and Inactive. |
Eukaryota | Metazoa, Arthropoda | Inactive of Drosophila melanogaster (fruit fly) |
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1.A.4.4.1 | Vacuolar, voltage-dependent cation-selective, Ca2+-activated channel, YVC1. (Yeast vacuolar conductance protein 1; also called TrpY1; Yor088w) (Chang et al., 2009). Activated by stretch to release vacuolar Ca2+ into the cytoplasm upon osmotic upshock (Zhou et al. 2005). (Also activated by glucose, indole and other aromatic compounds (Haynes et al., 2008; Groppi et al. 2011)). Glutathione activates by reversible glutathionylation of specific cysteyl residues in YVC1 (Chandel et al. 2016). Channel activity is activated by cytoplasmic Ca2+ and inhibited by vacuolar lumen Ca2+, and two residues, D401 and D405, are involved in Ca2+ sensing in the lumen (Amini et al. 2018). The cryoEM structure of TRPY1 at 3.1 Å resolution in a closed state has been determined (Ahmed et al. 2021). The structure, despite containing an evolutionarily conserved and archetypical transmembrane domain, reveals distinctive structural folds for the cytosolic N and C termini compared with other eukaryotic TRP channels. An inhibitory phosphatidylinositol 3-phosphate (PI(3)P) lipid-binding site, along with two Ca2+-binding sites were identified: a cytosolic site, implicated in channel activation, and a vacuolar lumen site, implicated in inhibition. TRPY1 channel modulation by lipids and Ca2+ have been revealed, and the molecular evolution of TRP channels has been suggested (Ahmed et al. 2021). |
Eukaryota | Fungi, Ascomycota | YVC1 or TrpY1 (Yor088w) of Saccharomyces cerevisiae (Q12324) |
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1.A.4.4.2 | Yvc1 or TrpY2 of 678 aas and 9 apparent TMSs. It has the same mechanosenstivity as does the S. cereviseae ortholog (Zhou et al. 2005). 45% identical to the latter protein. |
Eukaryota | Fungi, Ascomycota | Yvc1 of Kluyveromyces lactis |
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1.A.4.4.3 | Yvc-1, Yvc1 or TrpY3 of 676 aas and 9 apparent TMSs. It has the same mechanosensitive properties of the S. cerevisiae ortholog with TC# 1.A.4.4.1 (Zhou et al. 2005). 57% identical to the latter protein. |
Eukaryota | Fungi, Ascomycota | TrpY3 of Candida albicans |
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1.A.4.5.1 | Mg2+-selective channel/kinase-1; Mg2+-ATP-regulated divalent cation channel, LTRPC7, TRPM7, or TRP-PLIK, of 1862 aas. Bradykinin regulates TRPM7 and its downstream target annexin-1 through a phospholipase C-dependent, protein kinase C-dependent and c-Src-dependent pathway that is cAMP-independent; effects are mediated through the bradykinin type 2 receptor (Callera et al. 2009). TRPM7 is a Mg2+ sensor and transducer of signaling pathways during stressful environmental conditions. Its kinase can act on its own in chromatin remodeling processes, but TRPM6's kinase activity regulates intracellular trafficking of TRPM7 and TRPM7-dependent cell growth (Cabezas-Bratesco et al. 2015). Syndecans (proteoglycans) regulate TRPC channels to control cytosolic calcium equilibria and consequent cell behavior. In fibroblasts, ligand interactions with heparan sulfate of syndecan-4 recruit cytoplasmic protein kinase C to target serine714 of TRPC7 with subsequent control of the cytoskeleton and the myofibroblast phenotype (Gopal et al. 2015). May be associated with melanocytic tumors. Phenanthrenes, naltriben derivatives, are stimulatory agonist of the TRPM7 channel (Liu et al. 2016). TRP7 ion channels regulate magnesium homeostasis in vascular smooth muscle cells, and its activity is positively regulated by aldosterone and angiotensin II (He et al. 2005). TRPM7 plays an important role in cellular Ca2+, Zn2+ and Mg2+ homeostasis. The protein is abundantly expressed in ameloblasts and, in the absence of TRPM7, dental enamel is hypomineralized. A role of TRPM7 channels in Ca2+ transport during amelogenesis is likely as it serves both as a modulator of Orai-dependent Ca2+ uptake and as an independent Ca2+ entry pathway, sensitive to pH (Kádár et al. 2021). Recurrent hemiplegic migraine attacks are accompanied by intractable hypomagnesemia due to a de novo TRPM7 gene variant (Lei et al. 2022). TrpM6 is palmitoylated on the C terminal side of its Trp domain, and palmitoylation controls ion channel activity of TrpM7; TrpM7 trafficking is also dependant on its palmitoylation (Gao et al. 2022). The TRPM7-A931T mutation, located in the S3 segment at the interface with the transmembrane region S4, generates an omega current that carries Na+ influx under physiological conditions. A931T produces hyperexcitability and a sustained Na+ influx in trigeminal ganglion neurons that may underlie pain in this kindred with trigeminal neuralgia (Gualdani et al. 2022). In addition to ion homeostasis, TrpM7 functions in hypomagnesemia, mitochondrial activities, and inflammation (Liu and Dudley 2023). TRPM7 regulates glioma cells' stemness through STAT3. Guo et al. 2023 showed that FOSL1 (271 aas) a cytoplasmic protein with Uniprot acc# P15407) is a response gene for TRPM7 and serves as an oncogene to promote glioma proliferation and invasion. They also showed that TRPM7 transactivates the FOSL1 gene through STAT3 and enhances glioma stemness (Guo et al. 2023). Expression profiling has identified TRPM7 and HER2 as potential targets for the combined treatment of cancer cells (Egawa et al. 2024). Knockdown of circ-Gatad1 alleviates LPS induced HK2 cell injury via targeting miR-22-3p/TRPM7 axis in septic acute kidney (Zhang et al. 2024).
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Eukaryota | Metazoa, Chordata | Channel-kinase-1 (LTRPC7 or TRPM7) of Homo sapiens |
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1.A.4.5.10 | TrpCC family member, Gon2. Required for initiation and continuation of postembryonic mitotic cell division of gonadal cells Z1 and Z4. Zygotic expression is necessary for hermaphrodite fertility. Probably a cation channel that functions together with Gem1 (TC#2.A.1.13.22) (Kemp et al. 2009). |
Eukaryota | Metazoa, Nematoda | Gon-2 of Caenorhabditis elegans |
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1.A.4.5.12 | TrpM4 of 1213 aas and 6 TMSs. Calcium-activated non selective cation channel that mediates membrane depolarization. While it is activated by increases in intracellular Ca2+, it is impermeable to it. It does mediate transport of monovalent cations (Na+ > K+ > Cs+ > Li+), leading to depolarize the membrane. It thereby plays a central role in the function of cardiomyocytes, neurons from entorhinal cortex, dorsal root and vomeronasal neurons, endocrine pancreas cells, kidney epithelial cells, cochlea hair cells etc. It also participates in T-cell activation by modulating Ca2+ oscillations after T lymphocyte activation (Demion et al. 2007). The structure has been determined by cryo EM both with and without ATP (Guo et al. 2017). It consists of multiple transmembrane and cytosolic domains, which assemble into a three-tiered architecture. The N-terminal nucleotide-binding domain and the C-terminal coiled-coil participate in the tetrameric assembly of the channel; ATP binds at the nucleotide-binding domain to inhibit channel activity. TRPM4 has an exceptionally wide filter although it is only permeable to monovalent cations; filter residue Gln973 is essential in defining monovalent selectivity. The S1-S4 domain and the post-S6 TRP domain form the central gating apparatus that probably houses the Ca2+- and PtdIns(4,5)P2-binding sites (Guo et al. 2017). TRPM4 currents are activated by micromolar concentrations of cytoplasmic Ca2+and progressively desensitized. Zhang et al. 2005 showed that desensitization can be explained by a loss of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) from the channels. TrpM4 interacts directly with glutamate N-methyl-D-aspartate receptor channels (NMDARs) to promote excitotoxicity. Small-molecule interface inhibitors prevent NMDAR-TRPM4 physical coupling and eliminate excitotoxicity. They are therefore neuroprotectants (Yan et al. 2020). Knockdown of the TRPM4 channel alters cardiac electrophysiology and hemodynamics in a sex- and age-dependent manner in mice (Arullampalam et al. 2023). |
Eukaryota | Metazoa, Chordata | TRPM4 of Mus musculus |
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1.A.4.5.13 | TRPM8 of the collared flycatcher of 1103 aas. It is 83% identical to the human ortholog. Its structure has been determined to ~4.1 Å resolution by cryo EM (Yin et al. 2018). The structure reveals a three-layered architecture. The amino-terminal domain with a fold distinct among known TRP structures, together with the carboxyl-terminal region, forms a large two-layered cytosolic ring that extensively interacts with the transmembrane channel layer. The structure suggests that the menthol-binding site is located within the voltage-sensor-like domain and thus provides a structural glimpse of the design principle of the molecular transducer for cold and menthol sensation (Yin et al. 2018). TrpM8 is the primary cold and menthol receptor in humans. The structure has been solved for the collared flycatcher at 4.1 Å resolution (6BPQ_A - D (Yin et al. 2017). Transient receptor potential cation channel subfamily M member 8, TrpM8, the primary cold and menthol receptor in humans. The structure has been solved for the collared flycatcher TrpM8 at 4.1 Å resolution (6BPQ_A - D (Yin et al. 2017). Transient receptor potential cation channel subfamily M member 8, TrpM8 is the primary cold and menthol receptor in humans. The structure has been solved for the collared flycatcher at 4.1 Å resolution (6BPQ_A - D (Yin et al. 2017). Cold thermoreceptor neurons detect temperature drops with highly sensitive molecular machinery concentrated in their peripheral free nerve endings. The main molecular entity responsible for cold transduction in these neurons is the thermo-TRP channel TRPM8. Cold, cooling compounds such as menthol, voltage, and osmolality rises activate this polymodal ion channel. Dysregulation of TRPM8 activity underlies several physiopathological conditions, including painful cold hypersensitivity in response to axonal damage, migraine, dry-eye disease, an overactive bladder, and several forms of cancer. TRPM8 could be an attractive target for treating these highly prevalent diseases. Different mutagenesis approaches have allowed the identification of specific amino acids in the cavity comprised of the S1-S4 and TRP domains that determine modulation by chemical ligands (Pertusa et al. 2023). Different studies revealing specific regions within the N- and C-termini and the transmembrane domain contribute to cold-dependent TRPM8 gating. Pertusa et al. 2023 highlight the milestones in the field: cryo-EM structures of TRPM8 that have provided a better comprehension of the 21 years of research on this ion channel, shedding light on the molecular bases underlying its modulation, and promoting the future rational design of novel drugs to selectively regulate abnormal TRPM8 activity under pathophysiological conditions (Pertusa et al. 2023). |
Eukaryota | Metazoa, Chordata | TRPM8 of Ficedula albicollis (Collared flycatcher) (Muscicapa albicollis) |
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1.A.4.5.14 | TrpM5 of 1165 aas and 8 - 10 TMSs. cryo-EM structures have been solved in an apo closed state, a Ca2+-bound open state, and an antagonist-bound inhibited state. Ruan et al. 2021 defined two novel ligand binding sites: a Ca2+ site (CaICD) in the intracellular domain and an antagonist site in the transmembrane domain (TMD). The CaICD site is unique to TRPM5 and has two roles: modulating the voltage dependence and promoting Ca2+ binding to the CaTMD site, which is conserved throughout TRPM channels. Conformational changes initialized from both Ca2+ sites cooperatively open the ion-conducting pore. The antagonist NDNA wedges into the space between the S1-S4 domain and the pore domain, stabilizing the transmembrane domain in an apo-like closed state (Ruan et al. 2021). It and phospholipase C-β2 colocalize in taste receptor cells (Yoshida et al. 2007). |
Eukaryota | Metazoa, Chordata | TrpM45 of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.A.4.5.2 | Melastatin 1 or transient receptor potential melastatin-1 (TRPM1; LTRPC1, MLSN, MLSN1) (a non-selective, Ca2+-permeable cation channel, implicated in cell death (Wilkinson et al., 2008). Required for dim light vision. Purified TRPM1 is mostly dimeric. The three-dimensional structure of TRPM1 dimers is characterized by a small putative transmembrane domain and a larger domain with a hollow cavity (Agosto et al. 2014). Since dimers are not likely to be functional ion channels, the authors suggested that additional partner subunits participate in forming the transduction channel required for dim light vision and the ON pathway. The N-terminal region of TRPM1 (residues L242 to E344) regulates activity by direct interaction by the S100A1 calcium-binding protein (TC# 8.A.81) (Jirku et al. 2016). TRPM1 is required for synaptic transmission between photoreceptors and the ON subtype of bipolar cells (Agosto et al. 2018). Abnormal levels occur in plasma neuron-derived extracellular vesicles of early schizophrenia and other neurodevelopmental diseases (Goetzl et al. 2022). |
Eukaryota | Metazoa, Chordata | Melastatin 1 of Homo sapiens |
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1.A.4.5.3 | MLSN1- and TRP-related MTR1 (TrpM5; LTRPC5) of 1165 aas and 6 TMSs. Associated with the Beckman-Wiedemann Syndrum and causes a predisposition for neoplasia (Prawitt et al. 2000). Involved in taste to bitter, sweet and umami, but not absolutely required for these. Thus, TrpM5-dependent and TrpM5-independent pathways underlie bitter, sweet, and umami tastes (Damak et al. 2006). It plays a role in insulin secretion. It and phospholipase C-β2 colocalize in taste receptor cells of zebrafish (Yoshida et al. 2007). It is a voltage-modulated, Ca2+-activated, monovalent cation (Na+, K+, Cs+) channel (VCAM) that mediates transient membrane depolarization. It is blocked by extracellular acidification but activated by arachidonic acid (Prawitt et al. 2003). The cryoEM structure of TrpM5 in Zebrafish is known (See TC# 1.A.4.5.14). |
Eukaryota | Metazoa, Chordata | MTR1 of Homo sapiens |
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1.A.4.5.4 | Intracellular Ca2+-activated nonselective monovalent cation (Na+ and K+) channel (non-permeable to Ca2+), TRPM4b, involved in inherited cardiac arrhythmia syndromes (Amarouch and El Hilaly 2020). It interacts with the TRPC3 channel and suppresses store-operated Ca+ entry (Park et al., 2008). Contributes to the mammalian atrial action potential (Simard et al. 2013). TRPM4 is widely expressed and is associated with a variety of cardiovascular disorders. Autzen et al. 2018 presented two structures of full-length human TRPM4 embedded in lipid nanodiscs at ~3-angstrom resolution, as determined by single-particle cryo-electron microscopy. These structures, with and without calcium bound, reveal the general architecture for this major subfamily of TRP channels and a well-defined calcium-binding site within the intracellular side of the S1-S4 domain. The structures correspond to two distinct closed states. Calcium binding induces conformational changes that likely prime the channel for voltage-dependent opening (Autzen et al. 2018). TRPM4 functions as a limiting factor for antigen evoked calcium rise in connective tissue type mast cells, and concurrent translocation of TRPM4 into the plasma membrane is part of this mechanism (Rixecker et al. 2016). Gain-of-function mutations in the TRPM4 activation gate caused progressive symmetric erythrokeratoderma (Wang et al. 2018). Substitution of the 4 residue motif, EPGF, with other amino acids reduced cation binding affinity. Analysis of the human TRPM4 structure indicated that EPGF is located externally to the channel pore (Wei et al. 2022). |
Eukaryota | Metazoa, Chordata | TRPM4b of Homo sapiens |
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1.A.4.5.5 | ADP-ribose/NAD/pyrimidine nucleotide-gated Ca2+ permeable, cation nonselective, long transient receptor potential channel-2, LTRPC2; Melastatin 2; TRPM2 (ATP inhibitable). The 3-D structure resembles a swollen bell shaped structure (Maruyama et al., 2007). It can be converted to an anion-selective channel by introducing a lysyl residue in TMS 6 (Kuhn et al., 2007). It transports Ca2+ and Mg2+ with equal facility (Xia et al., 2008). Four Ca2+ ions activate TRPM2 channels by binding in deep crevices near the pore but intracellularly of the gate (Csanády and Törocsik, 2009). Protons also regulate activity (Starkus et al., 2010). It is present in the plasma membrane and lysosomes, and plays a role in ROS-induced inflammatory processes and cell death. Melastatin is required for innate immunity against Listeria monocytogenes (Knowles et al., 2011). It functions in pathogen-evoked phagocyte activation, postischemic neuronal apoptosis, and glucose-evoked insulin secretion, by linking these cellular responses to oxidative stress (Tóth and Csanády, 2012). Pore collapse upon prolonged stimulation underlies irreversible inactivation (Tóth and Csanády 2012). TRPM2 is preferentially expressed in cells of the myeloid lineage and modulates signaling pathways converging into NF-kB but does not seem to play a major role in myeloid leukemogenesis. Its loss does not augment the cytotoxicity of standard AML chemotherapeutic agents (Haladyna et al. 2016). TrpM2, expressed in hypothalamic neurons in the brain is a thermosensitive, redox-sensitive channel, required for thermoregulation. It regulates body temperature, limiting fever and driving hypothermia (Song et al. 2016). Tseng et al. 2016 suggested a mechanistic link between TRPM2-mediated Ca2+ influx and p47 phox signaling to induce excess ROS production and TXNIP-mediated NLRP3 inflammasome activation under high gllucose in Type 2 diabetes Mellitus. The cryoEM strcuture reveals a C-terminal NUDT9 homology (NUDT9H) domain responsible for binding ADP-ribose(ADPR) (Wang et al. 2018). Both ADPR and Ca2+ are required for TRPM2 activation, and structures with ADPR and Ca2+ show both intra- and inter-subunit interactions with the N-terminal TRPM homology region (MHR1/2/3) in the apo state, but undergoing conformational changes upon ADPR binding, resulting in rotation of MHR1/2 and disruption of the inter-subunit interaction. Ca2+ binding further engages transmembrane helices and the conserved TRP helix to cause conformational changes at the MHR arm and the lower gating pore to potentiate channel opening (Wang et al. 2018). Consecutive structural rearrangements and channel activation are induced by binding of ADPR in two indispensable locations, and the binding of Ca2+ in the transmembrane domain (Huang et al. 2019). An N-terminal TRPC2 splice variant of 213 aas inhibits calcium influx (Chu et al. 2005). An antogonists of channel function has been identified (Cruz-Torres et al. 2020). A point mutant of TrpM2 (rs93315) has been identified as a risk factor for bipolar disorder (Mahmuda et al. 2020). Two gates orchestrate the opening of human TRPM2 (Rish et al. 2022). Protein kinase C (PKC)-mediated phosphorylation of TRPM2 Thr738 counteracts the effect of cytosolic Ca2+ and elevates the temperature threshold (Kashio et al. 2022). Citronellal suppresses the expression of NHE1 and TPRM2, alleviates oxidative stress-induced mitochondrial damage, and imposes a protective effect on endothelial dysfunction in type 2 diabetes mellitus rats (Yin et al. 2022). Key residues, E829 and R845, are involved in TRPM2 channel gating (Luo et al. 2022). TRPM2 is a prognostic factor correlated with immune infiltration in ovarian cancer (Huang et al. 2023). The TRPM2 ion channel regulates metabolic and thermogenic adaptations in adipose tissue of cold-exposed mice (Benzi et al. 2023). |
Eukaryota | Metazoa, Chordata | LTRPC2 of Homo sapiens |
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1.A.4.5.6 | Transient receptor potential cation channel subfamily, member 3, TRPM3. It is subject to muscarinic receptor activation. An alternative ion permeation pathway in TRPM3 allows large inward currents upon hyperpolarization, independently of the central pore. Four residues in S4 (W982, R985, D988 and G991) are determinants of the properties of the alternative ion permeation pathway (Held et al. 2018). TRPM3 is a thermosensitive TRP channel, playing a central role in noxious heat sensation. Volitile anesthetics (VAs) inhibit TRPM3-mediated transmembrane currents. Chloroform, halothane, isoflurane and sevoflurane inhibited both the agonist-induced (pregnenolone sulfate, CIM0216) and heat-activated Ca2+ signals and transmembrane currents in a concentration dependent way in cells overexpressing recombinant TRPM3 (Kelemen et al. 2020). Among the tested VAs, halothane was the most potent blocker (IC50=0.52+/-0.05 mM). VAs exerted their effects on native TRPM3 channels expressed in sensory neurons of the dorsal root ganglia. While volatile anesthetics activate certain sensory neurons independently of TRPM3, they strongly and reversibly inhibit the agonist-induced TRPM3 activity (Kelemen et al. 2020). |
Eukaryota | Metazoa, Chordata | TrpM3 of Homo sapiens (Q9HCF6) |
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1.A.4.5.7 | Cold-sensitive (opens with decreasing temperatures; e.g., <22°C) and menthol-sensitive cation-selective channel, transient receptor potential melastatin 8 (TRPM8). TRPM8 is activated by low temperatures and cooling agents such as menthol. It underlies the cold-induced excitation of sensory neurons. Its gating is regulated by voltage and lysophospholipids which induce prolonged channel opening (Vanden Abeele et al., 2006; Bautista et al., 2007; Matta and Ahern, 2007). It can be converted to an anion-selective channel by introducing a lysyl residue in TMS 6 (Kuhn et al., 2007). Gating of TRPM8 channels is activated by cold and chemical agonists in planar lipid bilayers (Zakharian et al., 2010). Residues involved in intra- and intersubunit interactions have been identified, and their link with
channel activity, sensitivity to icilin, menthol and cold, and their impact on channel oligomerization have been measured (Bidaux et al. 2015). Targeting the small isoform of TRPM8 may be useful to fight prostate cancer (Bidaux et al. 2016). The human isoform is 83% identical to the TRPM8 of the collared flycatcher (TC# 1.A.4.5.13), the structure of which has been characterized to 4.1 Å resolution (Yin et al. 2018). Activation of TRPM8 by cooling compounds relies on allosteric actions of
agonist and the membrane lipid, phosphatidylinositol 4,5-bisphosphate (PIP2). The cryoEM structures of TRPM8 in complex with the
synthetic cooling compound icilin, PIP2, and Ca2+, as well as in complex with the menthol analog WS-12 and PIP2 revealed the binding sites for cooling agonists and PIP2 in TRPM8. PIP2 binds to TRPM8 in two different modes, which illustrate the mechanism of allosteric coupling between PIP2 and agonists. |
Eukaryota | Metazoa, Chordata | TRPM8 of Homo sapiens |
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1.A.4.5.8 | The intestinal/renal Mg2+ absorption Mg2+ influx channel, Melastatin6 or TRPM6 (5x higher affinity for Mg2+ than Ca2+; regulated by internal Mg2+) (Voets et al., 2004). TRPM6 and its closest homologue TRPM7 (also a Mg2+-permeable cation channel) assemble to form a functional heterooligomeric channel (Chubanov et al., 2004). Mutations in TRPM6 promotes hypomagnesemia with secondary hypocalcemia (Chubanov et al., 2007). TRPM6 and the closely related TRPM7 are large channel-kinase proteins (Li et al., 2007; Schmitz et al., 2007). TRPM7 also transports protons competitively with Mg2+ and Ca2+ (Numata and Okada, 2008). Intracellular ATP regulates TRPM6 channel activity via its α-kinase domain independently of α-kinase activity (Thébault et al., 2008). Also plays a role in Zn2+ homeostasis and Zn2+- mediated neuronal injury (Inoue et al., 2010). The protein is cleaved to release a chromatin-modifying kinase (Krapivinsky et al. 2014). TRPM7 is a Mg2+ sensor and transducer of signaling pathways under stressful environmental conditions. Its kinase can act on its own in chromatin remodeling processes, but TRPM6's kinase activity regulates intracellular trafficking of TRPM7 and TRPM7-dependent cell growth (Cabezas-Bratesco et al. 2015). Residues involved in cation selectivity have been identified (Topala et al. 2007); reviewed by Schäffers et al. 2018. Calmodulin (CaM) and S100A1 share the same binding domain at the TRPM6 N-terminus although the ligand-binding mechanisms may be different (Zouharova et al. 2019). TRPM7 activation potentiates store-operated Ca2+ entry (SOCE) in enamel cells but requires ORAI (Souza Bomfim et al. 2020). TRPM7 is a cation channel that regulates transmembrane Mg2+ and Ca2+ and is involved in a variety of (patho)physiological processes in the cardiovascular system, contributing to hypertension, cardiac fibrosis, inflammation, and atrial arrhythmias (Liu et al. 2023). TRPM7 is a master regulator of the organismal balance of divalent cations that plays an essential role in embryonic development, immune responses, cell mobility, proliferation, and differentiation. It is implicated in neuronal and cardiovascular disorders, tumor progression and is a drug target. Cryo-EM, functional analysis, and molecular dynamics simulations uncovered two distinct structural mechanisms of TRPM7 activation (Nadezhdin et al. 2023). Specific roles may be played by TRPM7 channels in several different neurodegenerative conditions, and the factors that are responsible for TRPM7 channel regulation have the same potential (Soni et al. 2024). Clinical features due to TRPM6 mutations in an infant with hypomagnesemia and secondary hypocalcemia (Yang et al. 2019). TRPM7 channel activity promotes the pathogenesis of abdominal aortic aneurysms (Zong et al. 2025).
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Eukaryota | Metazoa, Chordata | TRPM6 of Homo sapiens (NP_060132) |
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1.A.4.5.9 | Transient receptor potential cation channel TrpM |
Eukaryota | Metazoa, Arthropoda | T9.a.14.4.12 rpM of Drosophila melanogaster |
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1.A.4.6.1 | Cold-activated cation channel in nociceptive sensory neurons, ANKTM1 (TRPA1; the Wasabi receptor), with lower activation temperature (in the noxious cold range) than TRPM8 (TC #1.A.4.5.7) (Story et al., 2003). It translates sound into electric signals in the ear. It sits at the tips of cilia in the inner ear and allows passage of K+ and Ca2+ into the cell. Vibrations in the hair cause the channel to open and close. The frequency of the sound waves generate an electrical signal of the same frequency (Jordt et al., 2004). (Shows 25% identity with α-latrotoxin precursor (TC #1.C.63.1.1) in its N-terminal half.) TRPA1 is a polyunsaturated fatty acid sensor in mammals, but not in flies and fish (Motter and Ahern, 2012). TRPA1 is regulated by its N-terminal ankyrin repeat domain (Zayats et al., 2012). Agonistic/antagonistic properties of lactones in food flavors on the sensory ion channels, TRPV1 and TRPA1 have been reviewed (Ogawa et al. 2022). TRPA1 is a homotetrameric non-selective calcium-permeable channel. It contributes to chemical and temperature sensitivity, acute pain sensation, and development of inflammation (Kvetkina et al. 2024). HCIQ2c1 is a peptide from the sea anemone, Heteractis magnifica, that inhibits serine proteases. HCIQ2c1 significantly reduces AITC- and capsaicin-induced pain and inflammation in mice. Electrophysiology recordings in Xenopus oocytes expressing rat TRPA1 channel revealed that HCIQ2c1 binds to open TRPA1 and prevents its transition to closed and inhibitor-insensitive 'hyperactivated' states. NMR study of the 15N-labeled recombinant HCIQ2c1 analog described a classical Kunitz-type structure and revealed two dynamic hot-spots (loops responsible for protease binding and regions near the N- and C-termini) that exhibit simultaneous mobility on two timescales (ps-ns and μs-ms). In modelled HCIQ2c1/TRPA1 complex, the peptide interacts simultaneously with one voltage-sensing-like domain and two pore domain fragments from different channel's subunits, and with lipid molecules. The model explains stabilization of the channel in the open conformation and the restriction of 'hyperactivation', which are probably responsible for the observed analgetic activity. HCIQ2c1 is the third peptide ligand of TRPA1 from sea anemones and the first Kunitz-type ligand of this channel. HCIQ2c1 is a prototype of efficient analgesic and anti-inflammatory drugs (Kvetkina et al. 2024). TRPA1 channels modulate cutaneous vasodilation during exercise in the heat in young adults when Nitric oxide synthase (NOS) is inhibited (Hattori et al. 2025). |
Eukaryota | Metazoa, Chordata | ANKTM1 of Mus musculus (Q8BLA8) |
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1.A.4.6.2 | Warm-activated thermosensory cation channel of insects, ThermoTRPV, ANKTM1 or TrpA1 (Viswanath et al., 2003). It is required to control activity during the warm part of the day (Roessingh et al. 2015). The TrpA1(A) transcript spliced with exon10b (TrpA1(A)10b) that is present in a subset of midgut enteroendocrine cells (EECs) is critical for uracil-dependent defecation of microorganisms (Du et al. 2016). TrpA1 is a shear stress mechanosensing channel regulating intestinal stem cell proliferation in Drosophila (Gong et al. 2023). Linkage of alternative exon assembly in Drosophila TrpA1 transcripts has been demonstrated (Du et al. 2024). TRPA1 in Aedes albopictusis 72% identical to this protein. It has been cloned and functionally characterized (Lv et al. 2025). |
Eukaryota | Metazoa, Arthropoda | ANKTM1 of Drosophila melanogaster (1197 aas; Q7Z020) |
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1.A.4.6.3 | The nociceptive neuron TRPA1 (Trp-ankyrin 1) (also called the Wasabi Receptor) senses peripheral damage by transmitting pain signals (activated by cold temperatures, pungent compounds and environmental irritants). Noxious compounds also activate through covalent modification of cysteyl residues (Macpherson et al., 2007). TRPA1 is an excitatory, nonselective cation channel implicated in somatosensory function, pain, and neurogenic inflammation. Through covalent modification of cysteine and lysine residues, TRPA1 can be activated by electrophilic compounds, including active ingredients of pungent natural products (e.g., allyl isothiocyanate), environmental irritants (e.g., acrolein), and endogenous ligands (4-hydroxynonenal) (Chen et al., 2008). General anesthetics activate TRPA1 nociceptive ion channels to enhance pain and inflammation (Matta et al., 2008; Leffler et al., 2011). TMS5 is a critical molecular determinant of menthol sensitivity (Xiao et al., 2008) and a variety of inhibitors which are analgesics. Another class of inhibitors are in the thiadiazole structural class of compounds, and they bind to the TRPA1 ankyrin repeat 6 (Tseng et al. 2018). Inhibitors are potential analgesics. The majority of TRPA1 inhibitors interact with the S5 transmembrane helices, forming part of the pore region of the channel. TRPA1 is a component of the nociceptive response to CO2 (Wang et al., 2010). TRPA1 is a polyunsaturated fatty acid sensor in mammals but not in flies and fish (Motter and Ahern, 2012). It is regulated by its N-terminal ankyrin repeat domain (Zayats et al., 2012). Mutations in TrpA1 cause alterred pain perception (Kremeyer et al. 2010). The hop compound, eudesmol, an oxygenated sesquiterpene, activates the channel (Ohara et al. 2015). These channels regulate heat and cold perception, mechanosensitivity, hearing, inflammation, pain, circadian rhythms, chemoreception, and other processes (Laursen et al. 2014). TRPA1 is a polymodal ion channel sensitive to temperature and chemical stimuli, but its resposes are species specific (Laursen et al. 2015). A probable binding site for general anesthetics has been identified (Ton et al. 2017), and specific residues involved in binding of the anesthetic, propofol, are known (Woll et al. 2017). TrpV1 and TrpA1 are inflammatory mediators causing cutaneous chronic itch in several diseases (Xie and Li 2018). TRPA1 is specifically activated by natural products including allyl isothiocyanate (mustard oil), cinnamaldehyde (cinnamon), allicin (garlic) and trans-anethole in Fennel Oil (FO) (Memon et al. 2019). Mutations in TRPA1 result in insensitivity to pain promoting algogens such as capsaicin, acid, and allyl isothiocyanate (AITC), have been documented (Eigenbrod et al. 2019). TRPA1 transduces noxious chemical stimuli into nociceptor electrical excitation and neuropeptide release, leading to pain and neurogenic inflammation. It is regulated by the membrane environment. Startek et al. 2019 found that mouse TRPA1 localizes to cholesterol-rich domains, and that cholesterol depletion decreases channel sensitivity to chemical agonists. Two structural motifs in TMSs 2 and 4 are involved in cholesterol interactions that are necessary for normal agonist sensitivity and plasma membrane localization. TRPA1 is an irritant sensor and a therapeutic target for treating pain, itch, and respiratory diseases. It can be activated by electrophilic compounds such as allyl isothiocyanate (AITC). A class of piperidine carboxamides (PIPCs) are potent noncovalent agonists (Chernov-Rogan et al. 2019). Saikosaponins are channel antogonists (Lee et al. 2019). hTRPA1 is activated by electrophiles such as N-methyl maleimide (NMM). A conformational switch of the protein, possibly associated with activation or desensitization of the ion channel, involves covalent derivatization of several cysteyl and lysyl residues in the transmembrane domain and the proximal N-terminal region as targets for electrophilic activation (Moparthi et al. 2020). Altering expression of the genes encoding Kv1.1, Piezo2, and TRPA1 regulate the response of mechanosensitive muscle nociceptors (Nagaraja et al. 2021). As a polymodal nocisensor, TRPA1 can be activated by thermal and mechanical stimuli as well as a wide range of chemically damaging molecules including small volatile environmental toxicants and endogenous algogenic lipids (Zsidó et al. 2021). After activation by such compounds, the ion channel opens up, allowing calcium influx into the cytosol, inducing signal transduction pathways. Then, calcium influx desensitizes irritant evoked responses and results in an inactive state of the ion channel. It was shown how reversible interactions with binding sites contribute to structural changes of TRPA1, leading to covalent bonding of agonists (Zsidó et al. 2021). The binding site(s) for antagonists have been determined for the TRPA1 ion channel (Gawalska et al. 2022). The hTRPA1 C-terminial domain (CTD) harbors cold and heat sensitive domains allosterically coupled to the S5-S6 pore region and the VSLD, respectively (Moparthi et al. 2022). TRPA1 is a sensor for inflammation and oxidative stress which contribute to the pathophysiology of major depressive disorder (MDD), and TRPA1 channels appear crucial to mediate behavioral impairment induced by chronic corticosterone administration (CCA) (Pereira et al. 2023). Neuronal and non-neuronal TRPA1 are therapeutic targets for pain and headache relief (Iannone et al. 2023). A TRPA1 mutant (R919*), identified in CRAMPT syndrome patients, confers hyperactivity when co-expressed with wild type TRPA1. The R919* mutant co-assembles with WT TRPA1 subunits into heteromeric channels at the plasma membrane. The R919* mutant hyperactivates channels by enhancing agonist sensitivity and calcium permeability, which could account for the observed neuronal hypersensitivity-hyperexcitability symptoms. Possibly, R919* TRPA1 subunits contribute to heteromeric channel sensitization by altering pore architecture and lowering energetic barriers to channel activation (Bali et al. 2023). Platycodonis Radix, a widely consumed herbal food produces a bioactive constituents, platycodins, alleviates LPS-induced lung inflammation through modulation of TRPA1 channels (Yang et al. 2023). The TRPA1 ion channel mediates oxidative stress-related migraine pathogenesis (Fila et al. 2024). TRPA1 influences Staphylococcus aureus skin infection in mice and associates with HIF-1a and MAPK pathway modulation (Yadav et al. 2024). |
Eukaryota | Metazoa, Chordata | TRPA1 of Homo sapiens (O75762) |
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1.A.4.6.4 | The Pyrexia (Pyx) thermal TRP channel allowing increased tolerance to high temperature (Lee et al., 2005) | Eukaryota | Metazoa, Arthropoda | Pyx of Drosophila melanogaster (Q9W0T5) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.4.6.5 | Thermosensitive TPR channel TRPA1 (TrpA-1) of 1211 aas. Detects a temperature drop promoting increased longevity. This requires TPRA1-mediated Ca2+ influx and activation of protein kinase C. Human TRPA1 (TC# 1.A.4.6.3) can functionally substitute for worm TRPA-1 in promoting longevity (Xiao et al. 2013). Also mediates touch sensation. |
Eukaryota | Metazoa, Nematoda | TRPA1 of Caenorhabditis elegans |
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1.A.4.6.6 | Water witch (Wtrw) of 986 aas, the "moist" humidity receptor, one of two hygrosensation receptors. These two transient receptor potential channels are needed for sensing humidity. The other is Nanchung (Nan), involved in detecting dry air. Neurons associated with specialized sensory hairs in the third segment of the antenna express these channels, and neurons expressing Wtrw and Nan project to central nervous system regions associated with mechanosensation. Construction of the hygrosensing system with opposing receptors may allow an organism to very sensitively detect changes in environmental humidity (Liu et al. 2007). |
Eukaryota | Metazoa, Arthropoda | WtrW of Drosophila melanogaster |
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1.A.4.6.7 | TRP ankyrin 1 (TRPA1 of 1188 aas). It is a homotetrameric, non-selective, cation channel with multiple ankyrin repeats at the N-terminus. The systems from insects to birds are heat activatable, and this activation is dependent on an extracellular Ca2+ binding site near the vestibule surface. Neutralization of acidic amino acids by extracellular Ca2+ seems to be important for heat-evoked activation (Kurganov et al. 2017). |
Eukaryota | Metazoa, Chordata | TRPA1 of Anolis carolinensis (Green anole) (American chameleon) |
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1.A.4.7.1 | The mechanically gated hearing and balance ion channel in sensory hair cells of the vertebrate inner ear, NompC (Sidi et al., 2003) | Eukaryota | Metazoa, Chordata | NompC of Danio rerio (zebrafish) (1614 aas; Q7T1G6) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.4.7.2 | The sensory ion channel in tactile bristles of insects, NompC. The atomic structure of Drosophila NOMPC has been determined by single-particle electron cryo-microscopy. Structural analyses suggested that the ankyrin repeat domain (29 repeats) of NOMPC resembles a helical spring, suggesting its role of linking mechanical displacement of the cytoskeleton to the opening of the channel (Jin et al. 2017). Compression of the ankyrin chains imparts a rotational torque on the TRP domain, which may result in channel opening (Argudo et al. 2019). |
Eukaryota | Metazoa, Arthropoda | NompC of Drosophila melanogaster (1619 aas; AAF59842) |
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1.A.4.7.3 | The pore forming subunit, Trp-4, a mechanosensitive cation/Ca2+ channel. Present in ciliated mechanosensitive neurons; Activation and latency occur in the microsecond range. trp-4 mutations alter ion selectivity (Kang et al., 2010; Xiao and Xu 2009). |
Eukaryota | Metazoa, Nematoda | Trp-4 of Caenorhabditis elegans (Q9GRV5) |
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1.A.40.1.1 | The ion channel viral protein U, Vpu of 81 aas and 1 TMS. Vpu(1-32), forms a helix bundle with characteristic open states. Different amilorides inhibit channel activity (Römer et al. 2004). The mutation A18H converts a non-specific channel to a selective proton channel that is sensitive to rimantadine (Sharma et al., 2011). Vpu forms stable pentamers (Padhi et al. 2013). The mechanism of Vpu, a weakly conducting cation-selective channel that assists in detachment of the virion from infected cells, has been proposed (Padhi et al. 2014). Interactions of Vpu with host cellular constituents have been reviewed (González 2015). Vpu forms large homo aggregates of 16 or 32 subunits (Lin et al. 2016). Vpu is involved in the enhancement of virion release via formation of an ion channel. Cyclohexamethylene amiloride (Hma) inhibits ion channel activity. A putative binding site for Hma blockers in a pentameric model bundle built of parallel aligned helices of the first 32 residues of Vpu was found near Ser-23. Hma orientates along the channel axis with its alkyl ring pointing inside the pore, which leads to a blockage of the pore (Lemaitre et al. 2004). |
Viruses | Pararnavirae, Artverviricota | Vpu of HIV-1 virus |
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1.A.40.1.2 | Vpu protein of 81 aas and 1 TMS. It preferentially transports monovalent cations, Na+ and K+ (Scott and Griffin 2015). |
Viruses | Pararnavirae, Artverviricota | Vpu of HIV1 |
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1.A.40.2.1 | Simian immunodeficiency virus (SIV) Vpu of 79 aas and 1 TMS. |
Viruses | Pararnavirae, Artverviricota | Vpu of Simian immunodeficiency virus (SIV) |
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1.A.40.2.2 | Simian immunodeficiency virus (SIV) Vpu protein of 83 aas and 1 TMS |
Viruses | Pararnavirae, Artverviricota | Vpu of Simian immunodeficiency virus (SIV) |
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1.A.40.2.3 | Simian immunodeficiency virus (SIV) Vpu of 79 aas and 1 TMS. |
Viruses | Pararnavirae, Artverviricota | Vpu of Simian immunodeficiency virus (SIV) |
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1.A.40.2.4 | Vpu of 85 aas and 1 TMS of Human immunodeficiency virus 1 |
Viruses | Pararnavirae, Artverviricota | Vpu of Human immunodeficiency virus 1 |
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1.A.41.1.1 | The avian reovirus p10 protein of 98 aas and 1 TMS. |
Viruses | Orthornavirae, Duplornaviricota | p10 of avian reovirus strain S1133 |
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1.A.41.1.2 | Duck reovirus protein 10 (p10) of 97 aas and 1 TMS. |
Viruses | Orthornavirae, Duplornaviricota | p10 of duck reovirus |
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1.A.41.1.3 | p10 protein of 91 aas and 1 TMS. |
Viruses | Orthornavirae, Pisuviricota | p10 of Rousettus bat coronavirus |
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1.A.41.1.4 | Membrane fusion protein, p10, of 95 aas and 1 central TMS. It has a cytoplasmic basic region and an N-terminal hydrophobic domain (HD) that has been hypothesized to function as a fusion peptide. Bulky aliphatic residues were found to be essential for optimal fusion, and an aromatic or highly hydrophobic side chain was found to be required at position 12 (Cheng et al. 2005). The requirement for hydrophilic residues within the HD was also examined: substitution of 10-Ser or 14-Ser with hydrophobic residues was found to reduce cell surface expression of p10 and delayed the onset of syncytium formation. Nonconservative substitutions of charged residues in the HD did not have an effect on fusion activity (Cheng et al. 2005). |
Viruses | Orthornavirae, Duplornaviricota | p10 of Nelson Bay Virus |
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1.A.41.2.1 | Uncharacterized protein of 103 aas and 1 TMS. |
Eukaryota | Viridiplantae, Streptophyta | UP of Capsicum baccatum |
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1.A.41.2.2 | Glutamine Dumper 1 (GDU1) (158aas; 1 N-terminal TMS). Nonselective passive amino acid export stimulatory protein (Pratelli et al., 2010). Mutations affecting activity have been studied (Yu et al. 2015). |
Eukaryota | Viridiplantae, Streptophyta | GDU1 of Arabidopsis thaliana (O81775) |
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1.A.41.2.3 | GDU1 homologue of 178 aas and 1 TMS. |
Eukaryota | Viridiplantae, Streptophyta | GDU1 homologue of Solanum lycopersicum (Tomato) (Lycopersicon esculentum) |
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1.A.41.2.4 | Uncharacterized protein of 171 aas and 1 TMS |
Eukaryota | Viridiplantae, Streptophyta | UP of Brachypodium distachyon |
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1.A.41.2.5 | Uncharacterized homologue of glutamine dumper of 139 aas and 1 TMS. |
Eukaryota | Viridiplantae, Streptophyta | UP of Handroanthus impetiginosus |
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1.A.41.2.6 | Glutamine dumper 6 of 117 aas and 1 TMS |
Eukaryota | Viridiplantae, Streptophyta | GDU1 of Capsella rubella |
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1.A.42.1.1 | Vpr of HIV of 96 aas and one C-terminal TMS. Vpr forms a cation-selective ion channel within the plasma membrane. The C-terminal helix (residues 56-77) effectively forms the transmembrane region, while the N-terminal helix exhibited an amphipathic nature by associating horizontally with a single leaflet (Majumder et al. 2024). Various oligomeric states (ranging from tetramer to heptamer) were considered to form the Vpr ion channel, and a pentamer was favored. |
Viruses | Pararnavirae, Artverviricota | Vpr of HIV type 1 virus |
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1.A.42.1.2 | Vpr of 119 aas and 1 putative TMS |
Viruses | Pararnavirae, Artverviricota | Vpr of Simian immunodeficiency virus (SIV) |
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1.A.42.1.3 | Protein Vpr of 101 aas. |
Viruses | Pararnavirae, Artverviricota | Vpr of Simian immunodeficiency virus (SIV-sm) (Simian immunodeficiency virus sooty mangabey monkey) |
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1.A.42.1.4 | Vpr protein of 116 aas |
Viruses | Pararnavirae, Artverviricota | Vpr of simian immunodeficiency virus |
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1.A.42.1.5 | Vpr of 138 aas |
Viruses | Pararnavirae, Artverviricota | Vpr of simian immunodeficiency virus |
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1.A.43.1.1 | The camphor resistance protein, CrcB or FluC (Hu et al. 1996; Sand et al. 2003). Exports fluoride selectively over chloride by an anion open channel mechanism (Stockbridge et al. 2013). The active transporter is a dimer of 4 TMS subunits arranged in an antiparallel transmembrane orientation (Stockbridge et al. 2014). In bacteria lacking Fluc, F- accumulates when the external medium is acidified as a predicted function of the transmembrane pH gradient. This weak acid accumulation effect, which results from the high pKa (3.4) and membrane permeability of HF, is abolished by Fluc channels (Ji et al. 2014). A proper tubulin network is required for functional Cx43 GJ channels, and mefloquineis a gap junction inhibitor (Picoli et al. 2019). . |
Bacteria | Pseudomonadota | CrcB of E. coli (P37002) |
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1.A.43.1.10 | CrcB-like protein of 164 aas and 4 TMSs |
Bacteria | Actinomycetota | CreB of Mobiluncus curtisii (Falcivibrio vaginalis) |
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1.A.43.1.11 | Putative fluoride transporter of 122 aas, CrcB |
Bacteria | Campylobacterota | CrcB of Campylobacter jejuni |
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1.A.43.1.12 | CreB of 168 aas and 4 TMSs |
Bacteria | Actinomycetota | CreB of Brachybacterium faecium |
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1.A.43.1.13 | CreB of 123 aas and 4 TMSs. |
Bacteria | Bacteroidota | CreB of Aequorivita sublithincola |
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1.A.43.1.14 | CrcB, putative fluoride channel protein of 124 aas and 4 TMSs |
Bacteria | Bacillota | CrcB of Lactobacillus kefiranofaciens |
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1.A.43.1.15 | CrcB of 133 aas and 4 TMSs. |
Archaea | Euryarchaeota | CrcB of Halorubrum coriense |
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1.A.43.1.16 | Fluc homologue of 453 aas and 9 putative TMSs. |
Eukaryota | Discosea | Fluc of Acanthamoeba castellanii |
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1.A.43.1.17 | Fluoride ion channel of 128 aas and 4 TMSs, Fluc or CrcB. The crystal structure is known (PDB5A40; 5A43). |
Bacteria | Pseudomonadota | Fluc of Bordetella pertussis |
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1.A.43.1.18 | Fluoride transporter,CrcB of 122 aas and 4 TMSs (Baker et al. 2012). It is important for reducing fluoride concentrations in the cell, thus reducing its toxicity. Several of these fluoride exporter genes are regulated by fluoride-regulated riboswitches. M. extorquens has several F- exporters that are regulated by F--riboswithches because this organims can use halogenated hydrocarbons as carbon sources, and they release the toxic halogen ion into the cytoplasm. They need to pump it out to survive. (Baker et al. 2012) |
Pseudomonadota | CrcB of Methylorubrum extorquens (strain DSM 6343 / CIP 106787 / DM4) (Methylobacterium extorquens) |
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1.A.43.1.2 | Protein CrcB homologue 2 |
Bacteria | Bacillota | crcB2 of Bacillus subtilis |
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1.A.43.1.3 | Putative fluoride-selective channel of 143 aas and 4 TMSs, CrcB. |
Bacteria | Actinomycetota | CreB of Propionibacterium acnes |
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1.A.43.1.4 | CreB homologue of 124 aas |
Archaea | Euryarchaeota | CrcB homologue of Methanocaldococcus fervens |
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1.A.43.1.5 | CrcB homologue of 172 aas and 4 TMSs |
Bacteria | Pseudomonadota | CrcB of Parvularcula bermudensis |
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1.A.43.1.6 | Putative fluoride exporter, CrcB. |
Bacteria | Chlorobiota | CrcB of Pelodictyon luteolum (Chlorobium luteolum) |
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1.A.43.1.7 | Putative fluoride exporter, CrcB if 114 aas and 4 TMSs. |
Archaea | Euryarchaeota | CrcB of Thermococcus barophilus |
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1.A.43.1.8 | Uncharacterized protein of 151 aas and 4 TMSs. |
Bacteria | Actinomycetota | UP of Rothia mucilaginosa (Stomatococcus mucilaginosus) |
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1.A.43.1.9 | Putative fluoride exporter, CrcB of 113 aas and 4 TMSs. |
Archaea | Euryarchaeota | UP of Haloquadratum walsbyi |
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1.A.43.2.1 | CrcB-like protein of 307 aas and 6 TMSs in an apparent 3 + 3 arrangement. |
Eukaryota | Ciliophora | CrcB homologue of Tetrahymena thermophila |
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1.A.43.2.2 | Uncharacterized protein of 372 aas and 9 - 10 TMSs |
Eukaryota | Fungi, Ascomycota | UP of Kazachstania africana (Kluyveromyces africanus) |
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1.A.43.2.3 | CrcB domain containing protein of 310 aas and 9 TMSs in a 4 + 5 arrangement, with both halves showing sequence similarity with the 4 TMS CrcB of E. coli. |
Eukaryota | Fungi, Ascomycota | CrcB homologue of Schizosaccharomyces cryophilus |
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1.A.43.2.4 | Plasma membrane fluoride ( > chloride) export channel of 375 aas and 8 TMSs, FEX1 (Li et al. 2013). The two homologous 4 TMS domains are functionally assymetric (Smith et al. 2015). There are two very similar fex genes in S. cerevisiae, the other having TC# 1.A.43.2.5. Fex1 is consitutively synthesized (Smith et al. 2015). |
Eukaryota | Fungi, Ascomycota | FEX1 of Saccharomyces cerevisiae |
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1.A.43.2.5 | Fluoride exporter, FEX2 of 375 aas and 8 TMSs (Li et al. 2013). Overexpression of five genes in a FEX1/FEX2 deletion strain, SSU1, YHB1, IPP1, PHO87, and PHO90, concerned with nitrate and phosphate transport, increase fluoride tolerance by 2- to 10-fold (Johnston and Strobel 2019). |
Eukaryota | Fungi, Ascomycota | FEX2 of Saccharomyces cerevisiae |
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1.A.43.2.6 | Fluoride exporter, FEX, of 526 aas and 10 putative TMSs (Li et al. 2013). |
Eukaryota | Fungi, Ascomycota | FEX of Neurospora crassa |
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1.A.43.2.7 | Camphor resistance CrcB protein of 461 aas and 9 putative TMSs. |
Eukaryota | Viridiplantae, Streptophyta | CrcB of Arabidopsis thaliana |
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1.A.43.2.8 | Uncharacterized protein of 405 aas and 8 putative TMSs. |
Eukaryota | Metazoa, Chordata | UP of Ciona intestinalis (Transparent sea squirt) (Ascidia intestinalis) |
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1.A.43.2.9 | Uncharacterized protein of 460 aas and 9 TMSs/ |
Eukaryota | Oomycota | UP of Phytophthora parasitica |
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1.A.43.3.1 | CreB of 346 aas and 4 TMSs. |
Bacteria | Actinomycetota | CreB of Bifidobacterium longum |
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1.A.43.3.2 | Putative fluoride channel, CrcB, of 180 aas and 4 TMSs. |
Bacteria | Actinomycetota | CrcB of Scardovia wiggsiae |
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1.A.43.3.3 | Putative fluoride ion channnel, CrcB, of 178 aas and 4 TMSs |
Bacteria | Actinomycetota | CrcB of Bifidobacterium longum |
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1.A.43.3.4 | Putative fluoride ion channel, CrcB, with 310 aas and 4 TMSs. |
Bacteria | Actinomycetota | CrcB of Bifidobacterium animalis subsp. lactis |
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1.A.44.1.1 | The pore-forming tail tip protein Pb2 | Viruses | Heunggongvirae, Uroviricota | Pb2 of phage T5 (Q7Y5E2) |
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1.A.46.1.1 | Bestrophin-1 (Best1) anion channel; VMD2 gene product (NO3- > I- > Br- > Cl-; PNO3-/PCl- = 5.8) (Sun et al., 2002). Regulated by ceramide-induced dephosphorylation (Xiao et al., 2009). Best1 mediates fast and slow glutamate release in astrocytes upon GPCR activation (Woo et al. 2012). Progressive posterior chorioretinal changes occur over time in the initial ADVIRC proband, leading to visual loss. The causative mutation is in the transmembrane domain of BEST1 (Chen et al. 2016). Autosomal dominant vitreoretinochoroidopathy (ADVIRC), caused by mutation in BEST-1, is a rare, early-onset retinal dystrophy characterised by distinct bands of circumferential pigmentary degeneration in the peripheral retina accompanied by developmental eye defects. It is an ion channel in the basolateral membrane of retinal pigment epithelial (RPE) cells. In patients, BEST1 is expressed at the basolateral membrane and the apical membrane. PolarProtPred is a program for predicting apical and basolateral localization of transmembrane proteins using putative short linear motifs and deep learning (Dobson et al. 2021). During human eye development, BEST1 is expressed more abundantly in peripheral RPE compared to central RPE and is also expressed in cells of the developing retina. Higher levels of mislocalised BEST1 expression in the periphery, from an early developmental stage, may provide the mechanism that leads to the distinct clinical phenotype observed in ADVIRC patients (Carter et al. 2016). Binding of Ca2+ induces conformational changes in the secondary structure leading to assembly of monomers and changes in molecular and macro-organization (Mladenova et al. 2016). BEST1 gene mutations are associated with at least two different forms of macular dystrophy (Chibani et al. 2019). intermolecular protein-lipid interactions may account for the conformational dynamics of hBest1 and its biological function as a multimeric ion channel (Videv et al. 2021). hBest1 is expressed in the retinal pigment epithelium, and mutations in the BEST1 gene cause ocular degenerative diseases colectivelly referred to as "bestrophinopathies". Videv et al. 2021 reviewed the current understanding of hBest1 surface organization, interactions with membrane lipids in model membranes, and its association with microdomains of cellular membranes. Shifts in phase separation/miscibility by cholesterol leads to changes in the structure and localization of hBest1 in the lipid rafts and its channel functions (Videv et al. 2022). Autosomal recessive bestrophinopathy (ARB), a retinal degenerative disease, is characterized by central visual loss, yellowish multifocal diffuse subretinal deposits, and a dramatic decrease in the light peak on electrooculogram. The potential pathogenic mechanism involves mutations in the BEST1 gene, which encodes Ca2+-activated Cl- channels in the retinal pigment epithelium (RPE), resulting in degeneration of RPE and photoreceptor (Li et al. 2024). Thus, novel BEST1 variants in autosomal recessive bestrophinopathy have been reported (Li et al. 2024). |
Eukaryota | Metazoa, Chordata | Bestrophin-1 of Homo sapiens (O76090) |
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1.A.46.1.2 |
Bestrophin-2 anion channel, BEST2 or VMD2L1 (PNO3-/PCl- = 2.7) (Sun et al., 2002). It also transports bicarbonate (HCO3-) (Qu and Hartzell 2008). The mouse orthologue is swell-insensitive, but the first 64 aas of Bestrophin 1 of Drosophila melanogaster allowed it to mediate cell swelling in response to hypo-osmotic stress (Stotz and Clapham 2012). BEST2 and BEST4 are expressed in colonic goblet cells (Ito et al. 2013). The structure of bovine BEST2 has been determined, and differences with BEST1 have been noted (Owji et al. 2020). |
Eukaryota | Metazoa, Chordata | Bestrophin-2 of Homo sapiens (AAM76995) |
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1.A.46.1.3 | Bestrophin family anion channel, YxaK (Protein R13.3) (Sun et al., 2002) | Eukaryota | Metazoa, Nematoda | YxaK of Caenorhabditis elegans (Q21973) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.46.1.4 | Bestrophin 3 vitelliform macular dystrophy 2-like protein 3 (possesses a C-terminal motif blocking its own channel activity (Qu et al., 2006). Ca2+ activates anion flux with SCN->I->Cl-. | Eukaryota | Metazoa, Chordata | Best3 of Mus musculus |
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1.A.46.1.5 | Bestrophin1, isoform B. Identified as the Cl- (swell) channel that allows swelling in hypo-osmotic solutions (Stotz and Clapham 2012). Its N-terminal 64 aas are essential for swell activation. |
Eukaryota | Metazoa, Arthropoda | Bestrophin1 of Drosophila melanogaster (B7Z0U6) |
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1.A.46.1.6 | Bestrophin-1 (Best1) of 689 aas and 4 TMSs in a 2 + 2 arrangement. The x-ray structure has been determined at 2.85 Å resolution with permeant anions and Ca2+ bound (Kane Dickson et al. 2014). The channel is formed from a pentameric assembly of subunits. Ca2+ binds to the channel's large cytosolic region. A single ion pore, approximately 95 Å in length, is located along the central axis and contains at least 15 binding sites for anions. A hydrophobic neck within the pore probably forms the gate. Phenylalanine residues within it may coordinate permeating anions via anion-π interactions. Conformational changes observed near the 'Ca2+ clasp' hint at the mechanism of Ca2+-dependent gating (Kane Dickson et al. 2014). |
Eukaryota | Metazoa, Chordata | Best1 of Gallus gallus (chicken) |
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1.A.46.1.7 | Bestrophin-4, BEST4, Vmd2L2, of 473 aas and 7 TMSs. BEST2 and BEST4 are expressed in colonic goblet cells (Ito et al. 2013). Both proteins transport a variety of monovalent anions. |
Eukaryota | Metazoa, Chordata | BEST4 of Homo sapiens |
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1.A.46.1.8 | Bestrophin-3, BEST3, Vmd2L3 of 668 aas and 7 TMSs. It forms calcium-sensitive chloride channels permeable to monovalent anions including bicarbonate (Tsunenari et al. 2003). It's expression prevents ER-stress-induced cell death in renal peithelial cells (Lee et al. 2012). It is expressed in glial cells of the brain (Wang et al. 2019), and when mutant may cause mandibular prognathism (Kajii et al. 2019). Vitamin C induces expression (Wang et al. 2019). |
Eukaryota | Metazoa, Chordata | BEST3 of Homo sapiens |
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1.A.46.2.1 | Plasma membrane Ca2+-activated anion-selective channel, Best1 (AN2251) of 499 aas and 4 TMSs. Transports citrate, propionate, benzoate, and sorbate (Roberts et al., 2011). |
Eukaryota | Fungi, Ascomycota | Best1 of Aspergillus nidulans (Q5BB29) |
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1.A.46.2.10 | Bestrophin homologue of 361 aas and 2 - 4 TMSs. |
Eukaryota | Rhodophyta | Best protein of Galdieria sulphuraria (Red alga) |
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1.A.46.2.11 | Bestrophin homologue of 446 aas and ~ 4 TMSs. |
Eukaryota | Viridiplantae, Chlorophyta | Best protein of Volvox carteri |
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1.A.46.2.12 | Uncharacterized protein of 396 aas with several TMSs, 2 - 4 TMSs near the N-terminus, and 2 - 3 TMSs near the C-terminus. |
Eukaryota | Viridiplantae, Streptophyta | UP of Klebsormidium nitens |
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1.A.46.2.2 | Fungal Best2 protein, AN6909 (Roberts et al., 2011) (29% identical to Best1 (TC# 1.A.46.2.1)). |
Eukaryota | Fungi, Ascomycota | Best2 of Aspergillus nidulans (Q5AXS1) |
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1.A.46.2.3 | Bestrophin homologue |
Bacteria | Cyanobacteriota | Bestrophin homologue of Cyanothece sp. PCC8801 (B7K217) |
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1.A.46.2.4 | Bestrophin homologue |
Bacteria | Bacillota | Bestrophin homologue of Bacillus cereus (C2UY63) |
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1.A.46.2.5 | Bestrophin homologue |
Bacteria | Bdellovibrionota | Bestrophin homologue of Bdellovibrio bacteriovorus (Q6MLK6) |
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1.A.46.2.6 | Bestrophin homologue, YneE |
Bacteria | Pseudomonadota | YneE of E. coli (B2N0W4) |
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1.A.46.2.7 | Chloroplast bestrophin homologue of 410 aas and 4 or 5 TMSs, VCCN1. Plants adjust photosynthetic light utilization by controlling electron transport and photoprotective mechanisms, and this involves the proton motive force (PMF) across the thylakoid membrane. VCCN1 is a voltage-dependent Cl- channel which localizes to the thylakoid membrane and fine-tunes the PMF by anion influx into the lumen during illumination, adjusting electron transport and photoprotective mechanisms (Herdean et al. 2016). The activity of AtVCCN1 accelerates the activation of photoprotective mechanisms on sudden shifts to high light. Thus, AtVCCN1 acts as an early component in the rapid adjustment of photosynthesis in variable light intensities. |
Eukaryota | Viridiplantae, Streptophyta | Bestrophin homologue of Arabidopsis thaliana (Q9M2D2) |
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1.A.46.2.8 | Functionally characterized bestrophin homologue, KpBEST, YneE or RFP-TM of 305 aas and 3 or 4 TMSs per subunit. KpBest is a pentamer that forms a five-helix transmembrane pore, closed by three rings of conserved hydrophobic residues, and has a cytoplasmic cavern with a restricted exit (Yang et al. 2014). From electrophysiological analysis of structure-inspired mutations in KpBest and hBest1, a sensitive control of ion selectivity was observed in the bestrophins, including reversal of anion/cation selectivity, and dramatic activation by mutations at the cytoplasmic exit. The wild type protein seems to be a cation (Na+) channel but the I66F mutation changed it into an anion (Cl-) channel (Yang et al. 2014). There are two constrictions in the channel, one provides the ion selectivity and the other serves as the gate. |
Bacteria | Pseudomonadota | KpBEST of Klebsiella pneumoniae |
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1.A.46.2.9 | Uncharacterized protein of 895 aas and 10 TMSs in a 2 + 2 + 2 + 2 + 2 arrangement. There appear to be two full length repeats, each of 4 TMSs, plus and extra C-terminal two TMSs, all homologous to each other. |
Eukaryota | Viridiplantae, Chlorophyta | UP of Ostreococcus lucimarinus |
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1.A.47.1.1 | The nucleotide-sensitive ion channel, ICln, of 237 aas and 0 TMSs, based on hydropathy plots. |
Eukaryota | Metazoa, Chordata | ICln of Homo sapiens (P54105) |
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1.A.47.2.1 | Homologue of ICln | Eukaryota | Fungi, Ascomycota | ICln homologue in Schizosaccharomyces pombe (O13777) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.47.3.1 | Anion transport channel homologue of ICln of 234 aas and 0 TMSs (Wunderlich 2022). |
Eukaryota | Apicomplexa | ICln homologue in Plasmodium falciparum (CAD52477) |
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1.A.47.4.1 | Homologue of ICln | Eukaryota | Viridiplantae, Streptophyta | ICln homologue in Arabidopsis thaliana (BAA97193) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.48.1.1 | Tweety maxi-Cl- anion channel | Eukaryota | Metazoa, Arthropoda | Tweety of Drosophila melanogaster (T08424) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.48.1.2 | TTYH1 maxi-Cl- anion channel |
Eukaryota | Metazoa, Chordata | Tweety homologue 1 (TTYH1) of Homo sapiens (Q9H313) |
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1.A.48.1.3 | TTYH2 maxi-Cl- anion channel | Eukaryota | Metazoa, Chordata | Tweety homologue 2 (TTYH2) of Homo sapiens (AAH05168) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.48.1.4 | TTYH3 maxi-Cl- anion channel | Eukaryota | Metazoa, Chordata | Tweety homologue 3 (TTYH3) of Homo sapiens (BAD20190) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.48.1.5 | Protein tweety-2 (Dttyh2) | Eukaryota | Metazoa, Arthropoda | CG3638 of Drosophila melanogaster | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.48.1.6 | Protein tweety -like protein 1 of 609 aas and 6 TMSs. |
Eukaryota | Metazoa, Nematoda | Tweety of Trichinella sp. T9 |
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1.A.48.2.1 | Tweety homolog of 455 aas and 5 TMSs in a 2 + 2 + 1 TMS arrangement. |
Eukaryote | Oomycota | TTYH of Globisporangium ultimum (Pythium ultimum) |
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1.A.48.2.2 | Tweety homolog of 590 aas and 2 TMSs. |
Eukaryote | Oomycota | TTYH of Phytophthora cactorum |
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1.A.48.2.3 | Tweety homolog of 401 aas and 1 - 3 TMSs. |
Eukaryote | Oomycota | Putative Tweety homolog of Globisporangium ultimum (Pythium ultimum) |
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1.A.49.1.1 | Pore forming, ion conducting viroporin of 109 aas and 1 C-terminal TMS, ns12.9 (Zhang et al. 2015). |
Viruses | Orthornavirae, Pisuviricota | ns12.9 of human coronavirus OC43 |
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1.A.49.1.2 | The non-structural protein, ns12.7 viroporin, of 112 aas and 1 putative C-terminal TMS. |
Viruses | Orthornavirae, Pisuviricota | ns12.7 of Murine coronavirus (Murine hepatitis virus) |
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1.A.49.1.3 | Non-structural protein, ns5 viroporin, of 104 aas and possibly 1 TMS (based on similarity to 1.A.49.1.1 and 1.2. |
Viruses | Orthornavirae, Pisuviricota | ns5 of β-coronavirus HKU2 |
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1.A.5.1.1 | Polycystin 1 (PKD1 or PC1) assembles with TRPP2 (Q86VP3) in a stoichiometry of 3TRPP2: 1PKD1, forming the receptor/ion channel complex (Yu et al., 2009). The C-terminal coiled-coil complex is critical for proper assembly (Zhu et al., 2011). Missense mutations have been identified that affect membrane topogenesis (Nims et al. 2011). Biomarkers for polycystic kidney diseases have been identified (Hogan et al. 2015). Extracellular divalent ions, including Ca2+, inhibit permeation of monovalent ions by directly blocking the TRPP2 channel pore. D643, a negatively charged amino acid in the pore, is crucial for channel permeability (Arif Pavel et al. 2016). Polycystin (TRPP/PKD) complexes, made of transient receptor potential channel polycystin (TRPP)4 and polycystic kidney disease (PKD) proteins, play key roles in coupling extracellular stimuli with intracellular Ca2+ signals. PKD1 and PKD2 form a complex, the structure of which has been solved in 3-dimensions at high resolution. The complex consists of PKD1:PKD2 = 3:1. PKD1 consists of a voltage-gated ion channel fold that interacts with PKD2 to complete a domain-swapped TRP architecture with unique features (Su et al. 2018; Su et al. 2018). The C-terminal tail of PKD1 may play a role in the prognosis of renal disease (Higashihara et al. 2018). TRPP2 uses 2 gating charges found in its fourth TMS (S4) to control its conductive state (Ng et al. 2019). Rosetta structural predictions demonstrated that the S4 undergoes approximately 3- to 5-Å transitional and lateral movements during depolarization coupled to opening of the channel pore. Both gating charges form state-dependent cation-pi interactions within the voltage sensor domain (VSD) during membrane depolarization. The transfer of a single gating charge per channel subunit is required for voltage, temperature, and osmotic swell polymodal gating. Thus, TRPP2 channel opening is dependent on activation of its VSDs (Ng et al. 2019). Polycystin-1 assembles with Kv channels to govern cardiomyocyte repolarization and contractility (Altamirano et al. 2019). Three-dimensional in vitro models answer questions about ADPKD cystogenesis (Dixon and Woodward 2018). The polycystin-1 subunit directly contributes to the channel pore, and its eleven TMSs are sufficient for its channel function (Wang et al. 2019). Polycystin-1 inhibits cell proliferation through phosphatase PP2A/B56alpha (Tang et al. 2019). Polycystin-1 regulates cardiomyocyte mitophagy (Ramírez-Sagredo et al. 2021). Maser and Calvet 2020 reviewed structural and functional features shared by polycystin-1 and the adhesion GPCRs (TC# 9.A.14.6.2) and discussed the implications of such similarities for our understanding of the functions of these proteins. Mutations in PKD1 and PKD2 cause autosomal dominant polycystic kidney disease (ADPKD). Polycystins are expressed in the primary cilium, and disrupting cilia structure slows ADPKD progression following inactivation of polycystins. Dysregulation of cyclin-dependent kinase 1 (Cdk1) is an early driver of cyst cell proliferation in ADPKD due to Pkd1 inactivation (Zhang et al. 2021). Genetic removal of c-Jun N-terminal kinases, Jnk1 and Jnk2, suppresses the nuclear accumulation of phospho c-Jun, reduces proliferation and reduces the severity of cystic disease. While Jnk1 and Jnk2 are thought to have largely overlapping functions, Jnk1 loss is nearly as effective as the double loss of Jnk1 and Jnk2 (Smith et al. 2021). Polycystic kidney disease (PKD), comprising autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD), is characterized by incessant cyst formation in the kidney and liver. ADPKD and ARPKD represent the leading genetic causes of renal disease in adults and children, respectively. ADPKD is caused by mutations in PKD1 encoding polycystin1 (PC1) and PKD2 encoding polycystin 2 (PC2). PC1/2 are multi-pass transmembrane proteins that form a complex localized in the primary cilium. Predominant ARPKD cases are caused by mutations in polycystic kidney (Ma 2021). The mechanism of tethered agonist-mediated signaling by polycystin-1 has been investigated (Pawnikar et al. 2022). PC1 is an 11 TMS protein encoded by the PKD1 gene. It has a complex posttranslational maturation process, with over five proteolytic cleavages, and is found at multiple cellular locations. The initial description of the binding and activation of heterotrimeric Galphai/o by the juxtamembrane region of the PC1 cytosolic C-terminal tail (C-tail) opened the door tothe possibility of potential functions as a novel G protein-coupled receptor (GPCR). Subsequent assays supported an ability of the PC1 C-tail to bind numerous members of the Galpha protein family and to either inhibit or activate G protein-dependent pathways involved in the regulation of ion channel activity, transcription factor activation, and apoptosis. PC1-mediated G protein regulation prevents kidney cyst development. Similarities between PC1 and the adhesion class of 7-TMS GPCRs, most notably a conserved GPCR proteolysis site (GPS) before the first TM domain, which undergoes autocatalyzed proteolytic cleavage, suggest potential mechanisms for PC1-mediated regulation of G protein signaling. reviewed the evidence supporting GPCR-like functions of PC1 and their relevance to cystic disease, discusses the involvement of GPS cleavage and potential ligands in regulating PC1 GPCR function, and explores potential connections between PC1 GPCR-like activity and regulation of the channel properties of the polycystin receptor-channel complex (Maser et al. 2022). Drug targets and repurposing candidates may effectively treat pre-cystic as well as cystic ADPKD (Wilk et al. 2023). Vascular polycystin proteins (PKD1 and PKD2) have been reviewed togehter with their involvedment in health and disease (Mbiakop and Jaggar 2023). |
Eukaryota | Metazoa, Chordata | Polycystin 1 of Homo sapiens |
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1.A.5.1.2 |
Polycystic kidney disease protein 1-like 3 (PC1-like 3 protein or PKD1L3) (Polycystin-1L3). May particpate in formation of the TRP sour taste receptor (see 1.A.5.2.2) (Ishimaru et al. 2010). Mediates Ca2+ influx-operated Ca2+ entry that generates pronounced Ca2+ spikes. Triggered by rapid onset/offset of Ca2+, voltage, or acid stimuli, Ca2+-dependent activation amplifies a small Ca2+ influx via the channel which concurrently drives self-limiting negative feedback inactivation that is regulated by the Ca2+-binding EF hands of its partner protein, PKD2-L1 (Hu et al. 2015). Polycystin-1 inhibits eIF2alpha phosphorylation and cell apoptosis through a PKR-eIF2alpha pathway (Tang et al. 2017). |
Eukaryota | Metazoa, Chordata | PKD1L3 of Homo sapiens |
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1.A.5.1.3 | Heteromeric polycystic kidney disease proteins 1 and 2-like 1 (PKD1L1/PKD2L1/PC2) cation (calcium) channel of kidney primary cilia (DeCaen et al. 2013). PKD2L1 is probably orthologous to mouse TC# 1.A.5.2.2. The voltage dependence of PKD2L1 may reflect the charge state of the S4 domain (Numata et al. 2017). PKD2L1, (TRPP3) is involved in the sour sensation and other pH-dependent processes and is a nonselective cation channel that can be regulated by voltage, protons, and calcium. The 3-d structure has been determined by cryoEM at 3.4 Å resolution (Su et al. 2018). Unlike its ortholog PKD2, the pore helix and TMS6, which are involved in upper and lower-gate opening, adopt an open conformation. The pore domain dilation is coupled to conformational changes of voltage-sensing domains via a series of pi-pi interactions, suggesting a potential PKD2L1 gating mechanism (Su et al. 2018). Autosomal dominant polycystic kidney disease is caused by mutations in PKD1 or PKD2 genes; the latter encodes polycystin-2 (PC2, also known as TRPP2), a member of the transient receptor potential (TRP) ion channel family. Despite most pathogenic mutations in PKD2 being truncation variants, there are many point mutations, which cause small changes in protein sequences but dramatic changes in the in vivo function of PC2. Conformational consequences of these mutations based on the cryo-EM structures of PC2 provide insight into the structure and function of PC2 and the molecular mechanism of pathogenesis caused by these mutations (Wang et al. 2023). Polycystin-1 interacting protein-1 (CU062) interacts with the ectodomain of polycystin-1 (PC1) (Lea et al. 2023).
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Eukaryota | Metazoa, Chordata | PKD1L1/PKD2L1 of Homo sapiens |
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1.A.5.1.4 | One of 10 receptors for the egg jelly ligands (REJ, REJ1 or PKD-REJ1) inducing the acrosome reaction in sea urchin eggs. Could be a regulator of sperm ion channels (Gunaratne et al. 2007). |
Eukaryota | Metazoa, Echinodermata | REJ of Strongylocentrotus purpuratus (Purple sea urchin) |
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1.A.5.1.5 | PKD-REJ4 of 2829 aas and 2 TMSs, one N-terminal and one C-terminal (Gunaratne et al. 2007). Shows homology with hydrophilic domains in human PKDs. |
Eukaryota | Metazoa, Echinodermata | REJ4 of Strongylocentrotus purpuratus (Purple sea urchin) |
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1.A.5.1.6 | PKD-REJ3 of 2681 aas (Gunaratne et al. 2007). Polycystin-2 (TC# 1.A.5.2.3) associates with the polycystin-1 homolog, suREJ3, and localizes to the acrosomal region of sea urchin spermatozoa (Neill et al. 2004). |
Eukaryota | Metazoa, Echinodermata | REJ3 of Strongylocentrotus purpuratus (Purple sea urchin) |
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1.A.5.1.8 | Polycystin-1L2 G-protein receptor of 2459 aas and about 18 TMSs in a 1 (N-terminal) + 6-8 + 3 + 7 ( C-terminal) TMS arrangement. It probably functions as an ion-channel regulator as well as a G-protein-coupled receptor (Yuasa et al. 2004). |
Eukaryota | Metazoa, Chordata | Polycystin-1L2 of Homo sapiens |
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1.A.5.2.1 | Polycystin 2 (PKD2, PC2 or TRPP2) of 968 aas and 8 or 9 TMSs (Anyatonwu and Ehrlich, 2005). It is regulated by α-actinin (AAC17470) by direct binding, influencing its channel activity (Li et al., 2007), and is also regulated also by diaphanous-related formin 1 (mDia1) (Bai et al., 2008). It has 8 TMSs with 6 TMSs in the channel domain with N- and C- termini inside (Hoffmeister et al., 2010). PC2 interacts with the inositol 1,4,5-trisphosphate receptor (IP(3)R) to modulate Ca2+ signaling (Li et al. 2009). The PKD2 voltage-sensor domain retains two of four gating charges commonly found in voltage-gated ion channels. The PKD2 ion permeation pathway is constricted at the selectivity filter near the cytoplasmic end of S6, suggesting that two gates regulate ion conduction (Shen et al. 2016). 15% of cases of polycystic kidney disease result from mutations in the gene encoding this protein, while 85% are in PKD1 (Ghata and Cowley 2017). Topological changes between the closed and open sub-conductance states of the functional channel are observed with an inverse correlation between conductance and height of the channel. Intrinsic PC2 mechanosensitivity in response to external forces was also observed (Lal et al. 2018). PC2 is present in ciliary membranes of the kidney and shares a transmembrane fold with other TRP channels as well as an extracellular domain found in TRPP and TRPML channels. Wang et al. 2019 characterized the phosphatidylinositol biphosphate (PIP2) and cholesterol interactions with PC2. PC2 has a PIP binding site close to the equivalent vanilloid/lipid binding site in the TRPV1 channel and a binding site for cholesterol. The two classes of lipid binding sites were compared with sites observed in other TRPs and in Kv channels, suggesting that PC2, in common with other ion channels, may be modulated by both PIPs and cholesterol (Wang et al. 2019). Genetic removal of c-Jun N-terminal kinases, Jnk1 and Jnk2, suppresses the nuclear accumulation of phospho c-Jun, reduces proliferation and reduces the severity of cystic disease. While Jnk1 and Jnk2 are thought to have largely overlapping functions, Jnk1 loss is nearly as effective as the double loss of Jnk1 and Jnk2 (Smith et al. 2021). Polycystin-2 (TRPP2): ion channel properties and regulation have been described (Del Rocío Cantero and Cantiello 2022). Regulation of the PKD2 channel by TACAN (TC# 1.A.119.1.2) has been described (Liu et al. 2022). The mouse ortholog is 90% identical to the human protein. The cytoplasmic tail of mechanosensitive channel Pkd2 regulates its internalization and clustering in eisosome (Malla et al. 2023). Vascular polycystin proteins (PKD1 and PKD2) have been reviewed togehter with their involvedments in health and disease (Mbiakop and Jaggar 2023). |
Eukaryota | Metazoa, Chordata | Polycystin 2 of Homo sapiens (Q13563) |
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1.A.5.2.2 | Polycystic kidney disease Z-like protein, TrpP3 or PKD2L1 (50% identical to Polycystin 2 (1.A.5.2.1); regulated by α-actinin (AAC17470) by direct binding; Li et al, 2007). May form a heterodimeric complex with PKD1L3 (1.A.5.1.2) to form the TRP sour taste channel receptor (Ishimaru et al., 2006; Ishimaru et al. 2010). Polycystic kidney disease (PKD) protein 2 Like 1 (PKD2L1) is also called transient receptor potential
polycystin-3 (TRPP3). It regulates Ca2+-dependent hedgehog signalling in primary cilia, intestinal
development and sour taste. Two intra-membrane residues, aspartic acid 349 (D349) and
glutamic acid 356 (E356) in the third TMS are critical for PKD2L1 channel
function which may itself sense acids (Hussein et al. 2015). Extracellular loops are involved in assemby of the complex (Salehi-Najafabadi et al. 2017). It Component of a heteromeric calcium-permeable ion channel formed by PKD1
and PKD2 that is activated by interaction between PKD1 and a Wnt family
member, such as WNT3A and WNT9B. Can also form a functional,
homotetrameric ion channel (PubMed:27214281). It functions as a cation channel involved in fluid-flow mechanosensation by the primary cilium in the renal epithelium (Nauli et al. 2003). It functions as outward-rectifying K+ channel, but is also permeable to Ca2+, and to a much lesser degree, to Na+ (Kleene and Kleene 2017). It |
Eukaryota | Metazoa, Chordata | TrpP3 of Mus musculus (Q14B55) |
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1.A.5.2.3 | Polycystin-2, PKD2 or PKD-REJ2 of 907 aas and 8 TMSs (Gunaratne et al. 2007). Polycystin-2 associates with the polycystin-1 homolog, suREJ3 (TC# 1.A.5.1.6), and localizes to the acrosomal region of sea urchin spermatozoa (Neill et al. 2004). |
Eukaryota | Metazoa, Echinodermata | REJ2 of Strongylocentrotus purpuratus (Purple sea urchin) |
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1.A.5.2.4 | Polycystin-2 (CePc2) (Polycystic kidney disease 2 protein homologue) |
Eukaryota | Metazoa, Nematoda | Pkd-2 of Caenorhabditis elegans |
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1.A.5.3.1 | The lysosomal monovalent cation/Ca2+ channel, TRP-ML1 (Mucolipin-1) (associated with the human lipid storage disorder, mucolipidosis type IV (MLIV)) (Kiselyov et al., 2005; Luzio et al., 2007). TRPML1 is an endolysosomal iron release channel (Dong et al., 2008). It interacts with TMEM163, a CDF heavy metal transporter (TC# 2.A.4.8.3). Together these proteins function in Zn2+ homeostasis, possibly by exporting Zn2+ (Cuajungco et al. 2014). The MLIV disease could result from Zn2+ overload. TrpML1 is probably involved in Zn2+ uptake into lysosomes (Cuajungco and Kiselyov 2017). Asp residues within the luminal pore may control calcium/pH regulation. A synthetic agonist, ML-SA1, can bind to the pore region to force a direct dilation of the lower gate (Schmiege et al. 2018). This channel plays a role in vesicle contraction following phagocytosis or pinocytosis, allowing maintenance of cell volume (Freeman et al. 2020). A mutation gave rise to progressive psychomotor delay, and atrophy of the corpus callosum and cerebellum was observed on brain magnetic resonance images (Hayashi et al. 2020). LW-213 induces immunogenic tumor cell death via ER stress mediated by lysosomal TRPML1 (Zhu et al. 2023). TRPML1 overexpression conferred full resistance to PA-induced oxidative damage. Pharmacologically activating the TRPML1-TFEB pathway was sufficient to restore mitochondrial and redox homeostasis in saturated fatty acids (SFA)-damaged endothelial cells. These results suggest that lysosome activation represents a viable strategy for alleviating oxidative damage, a common pathogenic mechanism of metabolic and age-related diseases (Feng et al. 2025). |
Eukaryota | Metazoa, Chordata | TRP-ML1 (Mucolipin-1) of Homo sapiens (Q9GZU1) |
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1.A.5.3.2 | The TRP-ML3 or TRPML3 or Mcoln3 (Mucolipin-3) inward rectifying cation channel; associated with the mouse Viartini-Waddler phenotype when mutant (A419P) (Kim et al., 2007; Cuajungco and Samie 2008). H+-regulated Ca2+ channel that shuttles between intracellular vesicular compartments and the plasma membrane (Kim et al., 2010). |
Eukaryota | Metazoa, Chordata | Trp-ML3 of Mus musculus |
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1.A.5.3.3 | Mucolipin-2 (TRPML2) non-selective plasma membrane cation channel (Ca2+ permeable). Shows inward rectification like TRPML1 and TRPML3 (Lev et al., 2010). Induces cell degeneration. Causes embryonic lethality, pigmentation defects and deafness, and regulates the acidification of early endosomes (Noben-Trauth, 2011). Found in the plasma membrane and early- and late-endosomes as well as lysosomes. Activated by a transient reduction of extracellular sodium followed by sodium replenishment, by small chemicals related to sulfonamides, and by PI(3,5)P2, a rare phosphoinositide that naturally accumulates in the membranes of endosomes and lysosomes, and thus could act as a physiologically relevant agonist (García-Añoveros and Wiwatpanit 2014). TRPML2 can form heteromultimers with TRPML1 and TRPML3; in B-lymphocytes, TRPML2 and TRPML1 may play redundant roles. TRPML2 may play a role in immune cell development and inflammatory responses (Cuajungco et al. 2015). The TRPML family hallmark is a large extracytosolic/lumenal domain (ELD) between TMSs S1 and S2. Viet et al. 2019 presented crystal structures of the tetrameric human TRPML2 ELD. The structures reveal structural responses to the conditions the TRPML2 ELD encounters as the channel traffics through the endolysosomal system. |
Eukaryota | Metazoa, Chordata | TRPML2 of Homo sapiens (Q8IZK6) |
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1.A.5.3.4 | Mucolipin-3 (Mcoln3, TRPML3). Orthologue of 1.A.5.3.2. Asp residues within the luminal pores of all mucolipins may function to control calcium/pH regulation. A synthetic agonist, ML-SA1, can bind to the pore region of TRPMLs to force a direct dilation of the lower gate. These proteins have multiple ligand binding sites (Schmiege et al. 2018). |
Eukaryota | Metazoa, Chordata | TRPML3 of Homo sapiens |
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1.A.5.3.5 | Mucolipin of 496 aas and 7 TMSs in a 1 + 6 TMS arrangement. There is a ~200 aa loop between TMSs 1 and 2, and TMS 1 may be a leader sequence. |
Eukaryota | Euglenozoa | Mucolipin of Trypanosoma grayi |
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1.A.5.3.6 | Uncharacterized protein of 1844 aas and 5 - 6 TMSs. |
Eukaryota | Euglenozoa | UP of Leishmania major |
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1.A.5.3.7 | Mucolipin-1 or CUP-5 of 611 aas and 6 TMSs in a 1 + 5 TMS arrangement. This C. elegans ortholog of the human protein is required for lysosome biogenesis. Mutations in cup-5 result in the accumulation of large vacuoles in several cells, in increased cell death, and in embryonic lethality (Treusch et al. 2004). |
Eukaryota | Metazoa, Nematoda | CUP-5 of Caenorhabditis elegans |
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1.A.5.4.1 | The algal PDK2 cation channel in Chlamydomonas reinhardii, involved in coupling flagellar adhesion at the beginning of mating to the increase in flagellar calcium required for subsequent steps in mating (Huang et al., 2007). (Residues 1278-1346 (the PKD domain) are 25% identical, 54% similar to residues 107-176 in CcaA (TC# 1.A.1.14.2)) | Eukaryota | Viridiplantae, Chlorophyta | PDK2 of Chlamydomonas reinhardii (A9LE42) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.50.1.1 | Phospholamban (PLB or PLN) pentameric Ca2+/K+ channel (Kovacs et al., 1988; Smeazzetto et al. 2013; Smeazzetto et al. 2014). In spite of extensive experimental evidence, suggesting a pore size of 2.2 Å, the conclusion of ion channel activity for phospholamban has been questioned (Maffeo and Aksimentiev 2009). Phosphorylation by protein kinase A and dephosphorylation by protein phosphatase 1 modulate the inhibitory activity of phospholamban (PLN), the endogenous regulator of the sarco(endo)plasmic reticulum calcium Ca2+ ATPase (SERCA). This cyclic mechanism constitutes the driving force for calcium reuptake from the cytoplasm into the myocyte lumen, regulating cardiac contractility. PLN undergoes a conformational transition between a relaxed (R) and tense (T) state, an equilibrium perturbed by the addition of SERCA. Phosphoryl transfer to Ser16 induces a conformational switch to the R state. The binding affinity of PLN to SERCA is not affected ((Kd ~ 60 μM). However, the binding surface and dynamics in domain Ib (residues 22-31) change substantially upon phosphorylation. Since PLN can be singly or doubly phosphorylated at Ser16 and Thr17, these sites may remotely control the conformation of domain Ib (Traaseth et al. 2006). Phospholamban interests with SERCA with conformational memory (Smeazzetto et al. 2017). Under physiological conditions, PLB phosphorylation induces little or no change in the interaction of the TMS with SERCA, so relief of inhibition is predominantly due to the structural shift in the cytoplasmic domain (Martin et al. 2018). The phospholamban pentamer alters the function of the sarcoplasmic reticulum calcium pump, SERCA (Glaves et al. 2019). PLB phosphorylation serves as an allosteric molecular switch that releases inhibitory contacts and strings together the catalytic elements required for SERCA activation (Aguayo-Ortiz and Espinoza-Fonseca 2020). |
Eukaryota | Metazoa, Chordata | PLB of Homo sapiens (P26678) |
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1.A.50.1.2 | Cardiac phospholamban-like protein of 131 aas and 1 TMS. |
Eukaryota | Metazoa, Chordata | Phospholamban of Scleropages formosus |
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1.A.50.1.3 | Cardiac phospholamban isoform X1 of 55 aas and 1 TMS. |
Eukaryota | Metazoa, Chordata | Phospholamban of Esox lucius (northern pike) |
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1.A.50.1.4 | Uncharacterized protein of 101 aas and 1 C-terminal TMS. |
Eukaryota | Metazoa, Chordata | UP of Acipenser ruthenus (sterlet) |
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1.A.50.2.1 | Sarcolipin (SLN) anion pore-forming protein of 31 aas and 1 TMS, with selectivity for Cl- and H2PO4-. Oligomeric interactions of sarcolipin and the Ca-ATPase have been documented (Autry et al., 2011). Sarcolipin, but not phospholamban, promotes uncoupling of the SERCA pump (3.A.3.2.7; Sahoo et al. 2013). SNL forms pentameric pores that can transport water, H+, Na+, Ca2+ and Cl-. Leu21 serves as the gate (Cao et al. 2015). In the channel, water molecules near the Leu21 pore demonstrated a clear hydrated-dehydrated transition (Cao et al. 2016). Small ankyrin 1 (sAnk1; TC#8.A.28.1.2) and SLN interact with each other in their transmembrane domains to regulate SERCA (TC# 3.A.3.2.7) (Desmond et al. 2017). The TM voltage has a positive effect on the permeability of water molecules and ions (Cao et al. 2020). The conserved C-terminus is an essential element required for the dynamic control of SLN regulatory function (Aguayo-Ortiz et al. 2020). |
Eukaryota | Metazoa, Chordata | SLN of Homo sapiens (O00631) |
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1.A.50.2.2 | Sarcolipin protein of 32 aas and 1 TMS. |
Eukaryota | Metazoa, Chordata | Sarcolipin of Esox lucius (northern pike) |
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1.A.50.2.3 | Sarcolipin-like protein (SLN) of 31 aas and 1 TMS. This protein is homologous to a region of several proteins in the DMT family (e.g., TC# 2.A.7.24.10). |
Eukaryota | Metazoa, Chordata | SLN of Ovis aries (Sheep) |
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1.A.50.2.4 | Uncharacterized protein of 205 aas and 2 C-terminal TMSs |
Eukaryota | Metazoa, Chordata | UP of Etheostoma spectabile (orangethroat darter) |
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1.A.50.2.5 | Sarcoplipin of 119 aas and 1 C-terminal TMS |
Eukaryota | Metazoa, Chordata | Sarcolipin of Equus asinus (ass) |
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1.A.50.3.1 | Myoregulin of 46 aas and 1 C-terminal TMS (Anderson et al. 2015). Myoregulin (MLN) is a member of the regulin family, a group of homologous membrane proteins that bind to and regulate the activity of the sarcoplasmic reticulum Ca2+-ATPase (SERCA). MLN, which is expressed in skeletal muscle, contains an acidic residue in its transmembrane domain. The location of this residue, Asp35, is unusual. Asp35 controls SERCA inhibition by populating a bound-like orientation of MLN. Liu et al. 2023 proposed that Asp35 provides a functional advantage over other members of the regulin family by populating preexisting MLN conformations required for MLN-specific regulation of SERCA. |
Eukaryota | Metazoa, Chordata | Myoregulin of Homo sapiens |
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1.A.50.3.2 | Myoregulin of 43 aas and 1 C-terminal TMS. |
Eukaryota | Metazoa, Chordata | Myoregulin of Echinops telfairi |
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1.A.50.3.3 | Myoregulin of 105 aas and one C-terminal TMS. |
Eukaryota | Metazoa, Chordata | Myoregulin of Sarcophilus harrisii (Tasmanian devil) (Sarcophilus laniarius) |
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1.A.50.4.1 | DWORF of 34 aas and 1 TMS (Nelson et al. 2016). Counteracts the inhibitory effects of single transmembrane peptides, phospholamban (TC# 1.A.50.1), sarcolipin (1.A.50.2) and myoregulin (1.A.50.3), on SERCA (TC# 3.A.3.2). DWORF also activates SERCA in the absence of PLM (Li et al. 2021). Homology with the inhibitory peptides has been established for these peptides, all of which have about the same size with a single C-terminal TMS (D. Tyler & M. Saier, unpublished results). These single-pass membrane proteins are called regulins. Unlike other regulins, dwarf open reading frame (DWORF) expressed in cardiac muscle has a unique activating effect. Reddy et al. 2021 determined the structure and topology of DWORF in lipid bilayers using a combination of oriented sample solid-state NMR spectroscopy and replica-averaged orientationally restrained molecular dynamics. They found that DWORF's structural topology consists of a dynamic N-terminal domain, an amphipathic juxtamembrane helix that crosses the lipid groups at an angle of 64 degrees , and a transmembrane C-terminal helix with an angle of 32 degrees. A kink induced by Pro15, unique to DWORF, separates the two helical domains. A single Pro15Ala mutant significantly decreases the kink and eliminates DWORF's activating effect on SERCA. |
Eukaryota | Metazoa, Chordata | DWORF of Homo sapiens |
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1.A.50.4.2 | Sarcoplasmic/endoplasmic reticulum calcium ATPase regulator, DWORF-like protein, of 37 aas and 1 TMS. |
Eukaryota | Metazoa, Chordata | DWORF of Esox lucius |
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1.A.50.4.3 | DWARF open reading frameof 82 aas and 1 C-terminal TMS. |
Eukaryota | Metazoa, Chordata | DWARF of Oreochromis niloticus |
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1.A.50.4.4 | DWARF open reading frame isoform X1 of 99 aas and 1 C-terminal TMS. |
Eukaryota | Metazoa, Chordata | DWARF of Athene cunicularia |
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1.A.50.4.5 | Dwarf homolog, isoform X2, of 123 aas and 1 C-terminal TMS. |
Eukaryota | Metazoa, Chordata | DWARF of Paramormyrops kingsleyae |
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1.A.50.4.6 | DWARF or STRIT1 of 35 aas and 1 TMS. DWARF interacts with SERCA and phospholamban (PLB), counteracting the inhibitory effect of PLB on SERCA (Rustad et al. 2023). It enhances the activity of the ATP2A1/SERCA1 ATPase in the sarcoplasmic reticulum by displacing ATP2A1/SERCA1 inhibitors, thereby acting as a key regulator of skeletal muscle activity. It does not directly stimulate SERCA pump activity, but it enhances sarcoplasmic reticulum Ca2+ uptake and myocyte contractility by displacing the SERCA inhibitory peptides sarcolipin (SLN), phospholamban (PLN) and myoregulin (MRLN). |
Eukaryota | Metazoa, Chordata | DWARF of Homo sapiens |
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1.A.50.6.1 | "Another-regulin", ALN, of 66 aas and 1 TMS. Also called Protein C4orf3. This protein and the other members of the phospholamban family have been designated "micropeptides". Micropeptides function as regulators of calcium-dependent signaling in muscle. The sarco/endoplasmic reticulum Ca2+ ATPase (SERCA, TC# 3.A.3.2.7), is the membrane pump that promotes muscle relaxation by taking up Ca2+ into the sarcoplasmic reticulum. It is directly inhibited by three known muscle-specific micropeptides: myoregulin (MLN), phospholamban (PLN) and sarcolipin (SLN). In non muscle cells, there are two other such micopeptides, endoregulin (ELN) and "another-regulin" (ALN) (Anderson et al. 2016). These proteins share key amino acids with their muscle-specific counterparts and function as direct inhibitors of SERCA pump activity. The distribution of transcripts encoding ELN and ALN mirror that of SERCA isoform-encoding transcripts in nonmuscle cell types. Thus, these two proteins are additional members of the SERCA-inhibitory micropeptide family, revealing a conserved mechanism for the control of intracellular Ca2+ dynamics in both muscle and nonmuscle cell types (Anderson et al. 2016). |
Eukaryota | Metazoa, Chordata | ALN in Homo sapiens |
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1.A.50.6.2 | Uncharacterized protein of 93 aas and 1 TMS. |
Eukaryota | Metazoa, Chordata | UP of Larimichthys crocea (large yellow croaker) |
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1.A.50.6.3 | Uncharacterized protein of 104 aas and 1 TMS |
Eukaryota | Metazoa, Chordata | UP of Xenopus laevis (African clawed frog) |
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1.A.50.6.4 | Uncharacterized C4orf3 homologue of 77 aas and 1 TMS |
Eukaryota | Metazoa, Chordata | UP of Monodelphis domestica (Gray short-tailed opossum) |
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1.A.50.6.5 | Uncharacterized protein of 139 aas and one C-terminal TMS. |
Eukaryota | Metazoa, Chordata | UP of Oryzias melastigma (Indian medaka) |
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1.A.50.6.6 | Uncharacterized protein of 82 aas and 1 C-terminal TMS. |
Eukaryota | Metazoa, Chordata | UP of Platysternon megacephalum (big-headed turtle) |
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1.A.50.7.1 | Neuronatin, NNAT, of 81 aas and 1 TMS. NNAT, in the endoplasmic reticulum, is involved in metabolic regulation. It shares sequence similarity with sarcolipin (SLN; TC# 1.A.50.2.1), which negatively regulates the SERCA that maintains energy homeostasis in muscles. Braun et al. 2021 showed that NNAT could uncouple the Ca2+ transport activity of SERCA from ATP hydrolysis like SLN. NNAT reduced Ca2+ uptake without altering SERCA activity, ultimately lowering the apparent coupling ratio of SERCA. This effect of NNAT was reversed by the adenylyl cyclase activator forskolin. Soleus muscles from high fat diet-fed mice showed downregulation in NNAT content compared with chow-fed mice, whereas an upregulation in NNAT content was observed in fast-twitch muscles from high fat diet- versus chow-fed mice. Therefore, NNAT is a SERCA uncoupler and may function in adaptive thermogenesis (Braun et al. 2021). |
Eukaryota | Metazoa, Chordata | NNAT of Homo sapiens |
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1.A.50.7.2 | Neuronatin isoform X1 of 133 aas and 1 N-terminal TMS. |
Eukaryota | Metazoa, Chordata | NNAT of Phyllostomus discolor (pale spear-nosed bat) |
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1.A.51.1.1 | The voltage-gated proton channel, mVSOP (269 aas and 2 TMSs) (Sasaki et al., 2006). A hydrophobic plug functions as the gate (Chamberlin et al. 2013). Gating current measurements revealed that voltage-sensor (VS) activation and proton-selective aqueous conductance opening are thermodynamically distinct steps in the Hv1 activation pathway and showed that pH changes directly alter VS activation. Gating cooperativity, pH-dependent modulation, and a high degree of H+ selectivity have been demonstrated (De La Rosa and Ramsey 2018). |
Eukaryota | Metazoa, Chordata | mVSOP of Mus musculus (Q9DCE4) |
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1.A.51.1.2 |
The voltage-gated proton channel, Hv1, Hv1, HV1 or HVCN1 (273 aas) (Ramsey et al., 2006). Thr29 is a phosphorylation site that activates the HVCN1 channel in leukocytes (Musset et al., 2010). The condctivity pore has been delineated and depends of a carboxyl group (Asp or Glu) in the channel (Morgan et al. 2013). The four transmembrane helices sense voltage and the pH gradient, and conduct protons exclusively. Selectivity is achieved by the unique ability of H3O+ to protonate an Asp-Arg salt bridge. Pathognomonic sensitivity of gating to the pH gradient ensures HV1 channel opening only when acid extrusion will result, which is crucial to its biological functions (DeCoursey 2015). An exception occurs in dinoflagellates (see 1.A.51.1.4) in which H+ influx through HV1 triggers a bioluminescent flash. The gating mechanism of Hv1, cooperativity within dimers and the sensitivity to metal ions have been reviewed (Okamura et al. 2015). How this channel is activated by cytoplasmic [H+] and depolarization of the membrane potential has been proposed by Castillo et al. 2015. The extracellular ends of the first transmembrane segments form the intersubunit interface that mediates coupling between binding sites, while the coiled-coil domain does not directly participate in the process (Hong et al. 2015). Deep water penetration through hHv1 has been observed, suggesting a highly focused electric field, comprising two helical turns along the fourth TMS. This region likely contains the H+ selectivity filter and the conduction pore. A 3D model offers an explicit mechanism for voltage activation based on a one-click sliding helix conformational rearrangement (Li et al. 2015). Trp-207 enables four characteristic properties: slow channel opening, highly temperature-dependent gating kinetics, proton selectivity, and ΔpH-dependent gating (Cherny et al. 2015). The native Hv structure is a homodimer, with the two channel subunits functioning cooperatively (Okuda et al. 2016). Segment S3 plays a role in activating gating (Sakata et al. 2016). Two sites have been identified: one is the binding pocket of 2GBI (accessible to ligands from the intracellular side); the other is located at the exit site of the proton permeation pathway (Gianti et al. 2016). Crystal structures of Hv1 dimeric channels revealed that the primary contacts between the two monomers are in the C-terminal domain (CTD), which forms a coiled-coil structure. Molecular dynamics (MD) simulations of full-length and truncated CTD models revealed a strong contribution of the CTD to the packing of the TMSs (Boonamnaj and Sompornpisut 2018). Histidine-168 is essential for the ΔpH-dependent gating (Cherny et al. 2018). Proton transfer in Hv1 utilizes a water wire, and does not require transient protonation of a conserved aspartate in the S1 transmembrane helix (Bennett and Ramsey 2017). Hv1 channels are present in bull spermatozoa, and these regulate sperm functions like hypermotility, capacitation and acrosome reaction through a complex interplay between different pathways involving cAMP, PKC, and Catsper (Mishra et al. 2019). A zinc binding site influences gating configurations of HV1 (Cherny et al. 2020). The discovery and validation of Hv1 proton channel inhibitors with onco-therapeutic potential have been described (El Chemaly et al. 2023). Nitrates can stimulate the biosynthesis of hydrophilic yellow pigments (HYPs) in Monascus ruber (Huang et al. 2023). ATP influences Hv1 activity via direct molecular interactions, and its functional characteristics are required for the physiological activity of Hv1 (Kawanabe et al. 2023). Trp207 regulates voltage-dependent activation of the human Hv1 proton channel. (Zhang et al. 2024). |
Eukaryota | Metazoa, Chordata | Hv1 of Homo sapiens (Q96D96) |
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1.A.51.1.3 | Voltage-gated proton channel, HvCN1; VSOP; VSX1 (Sasaki et al., 2006). Exhibits voltage and pH-dependent gating as well as Zn2+-reactivity. In the dimeric strcuture, each subumit has a proton channel. TMS4 appears to be the voltage sensor. Subunit cooperativity has been demonstrated (Gonzalez et al. 2010). The activation of the Hv1 voltage sensor is governed by electrostatic-hydrophobic interactions, and S4 arginines, N264 and the selectivity filter (D160) are essential in the Ciona-Hv1 to understand the trapping of the voltage sensor (Fernández et al. 2023).
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Eukaryota | Metazoa, Chordata | HvCN1 of Ciona intestinalis (Q1JV40) |
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1.A.51.1.4 | Voltage-gated proton-specific monomeric channel, kHv1. Activated by depolarization; functions in signaling and excitability to trigger bioluminescence (Smith et al., 2011). Hv1 most likely forms an internal water wire for selective proton transfer, and interactions between water molecules and S4 arginines may underlie coupling between voltage- and pH-gradient sensing (Ramsey et al. 2010). |
Eukaryota | kHv1 of Karlodinium veneficum (G5CPN9) |
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1.A.51.1.5 | Proton channel protein, NpHv1 of 239 aas and 4 TMSs. Proton selectivity, and pH- and voltage-dependent gating have been demoonstrated. Mutations in the first transmembrane segment at position 66 (Asp66), the presumed selectivity filter, led to a loss of proton-selective conduction (Chaves et al. 2016). |
Eukaryota | Metazoa, Arthropoda | NpHv1 of Nicoletia phytophila |
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1.A.51.1.6 | Hv1 proton channel of 223 aas and 4 TMSs. It's proton transport activity has been demonstrated (Zhao and Tombola 2021). |
Eukaryota | Fungi, Basidiomycota | Hv1 of Suillus luteus |
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1.A.51.1.7 | Proton channel protein of 211 aas and 4 TMSs. It's proton channel activity has been demonstrated and shown to differ in its regulation from the fungal channel with TC# 1.A..51.1.6 (Zhao and Tombola 2021). The presence of protein sequences corresponding to such channels were demonstrated in all four types of fungi (Zhao and Tombola 2021). |
fungi | Fungi, Ascomycota | Hv1 of Aspergillus oryzae |
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1.A.51.2.1 | The voltage-sensor containing phosphatase, VSP, of 576 aas and 4 TMSs N-terminal to the phosphatase domain. The enzyme region of VSP contains the phosphatase and C2 domains, is structurally similar to the tumor suppressor phosphatase PTEN, and catalyzes the dephosphorylation of phosphoinositides. The transmembrane voltage sensor is connected to the phosphatase through a short linker region, and phosphatase activity is induced upon membrane depolarization (Zhang et al. 2018). The coupling between the two domains has been studied (Sakata et al. 2017). Membrane depolarization activates the phosphatase activity of the enzyme, presumably via electroconformational coupling between the sensor domain and the enzyme (Sanders and Hutchison 2018). Both the phosphatase domain and the C2 domain move with similar timing upon membrane depolarization (Sakata and Okamura 2018). Four states are visited sequentially in a stepwise manner during voltage activation, each step translocating one arginine or the equivalent of approximately 1 e0 across the membrane electric field, yielding a transfer of approximately 3 e0 charges in total for the complete process (Shen et al. 2022).
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Eukaryota | Metazoa, Chordata | VSP of Ciona intestinalis (Transparent sea squirt) (Ascidia intestinalis) |
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1.A.51.2.2 | Voltage-sensing phosphatase-2, VSP2, isoform X1, of 509 aas with 4 N-terminal TMSs that comprise the voltage sensor. |
Eukaryota | Metazoa, Chordata | VSP2 of Xenopus laevis (African clawed frog) |
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1.A.51.2.3 | Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase, TPTE2, isoform gamma of522 aas and 4 TMSs. |
Eukaryota | Metazoa, Chordata | TPTE2 of Homo sapiens |
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1.A.51.2.4 | Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase, PTEN of 403 aas and 1 N-terminal TMS. It acts as a dual-specificity lipid phosphatase and a protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins (Li and Sun 1997). It is involved in the regulation of synaptic function in excitatory hippocampal synapses, and is recruited to the postsynaptic membrane upon NMDA receptor activation. It is also required for the modulation of synaptic activity during plasticity. Enhancement of lipid phosphatase activity is able to drive depression of AMPA receptor-mediated synaptic responses, activity required for NMDA receptor-dependent long-term depression. Its expression is not affected by smoking of cigarettes or e-cigarettes (Shabestari et al. 2023). |
Eukaryota | Metazoa, Chordata | PTEN of Homo sapiens |
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1.A.52.1.1 | The CRAC channel protein, Orai1 (CRACM1) (Prakriya et al. 2006), complexed with the STIM1 or STIM2 protein (Feske et al., 2006). Replacement of the conserved glutamate in the first TMS with glutamine (E106Q) acts as a dominant-negative protein, and substitution with aspartate (E106D) enhances Na+, Ba2+, and Sr2+ permeation relative to Ca2+. Mutating E190Q in TMS3 also affects channel selectivity, suggesting that glutamate residues in both TMS1 and TMS3 face the lumen of the pore (Vig et al. 2006). The Orai1:Stim stoichiometry = 4:2 (Ji et al., 2008). Human Orai1 and Orai3 channels are dimeric in the closed resting state and open states. They are tetrameric when complexed with STIM1 (Demuro et al., 2011). A dimeric form catalyzes nonselective cation conductance in the STIM1-independent mode. STIM1 domains have been characterized (How et al. 2013). Alternative translation initiation of the Orai1 message produces long and short types of Ca2+ channels with distinct signaling and regulatory properties (Desai et al. 2015). STIM2 plays roles similar to STIM1 in regulating basal cytosolic and endoplasmic reticulum Ca2+ concentrations by controling Orai1, 2 and 3. STIM2 may inhibit STIM1-mediated Ca2+ influx. It also regulates protein kinase A-dependent phosphorylation and trafficking of AMPA receptors (TC# 1.A.10) (Garcia-Alvarez et al. 2015). A mechanistic model for ROS (H2O2)-mediated inhibition of Orai1 has been determined (Alansary et al. 2016). Regions that are important for the optimal assembly of hetero-oligomers composed of full-length STIM1 with its minimal STIM1-ORAI activating region, SOAR, have been identified (Ma et al. 2017). Orai1 may be multifunctional (Carrell et al. 2016). Activatioin of Orai1 requires communication between the N-terminus and loop 2 (Fahrner et al. 2017). STIM1 dimers unfold to expose a discrete STIM-Orai activating region (SOAR1) that tethers and activates Orai1 channels within discrete ER-PM junctions (Zhou et al. 2018). SOAR dimer cross-linking leads to substantial Orai1 channel clustering, resulting in increased efficacy and cooperativity of Orai1 channel function. In addition to being an ER Ca2+ sensor, STIM1 functions within the PM to exert control over the operation of SOCs. As a cell surface signaling protein, STIM1 represents a key pharmacological target to control fundamental Ca2+-regulated processes including secretion, contraction, metabolism, cell division, and apoptosis (Spassova et al. 2006). STIM1 also contributes to smooth muscle contractility (Feldman et al. 2017). STIM1-mediated Orai1 channel gating, involves bridges between TMS 1 and the surrounding TMSs 2/3 ring, and these are critical for conveying the gating signal to the pore (Yeung et al. 2018). A review article summarizes the current high resolution structural data on specific EF-hand, sterile alpha motif and coiled-coil interactions which drive STIM function in the activation of Orai1 channels (Novello et al. 2018). Orai1 and STIM1 are involved in tubular aggregate myopathy (Wu et al. 2018). Knowledge of the structure-function relationships of CRAC channels, with a focus on key structural elements that mediate the STIM1 conformational switch and the dynamic coupling between STIM1 and ORAI1 has been discussed (Nguyen et al. 2018). While STIM1 is the native channel opener, a chemical modulator is 2-aminoethoxydiphenyl borate (2-APB) (Ali et al. 2017). ORAI1 channel gating and selectivity iare differentially altered by natural mutations in the first and third transmembrane domains (Bulla et al. 2018). Stim1 responds to both ER Ca2+ depletion and heat, mediates temperature-induced Ca2+ influx in skin keratinocytes via coupling to Orai Ca2+ channels in the plasma membrane, and thereby brings about thermosensing (Liu et al. 2019). Possibly, the interplay between STIM1 alpha3 and Orai1 TM3 allows STIM1 coupling to be transmitted into physiological CRAC channel activation (Butorac et al. 2019). Blockage of store-operated Ca2+ influx by synta66 is mediated by direct inhibition of the Ca2+ selective orai1 pore (Waldherr et al. 2020). The carboxy terminal coiled-coil region modulates Orai1 internalization during meiosis (Hodeify et al. 2021). ORAI1 mutations disrupt channel trafficking, resulting in combined immunodeficiency (Yu et al. 2021). Orai channel C-terminal peptides are key modulators of STIM-Orai coupling and calcium signal generation (Baraniak et al. 2021). Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation (Grieve et al. 2021). STIM1-dependent peripheral coupling governs the contractility of vascular smooth muscle cells (Krishnan et al. 2022). Gating checkpoints in the Orai1 calcium channel have been identified (Augustynek et al. 2022). Photocrosslinking-induced CRAC channel-like Orai1 activation occurs independently of STIM1 (Maltan et al. 2023). The Ca2+ channel ORAI1 is a regulator of oral cancer growth and nociceptive pain (Son et al. 2023). In T cells, STIM and Orai are dispensable for conventional T cell development, but critical for activation and differentiation. Gross et al. 2023 reviewed novel STIM-dependent mechanisms for control of Ca2+ signals during T cell activation and its impact on mitochondrial function and transcriptional activation for control of T cell differentiation and function. Water in peripheral TM-interfaces of Orai1-channels triggers pore opening (Hopl et al. 2024). STIM1 and STIM2, single-pass ER-transmembrane proteins with their N- and C-termini located in the ER lumen and cytoplasm, respectively, are the primary regulatory protein that governs the function of Orai channels. The N-terminal EF-SAM domains of STIMs sense [Ca2+]ER changes, while the C-terminus mediates clustering in ER-PM junctions and gating of Orai1. ER-Ca2+ store depletion triggers activation of the STIM proteins, which involves their multimerization and clustering in ER-PM junctions, where they recruit and activate Orai1 channels (Narayanasamy et al. 2024). The N-terminal SAM regions in STIM1 play roles in multimerization and function (Sallinger et al. 2024). |
Eukaryota | Metazoa, Chordata | Orai1/STIM1 complex of Homo sapiens |
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1.A.52.1.2 | The ARC (Arachidonate-regulated Ca2+-selective) channel, a complex of STIM1, Orai1 and Orai3 (Mignen et al., 2008). It is a heteropentameric assembly of three Orai1 subunits and two Orai3 subunits (Mignen et al., 2009). (But see Demuro et al., 2011; 1.A.52.1.1). Molecular determinants within the N-terminus control channel activation and gating (Bergsmann et al., 2011). Specifically activated by high concentrations (>50 microM) of 2-aminoethyl diphenylborinate (2-APB) (Amcheslavsky et al. 2014). The CC1-SOAR region of STIM1 is a direct activation domain of temperature, leading to subsequent STIM1 activation, and the transmembrane (TM) region and K domain but not EF-SAM region were needed for this process. Furthermore, both the TM and SOAR domains exhibited similarities and differences between STIM1-mediated thermal sensation and store-operated calcium entry (SOCE), and the key sites of Orai1 showed similar roles in these two responses. Additionally, the TM23 (comprising TM2, loop2, and TM3) region of Orai1 was identified as the key domain determining the STIM1/Orai1 thermal response pattern (Liu et al. 2023). |
Eukaryota | Metazoa, Chordata | Orai3 of Homo sapiens (Q9BRQ5) |
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1.A.52.1.3 | The CRAC channel Orai2 (DUF 1650) (264 aas) (Gross et al., 2007). |
Eukaryota | Metazoa, Chordata | Orai2 of Mus musculus (Q8BH10) |
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1.A.52.1.4 |
Insect STIM1/Orai1 (Hull et al., 2010). Influences sex pheromone production in moths. |
Eukaryota | Metazoa, Arthropoda | Stim1/Orai1A or B of Bombyx mori |
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1.A.52.1.5 | Ca2+ release-activated Ca2+ (CRAC) channel subunit, Orai, which mediates Ca2+ influx following depletion of intracellular Ca2+ stores. In Greek mythology, the 'Orai' are the keepers of the gates of heaven. The crystal structure (3.35 Å), revealed a hexameric assembly of Orai subunits arranged around a central ion pore which traverses the membrane and extends into the cytosol. A ring of glutamate residues on its extracellular side forms the selectivity filter. A basic region near the intracellular side can bind anions that may stabilize the closed state. The architecture of the channel differs from those of other solved ion channels (Hou et al. 2012). Residues in the third TMS of orai affect the conduction properties of the channel (Alavizargar et al. 2018); a conserved glutamate residue (E262) contributes to selectivity. Mutation of this residue affected the hydration pattern of the pore domain, and impaired selectivity of Ca2+ over Na+. The crevices of water molecules are located to contribute to the dynamics of the hydrophobic gate and the basic gate, suggesting a possible role in channel opening and in selectivity function (Alavizargar et al. 2018). The Orai channel is characterized by voltage independence, low conductance, and high Ca2+ selectivity and plays a role in Ca2+ influx through the plasma membrane (PM). Liu et al. 2019 reported the crystal structure and cryo-EM reconstruction of a mutant (P288L) channel that is constitutively active. The open state showed a hexameric assembly in which 6 TMS 1 helices in the center form the ion-conducting pore, and 6 TMS 4 helices in the periphery form extended long helices. Orai channel activation requires conformational transduction from TM4 to TM1 and causes the basic section of TM1 to twist outward. The wider pore on the cytosolic side aggregates anions to increase the potential gradient across the membrane and thus facilitate Ca2+ permeation (Liu et al. 2019). |
Eukaryota | Metazoa, Arthropoda | Orai (Olf186-F) of Drosophila melanogaster |
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1.A.52.2.1 | Orai homologue (494aas; 4 or 5 TMSs) |
Eukaryota | Viridiplantae, Chlorophyta | Orai homologue in Ostreococcus tauri (Q012G5) |
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1.A.52.3.1 | Orai homologue (244aas; 4 TMSs) |
Eukaryota | Oomycota | Orai homologue in Phytophthora infestans T30-4 (D0NKP9) |
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1.A.53.1.1 | Hepatitis C Virus, HCV-P7, of 63 aas and 2 TMSs (Clarke et al., 2006). It's mechanism and function have been investigated in considerable detail (Gan et al. 2014). Histidine-17, which faces the lumen of the pore when protonated, allows Cl- entry, but deprotonation also allows Ca2+ entry. Imposition of voltage creates a Cl- current (Wang et al. 2014). The structure and dual pore/ion channel activity of p7 of different HCV genotypes have been reviewed (Madan and Bartenschlager 2015). It may transport protons (Scott and Griffin 2015); it's structure has been determined by NMR (Montserret et al. 2010) and by electron microscopy (Luik et al. 2009). The p7 N-terminal helical region is critical for E2/p7 processing, protein-protein interactions, ion channel activity, and infectious HCV production (Scull et al. 2015). HCV p7 is released from the viral polyprotein through cleavage at E2-p7 and p7-NS2 junctions by signal peptidase, but also exists as an E2p7 precursor. The retarded E2p7 precursor cleavage is essential to regulate the intracellular and secreted levels of E2 through p7-mediated modulation of the cell secretory pathway (Denolly et al. 2017). Chen et al. 2018 provided evidence that the oligomeric channel is a cation-selective hexamer. The his-9 in the hexameric model forms a first gate, acting as a selectivity filter for cations. while valines form a second gate, serving as a hydrophobic filter for dehydrated cations. The binding pocket for the channel blockers, amantadine and rimantadine, is composed of residues 20-26 in H2 helix and 52-60 in H3 helix (Ying et al. 2018). Two of the best inhibitors were ARD87 and ARD112 (Wei et al. 2021).
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Viruses | Orthornavirae, Kitrinoviricota | P7 of hepatitis C virus (63 aas; 2 TMSs; CAH23613) |
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1.A.53.1.10 | Channel forming Hepatitis C virus NS4a peptide (54 aas) (viroportin NS4a). The NS4a peptide has been shown to form pores (Madan et al. 2007). This protein is a peptide fragment of the large glycoproteins of the Hepatitis C Virus. |
Viruses | Flaviviridae | Hepatitis C virus NS4a peptide (D2K2A7) |
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1.A.53.1.11 | Hepatitis GB virus B (GBV-B) polyprotein of 2864 aas, containing the p13 viroporin. It is found between residues 614 and 733 in the polyprotein and has 4 predicted TMSs. It is homologous to but larger than the p7 protein of hepatitis C virus (Ghibaudo et al. 2004). |
Viruses | Riboviria | Polyprotein B of GBV-B virus |
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1.A.53.1.2 | p7 protein from the hepatitis C virus subtype 3a polyprotein. Molecular interactions between NS2 and p7 and E2 have been observed, and the NS2 transmembrane region is required for both E2 interaction and subcellular localization. Specific mutations in core, envelope proteins, p7 and NS5A abolish viral assembly (Popescu et al. 2011). |
Viruses | Orthornavirae, Kitrinoviricota | p7 of hepatitis C virus subtype 3a |
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1.A.53.1.3 | Polyprotein containing p7 of hepacivirus AK. Ion channel activity has been demonstrated in lipid bilayers (Walter et al. 2016). |
Viruses | Orthornavirae, Kitrinoviricota | Polyprotein of hepacivirus AK |
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1.A.53.1.4 | Classical Swine Fever Virus (CSFVA) p7 viroporin (70 aas; 2 TMSs) which probably transports Ca2+ and other inorganic cations (Scott and Griffin 2015). The p7 protein induces IL-1β secretion which is inhibited by the ion channel blocker amantadine. The p7 protein is a short-lived protein degraded by the proteasome (Lin et al. 2014). CSFV-p7 forms pores wide enough to allow ANTS (MW, 427 Da) release. Two pore structures with slightly different sizes and opposite ion selectivities were detected (Largo et al. 2016). The relative abundances of these pore types depend on membrane composition suggesting that the physicochemical properties of the lipid bilayers present in the cell endomembrane system modulate viroporin activity. Permeabilization of ER membranes by CSFV p7 depends on two sequence determinants: the C-terminal transmembrane helix (involved in pore formation), and the preceding polar loop that regulates its insertion and activity. The pore-forming domain of p7 may assemble into finite pores with approximate diameters of 1 and 5nm. Formation of the larger pores can hamper virus production without affecting ER localization or homo-oligomerization (Largo et al. 2018). p7 specifically interacts with host protein CAMLG, an integral ER transmembrane protein involved in intracellular calcium release regulation and signal response generation. Mutants of p7 have decreased virulence in swine (Gladue et al. 2018). |
Viruses | Orthornavirae, Kitrinoviricota | CSFVA P7 viroporin of Classical Swine Fever Virus (Q9YS30) |
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1.A.53.1.5 | The borine viral diarrhea virus (BVDV) p7 peptide, viral budding process initiator. It probably transports H+ and other cations (Scott and Griffin 2015). |
Viruses | Orthornavirae, Kitrinoviricota | p7 of Bovine viral diarrhea virus (AAB47140) polyprotein: Q96662. |
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1.A.53.1.6 | Genome polyprotein [Cleaved into: Core protein p21 (Capsid protein C) (p21); Core protein p19; Envelope glycoprotein E1 (gp32) (gp35); Envelope glycoprotein E2 (NS1) (gp68) (gp70); p7; Protease NS2-3 (p23) (EC 3.4.22.-); Serine protease NS3 (EC 3.4.21.98) (EC 3.6.1.15) (EC 3.6.4.13) (Hepacivirin) (NS3P) (p70); Non-structural protein 4A (NS4A) (p8); Non-structural protein 4B (NS4B) (p27); Non-structural protein 5A (NS5A) (p56); RNA-directed RNA polymerase (EC 2.7.7.48) (NS5B) (p68)]. The core protein (C) corresponds to residues 1 - 233 in the polyprotein (GenBank acc. # AFS60319.1) (Devi et al. 2022). Proteolytic intermediates of C with an intact transmembrane ER-anchor assemble into pore-like structures in the ER membrane (Devi et al. 2022). ATAD1 inhibits hepatitis C virus infection by removing the viral TA-protein NS5B from mitochondria (Zhou et al. 2023). |
Viruses | Orthornavirae, Kitrinoviricota | POLG_HCVVN of Hepatitis C virus genotype 6d |
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1.A.53.1.7 | Genome polyprotein [Cleaved into: Core protein p21 (Capsid protein C) (p21); Core protein p19; Envelope glycoprotein E1 (gp32) (gp35); Envelope glycoprotein E2 (NS1) (gp68) (gp70); p7; Protease NS2-3 (p23) (EC 3.4.22.-); Serine protease NS3 (EC 3.4.21.98) (EC 3.6.1.15) (EC 3.6.4.13) (Hepacivirin) (NS3P) (p70); Non-structural protein 4A (NS4A) (p8); Non-structural protein 4B (NS4B) (p27); Non-structural protein 5A (NS5A) (p56); RNA-directed RNA polymerase (EC 2.7.7.48) (NS5B) (p68)] | Viruses | Orthornavirae, Kitrinoviricota | POLG_HCVEU of Hepatitis C virus genotype 6a | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.53.1.8 | Hepatitis C virus p7 protein. The NMR structure is available. The channel is cation-selective and is inhibited by hexamethylene amiloride but not by amantadine. The protein has an N-terminal α-helix that precedes TMS1, and TMSs 1 and 2 are connected by a long cytosolic loop bearing a dibasic motif (Montserret et al. 2010). p7 forms an ion channel and is indispensable for HCV particle production. Although the main target of HCV p7 is the endoplasmic reticulum, it also targets mitochondria., causes mitochondrial depolarization and ATP depletion, and causes mitochondrial dysfunction to support HCV particle production (You et al. 2017). |
Viruses | Orthornavirae, Kitrinoviricota | p7 of Hepatitis C virus strain HCV-J (genotype 1b) |
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1.A.53.1.9 | Viroporin of 63 aas and 2 TMSs. |
Viruses | Orthornavirae, Kitrinoviricota | Viroporin of Bovine viral diarrhea virus (BVDV) (Mucosal disease virus) |
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1.A.54.1.1 | Presenilin-1 (PS-1; PS1; PSEN1; PSNL1; STM-1; E5-1; AD; AD3) of 467 aas and 9 or 10 TMSs in a 6 or 7 + 3 TMS arrangement. Ca2+ leak channel (part of the γ-secretase complex; expression alters the lipid raft composition in neuronal membranes (Eckert and Müller, 2009)). The first 5 TMSs of presenilin-1 are homologous to the 5 TMS CD47 antigenic protein, a constituent of the osteoclast fusion complex (1.N.1.1.1), and CD47 is therefore a presenilin homologue. The active site of gamma-secretase resides in an aqueous catalytic pore within the lipid bilayer and is tapered around the catalytic aspartates (Sato et al. 2006). TMS 6 and TMS 7 contribute to the hydrophilic pore. Residues at the luminal portion of TMS 6 are predicted to form a subsite for substrate or inhibitor binding on the α-helix facing the hydrophilic milieu, whereas those around the GxGD catalytic motif within TMS 7 are water accessible (Sato et al. 2006). Mutations in PSEN1 or PSEN2 (TC# 1.A.5.1.2) can lead to Altzheimer's disease (Romero-Molina et al. 2022). |
Eukaryota | Metazoa, Chordata | Presenilin-1 of Homo sapiens (P49768) |
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1.A.54.1.2 | Presenilin-2 (PS-2; STM-2; E5-2; AD3 LP; AD5 PSN-2) Ca2+ leak channel of 448 aas and 9 TMSs. Presenilins 1 and 2 (PS1 & PS2) are main genetic risk factors of familial Alzheimer's disease (AD) that produce the beta-amyloid (Abeta) peptides. They also function in calcium signaling (Dehury et al. 2019). Mutations in both cause AD. The 9-TMS channel structure is substantially controlled by major dynamics in the hydrophilic loop bridging TMS6 and TMS7, which functions as a "plug" in the PS2 membrane channel. TMS2, TMS6, TMS7 and TMS9 flexibility controls the size of this channel. Most pathogenic PS2 mutations reduce stability relative to random mutations (Dehury et al. 2019). |
Eukaryota | Metazoa, Chordata | Presenilin-2 of Homo sapiens (448 aas; P49810) |
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1.A.54.2.1 | Archaeal presenilin homologue (DUF1119; COG3389; PSN). Members of the peptidase A22B superfamily (found in many archaea, but not bacteria, shows some sequence similarity to members of the LIV-E family, e.g., 2.A.78.2.1)) |
Archaea | Euryarchaeota | PSN of Haloquadratum walsbyi (339 aas; 9 TMSs; CAJ51633) |
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1.A.54.2.2 | Presenilin homologue (DUF1119) of 301 aas and 9 TMSs with known 3-d structure. The amino-terminal domain, consisting of TM1-6, forms a horseshoe-shaped structure, surrounding TM7-9 of the carboxy-terminal domain. The two catalytic aspartate residues are located on the cytoplasmic side of TMS 6 and TMS 7, spatially close to each other and approximately 8 Å into the lipid membrane surface. Water molecules gain constant access to the catalytic aspartates through a large cavity between the amino- and carboxy-terminal domains. (Li et al. 2013). Both protease and ion channel activities have been demostrated, and these two activities share the same active site (Kuo et al. 2015). Cleavage is controlled by both positional and chemical factors (Naing et al. 2018). |
Archaea | Euryarchaeota | Presenilin homologue of Methanoculleus marisnigri |
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1.A.54.3.1 | Signal peptide peptidase-2A (SPP2A; 523 aas; 8TMSs) There is no evidence for a transport function for this protease. The functions of these SPP and SPPL proteases have been reviewed (Mentrup et al. 2020). |
Eukaryota | Metazoa, Chordata | SPP2A of Mus musculus (Q9JJF9) |
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1.A.54.3.2 | Signal peptide peptidase like 2A, SPPL2A |
Eukaryota | Metazoa, Chordata | SPPL2A of Homo sapiens |
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1.A.54.3.3 | Signal peptide peptidase, SppL3 of 385 aas and 9 TMSs. Cleaves the single TMS in the neuronal ceroid lipofuscinoses (NCLs), a group of proteins causing recessive disorders of childhood with overlapping symptoms including vision loss, ataxia, cognitive regression and premature death (Jules et al. 2017). CLN5 is implicated in the recruitment of the retromer complex to endosomes, which is required to sort the lysosomal sorting receptors from endosomes to the trans-Golgi network. It is initially translated as a type II transmembrane protein and subsequently cleaved by SPPL3 into a mature soluble protein consisting of residues 93-407 and an N-terminal fragment is then further cleaved by SPPL3 and SPPL2b and degraded in the proteasome (Jules et al. 2017). |
Eukaryota | Metazoa, Chordata | Spp of Homo sapiens |
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1.A.54.3.4 | Signal peptide peptidase, Spp |
Eukaryota | Metazoa, Arthropoda | Spp of Drosophila melanogaster |
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1.A.54.3.5 | Impas 1 (IMP1, HM13, PSL3, APP, MARP086) possesses endoproteolytic activity against multipass membrane protein substrates, cleaving the presenilin 1 holoprotein (Moliaka et al. 2004). |
Eukaryota | Metazoa, Chordata | Impas 1 of Homo sapiens |
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1.A.54.4.1 | The pre-flagelin peptidase of 230 aas and 6 TMSs, FlaK, with known 3-d structure (3.6Å resolution) (Hu et al. 2011). This protein is a member of the presenilin/GxGD membrane protein family; it plays a dual role as protease and ion-conducting channel and is therefore called a "channzyme" (Kuo et al. 2015). |
Archaea | Euryarchaeota | FlaK of Methanococcus maripaludis |
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1.A.54.4.2 | Leader peptidase of 342 aas |
Archaea | Euryarchaeota | Leader peptidase of Natrinema pellirubrum |
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1.A.54.4.3 | Type IV leader peptidase of 289 aas and 7 TMSs. |
Archaea | Euryarchaeota | peptidase of Methanobrevibacter smithii |
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1.A.54.4.4 | Peptidase of 375 aas and 10 TMSs in a 4 + 1 + 4 +1 TMS arrangement. |
Archaea | Euryarchaeota | Peptidase of Thermococcus sibiricus |
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1.A.54.4.5 | Peptidase of 260 aas |
Archaea | Euryarchaeota | Peptidase of Methanosphaerula palustris |
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1.A.54.5.1 | Prepilliin peptidase A24 of 167 aas and 6 TMSs. |
Bacteria | Bacillota | Peptidase of Desulfotomaculum hydrothermale |
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1.A.54.5.2 | Peptidase A24 prepilin type IV of 158 aas |
Bacteria | Synergistota | Peptidase of Aminobacterium colombiense |
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1.A.54.5.3 | Peptidase of 286 aas |
Bacteria | Pseudomonadota | Peptidase of Acinetobacter pittii |
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1.A.54.5.4 | Leader peptidase, PppA or YghH of 269 aas and 8 TMSs. May be able to flip phospholipids from one lipid monolayer to another as a scramblase (Smeijers et al. 2006). |
Bacteria | Pseudomonadota | PppA of E. coli |
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1.A.54.6.1 | Uncharacterized protein of 229 aas and 6 TMSs. |
Archaea | Candidatus Thermoplasmatota | UP of Thermoplasma volcanium |
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1.A.55.1.1 | Mammalian Ca2+ channel, Flower, homologue, isoform a (Yao et al., 2009). |
Eukaryota | Metazoa, Chordata | Flower of Homo sapiens (Q9UGQ2) |
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1.A.55.1.2 | Insect Ca2+ channel, Flower (194 aas; 4 putative TMSs) |
Eukaryota | Metazoa, Arthropoda | Flower of Drosophila melanogaster (Q95T12) |
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1.A.55.1.3 | Roundworm Flower homologue (166aas) |
Eukaryota | Metazoa, Nematoda | Flower homologue of Caenorhabditis elegans (Q93533) |
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1.A.55.2.2 | Flower homologue of 175 aas and 3 putative TMSs |
Eukaryota | Flower homologue of Capsaspora owczarzaki |
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1.A.55.2.3 | Flower homologue of 193 aas |
Eukaryota | Fower homologue of Salpingoeca rosetta |
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1.A.55.3.1 | Flatworm Flower homologue (195aas) |
Eukaryota | Metazoa, Platyhelminthes | Flower homologue of Schistosoma japonicum (Q5DFV8) |
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1.A.55.4.1 | Fungal flower homologue (149aas) |
Eukaryota | Fungi, Ascomycota | Flower homologue of Aspergillus flavus (B8N1Q6) |
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1.A.55.4.2 | The yeast Tvp18p protein of 102 aas and 2 TMSs. |
Eukaryota | Fungi, Ascomycota | Tvp180 of Saccharomyces cerevisiae |
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1.A.55.4.3 | Uncharacterized protein of 127 aas and 4 TMSs |
Eukaryota | UP of Blastocystis hominis |
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1.A.55.5.1 | Uncharacterized protein of 151 aas and 3-4 putative TMSs. |
Eukaryota | UP of Ectocarpus siliculosus (Brown alga) |
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1.A.55.6.1 | Uncharacterized protein of 176 aas and 3 TMSs |
Eukaryota | Evosea | UP of Dictyostelium fasciculatum |
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1.A.55.6.2 | Uncharacterized protein of 154 aas and 3 TMSs |
Eukaryota | Evosea | UP of Dictyostelium discoideum |
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1.A.56.1.1 | Plasma membrane copper uptake transporter; takes up Cu2+ into the cytoplasm (Andrés-Colás et al. 2010). Met-rich motifs in the N-terminal region, an MXXXM motif in TMS-2, and a GXXXG motif in TMS-3 could be essential for Cu transport since they are highly conserved in all analyzed species (Vatansever et al. 2016). High-affinity copper transporters in Solanum lycopersicum have been characterized (Romero et al. 2021). |
Eukaryota | Viridiplantae, Streptophyta | CopT1 of Arabidopsis thaliana |
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1.A.56.1.10 | The vacuolar copper transporter, Ctr2 (Involved in spore germination and pathogenesis (Barhoom et al., 2008)) | Eukaryota | Fungi | Ctr2 of Colletotrichum gloeosporioides (A9XIK8) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.56.1.11 | Vacuolar/tonoplast copper transporter 5 (AtCOPT5). It exports copper from the vacuole to the cytoplasm and is required for photosynthetic electron transport under comditions of copper deficiency. It also promotes interorgan allocation of copper (Garcia-Molina et al. 2011; Klaumann et al. 2011). |
Eukaryota | Viridiplantae, Streptophyta | COPT5 of Arabidopsis thaliana |
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1.A.56.1.12 | Putative copper transporter 5.2 (OsCOPT5.2) | Eukaryota | Viridiplantae, Streptophyta | COPT5.2 of Oryza sativa subsp. japonica | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.56.1.13 | Copper transporter 3 (OsCOPT3) | Eukaryota | Viridiplantae, Streptophyta | COPT3 of Oryza sativa subsp. japonica | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.56.1.14 | Copper uptake system, COPT6. Interacts with itself and its homologue, COPT1. Regulated by copper availability by using SPL7 (Jung et al., 2012). |
Eukaryota | Viridiplantae, Streptophyta | COPT6 of Arabidopsis thaliana (Q8GWP3) |
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1.A.56.1.15 | Copper transport channel, PF14_0369 or CTR1 of 235 aas and 4 TMSs in a 1 (N-terminal) + 1 (central) + 2 (C-terminal) TMS arrangement (Choveaux et al. 2012). It binds Cu+ and is present in both the erythrocyte and parasite plasma membranes (Choveaux et al. 2012). |
Eukaryota | Apicomplexa | Copper transporter of Plasmodium falciparum |
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1.A.56.1.16 | Plasma membrane copper uptake channel of 257 aas, CtrC (Park et al. 2014). |
Eukaryota | Fungi, Ascomycota | CtrC of Neosartorya fumigata (Aspergillus fumigatus) |
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1.A.56.1.17 | Grape vacuolar copper transporter, Ctr1 (Martins et al. 2012). |
Eukaryota | Viridiplantae, Streptophyta | Ctr1 of Vitis vinifera |
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1.A.56.1.18 | Putative copper uptake transporter of 242 aas, CtrB (Park et al. 2014). |
Eukaryota | Fungi, Ascomycota | CtrB of Neosartorya fumigata (Aspergillus fumigatus) |
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1.A.56.1.19 | High affinity copper uptake transporter, Ctr-1, Ctr1 or Slc31a1 of 188 aas and 3 or 4 TMSs in a 1 or 2 + 2 TMS arrangement. It is maternally loaded, and transcripts can be detected throughout development and in adult fish. Distribution of ctr1 message appears ubiquitous during early stages, becoming restricted to the brain and ventral tissues by 24 h post fertilization. Beginning at 3 days post fertilization, expression is found mainly in the developing intestine. Knockdown of ctr1 by antisense morpholino oligonucleotides causes early larval lethality (Mackenzie et al. 2004). |
Eukaryota | Metazoa, Chordata | Ctr1 of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.A.56.1.2 | High affinity copper (Cu+) and silver (Ag+) uptake transporter, Ctr1 of 190 aas and 3 TMSs. The trimeric channel (Eisses and Kaplan, 2005) forms an oligomeric pore with each subunit displaying 3 TMSs and 2 metal binding motifs (Lee et al., 2007). TMS2 is sufficient to form the trimer, and the MXXM motif bind Ag+ (Dong et al. 2015). Ctr1 mediates basolateral uptakes of Cu+ in enterocytes (Zimnicka et al., 2007) and shows copper-dependent internalization and recycling which provides a reversible mechanism for the regulation of cellular copper entry (Molloy and Kaplan, 2009). It acts as a receptor for the two extinct viruses, CERV1 and CERV2 (Soll et al., 2010). Ctr1 takes up platinum anticancer drugs, cisplatin and carboplatin (Du et al., 2012). The 3-d structure is known (Yang et al., 2012). Ctr1 has a low turn over number of about 10 ions/second/trimer (Maryon et al. 2013). Methionine and histidine residues in the transmembrane domain are essential for transport of copper, but when mutated, they stimulated uptake of cisplatin (Larson et al. 2010). Plays important roles in the developing embryo as well as in adult ionic homeostasis (Wee et al. 2013). (-)-Epigallocatechin-3-gallate (EGCG), a major polyphenol from green tea, can enhance CTR1 mRNA and protein expression in ovarian cancer cells. EGCG inhibits the rapid degradation of CTR1 induced by cisplatin (cDDP). The combination of EGCG and cDDP increases the accumulation of cDDP and DNA-Pt adducts, and subsequently enhances the sensitivity of ovarian cancer (Wang et al. 2015). Steroid inhibitors may be able to overcome cycplatin resistance (Kadioglu et al. 2015). ctr1 is upregulated in colorectal cancer cells (Barresi et al. 2016). The N-terminus of CTR1 binds Cu2+ following transfer from blood copper carriers such as human serum albumin to the transporter (Bossak et al. 2018). Once in the cytosol, enzyme-specific chaperones receive copper from the CTR1 C-terminal domain and deliver it to their apoenzymes (Ilyechova et al. 2019). Ctr1 is part of the Sp1-Slc31a1/Ctr1 copper-sensing system, and carnosine, a brain dipeptide, influences copper homeostasis in murine CNS-derived cells (Barca et al. 2019). A proteomic view of cellular responses of macrophages to copper has appeared (Dalzon et al. 2021). Tetrahedral framework nucleic acid delivered RNA therapeutics significantly attenuate pancreatic cancer progression via inhibition of CTR1-dependent copper absorption (Song et al. 2021). Electron paramagnetic resonance (EPR) has been used to study conformational changes during transport (Hofmann and Ruthstein 2022). Ctr1 is the main entry point for Cu' ions in eukaryotes. It contains intrinsically disordered regions, IDRs, both at its N-terminal (Nterm) and C-terminal ends. The former delivers copper ions from the extracellular matrix to the selectivity filter in the Ctr1 lumen. Aupič et al. 2022 showed that Cu+ ions and a lipidic environment drive the insertion of the N-terminus into the Ctr1 selectivity filter, causing its opening. Through a lipid-aided conformational switch of one of the transmembrane helices, the conformational change of the selectivity filter propagates down to the cytosolic gate of Ctr1. Polymorphic renal transporters and cisplatin's toxicity in urinary bladder cancer patients have been reviewed (Selim et al. 2023). Rosmarinic acid has a protective effect on Ctr1 expression in cisplatin-treated mice (Akhter et al. 2023). Disorders of copper metabolism can be caused by variants in CTR1 (Batzios et al. 2022). |
Eukaryota | Metazoa, Chordata | SLC31A1 or Ctr1 of Homo sapiens |
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1.A.56.1.20 | CTR2 of 160 aas and 4 TMSs in a 1 (N=terminal) + 1 (middle) + 2 TMS (C-terminal) arrangement (Wunderlich 2022). |
Eukaryota | Apicomplexa | CTR2 of Plasmodium falciparum |
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1.A.56.1.21 | Copper uptake transporter, COPT1, of 241 aas and 3 equally spaced TMSs. Copper (Cu) bioaccumulation and uptake are controlled by the cell cycle. A cyclical kinetics of Cu bioaccumulation and surge in the S/M growth phase were observed in the synchronized green algae Chlamydomonas reinhardtii.and COPT1 was responsible (Deng and Wang 2023). Additionally, ATX1 activity for Cu efflux was supressed simultaneously. |
Eukaryota | Viridiplantae, Chlorophyta | COPT1 of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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1.A.56.1.3 | Vacuolar copper transporter (exports Cu+ from the vacuole to the cytoplasm; acts with Fre6 (Q12473: TC# 5.B.1.7.1) (metalo-reductase that reduces Cu2+ to Cu+ in the vacuole) (Rees and Thiele, 2007). | Eukaryota | Fungi, Ascomycota | Ctr2p of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.56.1.4 | Copper uptake transporter | Eukaryota | Fungi, Ascomycota | Ctr3p of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.56.1.5 | The heterodimeric high affinity copper uptake transporter, Ctr4/Ctr5. The Ctr4 central domain may mediate Cu2+ transport in this hetero-complex, whereas the Ctr5 carboxyl-terminal domain functions in the regulation of trafficking of the Cu2+ transport complex to the cell surface (Beaudoin et al., 2011). |
Eukaryota | Fungi, Ascomycota | Ctr4/Ctr5 of Schizosaccharomyces pombe |
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1.A.56.1.6 | Vacuolar, trimeric copper release protein (Beaudoin et al. 2013). |
Eukaryota | Fungi, Ascomycota | Ctr6 of Schizosaccharomyces pombe |
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1.A.56.1.7 | The CtrlB Copper transporter (expressed during late embryonic and larval stages of development in response to copper deprivation (Zhou et al., 2003). | Eukaryota | Metazoa, Arthropoda | CtrlB of Drosophila melanogaster (Q9VHS6) |
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1.A.56.1.8 | The plasma membrane copper import transporter, Ctr1A (3 isoforms in Drosophila, Ctr1A, 1B and 1C; Ctr1A but not Ctr1B is required for development) (Turski and Thiele, 2007) | Eukaryota | Metazoa, Arthropoda | Ctr1A of Drosophila melanogaster (Q9W3X9) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.56.1.9 | Probable low affinity copper uptake protein 2 (Ctr2) (present in the plasma membrane and interbal membranes where it stimulates copper uptake into the cytoplasm) (Bertinato et al., 2007; Wee et al. 2013). |
Eukaryota | Metazoa, Chordata | SLC31A2 of Homo sapiens |
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1.A.56.2.1 | Plasma membrane high affinity copper transporter, Ctr1p (Puig et al., 2002); acts with Fre1 (P32791: TC# 5.B.1.5.1) (metalo-reductase that reduces Cu2+ to Cu+ at the cell surface (Rees and Thiele, 2007). | Eukaryota | Fungi, Ascomycota | Ctr1p of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.56.2.2 | High affinity copper transporter, Ctr1p (Marvin et al., 2004) of 251 aas with 4 putative TMSs, one N-terminal, a second at residue 100, and two more C-terminal. Chlorhexidine digluconate (CHG) is a broad-spectrum antimicrobial agent widely used in dental practice and has been recommended to treat oral candidiasis. It targets Ctr1p in C. albicans (Jiang et al. 2023). |
Eukaryota | Fungi, Ascomycota | Ctr1p of Candida albicans (CAB878806) |
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1.A.56.3.1 | Ctr1 assimilatory copper transporter (has a Cx2(Mx2)2 (C-x)5 motif) (Page et al. 2009). | Eukaryota | Viridiplantae, Chlorophyta | Ctr1 of Chlamydomonas reinhardtii (Q4U0V9) |
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1.A.56.3.2 | Copper uptake porter, CtrA2 (Park et al. 2014). |
Eukaryota | Fungi, Ascomycota | CtrA2 of Neosartorya fumigata (Aspergillus fumigatus) |
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1.A.56.3.3 | Uncharacterized protein of 244 aas and 3 TMSs |
Eukaryota | UP of Vitrella brassicaformis |
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1.A.57.1.1 | SARS-CoV Viroporin tetrameric ion channel. Protein 3a (ORF3a) is of 274 aas and 3 TMSs. It activates the Nod-like receptor family members which are pyrin domain-containing 3 (NLRP3)proteins that regulate the secretion of proinflammatory cytokines such as interleukin 1 beta (IL-1beta) and IL-18. K+ efflux and mitochondrial reactive oxygen species are important for SARS-CoV 3a-induced NLRP3 inflammasome activation (Chen et al. 2019). Viroporin 3a exhibits allosteric properties (Tee et al. 2021). The role of the tyrosine-based sorting signals of the ORF3a protein of SARS-CoV-2 on intracellular trafficking, autophagy, and apoptosis has been examined (Henke et al. 2023). It has been concluded that ORF3a is not an ion channel but a water channel (Michelucci et al. 2025). |
Viruses | Nidovirales | SARS-Caronavirus |
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1.A.57.1.2 | Orf3 of 249 aas and 3 putative TMSs |
Viruses | Orthornavirae, Pisuviricota | Orf3 of Zaria bat coronavirus (F1BYM0) |
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1.A.57.1.3 |
The NS3 protein of 230aas and 3 N-terminal TMSs as well as 3 potential C-terminal TMSs of low hydrophobicity. |
Viruses | Orthornavirae, Pisuviricota | NS3 of Bat coronavirus HKU9-5-1 (E0ZN37) |
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1.A.57.1.4 | Orf3 of 238aas and 3 putative TMSs |
Viruses | Orthornavirae, Pisuviricota | Orf3 of Eidolon bat coronavirus (F1DAZ2) |
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1.A.57.1.5 | Orf3a of 275 aas and 3 central TMSs. Orf3a forms homodimers and homotetramers and is a non-selective catioin channel that is blocked by polycation channel inhibitors (Kern et al. 2021). They carry a PDZ-binding domain, lending them the versatility to interact with more than 400 target proteins in infected host cells. Structural considerations have been discussed (Barrantes 2021). Naturally occurring mutations in ORF3a are common and have been analyzed, and 28 fully concerved residues in 70,000 sequences that probably have structural or functional roles were also identified (Bianchi et al. 2020). Viroporin 3a exhibits allosteric properties (Tee et al. 2021). It has been implicated in apoptosis and inhibition of autophagy. The structure of the dimer has been determined at 2.1 Å resolution by cryoEM (Kern et al. 2021). Pentamidine is a channel blocker of Orf3a (Zhang et al. 2022). ORF3a is inhibited by adamantanes and phenolic plant metabolites (Fam et al. 2023). SARS-CoV-2 ORF3A interacts with the Clic-like chloride channel-1 (CLCC1; TC# 1.A.36.1.1) and triggers an unfolded protein response (Gruner et al. 2023). SARS-CoV-2 and its ORF3a, E and M viroporins activate inflammasome in human macrophages (Ambrożek-Latecka et al. 2024). SARS-CoV-2 ORF3a positively regulates NF-κB activity by enhancing IKKβ-NEMO interaction (Nie et al. 2023). ORF3a is a lysosomal water-permeable channel, essential for lysosome deacidification and inactivation, key steps to promote virus egress (Michelucci et al. 2025). Thus, ORF3a is a lysosomal water-permeable channel, essential for lysosome deacidification and inactivation, key steps to promote virus egress. |
Viruses | Orthornavirae, Pisuviricota | Orf3a of severe acute respiratory syndrome (SARS) coronavirus 2 |
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1.A.58.1.1 | The Matrix protein BM2 (Pielak and Chou, 2010). The solution structure for the channel domain of 33 aas is known (PDB# 2KIK) (Wang et al. 2009). The channel transports H+ and K+ (Hyser and Estes 2015). Like M2, it is a tetrameric pore that acidifies the virion after endocytosis and it has a HxxxW motif (residues 19 - 23) in the single TMS responsible for proton selectivity and gating. This motif is within a 14 aa sequence with 35% identity and 86% similarity with M2 (1.A.19.1.1), both within the C-terminal part of the single TMS, suggesting homology. It also has a second histidine in a WxxxH motif involving the same W. The solvent-accessible His27 facilitates proton conduction of the channel by increasing the proton dissociation rates of His19 (Williams et al. 2017). The membrane environment is an important factor influencing the conformation and hydration of BM2 (Zhang et al. 2020).
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Viruses | Orthomyxoviridae | BM2 influenza virus type B |
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1.A.58.1.2 | Influenza Am2-Bm2 Chimeric Channel of 35 aas with 1 TMS. This hybrid sequence is RSNDSSDPLVVAASIIGILHFIAWTIGHLNQIKRG with the N-terminus derived from AM2 and the C-terminus derived from BM2 (PDB# 2LJB) (Pielak et al. 2011). The complex includes fragments of both proteins, but only the full length protein for BM2 (B4UQM4) is included in the TC entry. |
Viruses | Orthornavirae, Negarnaviricota | Chimeric AM2-BM2 35 aa peptide of A- and B-type Influenza viruses |
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1.A.58.1.3 | Influenza virus B Matrix Protein 2, BM2 protein, of 109 aas and 1 N-terminal TMS. 83% identical and 92% similar to 1.A.58.1.1. |
Viruses | Orthornavirae, Negarnaviricota | BM2 of Influenza B virus (B/Maryland) |
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1.A.58.1.4 | M2 protein of 124 aas and 1 TMS. |
Viruses | Orthornavirae, Negarnaviricota | M2 of Wuhan spiny eel influenza virus |
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1.A.59.1.1 | The pore-forming peptide, Pep46 (derived from the structural polyprotein (PP) precursor (1012 aas) (Galloux et al. 2007). The 3-D NMR structure of Pep46 is known: Acc# 2IMUA (Galloux et al. 2010). |
Viruses | Orthornavirae | PP precursor of Pep46 of Infectious Bursal Disease Virus (P61825) |
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1.A.59.1.2 | Pore-forming 46 aa peptide with 1 TMS. The NMR structure is known (2IMU_A) (Galloux et al. 2010). This peptide is a small part of the 1012 aa polyprotein (P61825). |
Viruses | Viridiplantae, Streptophyta | Pep46 of Infectious Bursal Disease Virus (Ibdv) |
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1.A.59.1.3 | Pore-forming polyprotein fragment of 103 aas and 1 TMS |
Viruses | Orthornavirae | Polyprotein fragment of Aquabirnavirus genogroup VII |
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1.A.6.1.1 | Epithelial Na+ channel, ENaC (regulates salt and fluid homeostasis and blood pressure; regulated by Nedd4 isoforms and SGK1, 2 and 3 kinases) (Henry et al., 2003; Pao 2012). Cd2+ inhibits α-ENaC by binding to the internal pore where it interacts with residues in TMS2 (Takeda et al., 2007). The channel is regulated by palmitoylation of the beta subunit which modulates gating (Mueller et al. 2010). ENaCs are more selective for Naa+ over other cations than ASICs (Yang and Palmer 2018). ENaC plays a role in chronic obstructive pulmonary diseases (COPD) (Zhao et al. 2014). The hetrodimeric complex can consist of αβγ or δβγ subunits, depending on the tissue (Giraldez et al. 2012). The α- and γ-subunits of the epithelial Na+ channel interact directly with the Na+:Cl- cotransporter, NCC, in the renal distal tubule with functional cosequences, and together they determine bodily salt balance and blood pressure (Mistry et al. 2016). ENaC is regulated by syntaxins (Saxena et al. 2006). The cryoEM structure has been solved (Noreng et al. 2018). Interactions between the epithelial sodium channel gamma-subunit and claudin-8 modulates paracellular sodium permeability in the renal collecting duct (Sassi et al. 2020). Tumer necrosis factor, TNF, of 233 aas, is the source of a modified cyclic peptide of 17 aas, solnatide or the TIP peptide, (CGQRETPEGAEAKPWYC), residues 177 - 195), that activates ENaC (Madaio et al. 2019; Martin-Malpartida et al. 2022). Acid-Sensing ion channels are inhibited by KB-R7943, a reverse Na+/Ca2+ exchanger (see TC# 1.D.208) (Sun et al. 2023). EGR-1 contributes to pulmonary edema by regulating the epithelial sodium channel in lipopolysaccharide-induced acute lung injury (Wang et al. 2023). Enhanced glycolysis causes extracellular acidification and activates acid-sensing ion channel 1a in hypoxic pulmonary hypertension (Tuineau et al. 2024). |
Eukaryota | Metazoa, Chordata | αβγ- or δβγ-ENaC heterotrimeric epithelial Na+ channel of Homo sapiens |
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1.A.6.1.10 | Acid-sensing ion channel 1, ACCN2 of 514 aas and 2 TMSs. |
Eukaryota | Metazoa, Chordata | ACCN2 of Lampetra fluviatilis (European river lamprey) (Petromyzon fluviatilis) |
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1.A.6.1.11 | (Bile) acid-sensitive ion channel, BASIC (ASIC, ACCN5, HINAC), of 505 aas. Cation channel that gives rise to very low constitutive currents in the absence of activation. The activated channel exhibits selectivity for sodium, and is inhibited by amiloride (Schaefer et al. 2000). A cytoplasmic amphipathic α-helix controls activity (Schmidt et al. 2016). This system may be present in mitochondria ().
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Metazoa, Chordata | BASIC of Homo sapiens |
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1.A.6.1.12 | Duplicated ENaC with 990 aas and 4 TMSs in a 1 + 2 + 1 TMS arrangement. |
Eukaryota | Metazoa | Duplicated ENaC of Exaiptasia pallida |
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1.A.6.1.13 | Acid-sensing ion channel 5 isoform X1 pf 639 aas and possibly 7 TMSs with 5 TMSs in an N-terminal domain not related to ASICs followed by two TMSs, one N-terminal and one C-terminal, all in the ASIC domain of the protein. |
Eukaryota | Metazoa, Rotifera | ASIC5 of Brachionus plicatilis |
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1.A.6.1.14 | FMRFamide (peptide)-gated ionotropic receptor Na+ channel, NaC2-4 or NaC2, 3 and 5 (gated by neuropeptides Hydra-RFamides I and II; present in tentacles) (Golubovic et al. 2007). Three homologous subunits, NaC2, 3 and 5, assemble to form a more typical high affinity peptide-gated ion channel (Durrnagel et al., 2010). |
Eukaryota | Metazoa | NaC2-5 of Hydra magnipapillata: |
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1.A.6.1.15 | Uncharacterized protein of 1029 aas and 4 TMSs, two near the N- and C-termini, and two more at residues 410 and 600. The region of homology with other members of the family are residues 570 to 1000, thus including the last two TMSs. |
Eukaryota | Metazoa, Arthropoda | UP of Cloeon dipterum |
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1.A.6.1.16 | Uncharacterized protein of 418 aas and 3 TMSs. |
Eukaryota | Metazoa, Arthropoda | UP of Allacma fusca |
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1.A.6.1.18 | Acid-sensing ion channel 1B-like of 524 aas and 3 TMSs. |
Eukaryota | Metazoa, Arthropoda | ASIC 1B of Daphnia pulex |
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1.A.6.1.2 | Amiloride-sensitive cation channel, ASIC1/ASIC3 (also called ASIC1a, BNC1, MDEG, ACCN2 and BNAC2), which is an acid-sensitive (proton-gated) homo- or hetero-oligomeric cation (Na+ (high affinity), Ca2+, K+) channel. It it 98% identical to the human ortholog and associates with DRASIC tomediate touch sensation, being a mechanosensor (lead inhibited) channel (Wang et al., 2006). In pulmonary tissue (lung epithelial cells) it and CFTR interregulate each other (Su et al., 2006). ASIC3 is a sensor of acidic and primary inflammatory pain (Deval et al., 2008). Acid sensing ion channel-1b (ASIC1b), virtually identical to the rat and human orthologs, is stimulated by hypotonic stimuli (Ugawa et al., 2007; Deval et al., 2008). This protein is 98% idientical to the human ortholog Z(as noted above), which is an excitatory neuronal cation channel, involved in physiopathological processes related to extracellular pH fluctuation such as nociception, ischaemia, perception of sour taste and synaptic transmission. The spider peptide toxin psalmotoxin 1 (PcTx1) inhibits its proton-gated cation channel activity (Salinas et al. 2006). ASIC1a localizes to the proximal tubular and contributes to ischaemia/reperfusion (I/)R induced kidney injury (Song et al. 2019). Stomatin (STOM; TC# 8.A.21.1.1) is an inhibitor of ASIC3, and it is anchored to the ASIC3 channel via a site on the distal C-terminus of the channel to stabilizes the desensitized state via an interaction with TMS1 (Klipp et al. 2020). Sun et al. 2020 presented single-particle cryo-EM structures of human ASIC1a (hASIC1a) and the hASIC1a-Mamba1 complex at resolutions of 3.56 and 3.90 Å, respectively. The structures revealed the inhibited conformation of hASIC1a upon Mamba1 binding. Mamba1 prefers to bind hASIC1a in a closed state and reduces the proton sensitivity of the channel, representing a closed-state trapping mechanism. Kinetic analyses of ASIC1a delineated conformational signaling from proton-sensing domains to the channel gate (Vullo et al. 2021). An arginine residue in the outer segment of hASIC1a TMS1 affects both proton affinity and channel desensitization (Chen et al. 2021). Acid-sensing ion channels (ASICs) are weakly sodium selective (sodium:potassium ratio approximately 10:1), while ENaCs show a high preference for sodium over potassium (>500:1). The pre-TMS1 and TMS1 regions of mASIC1a channels are major determinants of ion selectivity (Sheikh et al. 2021). ASIC1a shuttles between the membranous organellar fraction to the plasm membrane (Salinas Castellanos et al. 2022). Multiscale molecular dynamics simulations predict arachidonic acid binding sites in human ASIC1a and ASIC3 transmembrane domains (Ananchenko and Musgaard 2023). Rotundine inhibits the development and progression of colorectal cancer by regulating the expression of prognosis-related genes such as ASIC3 (ACCN3; SLNAC1, TNACT) in humans (Huang et al. 2023). Acid-sensing ion channel (ASIC)3 may be a therapeutic target for the control of glioblastoma cancer stem cells growth (Balboni et al. 2024). 4-(Azolyl)-benzamidines are a Novel Chemotype for ASIC1a Inhibitors (Platonov et al. 2024). |
Eukaryota | Metazoa, Chordata | αβγENaC of Rattus norvegicus. |
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1.A.6.1.3 | The epithelial Na+ channel, EnaC5 (involved in fluid and electrolyte homeostasis). The C-terminus of each subunit (α, β, and γ) contains a PPXY motif for interaction with the WW domains of the ubiquitin-protein ligases, Nedd4 and Nedd4-2. Disruption of this interaction, as in Liddle's syndrome where mutations delete or alter the PPXY motif of either the β or γ subunits, has been shown to result in increased ENaC activity and arterial hypertension. N4WBP5A (Nedd4-family interacting protein-2) plays a role (see 8.A.30; Konstas et al., 2002). Wiemuth & Grunder (2010) showed that an unknown ligand, interacting with an amino acyl residue in the extracellular domain, tunes Ca2+ inhibition in the rat protein, but not the mouse orthologue. |
Eukaryota | Metazoa, Chordata | ENaC5 of Rattus norvegicus (Q9R0W5) |
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1.A.6.1.4 | ACD-1 (degenerin-like glial acid-sensitive channel) is constitutively open and impermeable to Ca2+, yet is required with neuronal DEG/ENaC channel, DEG-1 (1.A.6.2.1) for acid avoidance and chemotaxis to the amino acid lysine (Wang et al. 2008). | Eukaryota | Metazoa, Nematoda | ACD-1 of Caenorhabditis elegans (P91102) |
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1.A.6.1.5 | Neuronal acid-sensing cation channel-1, ASIC1 (>90% identical to ASIC1 of Rat (TC#1.A.6.1.2)). 3D structure (1.9Å resolution) has been solved (Jasti et al., 2007). Regulated by the glucocorticoid-induced kinase-1 isoform 1 (SGK1.1) (Arteaga et al., 2008). Residues in the second transmembrane domain of the ASIC1a that contribute to ion selectivity have been defined (Carattino and Della Vecchia, 2012). Outlines of the pore in open and closed conformations describe the gating mechanism (Li et al., 2011). Interactions between two extracellular linker regions control sustained channel opening (Springauf et al., 2011). Can form monomers, trimers and tetramers, but the tetramer may be the predominant species in the plasma membrane (van Bemmelen et al. 2015). The C-terminal tail projects into the cytosol by approximately 35 Å, and the N and C tails from the same subunits are closer than those of adjacent subunits (Couch et al. 2021). |
Eukaryota | Metazoa, Chordata | ASIC-1 of Gallus gallus (Q1XA76) |
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1.A.6.1.6 | Acid sensing cation channel ASIC4.1 (senses and gated by extracellular pH) (forms homomers and heteromers with ASIC4.2) (Chen et al., 2007) | Eukaryota | Metazoa, Chordata | ASIC4.1 of Danio rerio (Q708S4) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.6.1.7 | Acid sensing cation channel ASIC4.2 (does not sense extracellular pH) (forms homomers and heteromers with ASIC4.1) (Chen et al., 2007). | Eukaryota | Metazoa, Chordata | ASIC4.2 of Danio rerio (Q708S3) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.6.1.8 | Amiloride and acid-sensitive cation channels, ASIC2a and ASIC2b are splice variants of the same gene (ACCN1, ACCN, BNAC1, MDEG) product. Regions involved in acid (proton) sensing and confering tachyphylasis have been identified (Schuhmacher et al. 2015). ASIC2 isoforms have different subcellular distributions: ASIC2a targets the cell surface while ASIC2b resides in the ER. TMS1 and the proximal post-TMS1 domain (17 amino acids) of ASIC2a are critical for membrane targeting, and replacement of corresponding residues in ASIC2b by those of ASIC2a conferred proton-sensitivity as well as surface expression to ASIC2b (Kweon et al. 2016). This protein is 99% identical to the human ortholog with acc# Q16515. Rapid resensitization of ASIC2a is conferred by three amino acid residues near the N terminus (Lee et al. 2019). The human ortholog of ASIC1 (UniProt acc # P783480 is 98% identical to the mouse ortholog. ASIC1 plays a role in the occurrence and development of several types of tumors (Wang et al. 2022). |
Eukaryota | Metazoa, Chordata | ASIC1b of Mus musculus |
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1.A.6.1.9 | Acid-sensing ion channel 2, ASIC2, of 520 aas and 2 TMSs. |
Eukaryota | Metazoa, Chordata | ASIC2 of Petromyzon marinus (Sea lamprey) |
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1.A.6.2.1 | Degenerin-1 | Eukaryota | Metazoa, Nematoda | Degenerin-1 of Caenorhabditis elegans (P24585) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.6.2.2 | Touch-responsive mechanosensitive degenerin channel complex (Mec-4/Mec-10 form the cation/Ca2+-permeable channel; Mec-2 and Mec-6 regulate) (Bianchi, 2007; Chelur et al., 2002; ). Mec-6 is a chaparone protein required for functional insertion (Matthewman et al. 2018). Mec-10 plays a role in the response to mechanical forces such as laminar shear stress (Shi et al. 2016). MEC-4 or MEC-10 mutants that alter the channel's LSS response are primarily clustered between the degenerin site and the selectivity filter, a region that likely forms the narrowest portion of the channel pore (Shi et al. 2018). TMS2 forms the Ca2+ channel of Mec-4. A C-terminal domain affects trafficking of a neuronally expressed DEG/ENaC. Neuronal swelling occurs prior to commitment to necrotic death (Royal et al. 2005). |
Eukaryota | Metazoa, Nematoda | Mec-2, 4, 6, 10 mechanosensitive degenerin channel complex in Caenorhabditis elegans |
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1.A.6.2.3 | Degenerin channel, UNC-105. (Activated by degeneration or hypercontraction-causing mutations) (Bianchi, 2007; García-Añoveros et al., 1998) | Eukaryota | Metazoa, Nematoda | UNC-105 of Caenorhabditis elegans (Q09274) |
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1.A.6.2.4 | Motility and anesthetic-sensitive degenerin, UNC-8 (Uncoordinated protein-8) Na+ (not Ca2+) channel (regulated by UNC-1 (a mammalian stomatin homologue)). UNC-1 and UNC-8 are found in cholesterol/sphingolipid rafts together with UNC-24 (Bianchi, 2007; Sedensky et al., 2004). UNC-8 is inhibited by μM concentrations of extracellular divalent cations mediated by the extracellular finger domain (Matthewman et al. 2018). |
Eukaryota | Metazoa, Nematoda | UNC-8 of Caenorhaditis elegans (Q21974) |
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1.A.6.2.5 | Mechanotransduction degenerin, DEL-1 (Bianchi, 2007). |
Eukaryota | Metazoa, Nematoda | DEL-1 of Caenorhabditis elegans (Q19038) |
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1.A.6.2.6 | Serum paraoxonase/arylesterase 1, PON 1 (Aromatic esterase 1) (A-esterase 1) (Serum aryldialkylphosphatase 1) |
Eukaryota | Metazoa, Chordata | PON1 of Homo sapiens |
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1.A.6.2.7 | Ion channel of 686 aas and 2 TMSs, one at the N-terminus and one at the C-terminus. The N-terminal half of this protein is cycsteine-rich and shows similarity with 9.B.87.1.12, while the C-terminal half shows extensive similarity with 1.A.6.2 proteins. |
Eukaryota | Metazoa, Nematoda | Ion channel of Pristionchus pacificus |
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1.A.6.3.1 | Peptide neurotransmitter-gated ionotropic receptor | Eukaryota | Metazoa, Mollusca | Phe-Met-Arg-Phe-NH2-activated Na+ channel of Helix aspersa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.6.3.2 |
FMRFamide (peptide)-gated sodium channel, FaNaC. The charge on aspartate-552 in TMS2 influcences the gating properties and potency of the channel (Kodani and Furukawa 2010; Kodani and Furukawa 2014). The FMRFamide-evoked current through AkFaNaC was depressed 2-3-fold by millimolar (1.8 mM) Ca2+ (Fujimoto et al. 2017). Both D552 and D556 were indispensable for the sensitivity of FaNaC to millimolar Ca2+. The Ca2+-sensitive gating was recapitulated by an allosteric model in which Ca2+-bound channels are more difficult to open. The desensitization of FaNaC was also inhibited by Ca2+ (Fujimoto et al. 2017). High-resolution cryo-EM structures of FaNaC in both apo and FMRFamide-bound states have been solved (Liu et al. 2023). AcFaNaC forms a chalice-shaped trimer and possesses several notable features, including two FaNaC-specific insertion regions, a distinct finger domain and non-domain-swapped TMS2 in the transmembrane domain (TMD). One FMRFamide binds to each subunit in a cleft located in the top-most region of the extracellular domain, with participation of residues from the neighboring subunit. Bound FMRFamide hass an extended conformation. FMRFamide binds tightly to A. californica FaNaC in an N terminus-in manner, which causes collapse of the binding cleft and induces large local conformational rearrangements. Such conformational changes are propagated downward toward the TMD via the palm domain, possibly resulting in outward movement of the TMD and dilation of the ion conduction pore (Liu et al. 2023). |
Eukaryota | Metazoa, Mollusca | FaNaC of Aplysia kurodai |
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1.A.6.3.3 | Uncharacterized protein of 577 aas and 2 TMSs, N- and C-terminal. |
Eukaryota | Metazoa, Platyhelminthes | UP of Taenia asiatica |
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1.A.6.3.4 | Uncharacterized protein of 616 aas and 2 TMSs, N- and C-terminal. |
Eukaryota | Metazoa, Platyhelminthes | UP of Hymenolepis diminuta |
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1.A.6.3.5 | Uncharacterized protein of 534 aas and 2 TMSs. |
Eukaryota | Metazoa, Annelida | UP of Helobdella robusta |
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1.A.6.4.1 | Ripped pocket (Rpk) fly gonad-specific Na+ channel (amiloride-sensitive) (Adams et al., 1998). |
Eukaryota | Metazoa, Arthropoda | Rpk of Drosophila melanogaster |
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1.A.6.4.2 | Pickpocket of 606 aas and 2 TMSs, N- and C-terminal (Adams et al., 1998; Zhong et al., 2010). |
Eukaryota | Metazoa, Arthropoda | Pickpocket of Drosophila melanogaster (Q7KT94) |
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1.A.6.4.3 | Putative Na+ channel |
Eukaryota | Metazoa, Arthropoda | Putative Na+ channel of Drosophila melanogaster (O61365) |
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1.A.6.4.4 | Na+ channel protein, NaCh, of 522 aas with 2 or 3 TMSs in a 1 (N-terminal) + 1 or 2 TMSs (C-terminal). |
Eukaryota | Metazoa, Arthropoda | NaCh of Cyphomyrmex costatus |
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1.A.6.4.5 | Uncharacterized protein of 509 aas and 2 TMSs, N- and C-terminal. |
Eukaryota | Metazoa, Arthropoda | UP of Laodelphax striatellus (small brown planthopper) |
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1.A.6.4.6 | Sodium channel protein Nach-like protein, NaCh, of 533 aas with the usual 2N- and C-terminal TMSs, but possibly as many as 6 smaller peaks of hydrophobicity (TMSs?) in between these two TMSs. |
Eukaryota | Metazoa, Arthropoda | NaCh of Vollenhovia emeryi |
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1.A.60.1.1 | Core protein Mu-1 (42aas; 1TMS) (Agosto et al., 2006). The reovirus myristoylated µ1N pore forming peptide derived from the N-terminus of the µ1 viral capsid protein (708aas). Permeability order: Cs+ > Rb+ > K+ > Na+ > Li+ (crystal structures are available for chains A-U). |
Viruses | Orthornavirae, Duplornaviricota | Mu-1 of mammalian reovirus (P12397) |
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1.A.60.1.2 | Outer shell protein of 638 aas and 0 - 8 TMSs, based on a hydropathy plot. |
Viruses | Orthornavirae, Duplornaviricota | Shell protein of Chinook aquareovirus |
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1.A.60.1.3 | Major virion structural protein of 652 aa |
Viruses | Orthornavirae, Duplornaviricota | Structural protein of Atlantic halibut reovirus |
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1.A.60.1.4 | VP4, the S6 gene outer membrane protein of 650 aas with possibly as many as 3 TMSs in the C-terminal region of the protein from Aquareovirus G. A smaller protein (the S10 gene protein of 273 aas) overlaps with the N-terminal 273aas of this one with identical aas in the entire region of overlap. |
Viruses | Orthornavirae, Duplornaviricota | VP4 of Grass Carp Reovirus, Aquareovirus |
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1.A.61.1.1 | Chain F or gamma-peptide (44aas; 1TMS), membrane active domain (Bong et al., 1999) | Viruses | Orthornavirae, Kitrinoviricota | Chain F of Flock House Nodamura Virus (P12871) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.61.1.2 | Flock House virus (FHV) capsid protein-α of 407 aas; Its C-terminal 44 aas comprise a lytic peptide, one of the γ-peptides that inserts into endomembranes forming pores. Capsid protein alpha self-assembles to form an icosahedral procapsid with a T=3 symmetry, about 30 nm in diameter, and consisting of 60 capsid proteins trimers. 240 calcium ions are incorporated per capsid during assembly. The capsid encapsulates the two genomic RNAs. Capsid maturation occurs via autoproteolytic cleavage of capsid protein alpha, generating capsid protein beta and the membrane-active peptide gamma. Peptide γ is a membrane-permeabilizing peptide produced during virus maturation, thereby creating the infectious virion. After endocytosis into the host cell, peptide gamma is exposed in endosomes, where it permeabilizes the endosomal membrane, facilitating translocation of viral capsid or RNA into the cytoplasm. Nangia et al. 2019 shed light on the actions of varied forms of the FHV lytic peptide including membrane insertion, trans-membrane stability, peptide oligomerization, water permeation activity and dynamic pore formation.
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Viruses | Orthornavirae, Kitrinoviricota | α-capsid protein, including the C-terminal γ-peptide of Flock House virus (FHV) |
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1.A.62.1.1 | The homotrimeric monovalent cation channel, TRIC-A (Mitsugumin-33A; 298 aas; 3-6TMSs; DUF714 domain) (Yazawa et al., 2007). PK+:Na+ = 1.5; impermeable to divalent cations. | Eukaryota | Metazoa, Chordata | TRIC-A of Mus musculus (Q3TMP8) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.62.1.2 | The homotrimeric monovalent cation channel, TRIC-B (TMEM38B; Mitsugumin-33B; 292 aas; 7 TMSs; DUF714 domain) (Yazawa et al., 2007). PK+:Na+ = 1.5; impermeable to divalent cations. Apparent subconductance openings provide most of the K+ flux when the SR membrane potential is close to zero (Matyjaszkiewicz et al. 2015). Mutations give rise to osteogenesis imperfecta (OI) in humans, a group of clinically and genetically heterogeneous disorders characterized by decreased bone mass and recurrent bone fractures (Lv et al. 2016). |
Eukaryota | Metazoa, Chordata | TRIC-B of Mus musculus (Q9DAV9) |
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1.A.62.1.3 | TMEM38B/TRIC-B of 291 aas and 6 TMSs. Monovalent cation channel required for maintenance of rapid intracellular calcium release. May act as a potassium counter-ion channel that functions in synchrony with calcium release from intracellular stores (Haralambieva et al. 2022). Required for intracellular homeostasis and is responsible for a mild form of recessive osteogenesis imperfecta. TRIC-B is proposed to counterbalance IP3R-mediated Ca2+ release from intracellular stores (Cabral et al. 2016). TMEM38B, whose expression is dependent on BACE2 (TC# 8.A.32.1.2), modulates calcium release from the ER in ocular melanoma, and inhibition of the BACE2/TMEM38B axis could trigger exhaustion of intracellular calcium release while inhibiting tumor progression (He et al. 2021). TMEM38B gene deletions are associated with recessive osteogenesis imperfecta (Ramzan et al. 2021). |
Eukaryota | Metazoa, Chordata | TRIC-B of Homo sapiens |
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1.A.62.1.4 | TRICB1 and TRICB2 of 313 aas and 295 aas, respectively. Yang et al. 2016 presented the structures of TRIC-B1 and TRIC-B2 channels from Caenorhabditis elegans in complex with endogenous phosphatidylinositol-4,5-biphosphate (PtdIns(4,5)P2, also known as PIP2) lipid molecules. The TRIC-B1/B2 proteins and PIP2 assemble into a symmetrical homotrimeric complex. Each monomer contains an hourglass-shaped hydrophilic por within a seven-transmembrane-helix domain. Structural and functional analyses revealed the central role of PIP2 in stabilizing the cytoplasmic gate of the ion permeation pathway and showed a marked Ca2+-induced conformational change in a cytoplasmic loop above the gate. A mechanistic model was proposed to account for the complex gating mechanism of TRIC channels (Yang et al. 2016). |
Eukaryota | Metazoa, Nematoda | TRICB1/B2 of Caenorhabditis elegans |
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1.A.62.1.5 | Uncharacterized protein of 303 aas and 6 TMSs. |
Eukaryota | Viridiplantae, Streptophyta | UP of Klebsormidium nitens |
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1.A.62.2.1 | Bacterial TRIC family homologue |
Bacteria | Bacteroidota | TRIC homologue of Gramella forsetii (A0M015) |
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1.A.62.2.2 | Uncharacterized protein of 204 aas and 7 TMSs. |
Bacteria | Pseudomonadota | UP of Yersinia pestis |
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1.A.62.2.3 | Uncharacterized protein, YicG, of 205 aas and 7 TMSs. |
Bacteria | Pseudomonadota | YicG of E. coli |
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1.A.62.2.4 | TRIC family homologue of 213 aas and 7 TMSs; it's high resolution 3-d structure is known (PDB# 5H36). TRIC channels are implicated in Ca2+ signaling and homeostasis. Kasuya et al. 2016 presented crystal structures of two prokaryotic TRIC channels in the closed state and conducted structure-based functional analyses of these channels. Each trimer subunit consists of seven TMSs with two inverted 3 TMS repeats (Silverio and Saier 2011). The electrophysiological, biochemical and biophysical analyses revealed that TRIC channels possess an ion-conducting pore within each subunit, and that trimer formation contributes to the stability of the protein. The symmetrically related TMS2 and TMS5 helices are kinked at conserved glycine clusters, and these kinks are important for channel activity. The kinks in TMS2 and TMS5 generate lateral fenestrations at each subunit interface that are occupied by lipid molecules (Kasuya et al. 2016). |
Bacteria | Pseudomonadota | TRIC channel of Rhodobacter spheroides |
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1.A.62.3.1 | Archaeal TRIC family homologue of 205 aas and 7 TMSs. In animals, Ca2+ release from the sarcoplasmic reticulum (SR) or endoplasmic reticulum (ER) is crucial for muscle contraction, cell growth, apoptosis, learning and memory. The eukaryotic TRIC channels are cation channels balancing the SR and ER membrane potentials, and are implicated in Ca2+ signaling and homeostasis. Kasuya et al. 2016 presented crystal structures of two prokaryotic TRIC channels in the closed state and conducted structure-based functional analyses of these channels. Each trimer subunit consists of seven TMSs with two inverted 3 TMS repeats (Silverio and Saier 2011). The electrophysiological, biochemical and biophysical analyses revealed that TRIC channels possess an ion-conducting pore within each subunit, and that trimer formation contributes to the stability of the protein. The symmetrically related TMS2 and TMS5 helices are kinked at conserved glycine clusters, and these kinks are important for channel activity. The kinks in TMS2 and TMS5 generate lateral fenestrations at each subunit interface that are occupied by lipid molecules (Kasuya et al. 2016). TRIC channels are involved in K+ uptake in prokaryotes, and have ion-conducting pores contained within each monomer. In a 2.2-Å resolution K+-bound structure, ion/water densities have been resolved inside the pore (PDB# 5H35) (Su et al. 2017). At the central region, a filter-like structure is shaped by the kinks on the second and fifth transmembrane helices and two nearby phenylalanine residues. Below the filter, the cytoplasmic vestibule is occluded by a plug-like motif attached to an array of pore-lining charged residues (Kasuya et al. 2016). The asymmetric filter-like structure at the pore center of SsTRIC may serve as a basis for the channel to bind and select monovalent cations, K+ and Na+ (Ou et al. 2017). |
Archaea | Thermoproteota | TRIC homologue of Sulfolobus solfataricus (Q981D4) |
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1.A.62.3.2 | UPF0126 of 7 TMSs. Adjacent to genes encoding a putative oligopeptide ABC uptake permease that controls sporulation and actinorhodin production (TC#3.A.1.5.34) (Shin et al. 2007). |
Bacteria | Actinomycetota | UPF0126 of Streptomyces coelicolor (Q9RKM3) |
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1.A.62.4.1 | Putative TRIC channel protein |
Eukaryota | Rhodophyta | Putative TRIC channel of Galdieria sulphuraria |
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1.A.62.4.2 | Putative TRIC channel protein |
Eukaryota | Putative TRIC channel of Blastocystis hominis |
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1.A.62.4.3 | Putative TRIC channel protein |
Eukaryota | Discosea | Putative TRIC channel protein of Acanthamoeba castellanii |
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1.A.63.1.1 | The α-helical pore-forming outer membrane nanomeric porin, Imp1227 or Ihomp1, of 85 aas and one TMS. The membrane protein Imp1227 is the main protein constituent of the unique outer sheath of the hyperthermophilic, chemolithoautotrophic archaeum Ignicoccus hospitalis. With its molecular mass of only 6.23 kDa, Imp1227 is found to be incorporated into the outer membrane to form large, stable complexes. When separated by SDS-PAGE, they exhibit apparent masses of about 150, 50, 45 and 35 kDa. Electron micrographs of negatively stained samples confirmed that isolated membranes are tightly packed with round complexes, about 7 nm in diameter, with a central, stain-filled 2 nm pore; a local two-dimensional crystalline arrangement in the form of small patches can be seen by tomographic reconstruction. Using secondary structure predictions and molecular modelling, an alpha-helical transmembrane domain is proposed; for the oligomer, a ring-shaped nonamer with a central 2 nm pore was a likely arrangement. |
Archaea | Thermoproteota | Imp1227 of Ignicoccus hospitalis (A8ABZ0) |
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1.A.63.2.1 | Transmembrane DUF4845 protein with 120 aas and one TMS. |
Bacteria | Pseudomonadota | Transmembrane protein of Acidovorax sp. KKS102 |
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1.A.63.2.2 | Uncharacterized protein of 129 aas and 1 TMS |
Bacteria | Pseudomonadota | UP of Congregibacter litoralis |
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1.A.63.2.3 | Uncharacterized protein of 130 aas and 1 TMS/ |
Bacteria | Pseudomonadota | UP of Legionella pneumophila |
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1.A.63.2.4 | Uncharacterized DUF4845 domain-containing protein of 192 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of Thiobacillus sp. |
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1.A.63.2.5 | Uncharacterized DUF4845 domain-containing protein of 131 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of Cupriavidus sp. |
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1.A.63.2.6 | Uncharacterized DUF4845 domain-containing protein of 92 aas and possibly two TMSs, N- and C-terminal. |
Bacteria | Pseudomonadota | UP of Betaproteobacteria bacterium |
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1.A.63.2.7 | Uncharacterized DUF4845 domain-containing protein of 122 aas and 2 TMSs, one N-terminal and possibly a second, near the C-terminus of the protein. |
Archaea | Euryarchaeota | UP of Halobacteria archaeon |
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1.A.64.1.1 | Channel-forming Plasmolipin (Fischer and Sapirstein, 1994) | Eukaryota | Metazoa, Chordata | Plasmolipin of Rattus norvegicus (P47987) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.64.1.2 | Plasmolipin, PllP, or MARVEL domain-containing protein of 173 aas and 4 TMSs. |
Eukaryota | Metazoa, Chordata | PllP of Taeniopygia guttata (Zebra finch) (Poephila guttata) |
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1.A.64.2.1 | Myelin and Lymphocyte Protein, MAL/VIP17 protein, a regulator of NKCC2 (2.A.30.1.1). It stabilizes kidney apical membranes, and facilitates sorting of proteins to these membranes (Carmosino et al., 2010). It has 4 TMSs that align with those of plasmolipin. |
Eukaryota | Metazoa, Chordata | MAL/VIP17 of Canis familiaris (Q28296) |
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1.A.64.2.2 | Myelin and lymphocyte protein, MAL, of 153 aas and 4 TMSs. This human ortholog is 88% identical to the dog protein, TC# 1.A.64.2.1. It may be a component in vesicular trafficking cycling between the Golgi complex and the apical plasma membrane, and could be involved in myelin biogenesis and/or myelin function. It (1) has lipid-like properties that qualify it as a member of the group of proteolipid proteins. (2) it partitions selectively into detergent-insoluble membranes, consistent with MAL being distributed in highly ordered membranes in the cell. The structure, expression and biochemical characteristics of MAL, the association of MAL with raft membranes and the function of MAL in polarized epithelial cells have been discussed (Rubio-Ramos et al. 2021).
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Eukaryota | Metazoa, Chordata | MAL of Homo sapiens |
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1.A.64.2.3 | T-cell differentiation protein A, MAL, of 163 aas and 4 TMSs. |
Eukaryota | Metazoa, Chordata | MAL of Tetraodon nigroviridis (Spotted green pufferfish) (Chelonodon nigroviridis) |
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1.A.64.3.1 | Myeloid-associated differentiation marker, MyADM (322 aas; 8 TMSs) |
Eukaryota | Metazoa, Chordata | MyADM of Homo sapiens (Q96S97) |
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1.A.64.3.2 | Uncharacterized protein of 299 aas and 8 TMSs. |
Eukaryota | Metazoa, Chordata | UP of Ovis aries (Sheep) |
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1.A.64.4.1 | 4 TMS MARVEL superfamily member |
Eukaryota | Metazoa, Nematoda | 4TMS homologue of Caenorhabditis elegans (P83387) |
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1.A.64.4.2 | Uncharacterized MARVEL domain-containing protein of 174 aas and 3 TMSs. |
Eukaryota | Metazoa, Arthropoda | UP of Tetranychus urticae (Two-spotted spider mite) |
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1.A.64.4.3 | MARVEL domain-containing protein of 192 aas and 4 TMSs. |
Eukaryota | Metazoa, Arthropoda | MARVEL protein of Strigamia maritima (European centipede) (Geophilus maritimus) |
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1.A.64.4.5 | Chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing protein 6, CMTM6, of 183 aas and 4 TMSs. It is recognized as one of its potential immunotherapy targets for treatment of endocrine cancer (Chen et al. 2024). CMTM6 mediates the Warburg effect and promotes the liver metastasis of colorectal cancer (Shaha et al. 2024). |
Eukaryota | Metazoa, Chordata | CMTM6 of Homo sapiens |
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1.A.64.5.1 | CKLF-like MARVEL transmembrane domain-containing protein 7, CMTM7 (175aas; 4 TMSs; Miyazaki et al., 2012). CMTM7 functions to link sIgM and BLNK in the plasma membrane, to recruit BLNK to the vicinity of Syk, and to initiate BLNK-mediated signal transduction (Miyazaki et al., 2012). No transport function is known. |
Eukaryota | Metazoa, Chordata | CMTM7 of Homo sapiens (Q96FZ5) |
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1.A.64.5.2 | Proteolipid protein 2 (Differentiation-dependent protein A4) (Intestinal membrane A4 protein) |
Eukaryota | Metazoa, Chordata |
A4 protein of Homo sapiens |
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1.A.64.5.3 | Uncharacterized protein of 208 aas |
Eukaryota | Metazoa, Nematoda | UP of Caenorhabditis elegans |
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1.A.64.5.4 | CKLF-like MARVEL transmembrane domain-containing protein 8 of 343 aas and 4 TMSs, CMTM8. A short splice variant, CMTM8-v2, retains the ability to induce apoptosis via caspase-dependent and -independent pathways to inhibit cell growth and colony formation. CMTM8 and CMTM8-v2 display different expression profiles and distinct subcellular localization patterns, while operating via different mechanisms to induce apoptosis. CMTM8-v2 does not affect EGFR internalization, implying that the MARVEL domain and/or the cytosolic YXXPhi motifs are necessary for CMTM8 to accelerate ligand-induced EGFR internalization (Li et al. 2007). |
Eukaryota | Metazoa, Chordata | CMTM8 of Anas platyrhynchos (Mallard) (Anas boschas) |
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1.A.64.5.5 | CKIF-like MARVEL transmembrane domain containing protein 1 of 169 aas and 4 TMSs, CMTM1, or chemokine-like factor superfamily member 1, of 169 aas and 4 TMSs. It is not required for mouse fertility although CMTM2A (TC# 1.A.64.5.6) and CMTM2B (TC#1.A.64.5.7 are required (Fujihara et al. 2018). |
Eukaryota | Metazoa, Chordata | CMTM1 of Homo sapiens |
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1.A.64.5.6 | CKIF-like MARVEL transmembrane domain containing protein, CMTM2A of 169 aas and 4 TMSs, also called chemokine-like factor superfamily member 2A. It and CMTM2B (TC#1.A.64.5.7) are required for mouse fertility although CMTM1 (TC# 1.A.64.5.5) is not required (Fujihara et al. 2018). |
Eukaryota | Metazoa, Chordata | CMTM2A of Mus musculus |
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1.A.64.5.7 | CKIF-like MARVEL transmembrane domain containing protein, CMTM2B of 210 aas and 4 TMSs, also called chemokine-like factor superfamily member 2B. It and CMTM2A (TC#1.A.64.5.6) are required for mouse fertility although CMTM1 (TC# 1.A.64.5.5) is not required (Fujihara et al. 2018). |
Eukaryota | Metazoa, Chordata | CMTM2B of Mus musculus |
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1.A.64.5.8 | CKLF-Like MARVEL Transmembrane Member 5, CMTM5, or Chemokine-like factor superfamily member 5, of 223 aas and 4 or 5 TMSs. CMTM5 associates with pathways in MARVEL domains, chemotaxis, cytokines, transmembrane structures, and integral component of membrane (Zhou et al. 2019). |
Eukaryota | Metazoa, Chordata | CMTM5 of Homo sapiens |
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1.A.64.6.1 | Marvel D3 tight junction-associated occludin of 401 aas and 4 TMSs; a determinant of paracellular permeability (Steed et al. 2009). |
Eukaryota | Metazoa, Chordata | MarvelD3 of Homo sapiens |
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1.A.64.6.2 | MARVEL domain containing 3, MARVELD3, of 314 aas and 4 TMSs, within the C-terminal half of the protein. |
Eukaryota | Metazoa, Chordata | MARVELD3 of Myotis lucifugus (Little brown bat) |
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1.A.65.1.1 | The envelope (E) viroporin protein of 85 aas and 2 TMSs. |
Viruses | Orthornavirae, Pisuviricota | E protein of Murine Hepatitis Virus (MHV) (83aas; P0C2R0) |
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1.A.65.1.2 | The SARS coronavirus pore-forming envelope (E) protein or protein 3a (76 aas; 1 TMS) forms a pentameric cation-selective pore (Torres et al. 2006; Scott and Griffin 2015) that binds amantadine (Torres et al., 2007). A single polar residue and distinct membrane topologies impact its function (Ruch and Machamer, 2012). The E protein ion channel (IC) activity is cation-specific and K+-selective and is specifically correlated with enhanced pulmonary damage, edema accumulation and death. Calcium ions together with pH modulated E protein pore charge and selectivity (Nieto-Torres et al. 2015). There is a single transmembrane domain in E, suggesting an allosteric interaction between extramembrane and transmembrane domains (To et al. 2016). |
Viruses | Nidovirales | Protein E of SARS (NP_828854) (Q19QW7) |
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1.A.65.1.3 | Envelope small membrane viroporin protein of 82 aas and 1 or 2 TMSs, protein E or sM. Viroporin inhibitors have been identified (Takano et al. 2015). |
Viruses | Orthornavirae, Pisuviricota | Viroporin of feline infectious peritonitis virus (FIPV) |
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1.A.65.1.4 | MERS CoV Viroporin of 82 aas and 1 TMS. Induces the formation of pentameric hydrophilic pores in cellular membranes followed by apoptosis (Surya et al. 2015). |
Viruses | Orthornavirae, Pisuviricota | Viroporin of Human Middle East respiratory syndrome coronavirus (MERS CoV) or EMC (HCoV-EMC) |
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1.A.65.1.5 | ORF5-E fusion protein of 194 aa |
Viruses | Orthornavirae, Pisuviricota | Orf5-E of Middle East respiratory syndrome-related coronavirus |
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1.A.65.1.6 | Envelope protein of 75 aas and 1 TMS. |
Viruses | Orthornavirae, Pisuviricota | Envelope small protein of Alphacoronavirus Bat-CoV/P. kuhlii |
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1.A.65.1.7 | Envelope (E) viroporin protein, ORF5, of 75 aas and 1 N-terminal TMS. The E-proteins of CoV, CoV-2 and MERS oligomerize to form homopentamers by aligning their TMSs into a pore-forming complex in phospholipid membranes (Surya et al. 2015). The pore is weakly cation selective with Ca2+ favored over K+, and Na+ favored over H+ (Castaño-Rodriguez et al. 2018). It is involved in various aspects of the virus life cycle including assembly, budding, envelope formation, virus release, and inflammasome activation (Breitinger et al. 2021). The structure and drug binding of the SARS-CoV-2 Envelope (E) protein in phospholipid bilayers has been determined (Hong et al. 2020). E forms a five-helix bundle surrounding a narrow central pore. The middle of the TM segment is distorted from the ideal α-helical geometry due to three regularly spaced phenylalanine residues, which stack within each helix and between neighboring helices. These aromatic interactions, together with interhelical Val and Leu interdigitation, cause a dehydrated pore compared to the viroporins of influenza and HIV viruses. Hexamethylene amiloride and amantadine bind shallowly to polar residues at the N-terminal lumen, while acidic pH affects the C-terminal conformation. Thus, SARS-CoV-2 E forms a structurally robust but bipartite channel whose N- and C-terminal halves can interact with drugs, ions and other viral and host proteins semi-independently (Hong et al. 2020). Mandala et al. 2020 reported a 2.1-Å structure and the drug-binding site of E's transmembrane domain (ETM), determined using solid-state NMR spectroscopy. In lipid bilayers that mimic the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) membrane, ETM forms a five-helix bundle surrounding a narrow pore. The protein deviates from the ideal alpha-helical geometry due to three phenylalanine residues, which stack within each helix and between helices. Together with valine and leucine interdigitation, these cause a dehydrated pore compared with the viroporins of influenza viruses and HIV. Hexamethylene amiloride binds the polar amino-terminal lumen, whereas acidic pH affects the carboxy-terminal conformation. Thus, the N- and C-terminal halves of this bipartite channel may interact with other viral and host proteins semi-independently. The structure sets the stage for designing E inhibitors as antiviral drugs (Mandala et al. 2020). Chenodeoxycholate(CDC) and ursodeoxycholate (UDC) bind to the envelope (E) protein of SARS-Cov2 and serve as candidates to hinder the survival of SARS-Cov2 by disrupting the structure of SARS-Cov2-E and facilitating the entry of solvents/polar inhibitors inside the viral cell (Yadav et al. 2022). Interactions of SARS-CoV-2 envelope protein with amilorides promote antiviral activity (Park et al. 2021). E-protein mediated currents were inhibited by amantadine and rimantadine, as well as 5-(N,N-hexamethylene)amiloride (HMA). Of 10 flavonoids, epigallocatechin and quercetin were most effective (Breitinger et al. 2021). The e-protein increases the intra-Golgi pH by forming a cation channel that is regulated by pH(Cabrera-Garcia et al. 2021). A cell-based system combined with flow cytometry has been used to evaluate antibody responses against SARS-CoV-2 transmembrane proteins in patients with COVID-19 (Martin et al. 2022). An intricate aromatic network regulates the opening of the ETM channel pore (Medeiros-Silva et al. 2022). Rotational dynamics of the transmembrane domains play important roles in peptide dynamics of viral fusion and ion channel forming proteins (Wang and Fischer 2022). Hexamethylene amiloride derivatives are potential luminal inhibitors of the SARS-CoV-2 E Protein (Jalily et al. 2022). The envelope proteins from SARS-CoV-2 and SARS-CoV potently reduce the infectivity of human immunodeficiency virus type 1 (HIV-1) (Henke et al. 2022). The cytoplasmic domain of the SARS-CoV-2 envelope protein assembles into a beta-sheet bundle in lipid bilayers (Dregni et al. 2023). The E protein of SARS-CoV-2 efficiently down-regulates the cell surface expression of the antigen-presenting molecule, CD1d, to suppress the function of iNKT cells. E protein plays roles in virion packaging and envelopment during viral morphogenesis. The transmembrane domain of E protein is responsible for suppressing CD1d expression by specifically reducing the level of mature, post-ER forms of CD1d, suggesting that it suppressed the trafficking of CD1d proteins and leads to their degradation. Point mutations demonstrated that the putative ion channel function is required for suppression of CD1d expression, and inhibition of the ion channel function using small chemicals rescued CD1d expression (Lu et al. 2023). However, Zhang et al. 2023 identified a symmetric helix-helix interface, leading to the prediction of a dimeric structure that does not support channel activity. The two helices have a tilt angle of only 6 degrees , resulting in an extended interface dominated by Leu and Val side chains. While residues Val14-Thr35 are almost all buried in the hydrophobic region of the membrane, Asn15 lines a water-filled pocket that potentially serves as a drug-binding site. The E and other viral proteins may adopt different oligomeric states to help perform multiple functions (Zhang et al. 2023). Umbelliferone and eriodictyol suppress the cellular entry of SARS-CoV-2 (Cheng et al. 2023). Hexamethylene amiloride binds the SARS-CoV-2 Envelope (E) protein at the protein-lipid interface (Somberg et al. 2023). The atomic structure of the open SARS-CoV-2 E viroporin has been determined (Medeiros-Silva et al. 2023). This E protein is a specific dimer, VP4 of poliovirus is exclusively monomeric, and Vpu of HIV assembles into a polydisperse mixture of oligomers under these conditions. Overall, these results revealed the diversity in the oligomerization of viroporins (Townsend et al. 2024). The E protein perturbes Ca2+ homeostasis. It is structurally similar to regulins such as phospholamban, that regulate the sarco/endoplasmic reticulum calcium ATPases (SERCA). The SARS-CoV-2 E protein affects SERCA as an exoregulin and forms oligomers with regulins, and thus alters the monomer/multimer regulin ratio thereby influencing their interactions with SERCAs. A direct interaction between E protein and SERCA2b results in a decrease in SERCA-mediated ER Ca2+ reload (Berta et al. 2024). |
Viruses | Orthornavirae, Pisuviricota | E-protein of severe acute respiratory syndrome coronavirus 2, SARS-CoV-2 |
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1.A.65.1.8 | Protein-E of 78 aas and 2 TMSs. |
Viruses | Orthornavirae, Pisuviricota | E-protein of rodent coronavirus |
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1.A.65.1.9 | E-protein of 89 aas and 2 TMSs |
Viruses | Orthornavirae, Pisuviricota | E-protein of rabbit coronavirus |
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1.A.66.1.1 | Bactericidal pore-forming pardaxin (Pa4) permeabilized both lipid and lipopolysaccharide membranes. Five paralogues are known: Pa1, 2, 3, 4, and 5, all nearly identical to each other. The 3-d structure of Pa4 is known. It forms a helix-turn-helix conformation resembling a horseshoe (Bhunia et al., 2010). |
Eukaryota | Metazoa, Chordata | Pardaxin of Pardachirus marmoratus (P81861) |
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1.A.67.1.1 | Magnesium transporter-1, MMgT1. As of 2018, the function of this protein as a Mg2+ transporter was under debate (Schäffers et al. 2018). |
Eukaryota | Metazoa, Chordata | MMgT1 of Mus musculus (A7UH87) |
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1.A.67.1.2 | Magnesium transporter-2, MMgT2. As of 2018, the function of this protein as a Mg2+ transporter was under debate (Schäffers et al. 2018). |
Eukaryota | Metazoa, Chordata | MMgT2 of Mus musculus (Q8R3L0) |
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1.A.67.1.3 | Uncharacterized protein of 107 aas and 2 TMSs. |
Eukaryota | Fungi, Basidiomycota | UP of Ustilago hordei (Barley covered smut fungus) |
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1.A.67.1.4 | Uncharacterized protein of 487 aas and 2 C-terminal TMSs. |
Eukaryota | Viridiplantae, Streptophyta | UP of Brassica rapa (Chinese cabbage) (Brassica pekinensis) |
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1.A.67.1.5 | Uncharacterized protein of 137 aas and 2 N-terminal TMSs |
Eukaryota | Fungi, Ascomycota | UP of Leptosphaeria maculans (Blackleg fungus) (Phoma lingam) |
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1.A.67.1.6 | Uncharacterized protein of 126 aas and 2 N-terminal TMSs. |
Eukaryota | Heterolobosea | UP of Naegleria gruberi (Amoeba) |
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1.A.67.1.7 | ER membrane protein complex subunit 5, Emc5 of 141 aas and 2 TMSs. The EMC seems to be required for efficient folding of proteins in the endoplasmic reticulum (ER) and also for insertion of integral membrane proteins into the ER membrane (Guna et al. 2018). |
Eukaryota | Fungi, Ascomycota | Emc5 of Saccharomyces cerevisiae (Baker's yeast) |
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1.A.67.1.8 | Membrane magnesium transporter, MmgT, of 112 aas and 2 TMSs. |
Eukaryota | Apicomplexa | MmgT of Toxoplasma gondii |
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1.A.67.1.9 | Uncharacterized protein of 103 aas and 2 TMSs |
Eukaryota | Fungi, Basidiomycota | UP of Piriformospora indica |
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1.A.67.2.1 | Uncharacterized protein of 132 aas and 2 TMSs. |
Eukaryota | Euglenozoa | UP of Leishmania braziliensis |
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1.A.67.2.2 | Uncharacterized protein of 143 aas and 2 TMSs. |
Eukaryota | Euglenozoa | UP of Trypanosoma cruzi |
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1.A.67.2.3 | Uncharacterized protein of 133 aas and 2 TMSs |
Eukaryota | Euglenozoa | UP of Strigomonas culicis |
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1.A.67.3.1 | ER membrane protein complex subunit 5, EMC5, putative, MMgT of 116 aas and 2 N-terminal TMSs (Wunderlich 2022). |
Eukaryota | Apicomplexa | MMgT of Plasmodium falciparum |
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1.A.67.3.2 | ER membrane protein complex subunit 5 of 115 aas and 2 TMSs. |
Eukaryota | Apicomplexa | ER membrane protein of Plasmodium yoelii |
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1.A.67.3.3 | ER membrane protein complex subunit 5 of 115 aas and 2 N-terminal TMSs. |
Eukaryota | Apicomplexa | ER membrane protein of Plasmodium berghei |
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1.A.68.1.1 | The viral small hydrophobic protein (V-SHP; hRSV-SH) of 64 aas with 1 TMS, It forms a pentameric ion conducting pore in the membrane (Surya and Torres 2015) that transports monovalent cations (Hyser and Estes 2015). The SH protein has two protonatable His residues in its transmembrane domain that are oriented facing the lumen of the channel. Their protonation may serve as a pH sensor, to promote electrostatic repulsion and reduced oligomer stability at low pH (Surya and Torres 2015). Pyronin B can reduce SH channel activity, and its likely binding site on the SH protein channel has been identified. Black lipid membrane experiments confirmed that protonation of both histidine residues reduces stability and channel activity (Li et al. 2014). Water transport was observed with histidine residues of five chains (His22 and His51) playing a key role in pore permeability (Araujo et al. 2016). The assembly of the transmembrane domains of viral channel-forming proteins and peptide drug screening has been achieved using a docking approach (Huang and Fischer 2022). |
Viruses | Orthornavirae, Negarnaviricota | SH protein of human respiratory syncytial virus (P04852) |
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1.A.68.1.2 | BSV small hydrophobic (SH) protein of 81 aas (Karger et al. 2001). |
Viruses | Orthornavirae, Negarnaviricota | SH of bovine respiratory syncytial virus |
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1.A.68.1.3 | Small hydrophobic viroporin protein (SH), also called small protein 1A, of 65 aas and 1 TMS. Forms a proton-selective cation channel that may also be capable of transporting Na+ and K+, playing a role in budding and /or virus entry (Scott and Griffin 2015). May also play a role in counteracting host innate immunity (Russell et al. 2015). The SH protein is stable in its pentameric membrane-integrated form. Simulations also showed the presence of water molecules within the bilayer by density distribution, thus confirming that the SH protein is a viroporin (Araujo et al. 2016). |
Viruses | Orthornavirae, Negarnaviricota | Viroporin SH of human respiratory syncytial virus B |
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1.A.69.1.1 | Heteromeric odorant receptor, OR (Sato et al., 2008). OR22a senses fruit-derived esters. These olfactory receptors may have 3-d structures resembling animal rhodopsins, human citronellic terpenoid receptors, OR1A1 and OA1A2 and the mouse eugenol receptor, OR-EG (Ramdya and Benton, 2010). Molecular modelling of oligomeric states of DmOR83b has been reported (Harini and Sowdhamini, 2012). Recombinant receptor together with the co-receptor, Orco, has been overproduced, purified and reconstituted in a lipid bilayer (Carraher et al. 2013). Orco (Or83b) forms a dimer that is fully functional for Ca2+ transport, is regulated by calmodulin and interacts normally with Or22a. The native Orco is therefore probably a dimer (Mukunda et al. 2014). Fertility decline in female mosquitoes is regulated by the orco olfactory co-receptor (David et al. 2023). OR46 is a potential sensory receptor associated with host detection in the livestock pest Lucilia cuprina (Wulff et al. 2024). |
Eukaryota | Metazoa, Arthropoda | Heterometic odorant receptor (OR) of Drosophila melanogaster: |
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1.A.69.1.2 | Odorant receptor, OR2 (Carraher et al., 2012) of 378 aas and 7 TMSs. |
Eukaryota | Metazoa, Arthropoda | OR2 of Anopheles gambiae (Q8WTE6) |
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1.A.69.1.3 | Odorant receptor 56a of419 aas and 7 TMSs. Mediates aversive responses to harmful microbial (bacterial and fungal) products such as geosmin (trans-1,10-dimetnyl-trans-9-decalol). (Stensmyr et al. 2012). |
Eukaryota | Metazoa, Arthropoda | OR56a of Drosophila melanogaster |
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1.A.69.1.4 | Ordorant receptor 67b of 421 aas and 8 TMSs (Identical to Or67b of D. melanogaster) |
Eukaryota | Metazoa, Arthropoda | Or67b of Drosophila simulans |
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1.A.69.1.5 | Odorant receptor 10b of 406 aas and 7 TMSs |
Eukaryota | Metazoa, Arthropoda | Or10b of Drosophila melanogaster |
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1.A.69.1.6 | Odorant receptor co-receptor, Orco of 478 aas and 7 TMSs in a 4 + 3 TMS arrangement. Also called AgDr7, GPR-7, ORF_ANOGA. It has been used to develop a Pichia biosensor for high-throughput analyses of compounds that influence mosquito behavior (Varela and Yadav 2021). |
Eukaryota | Metazoa, Arthropoda | Orco odorant receptor of Anopheles gambiae (African malaria mosquito) |
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1.A.69.2.1 | The insect heteromeric CO2 receptor: GR21a (Olfactory receptor 21a; 454 aas with 7 or 8 TMSs) GR63a (Olfactory receptor 63a; 512 aas) are coexpressed in antennal neurons of insects and together comprise the peripheral sensory receptor for CO2 (Ramdya and Benton, 2010). These proteins are members of the 7Tm-7 superfamily of putative 7TMS proteins. |
Eukaryota | Metazoa, Arthropoda | The gustatory receptor for CO2, GR21a/GRG3a of Drosophila melanogaster |
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1.A.69.2.2 | Uncharacterized protein of 382 aas and 9 TMSs. |
Eukaryota | Metazoa, Arthropoda | UP of Frankliniella occidentalis (western flower thrips) |
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1.A.69.2.3 | Gustatory receptor for sugar taste 64e-like protein, GR64e, of 486 aas and 8 TMSs. |
Eukaryota | Metazoa, Arthropoda | GR64e protein of Atta cephalotes (Leafcutter ant) |
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1.A.69.2.4 | Uncharacterized protein of 416 aas and 7 TMSs. |
Eukaryota | Metazoa, Arthropoda | UP of Aphis gossypii (cotton aphid) |
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1.A.69.2.5 | Uncharacterized protein of 425 aas and 7 TMSs. |
Eukaryota | Metazoa, Arthropoda | UP of Amphibalanus amphitrite |
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1.A.69.2.6 | Gustatory receptor-like (Grl or Gr5a) protein of 444 aas and 8 TMSs. Insect odorant receptors and gustatory receptors define a superfamily of seven- or 8-TMS ligand-gated ion channels (referred to here as 7TMICs), with homologs identified across Animalia, except Chordata, as well as in plants and uncellular eukaryotes (DUF3537 proteins). Several Drosophila melanogaster Grls display selective expression in subsets of taste neurons, suggesting that they are previously- unrecognized insect chemoreceptors. Their origin may be in a eukaryotic common ancestor (Benton and Himmel 2023). It is required for a response to the sugar trehalose in taste neurons (Ueno et al. 2001). Gr5a neurons selectively respond to sugars, in contrast to Gr66a cells which respond to bitter compounds. Flies are attracted to sugars and avoid bitter substances, suggesting that Gr5a neuron activity is sufficient to mediate acceptance behavior. Sugar signal transduction occurs through coupling with G-proteins such as Galpha49B and G-salpha60A. |
Eukaryota | Metazoa, Arthropoda | Grl of Drosophila melanogaster |
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1.A.69.2.7 | Gustatory receptor GR64a specific for sugars (sucrose, maltose and glucose). The structures of two sugar GRs have been determined (Ma et al. 2024), the Drosophila sweet taste receptors GR43a and GR64a in the apo and sugar-bound states. Both GRs form tetrameric sugar-gated cation channels composed of one central pore domain (PD) and four peripheral ligand-binding domains (LBDs). Whereas GR43a is specifically activated by the monosaccharide fructose that binds to a narrow pocket in LBDs, disaccharides sucrose and maltose selectively activate GR64a by binding to a larger and flatter pocket in LBDs. Sugar binding to LBDs induces local conformational changes, which are subsequently transferred to the PD to cause channel opening (Ma et al. 2024). |
Eukaryota | Metazoa, Arthropoda | GR64a of |
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1.A.69.2.8 | Uncharacterized protein of 442 aas and 7 TMSs in a 2 + 2 + 2 + 1 TMS arrangement. |
Eukaryota | Metazoa, Annelida | UP of Capitella teleta |
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1.A.69.3.1 | Fructose-regulated Ca2+/cation channel, Gustatory (fructose) receptor-9, Gr9 (Sato et al., 2011),which has 8 TMSs in a 5 + 2 + 1 TMS arrangement. Gr9 is widely expressed in the central nervous system (CNS), as well as oral sensory organs and is involved in the promotion of feeding behaviors (Mang et al. 2016). GRs play roles in sensing tastants, such as sugars and bitter substances. The BmGr9 silkworm GR is a d-fructose-gated ion channel receptor. Morinaga et al. 2022 presented a structural model for a channel pore and a D-fructose binding site in BmGr9. Since the membrane topology and oligomeric state of BmGr9 appears similar to those of an insect odorant receptor co-receptor, Orco, they constructed a structural model of BmGr9 based on the cryo-EM Orco structure. Their site-directed mutagenesis data suggested that transmembrane region 7 forms channel pore and controls channel gating. This model also suggested that a pocket formed by transmembrane helices 2-4 and 6 binds D-fructose. They determined the potent binding mode of D-fructose. They proposed a conformational change that leads to channel opening upon D-fructose binding (Morinaga et al. 2022). Structures of BmGr9, a fructose-gated cation channel, in agonist-free and fructose-bound states have been determined (Frank et al. 2023). BmGr9 forms a tetramer similar to distantly related insect Olfactory Receptors (ORs). Upon fructose binding, BmGr9's ion channel gate opens through helix S7b movements. In contrast to ORs, BmGR9's ligand-binding pocket, shaped by a kinked helix S4 and a shorter extracellular S3-S4 loop, is larger and solvent accessible in both agonist-free and fructose-bound states. Also unlike ORs, fructose binding by BmGr9 involves helix S5 and a binding pocket lined with aromatic and polar residues. Structure-based sequence alignments revealed distinct patterns of ligand-binding pocket residue conservation in GR subfamilies associated with distinct ligand classes (Frank et al. 2023). |
Eukaryota | Metazoa, Arthropoda | GR-9 of Bombyx mori (B3GTD7) |
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1.A.69.3.2 |
Gustatory receptor 43a isoform A. Functions as a narrowly tuned fructose receptor in taste neurons (Miyamoto et al. 2012), being both necessary and sufficient to sense hemolymph fructose. The structures of two sugar GRs have been determined (Ma et al. 2024), the Drosophila sweet taste receptors GR43a and GR64a in the apo and sugar-bound states. Both GRs form tetrameric sugar-gated cation channels composed of one central pore domain (PD) and four peripheral ligand-binding domains (LBDs). Whereas GR43a is specifically activated by the monosaccharide fructose that binds to a narrow pocket in LBDs, disaccharides sucrose and maltose selectively activate GR64a by binding to a larger and flatter pocket in LBDs. Sugar binding to LBDs induces local conformational changes, which are subsequently transferred to the PD to cause channel opening (Ma et al. 2024). |
Eukaryota | Metazoa, Arthropoda | GR43a of Drosophila melanogaster (Q9V4K2) |
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1.A.69.3.3 | Gustatory receptor 28b isoform D of 470 aas and 8 TMSs. It mediates acceptance or avoidance behavior, depending on its substrates. Its atypical expression suggests additional nongustatory roles in the nervous system and tissues involved in proprioception (warmth receptor), hygroreception, and other sensory modalities. It is also possible that it has chemosensory roles in the detection of internal ligands (Thorne and Amrein 2008). Saponins function in natural self-defense for plants to deter various insects due to their unpleasant taste and toxicity. Sang et al. 2019 provided evidence that saponin from Quillaja saponaria functions as an antifeedant as well as an insecticide to ward off insects in both the larval and the adult stages. |
Eukaryota | Metazoa, Arthropoda | GR28b of Drosophila melanogaster (Q9VM08) |
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1.A.69.3.4 | Gustatory receptor 2a isoform B |
Eukaryota | Metazoa, Arthropoda | GR2a of Drosophila melanogaster (Q9W594) |
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1.A.69.3.5 | High energy light unresponsive protein 1, Lite1; chemoreceptor GUR-2 of 439 aas and 8 TMSs. It is a photoreceptor for short wavelength (UV) light that mediates UV-light-induced avoidance behavior (Edwards et al. 2008, Liu et al. 2010, Gong et al. 2016). It directly senses and absorbs both UV-A and UV-B light with very high efficiency (Gong et al. 2016). Absorption of UV-B but not UV-A light shows resistance to photobleaching. In contrast to other photoreceptors, it does not use a prosthetic chromophore to capture photons and only depends on its protein conformation. It may play a role in response to white light exposure (De Magalhaes Filho et al. 2018) as well as color detection (Ghosh et al. 2021). |
Eukaryota | Metazoa, Nematoda | GUR-2 of Caenorhabditis elegans |
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1.A.69.3.6 | Gustatory receptor, GPRGR53, of 430 aas and 7 TMSs. It mediates acceptance or avoidance behavior, depending on its substrates. |
Eukaryota | Metazoa, Arthropoda | GPRGR53 of Anopheles gambiae (African malaria mosquito) |
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1.A.69.3.7 | Putative gustatory receptor 98b of 402 aas and 7 TMSs. |
Eukaryota | Metazoa, Arthropoda | GR98b of Bactrocera latifrons |
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1.A.69.3.8 | Gustatory receptor family protein 3, Gur-3, of 447 aas and 8 - 9 TMSs. It is a chemoreceptor involved in light-induced avoidance behavior (Bhatla and Horvitz 2015) and probably acts as a molecular sensor in I2 pharyngeal neurons, required for the inhibition of feeding in response to light and hydrogen peroxide. It may be involved in circadian rhythms, probably by acting as a light sensor (Goya et al. 2016). Although it acts with Lite-1 in color detection, it does not act as a photoreceptor (Ghosh et al. 2021). |
Eukaryota | Metazoa, Nematoda | Gur-3 of Caenorhabditis elegans |
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1.A.69.3.9 | Gustatory receptor Gr66a of 527 aas and 8 TMSs, specific for bitter compounds (Thorne et al. 2004). Gr66a cells respond to bitter compounds such as caffeine, theophylline, threonine or valine. Flies avoid bitter substances, suggesting that Gr66a neuron activity is sufficient to mediate avoidance behavior. This receptor is required for sensing and avoiding N,N-Diethyl-meta-toluamide (DEET), the most widely used insect repellent worldwide, as well as L-canavanine, a plant-derived insecticide. Gr66a neurons are also involved in the sex-specific perception of molecules inducing male avoidance behavior, probably through sensing 7-tricosene (7-T), a male cuticular pheromone and leading to inhibition of male-male courtship. |
Eukaryota | Metazoa, Arthropoda | Gr66a of Drosophila melanogaster (fruit fly) |
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1.A.69.4.1 | The pheromone receptor, Or-1 (Nakagawa et al., 2012) |
Eukaryota | Metazoa, Arthropoda | Or-1 of Bombyx mori (Q5WA61) |
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1.A.69.4.2 | Sex pheromone receptor of 416 aas and 7 TMSs (Miura et al. 2010). |
Eukaryota | Metazoa, Arthropoda | pheromone receptor of Ostrinia nubilalis (European corn borer) (Pyralis nubilalis) |
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1.A.69.4.3 | Odorant receptor 3, Or3 of 410 aas and 7 TMSs. |
Eukaryota | Metazoa, Arthropoda | Or3 of Epiphyas postvittana (Light brown apple moth) |
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1.A.69.4.4 | Odorant (pheromone) receptor, OR-3, BmOR3, Or-3, PR-3, of 439 aas and 7 TMSs in a 2 + 1 + 2 + 2 TMS arrangement. The activation of PRs is coupled to the calcium permeability of their coreceptor (Orco (see TC# 1.A.69.1.1)) or putatively with G proteins (Lin et al. 2021). Using the PR BmOR3 from the silk moth B. mori and its coreceptor BmOrco as a template, Lin et al. 2021 showed that an agonist-induced conformational change of BmOR3 is transmitted to BmOrco through TMS7s of both receptors, resulting in the activation of BmOrco. Key interactions, including an ionic lock and a hydrophobic zipper, are essential for mediating the functional coupling between BmOR3 and BmOrco. BmOR3 also selectively coupled with Gi proteins, which is dispensable for BmOrco coupling. Moreover, trans-7TM BmOR3 recruited arrestin (see TC# 8.A.136) in an agonist-dependent manner, which indicated an important role for BmOR3-BmOrco complex formation in ionotropic functions. Thus, the coupling of G protein and arrestin to a prototype trans-7TMS PR, BmOR3, has been demonstrated (Lin et al. 2021). |
Eukaryota | Metazoa, Arthropoda | OR3 of Bombyx mori (Silk moth) |
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1.A.69.5.1 | Odorant receptor 85b (or85b) of 302 aas and 5 putative TMSs. Binds the odorant, heptanone, for activation; 2-nananone is a competitive antagonist. The second half of TMS3 is involved in odorant binding and activation (Nichols and Luetje 2010). |
Eukaryota | Metazoa, Arthropoda | Or85b of Drosophila melanogaster |
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1.A.69.5.2 | Odorant Receptor 4, OR4 or GPROR4, of 406 aas and 7 or 8 TMSs; if 8, the C-terminal TMS may not be a TMS. This odorant receptor specifically recognizes the human odorant sulcatone (6-methylhept-5-en-2-onesul), a volatile odorant emitted at uniquely high levels in humans, thereby playing a key role in mosquito's preference in biting human compared to other animals (McBride et al. 2014). Aedes aegypti is a vector for viruses that spread diseases like dengue, Zika and Chikungunya. Tiwari and Sowdhamini 2023 have modeled the full-length structure of OR4 and the ORco of A. aegypti. |
Eukaryota | Metazoa, Arthropoda | OR4 of Aedes aegypti (Yellowfever mosquito; Culex aegypti) |
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1.A.69.5.3 | Odorant receptor 85b of 384 aas and 7 TMSs in a 2 + 2 + 2 + 1 TMS arrangement. |
Eukaryota | Metazoa, Arthropoda | OR of Vanessa atalanta |
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1.A.69.5.4 | Uncharacterized protein of 399 aas and 7 TMSs in a 2 + 2 + 2 + 1 TMS arrangement. |
Eukaryota | Metazoa, Arthropoda | UP of Phymastichus coffea |
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1.A.69.5.5 | Odorant receptor 13a-like isoform X1 of 412 aas and possibly 7 TMSs in a 2 + 2 + 2 + 1 TMS arrangement. |
Eukaryota | Metazoa, Arthropoda | OR of Ceratina calcarata |
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1.A.69.5.6 | Odorant receptor 13a of 417 aas and 7 TMSs in a 2 + 2 + 2 + 1 TMS arrangement. |
Eukaryota | Metazoa, Arthropoda | OR of Drosophila simulans (Fruit fly) |
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1.A.69.6.1 | Odorant receptor 22 of 312 aas and 6 TMSs |
Eukaryota | Metazoa, Arthropoda | Or22 of Bombyx mori |
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1.A.69.6.2 | Odorant receptor 17 of 401 aas and 8 TMSs |
Eukaryota | Metazoa, Arthropoda | Or17 of Bombyx mori (Silk moth) |
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1.A.69.7.1 | Odorant recpetor 278 if 385 aas and 8 TMSs |
Eukaryota | Metazoa, Arthropoda | Or278 of Tribolium castaneum (Red flour beetle) |
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1.A.69.7.2 | Odorant receptor 205 of 406 aas and 9 putative TMSs. |
Eukaryota | Metazoa, Arthropoda | Or205 of Tribolium castaneum (Red flour beetle) |
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1.A.69.8.1 | DUF3537, MRB1, Bigger1, of 437 aas and 7 or 8 TMSs. |
Eukaryota | Viridiplantae, Streptophyta | DUF3537 oF Arabidopsis thaliana |
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1.A.69.8.2 | Uncharacterized protein of 446 aas and 7 TMSs in a 2 + 2 + 2 + 1 TMS arrangement. |
Eukaryota | Viridiplantae, Streptophyta | UP of Amborella trichopoda |
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1.A.69.8.3 | DUF3537 domain-containing protein of 691 aas and 7 TMSs/ |
Eukaryota | Viridiplantae, Chlorophyta | DUF3537 prtein of Chloropicon roscoffensis |
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1.A.69.9.1 | Uncharacterized protein of 347 aas and 7 TMSs in a 2 + 2 + 2 + 1 TMS arrangement. |
Archaea | Methanobacteriati, Methanobacteriota | UP of Haloarcula japonica |
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1.A.69.9.10 | Uncharacterized proteini of 369 aas and 7 TMSs. |
Archaea | Methanobacteriati, Methanobacteriota | UP of Methanobacteriota archaeon |
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1.A.69.9.11 | Uncharacterized protein of 357 aas and 7 TMSs |
Bacteria | Bacillati, Chloroflexota | UP of Chloroflexota (Chlorofoxi) bacterium |
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1.A.69.9.12 | Uncharacterized protein iof 397 aas and 7 TMSs. |
Bacteria | Bacillati, Chloroflexota | UP of Anaerolineales bacterium (salt marsh metagenome) |
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1.A.69.9.13 | WD40 repeat domain-containing protein of 795 aas and 9 TMSs, one at the N-terminus, one at residue 360, and 7 TMSs within residues 420 - 795. |
Archaea | Methanobacteriati, Thermoplasmatota | WD40 protein of Thermoplasmatota archaeon |
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1.A.69.9.14 | Uncharacterized protein of 313 aas and 7 TMSs in a 2 + 2 + 2 + 1 TMS arrangement. |
Bacteria | Pseudomonadati, Pseudomonadota | UP of Halieaceae bacterium |
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1.A.69.9.2 | Uncharacterized protein of 390 aas and 7 TMSs in a 2 + 2 + 2 + 1 TMS arrangement. |
Archaea | Methanobacteriati, Methanobacteriota | UP of Halobellus litoreus |
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1.A.69.9.3 | Uncharacterized protein of 382 aas with 7 TMSs in a 2 + 2 + 2 + 1 TMS arragngement. |
Archaea | Methanobacteriati, Methanobacteriota | UP of Unclassified Salinibaculum |
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1.A.69.9.4 | Uncharacterized protein of 350 aas and 7 TMSs. |
Archaea | Methanobacteriati, Methanobacteriota | UP of Halosegnis marinus |
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1.A.69.9.5 | Uncharacterized protein of 3261 aas and 7 TMSs |
Bacteria | Pseudomonadati, Bacteroidota | UP of Cytophagaceae bacterium |
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1.A.69.9.6 | Uncharacterized protein of 380 aas and 7 TMSs in a 2 + 2 + 2 + 1 TMS arrangement. |
Bacteria | Bacillati, Cyanobacteriota | UP of Nostoc sp. |
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1.A.69.9.7 | Uncharacterized protein of 394 aas and 7 TMSs. |
Bacteria | Bacillati, Actinomycetota | UP of Rugosimonospora africana |
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1.A.69.9.8 | Uncharacterized protein of 370 aas and 7 TMSs |
Bacteria | Bacillati, Chloroflexota | UP of Dehalococcoidia bacterium |
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1.A.69.9.9 | Uncharacterized protein of 356 aas and 7 TMSs. |
Archaea | Methanobacteriati, Methanobacteriota | UP of Haloplanus aerogenes |
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1.A.7.1.1 | ATP-gated cation channel (purinoceptor or ATP-neuroreceptor). Residues Glu52-Gly96 play roles in agonist binding and channel gating (Allsopp et al., 2011). The rat protein is 89% identical to the human ortholog. Mutations likely to confer ivermectin sensitivity to human P2X1 have been proposed (Pasqualetto et al. 2018). The P2X1 receptor is a trimeric ligand-gated ion channel that plays an important role in urogenital and immune functions. Bennetts et al. 2024 employed cryogenic electron microscopy (cryo-EM) to elucidate the structures of the P2X1 receptor in an ATP-bound desensitised state and an NF449-bound closed state. NF449, a potent P2X1 receptor antagonist, engages the receptor distinctively, while ATP, the endogenous ligand, binds in a manner consistent with other P2X receptors. To explore the molecular basis of receptor inhibition, activation, and ligand interactions, key residues involved in ligand and metal ion binding were mutated. Radioligand binding assays with [3H]-α,β-methylene ATP and intracellular calcium ion influx assays were used to evaluate the effects of these mutations. These experiments validated key ligand-receptor interactions and identified conserved and non-conserved residues critical for ligand binding or receptor modulation (Bennetts et al. 2024). |
Eukaryota | Metazoa, Chordata | P2X1 of Homo sapiens |
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1.A.7.1.10 | Green algal ATP-gated cation channel receptor P2X4 of 384 aas, 2 TMSs (Fountain et al., 2008). |
Eukaryota | Viridiplantae, Chlorophyta | P2X4 of Ostreococcus lucimarinus |
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1.A.7.1.11 | P2X5 ATP-activated receptor, P2X5R or P2RX5, of 422 aas and 2 TMSs, N- and C-terminal (Sun et al. 2019). This receptor can transport both cations and anions, in contrast to most other P2X channels (Tam et al. 2023). |
Eukaryota | Metazoa, Chordata | P2X5R of Homo sapiens |
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1.A.7.1.12 | P2X7 purinoceptor of 595 aas and 2 TMSs. All residues that are conserved among the P2X receptor subtypes respond to alanine mutagenesis with an inhibition (Y51, Q52, and G323) or a significant decrease (K49, G326, K327, and F328) of 2',3'-O-(benzoyl-4-benzoyl)-ATP (BzATP)-induced current and permeability to ethidium bromide, while the nonconserved residue (F322), which is also present in P2X4 receptors, responds with a 10-fold higher sensitivity to BzATP, much slower deactivation kinetics, and a higher propensity to form the large dye-permeable pore. Rupert et al. 2020 examined the membrane expression of conserved mutants and found that Y51, Q52, G323, and F328 play a role in the trafficking of the receptor to the plasma membrane, while K49 controls receptor responsiveness to agonists. The K49R, F322Y, F322W, and F322L mutants reversed the receptor function, indicating that positively charged and large hydrophobic residues are important at positions 49 and 322, respectively. Thus, clusters of conserved residues above the transmembrane domain 1 (K49-Y51-Q52) and transmembrane domain 2 (G326-K327-F328) are important for receptor structure, membrane expression, and channel gating and that the nonconserved residue (F322) at the top of the extracellular vestibule is involved in hydrophobic inter-subunit interaction which stabilizes the closed state of the P2X7 receptor channel (Rupert et al. 2020). This protein is 80% identical to the human ortholog (TC# 1.A.7.1.3). The P2X7 receptor in normal and cancer cells, in the perspective of nucleotide signaling, has been reviewed (Matyśniak et al. 2022). N-Methyl-(2S, 4R)-trans-4-hydroxy-L-proline, the major bioactive compound from Sideroxylon obtusifolium, attenuates pilocarpine-induced injury in cultured astrocytes. The improvement of ROS accumulation, VDAC-1 overexpression, and mitochondrial depolarization are possible mechanisms of the NMP protective action on reactive astrocytes (Aquino et al. 2022). The large intracellular C-terminus of the pro-inflammatory P2X7 ion channel receptor (P2X7R) is associated with diverse P2X7R-specific functions. Cryo-EM structures of the closed and ATP-bound open full-length P2X7R identified a membrane-associated anchoring domain, an open-state stabilizing 'cap' domain, and a globular 'ballast domain' containing GTP/GDP and dinuclear Zn2+-binding sites with unknown functions. To investigate protein dynamics during channel activation, Durner et al. 2023 incorporated the environment-sensitive fluorescent unnatural amino acid, L-3-(6-acetylnaphthalen-2-ylamino)-2-aminopropanoic acid (ANAP) into Xenopus laevis oocyte-expressed P2X7Rs and performed voltage clamp fluorometry (VCF). Predicted conformational changes within the extracellular and the transmembrane domains were confirmed. The ballast domain functions fairly independently of the extracellular ATP binding domain and may require activation by additional ligands and/or protein interactions (Durner et al. 2023). The P2X7 receptor provides a mechanistic biomarker for epilepsy (Engel 2023). Puerarin inhibits NLRP3-caspase-1-GSDMD-mediated pyroptosis via the P2X7 receptor in cardiomyocytes and macrophages (Sun et al. 2023).
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Eukaryota | Metazoa, Chordata | P2X7 of Rattus norvegicus (Rat) |
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1.A.7.1.2 | ATP-gated cation channel (purinoceptor or ATP-neuroreceptor), P2X2. His33 and Ser345 are proximal to each other across an intra-subunit interface, and the relative movement between the two TMSs is likely important for transmitting the action of ATP binding to the opening of the channel (Liang et al. 2013). Two processes contribute to receptor desensitization, one, bath calcium-independent and the other, bath calcium-dependent, the latter being more important (Coddou et al. 2015). ATP dissociation causes reduction in outer pore expansion compared to the ATP-bound state. Moreover, the inner and outer ends of adjacent pore-lining helices come closer during opening, likely through a hinge-bending motion (Habermacher et al. 2016). Hearing loss mutations alter the functional properties of human P2X2 receptor channels through more than one mechanism (George et al. 2019). Residues in TMSs of the P2X4 receptor that contribute to channel function and ethanol sensitivity have been identified (Popova et al. 2020). Self-assembly of mammalian cell membranes on bioelectronic devices with P2X2 channel has been achieved (Liu et al. 2020). Lithocholic acid inhibits P2X2 and potentiates P2X4 receptor channel gating (Sivcev et al. 2020). |
Eukaryota | Metazoa, Chordata | P2X2 of Rattus norvegicus |
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1.A.7.1.3 | ATP-gated NaCl-regulated nonselective cation (Na+, K+ and Ca2+) channel, the P2X purinoreceptor 7, P2X7, P2RX7 or P2X7R. It expands to accommodate large molecules such as NAD, N-methyl-D-glucamine and triethyl ammonium) (Li et al., 2005; Lu et al., 2007) and plays a role in changing pain thresholds. A region called ADSEG in all P2X receptors is located in the M2 domain which aligns with TMS 5 in VIC K+ channels (1.A.1). ADSEG from P2X(7)R forms cation-selective channels in artificial lipid bilayers and biological membranes similar to those of the full length protein (de Souza et al., 2011). Channel activity is regulated by calmodulin (Roger et al., 2008). P2XRs allow direct permeation of nanometer-sized dyes (Browne et al. 2013). Macrophage P2X7 receptors are modulated in response to infection with Leishmania amazonensis so that they become more permeable to anions and less permeable to cations (Marques-da-Silva et al. 2011). Residues involved in pore conductivity and agonist sensitivity have been identified (Jindrichova et al. 2015) as have residues involved in channel activation (Caseley et al. 2016). The channel opening extends from the pre-TMS2 region through the outer half of the trihelical TMS2 channel; the gate and the selectivity filter have been identified (Pippel et al. 2017). The purinergic receptors, P2RX4 and P2RX7, when mutated, affect susceptibility to multiple sclerosis (MS) (Sadovnick et al. 2017). P2X7 may serve as a receptor for the regulation of annexin secretion during macrophage polarization (de Torre-Minguela et al. 2016). These receptors can reduce salivary gland inflammation (Khalafalla et al. 2017). The P2X7 receptor forms ion channels dependent on lipids but independently of its cytoplasmic domain (Karasawa et al. 2017). A truncated naturally occurring variant of P2X7, P2X7-j of 258 aas, lacks the entire intracellular carboxyl terminus, the second TMS, and the distal third of the extracellular loops of the full-length P2X7 receptor. P2X7-j, expressed in the plasma membrane, failed to form pores and mediate apoptosis (Feng et al. 2006). P2X7-j formed heterooligomers with and blocked P2X7-mediated channel formation. Alternative splicing of P2X7 controls gating of the ion channel by ADP-ribosylation (Schwarz et al. 2012). Three distinct roles for P2X7 during adult neurogenesis have been demonstrated, and these depend on the extracellular ATP concentrations: (i) P2X7 receptors can form transmembrane pores leading to cell death, (ii) P2X7 receptors can regulate rates of proliferation, likely via calcium signalling, and (iii) P2X7 can function as scavenger receptors in the absence of ATP, allowing neural progenitor cells (NPCs) to phagocytose apoptotic NPCs during neurogenesis (Leeson et al. 2018). P2X7 also plays a role in purinergic vasotoxicity and cell death (Shibata et al. 2018). NAD+ covalently modifies the P2X7R of mouse T lymphocytes, thus lowering the ATP threshold for activation. Other structurally unrelated agents have been reported to activate P2X7R: (a) the antibiotic polymyxin B, possibly a positive allosteric P2X7R modulator, (b) the bactericidal peptide LL-37, (c) the amyloidogenic β peptide, and (d) serum amyloid A (Di Virgilio et al. 2018). Some agents, such as Alu-RNA, have been suggested to activate P2X7R, acting on the intracellular N- or C-terminal domains. P2X7R of enteric neurons may be involved in diabetes-induced nitrous oxide (NOS) neuron damage via combining with pannexin-1 to form transmembrane pores which transport macromolecular substances and calcium into the cells (Zhang et al. 2019). ATP-gated P2X7 receptors require chloride channels to promote inflammation in human macrophages (Janks et al. 2019). P2X7 overexpression is can be associated with cancer progression. P2X7 plays also an important role in glioma biology (Matyśniak et al. 2020). Upon activation by its main ligand, extracellular ATP, P2X7 can form a nonselective channel for cations to enter the cell, but prolonged activation, via high levels of extracellular ATP over an extended time period can lead to the formation of a macropore, leading to depolarization of the plasma membrane and ultimately to cell death. Thus, dependent on its activation state, P2X7 can either drive cell survival and proliferation, or induce cell death. It is relevant to cancerous growth (Lara et al. 2020). The human P2X7 receptor is a ligand gated ion channel opened by binding of ATP, like the other P2X receptor subtypes. P2X7 receptors become activated under pathological conditions of ATP release like hypoxia or cell destruction. They are involved in inflammatory and nociceptive reactions of the organism to these pathological events. Polar residues of the second TMS of the three protein subunits are important for ion conduction, with S342 constituting the ion selectivity filter and the gate of the channel. The specific long C-terminal domains are important for hP2X7 receptor ion channel function, as their loss strongly decreases ion channel currents (Markwardt 2020). Studies of the enhancement of P2X(7)-induced pore formation and apoptosis revealed an early effect of diabetes on retinal microvasculature; diabetes appears to facilitate the channel-to-pore transition that occurs during activation of these purinoceptors (Sugiyama et al. 2004). Regorafenib exhibits antitumor activity on the breast cancer cell line via modulation of the P2X7/HIF-1alpha/VEGF, P2X7/P38, P2X7/ERK/NF-kappaB, and P2X7/beclin 1 pathways (Salahuddin et al. 2021). The involvement of the P2RX7 purinoreceptor in triggering mitochondrial dysfunction during the development of neurodegenerative disorders has been reviewed (Zelentsova et al. 2022). The P2X7 receptor and purinergic signaling play roles in orchestrating mitochondrial dysfunction in neurodegenerative diseases (Zelentsova et al. 2022). The P2X7 purinergic receptor represents a potential target in heart diseases (Bin Dayel et al. 2023). Conserved and receptor specific TMS1 residues control surface expression of the P2X7 protein, nonpolar residues control receptor sensitization, and D48 regulates intrinsic channel properties (Rupert et al. 2023). The P2X7 receptor of microglia in the olfactory bulb mediates the pathogenesis of olfactory dysfunction in a mouse model of allergic rhinitis (Ren et al. 2023). P2RX7 variants interact with distal and more etiological stressors in influencing the severity of anxiety symptoms (Kristof et al. 2023). P2X7 receptor inhibition ameliorates ubiquitin-proteasome system dysfunction associated with Alzheimer's disease (Bianchi et al. 2023). P2X7R radioligands are reliable tools for the diagnosis of neuroinflammation in clinical studies, and detection and measurement of free P2X7 receptor (or the P2X7 subunit) in human blood suggested its potential use as a circulating marker of inflammation (Di Virgilio et al. 2023). There are three frequent coding polymorphisms in the gene for the human P2X7 ion channel, and their functions are known (Schäfer et al. 2022). A P2X7 receptor blockade reduces pyroptotic inflammation and promotes phagocytosis in Vibrio vulnificus infection (Wann et al. 2023). Niemann-Pick disease type C is a rare autosomal recessive of lysosomal storage disorder characterized by impaired intracellular lipid transport and has a tendency to accumulate the fatty acids and glycosphingolipids in a variety of neurovisceral tissues, and the mutational impact in causing Niemann-Pick disease type C has been studied (Kannan et al. 2023). Receptor agonists and antagonists and other modulators of purinergic signalling have potential as novel therapeutics for a broad range of diseases and conditions. An up-to-date description of selected efforts to discover and develop new small molecular purinergic drugs has appeared (Jacobson and Salvemini 2023). Astrocytes induce ischemic tolerance via P2X7 receptor-mediated lactate release (Hirayama et al. 2024). P2X7 receptors in dendritic cells and macrophages have implications in antigen presentation and T lymphocyte activation (Acuña-Castillo et al. 2024). Huang et al. demonstrate that the complex of sodium/potassium-transporting ATPase subunit alpha (NKAα1) and purinergic P2X7 receptor (P2X7R) maintains the resting state of microglial membranes. Stress increases free P2X7R that then binds to ATP to activate microglia, which may promote anxious behaviors (Fang and Lai 2024). High-affinity P2Y2 and low-affinity P2X7 receptors interact to modulate ATP-mediated calcium signaling in murine osteoblasts (Mikolajewicz et al. 2021). Mutations in this purinergic ATP-dependent cation channel can give rise to chronic nonbacterial oteomyelitis (CNO) (Roberts et al. 2024). P2RX7 gene variants associate with altered inflammasome assembly and reduced pyroptosis in chronic nonbacterial osteomyelitis (CNO) (Charras et al. 2024). |
Eukaryota | Metazoa, Chordata | P2X7 of Homo sapiens (Q99572) |
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1.A.7.1.4 | The P2X4 receptor (P2X4R) of the zebrafish of 389 aas and 2 TMSs. The 3-d structure is known in its closed, resting state (Kawate et al., 2009). A hift of L340 packing between different sites may alter the side-chain orientation that frees or occludes the pore. L340, A344 and A347 may also gate the pore by a expansion-contraction mechanism (Li 2015). Ivermectin binds to the transmembrane domain while Zn2+ binds to the extracellular domain, but they exhbit additive cooperativity (Latapiat et al. 2017). |
Eukaryota | Metazoa, Chordata | P2X(4) purinoceptor (ATP) gated ionotropic receptor, subunit 4 of Danio rerio (Q98TZ0) |
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1.A.7.1.5 |
The purinergic receptor, P2X4, is sensitive to the macrocyclic lactone, ivermectin, which allosterically modulates both ion conduction and channel gating (Samways et al., 2012). The secondary structure and gating rearrangements of TMSs in rat P2X4 receptor channels have been proposed (Silberberg et al. 2005). Bile acids inhibit the human P2X4 (Ilyaskin et al. 2019). The gating mechanism has been discussed (Du et al., 2012) and considered to be determined by the conformation of the transmembrane domain (Minato et al. 2016; Pierdominici-Sottile et al. 2016). The crystal structure of the ATP-gated P2X4 ion channel in the closed state has been reported (Kawate et al., 2009). Unobstructed lateral portals are preferentially used as access routes to the pores of P2X receptors (Samways et al., 2011). Activation is ATP-dependent and rapid, but desensitization occurs within seconds and is ATP-independent (Stojilkovic et al. 2010). Ectodomain cysteines play roles in agonist binding and channel gating (Rokic et al. 2010). Evermectin has distinct effects on opening and dilation of the channel pore, the first accounting for increased peak current amplitude, and the latter correlating with changes in the kinetics of receptor deactivation (Zemkova et al. 2014). Conserved amino acids within the regions linking the ectodomain with the pore-forming transmembrane domain may contribute to signal transduction and channel gating (Gao et al. 2015; Jelínkova et al. 2008). Binding of ATP produces distortions in the chains that eliminate restrictions on the interchain displacements, leading to the opening of the pore (Pierdominici-Sottile et al. 2016). The purinergic receptors, P2RX4 and P2RX7, affect susceptibility to multiple sclerosis (MS) (Sadovnick et al. 2017). P2X4 modulators are used for the treatment of alcohol use disorders (Reyes-Espinosa et al. 2020). Lithocholic acid inhibits P2X2 and potentiates P2X4 receptor channel gating (Sivcev et al. 2020). Therapeutic targeting of the P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma modelshas been achieved (Rupert et al. 2023). A role for KATP channels in cytotoxicity of cells that are primed for a rapid immune response has been reported (Feske et al. 2024). |
Eukaryota | Metazoa, Chordata | P2X4 of Homo sapiens (Q99571) |
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1.A.7.1.6 | ATP-gated P2X3 receptor. Tyr-37 stabilizes desensitized states and restricts calcium permeability (Jindrichova et al., 2011). Exhibits "high affinity desensitization" but slow reactivation from the desensitized state (Giniatullin and Nistri 2013). An endogenous regulator of P2X3 in bladder is the Pirt protein (TC#8.A.64.1.1) Gao et al. 2015). X-ray crystal structures of the human P2X3 receptor in apo/resting, agonist-bound/open-pore, agonist-bound/closed-pore/desensitized and antagonist-bound/closed states have been determined (Mansoor et al. 2016). The open state structure harbours an intracellular motif termed the 'cytoplasmic cap', which stabilizes the open state of the ion channel pore and creates lateral, phospholipid-lined cytoplasmic fenestrations for water and ion egress. P2X3 receptor antagonism attenuates the progression of heart failure (Lataro et al. 2023). Standardized Centella asiatica extract ECa 233 alleviates pain hypersensitivity by modulating P2X3 (Wanasuntronwong et al. 2024). When P2X3 is in its apo state, its ICD architecture is fairly ordered rather than an unstructured outward folding, enabling allosteric modulation of the signaling of P2X3 receptors (Lin et al. 2024). |
Eukaryota | Metazoa, Chordata | P2X3 receptor of Homo sapiens (P56373) |
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1.A.7.1.7 | P2X purinoceptor |
Eukaryota | Metazoa, Chordata | P2X purinoceptor of Tetaodon nigroviridis |
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1.A.7.1.8 | The p2X purinoreceptor 4a of 389 aas and 2 TMSs, P2X4a of 388 aas and 2 TMSs. A splice variant of 361 aas also exists and may form heterotrimers with P2RX4a (Townsend-Nicholson et al. 1999). Plays a role in alcoholism (Franklin et al. 2014). P2RX4 deficiency alleviates allergen-induced airway inflamation (Zech et al. 2016). |
Eukaryota | Metazoa, Chordata | P2X4a of Mus musculus (Mouse) |
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1.A.7.1.9 | Purinorepector, P2X7 (P2RX7) of 595 aas and 2 TMSs. The crystal structure in complex with a series of allosteric antagonists were published, giving insight into the mechanism of channel antagonism (Pasqualetto et al. 2018). A P2RX7 single nucleotide polymorphism haplotype promotes exon 7 and 8 skipping and disrupts receptor function (Skarratt et al. 2020). |
Eukaryota | Metazoa, Chordata | P2X7 of Ailuropoda melanoleuca (Giant panda) |
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1.A.7.2.1 | The osmoregulatory intracellular P2X receptor, P2XA gated by ATP (present in the osmoreulatory organelle, the contractile vacuole) (Fountain et al., 2007). One of five P2X receptors in D. discoideum is localized to the contractile vacuole with the ligand binding domain facing the lumen. Plays a role in Ca2+ signaling, but also is Cl- permeable. May function in osmoregulation (Ludlow et al., 2009). Four of the five receptors operate as ATP-gated channels (P2XA, P2XB, P2XD, and P2XE). For the P2XA receptor, ATP was the only effective agonist, but extracellular sodium, compared with potassium, strongly inhibited ATP responses in P2XB, P2XD, and P2XE receptors. Increasing the proton concentration (pH 6.2) accelerated desensitization at P2XA receptors and decreased currents at P2XD receptors, but increased the currents at P2XB and P2XE receptors. Dictyostelium lacking P2XA receptors showed an impaired regulatory volume decrease in hypotonic solution. This phenotype was rescued by overexpression of P2XA and P2XD receptors, partially rescued by P2XB and P2XE receptors, and not rescued by P2XC receptor which appeared to be inactive (Baines et al. 2013). |
Eukaryota | Evosea | P2XA of Dictyostelium discoideum (Q55A88) |
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1.A.7.2.10 | Partial seqence of a putative P2XR of 273 aas and 1 TMS at residue 150 in the protein. |
Archaea | Putative P2XR of an archaeon (phyllosphere metagenome) |
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1.A.7.2.11 | Uncharacterized protein of 507 aas and 2 TMSs, N- and C-terminal. |
Eukaryota | UP of Cafeteria roenbergensis |
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1.A.7.2.12 | Uncharacterized protein of 521 aas and 5 TMSs in a 3 (N-terminal) + 1 (residues 145 - 165) + 1 (residues 430 - 455). |
Eukaryota | UP of Capsaspora owczarzaki |
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1.A.7.2.13 | Uncharacterized protein of 477 aas and 2 TMSs, near the N- and C-termini. |
Eukaryota | UP of Polarella glacialis |
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1.A.7.2.14 | p2x receptor of 448 aas and 2 TMSs, near the N- and C-termini.
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Eukaryota | Haptophyta | p2x receptor of Chrysochromulina tobinii |
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1.A.7.2.2 | Uncharacterized P2X recpetor of 399 aas and 2 TMSs/ |
Eukaryota | UP of Guillardia theta |
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1.A.7.2.3 | Uncharacterized P2X receptor of 524 aas and 2 TMSs. |
Eukaryota | Haptophyta | UP of Emiliania huxleyi (Pontosphaera huxleyi) |
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1.A.7.2.4 | Uncharacterized protein of 488 aas and 2 TMSs. |
Eukaryota | UP of Vitrella brassicaformis |
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1.A.7.2.5 | P2X receptor E isoform X1 of 397 aas and 2 TMSs, N- and C-terminal. |
Eukaryota | Metazoa, Cnidaria | P2XR of Nematostella vectensis |
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1.A.7.2.6 | P2X receptor of 373 aas and 2 TMSs, N- and C-terminal. |
Eukaryota | Evosea | P2XR of Planoprotostelium fungivorum |
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1.A.7.2.7 | Uncharacterized P2X receptor of 458 aas and 2 TMSs, N- and C-terminal. |
Eukaryota | Fungi, Blastocladiomycota | UP of Catenaria anguillulae |
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1.A.7.2.8 | Uncharacterized protein of 396 aas and 2 TMSs, N- and C-terminal. |
Eukaryota | Fungi, Mucoromycota | UP of Rhizophagus diaphanus |
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1.A.7.2.9 | P2X receptor E of 1271 aas and 4 TMSs roughly equidistant from each other, at positions 311, 627, 918, and at the C-terminus. The region showing sequence similarity with other members of the P2XR family is residues 300 to 640, including TMSs 1 and 2 of the 3 distinct TMSs. |
Eukaryota | P2XR E of Symbiodinium microadriaticum |
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1.A.70.1.1 | Channel-forming molecule against Microbes A (MamA) (81aas; 1TMS; n-terminal inside) (Fedders et al., 2008) | Eukaryota | Metazoa, Chordata | MamA of Ciona intestinalis (B1PVV5) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.70.1.2 | MamA homologue (81 aas and one TMS; 8% identical to MamA) |
Eukaryota | Metazoa, Chordata | MamA homologue of Ciona intestinalis (XP_002127232) (198415263) |
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1.A.71.1.1 | Brain acid soluble protein, BASP1. (Ostroumova et al., 2011) |
Eukaryota | Metazoa, Chordata | BASP1 of Homo sapiens (P80723) |
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1.A.71.2.1 | Growth-associated protein 43 (GAP-43); Neuromodulin isoform 2, neural phosphoprotein B-50; A major component of the motile "growth cones" that forms the tips of elongated axons. Binds calmodulin with high affinity without Ca2+ and low affinity with Ca2+. It has been reported not to form channels (Ostroumova et al., 2011). It has been reviewed (Holahan 2017). |
Eukaryota | Metazoa, Chordata | GAP-43 of Homo sapiens (P17677) |
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1.A.72.1.1 | The MerF mercuric ion uptake transporter of 81 aas and 2 TMSs. The NMR structure of the helix-loop-helix core domain of MerF has been determined with a backbone RMSD of 0.58 Å (Howell et al. 2005). Moreover, the fold of this polypeptide demonstrates that the two vicinal pairs of cysteine residues, shown to be involved in the transport of Hg++ across the membrane, are exposed to the cytoplasm. This finding differs from earlier structural and mechanistic models that were based primarily on the somewhat atypical hydropathy plot for MerF and related transport proteins (Howell et al. 2005). The apo state positions one of the cysteine pairs closer to the periplasmic side of the membrane, while in the bound state, the same pair approaches the cytoplasmic side (Hwang et al. 2019). This is consistent with the functional requirement of accepting Hg2+ from the periplasmic space, sequestering it on acceptance, and transferring it to the cytoplasm. Conformational changes in the TMSs facilitate the functional interaction of the two cysteine pairs. Free-energy calculations provide a barrier of 16 kcal/mol for the association of the periplasmic Hg2+-bound protein, MerP, with MerF, and 7 kcal/mol for the subsequent association of MerF's two cysteine pairs (Hwang et al. 2019). |
Bacteria | Pseudomonadota | MerF of plasmid pMER327/419 of Pseudomonas aeruginosa |
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1.A.72.1.2 | Heavy metal transporter |
Bacteria | Campylobacterota | HM transporter of Arcobacter butzleri (A8EUY8) |
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1.A.72.1.3 | MerT (97aas)/MerP (93aas) (in a single operon with a transglutaminase (COG1305)). |
Bacteria | Pseudomonadota | MerTP of Haemophilus influenzae |
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1.A.72.2.1 | Hg2+ transporter, MerH (171aas; 4 TMSs) (transports mercuric ions via a pair of essential cysteine residues, but only when coexpressed with the mercuric reductase) (Schué et al., 2009). |
Bacteria | Actinomycetota | MerH of Mycobacterium marinum (B2I419) |
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1.A.72.2.2 | MerC homologue (129aas; 4 TMSs) |
Bacteria | Gemmatimonadota | MerC homologue of Gemmatimonas aurantiaca |
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1.A.72.3.1 | MerT/P |
Bacteria | Pseudomonadota | MerT/P of Ralstonia eutropha (Q6UP69) |
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1.A.72.3.2 | Putative MerT-MerP fusion protein of 200 aas (3 TMSs) |
Bacteria | Bacteroidota | MerT-MerP of Chryseobacterium gleum (C0YI47) |
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1.A.72.3.3 | Putative MerT-MerP fusion protein of 199 aas (3-4 TMSs) |
Bacteria | Verrucomicrobiota | MerT-MerP of Methylacidiphilum infernorum (B3DYY6) |
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1.A.72.3.4 | Putative MerT-MerP fusion protein of 196 aas (3 TMSs) |
Bacteria | Bacteroidota | MerT-MerP of Spirosoma linguale (D2QV66) |
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1.A.72.3.5 | Mercuric ion uptake system, MerT-P/MerP |
Bacteria | Bacteroidota | MerT-P/MerP of Tenacibaculum discolor |
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1.A.72.3.6 | Mercury transporter, MerT, of 129 aas and 3 TMSs. |
Bacteria | Pseudomonadota | MerT of Histidinibacterium lentulum |
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1.A.72.4.1 | MerC |
Bacteria | Pseudomonadota | MerC of the IncJ plasmid pMERPH of Shewanella putrefaciens |
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1.A.72.4.2 | Mercuric transport channel protein, MerC, of 144 aas and 4 TMSs. Cys-23 and Cys-26 of the protein were involved in Hg2+-recognition/uptake, but Cys-132 and Cys-137 were not (Sasaki et al. 2005). E. coli cells producing MerC were hypersensitive to CdCl2. In this case, mutation of His72 rendered the host cells less CdCl2 sensitive, whereas none of the Cys residues affected it. E. coli cells expressing a merC-deletion mutant, in which the coding-sequence of the carboxy-terminal cytoplasmic region was removed, retained Hg2+ hypersensitivity and showed about 55% HgCl2 uptake ability compared to that of the one expressing the intact merC, indicating that this region is not essential for Hg2+ uptake. Coexpression of the A. ferrooxidans gene encoding mercuric reductase (merA) and the merC deletion mutation conferred HgCl2 tolerance to E. coli host cells. Under this condition, the merC deletion gene product was exclusively present as a monomer (Sasaki et al. 2005). |
Bacteria | Pseudomonadota | MerC of Acidithiobacillus ferrooxidans (Thiobacillus ferrooxidans) |
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1.A.72.5.1 | The Mercuric ion (Hg2+) uptake transporter, MerE (78aas; 2 TMSs). |
Bacteria | Pseudomonadota | MerE of transposon Tn21 of E. coli (Q57069) |
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1.A.72.5.2 | MerE mercury resistance protein of 89 aas and 2 TMSs. It has been purified and characterized, and has proven useful for bioremediation (Amin et al. 2019). |
Bacteria | Bacillota | MerE of Bacillus cereus |
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1.A.73.1.1 | The colicin E1 lysis protein, Lys3 |
Bacteria | Pseudomonadota | Lys3 of E. coli (P05821) |
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1.A.73.1.2 | The colicin A lysis protein, Cal |
Bacteria | Pseudomonadota | Cal of E. coli (P06962) |
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1.A.73.1.3 | Lysis protein for Colicin E7 (LysE7) |
Bacteria | Pseudomonadota | LysE7 of E. coli (Q03709) |
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1.A.73.1.4 | Lysis protein for colicin E6 of 46 aas with 1 N-terminal TMS. |
None | Pseudomonadati, Pseudomonadota | Lysis colicin E6 of Shigella boydii |
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1.A.74.1.1 | Mitsugumin 23 (MG23) of 243 aas and 5 TMSs, also called TM protein 109 (Venturi et al., 2011). MG23 is a Ca2+ channel protein that is regulated by cytoplasmic Zn2+, and dysregulation of this ion channel plays a role in diastolic sarcoplasmic reticulum Ca2+ homeostasis, promoting leakage from the SR (Reilly-O'Donnell et al. 2017). |
Eukaryota | Metazoa, Chordata | MG23 of Mus musculus (Q3UBX0) |
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1.A.74.1.2 | Mitsugumin23 (TMEM109) of 243 aas and 5 TMSs (Takeshima et al. 2015). |
Eukaryota | Metazoa, Chordata | Mitsugumin23 of Homo sapiens |
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1.A.74.2.1 | Bri3 binding protein, isoform CRA_a |
Eukaryota | Metazoa, Chordata | Bri3 of Mus musculus (Q8BXV2) |
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1.A.74.2.2 | BRI3 binding protein. Plays a role in tumorigenesis. BRI3 is a member of the BRI gene family that includes the familial British and Danish dementia gene BRI2. BRI3 interacts with the Amyloid Precursor Protein, APP, and serves as an endogenous negative regulator of Abeta production (Matsuda et al. 2009). |
Eukaryota | Metazoa, Chordata | BRI3 BP of Homo sapiens |
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1.A.74.3.1 | Uncharacterized protein of 234 aas and 5 TMSs |
Eukaryota | Metazoa, Chordata | UP of Tetraodon nigroviridis (Spotted green pufferfish) (Chelonodon nigroviridis) |
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1.A.75.1.1 | Piezo1 (FAM38a) mechanosensitive ion channel of 2521 aas and ~ 38 TMSs in a 4 x 9 + 2 TMS arrangement. The protein has a C-terminal DUF3595 (pfam 12166) domain (Coste et al., 2010). Fam38A expression may cause increased cell migration and metastasis in lung tumours (McHugh et al. 2012). It is imporatnt for gastrointestinal tract function (Alcaino et al. 2017). A high-resolution cryo-electron microscopy structure of the mouse Piezo1 trimer has been determined (Saotome et al. 2017). The detergent-solubilized complex adopts a three-blade propeller shape with a curved transmembrane region containing at least 26 transmembrane helices per protomer. The flexible propeller blades can adopt distinct conformations, and consist of a series of four-TMS bundles termed 'Piezo repeats'. Carboxy-terminal domains line the central ion pore, and the channel is closed by constrictions in the cytosol. A kinked helical beam and anchor domain link the Piezo repeats to the pore, and are poised to control gating allosterically (Saotome et al. 2017). The Piezo1 pore remains fully open if only one subunit is activated, for example by binding the agonist, Yoda1 (Lacroix et al. 2018). The channel mediates uterine artery shear stress mechanotransduction and vasodilation during pregnancy (John et al. 2018). The channel can transport alkali monovalent cations (Na+, K+, Rb+, Cs+ and Li+ as well as Ca2+, tetramethyl ammonium and tetraethyl ammonium, although these last four cations are transported at slow rates (Gnanasambandam et al. 2017). Agonist-induced Piezo1 activation promotes mitochondrial-dependent apoptosis in vascular smooth muscle cells (Yin et al. 2022). Piezo1 is the stretch activated Ca2+ channel in red blood cells that mediates homeostatic volume control. Vaisey et al. 2022 studied the organization of Piezo1 in red blood cells. Piezo1 adopts a non-uniform distribution on the red blood cell surface, with a bias toward the biconcave 'dimple'. Trajectories of diffusing Piezo1 molecules, which exhibit confined Brownian diffusion on short timescales and hopping on long timescales, also reflect a bias toward the dimple. This bias can be explained by 'curvature coupling' between the intrinsic curvature of the Piezo dome and the curvature of the red blood cell membrane. Piezo1 does not form clusters with itself, nor does it colocalize with F-actin, Spectrin, or the Gardos channel. Thus, Piezo1 exhibits the properties of a force-through-membrane sensor of curvature and lateral tension in the red blood cell (Vaisey et al. 2022). Mechanosensitive Piezo1 channels trigger migraine pain in trigeminal nociceptive neurons (Della Pietra et al. 2023). Gain-of-function mutations in PIEZO1 cause dehydrated hereditary stomatocytosis (DHS) or hereditary xerocytosis, an autosomal dominant hemolytic anemia characterized by high reticulocyte count, a tendency to macrocytosis, and mild jaundice, as well as by other variably penetrant clinical features, such as perinatal edema, severe thromboembolic complications after splenectomy, and hepatic iron overload (Andolfo et al. 2023). Mechanical stretching induces fibroblast apoptosis by activating Piezo1 and then destroying the actin cytoskeleton (Li et al. 2023). Force-induced motions of the PIEZO1 blade have been probed with fluorimetry (Ozkan et al. 2023). Low-intensity fluid shear stress causes a unique form of mechanical stress to the cell. A light-gated mouse PIEZO1 channel, in which an azobenzene-based photoswitch covalently tethered to an engineered cysteine, Y2464C, localized at the extracellular apex of the TMS 38, rapidly triggers channel gating upon 365-nm-light irradiation. Peralta et al. 2023 provided evidence that this light-gated channel recapitulates mechanically-activated PIEZO1 functional properties, and show that light-induced molecular motions are similar to those evoked mechanically. GenEPi is a genetically-encoded fluorescent reporter for non-invasive optical monitoring of Piezo1-dependent activity. Yaganoglu et al. 2023 demonstrated that GenEPi has high spatiotemporal resolution for Piezo1-dependent stimuli from the single-cell level to that of the entire organism. GenEPi reveals transient, local mechanical stimuli in the plasma membrane of single cells, resolves repetitive contraction-triggered stimulation of beating cardiomyocytes within microtissues, and allows for robust and reliable monitoring of Piezo1-dependent activity in vivo (Yaganoglu et al. 2023). Membrane stretch provides a mechanism for activation of PIEZO1 channels in chondrocytes (Savadipour et al. 2023). Zhou et al. 2023 found that MyoD (myoblast determination)-family inhibitor proteins (MDFIC and MDFI) are PIEZO1/2 interacting partners. These transcriptional regulators bind to PIEZO1/2 channels, regulating channel inactivation. Using single-particle cryoEM, the authors mapped the interaction site in MDFIC to a lipidated, C-terminal helix that inserts laterally into the PIEZO1 pore module. These Piezo-interacting proteins fit all the criteria for auxiliary subunits, contribute to explaining the vastly different gating kinetics of endogenous Piezo channels observed in many cell types, and elucidate mechanisms potentially involved in human lymphatic vascular disease (Zhou et al. 2023). PIEZO1 is a distal nephron mechanosensor and is required for flow-induced K+ secretion (Carrisoza-Gaytan et al. 2024). The role and mechanism of PIEZO1 as a mechanical sensor in cardiovascular development, homeostasis, and disease processes, including embryo survival, angiogenesis, cardiac development repair, vascular inflammation, lymphangiogenesis, blood pressure regulation, cardiac hypertrophy, cardiac fibrosis, ventricular remodeling, and heart failure have been reviewed (Jin et al. 2024). Pain is one of the most severe manifestations in knee osteoarthritis (KOA) patients. The inflammatory response mediated by Piezo1 causes the release of inflammatory mediators and pro-inflammatory factors leading to pain (He et al. 2024). Results suggest a previously unknown regulatory mechanism involving Piezo1 and influencing Glucagon-like peptide 1 (GLP-1) production in L epithelial cells, could offer new insights into diabetes treatments (Huang et al. 2024). Loading directionality plays a role on PIEZO1 expression and the early-stage healing process of peri-implant bone (Mao et al. 2024). Piezo1 enhances macrophage phagocytosis and pyrin activation to ameliorate fungal keratitis (Yang et al. 2025). Mechanical stretch promotes the migration of mesenchymal stem cells via the Piezo1/F-actin/YAP axis (Ma et al. 2025). Smooth muscle cell Piezo1 depletion results in impaired contractile properties in murine small bowel (Bautista et al. 2025). Piezo1 deletion mitigates diabetic cardiomyopathy by maintaining mitochondrial dynamics via the ERK/Drp1 pathway (Niu et al. 2025). |
Eukaryota | Metazoa, Chordata | Piezo1 of Homo sapiens (Q92508) |
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1.A.75.1.10 | Piezo channel of 2470 aas |
Eukaryota | Ciliophora | Piezo of Paramecium tetraurelia |
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1.A.75.1.11 | Piezo channel of 2598 aas (Prole and Taylor 2013). |
Eukaryota | Euglenozoa | Piezo of Trypanosoma cruzi |
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1.A.75.1.12 | Piezo-like channel protein of 2533 aas and ~42 TMSs. |
Eukaryota | Euglenozoa | Piezo protein of Leishmania donovani |
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1.A.75.1.13 | Uncharacterized piezo channel homologue of 1931 aas and ~ 37 putative TMSs. |
Eukaryota | Euglenozoa | UP of Bodo saltans |
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1.A.75.1.14 | Piezo1 (Fam38a) of 2547 aas and ~ 38 TMSs. The three-bladed propeller-like cryoEM structure and its mechanotransduction components are known (Zhao et al. 2018). There are nine repeat units consisting of four transmembrane helices, each of which is termed a transmembrane helical unit (THU). These assemble into a highly curved blade-like structure. The last transmembrane helix encloses a hydrophobic pore, followed by three intracellular fenestration sites and side portals that contain pore-property-determining residues. The central region forms a 90 Å-long intracellular beam-like structure, which undergoes a lever-like motion to connect the THUs to the pore via the interfaces of the C-terminal domain, the anchor-resembling domain and the outer helix. Deleting extracellular loops in the distal THUs or mutating single residues in the beam impairs the mechanical activation of Piezo1. Thus, Piezo1 possesses a 38-transmembrane-helix topology with mechanotransduction components that enable a lever-like mechanogating mechanism (Zhao et al. 2018). The Piezo1 pore remains fully open if only one of the three subunits is activate, for example by binding the agonist, Yoda1 (Lacroix et al. 2018). Piezo1 mediates endothelial atherogenic inflammatory responses via regulation of YAP/TAZ activation (Yang et al. 2021). |
Eukaryota | Metazoa, Chordata | Piezo1 of Mus musculus |
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1.A.75.1.15 | Piezo-type mechanosensitive ion channel component 2 of 2023 aas and ~ 31 putative TMSs. G. soya and other plants often have multiple Piezo proteins. |
Eukaryota | Viridiplantae, Streptophyta | Piezo of Glycine soja |
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1.A.75.1.16 | Uncharacterized protein of 2321 aas and ~35 TMSs. |
Eukaryota | Ciliophora | UP of Stentor coeruleus |
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1.A.75.1.17 | Piezo homologue of 3315 aas and ~48 TMSs. |
Eukaryota | Piezo of Vitrella brassicaformis |
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1.A.75.1.18 | Piezo homologue of 2620 aas and ~47 TMSs. |
Eukaryota | Euglenozoa | Piezo of Leptomonas pyrrhocoris |
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1.A.75.1.19 | Fibronectin, type III of 2452 aas and ~38 TMSs iin a 4 x 9 + 2 TMS arrangement. |
Eukaryota | Viridiplantae, Chlorophyta | Piezo homologue of Ostreococcus tauri |
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1.A.75.1.2 | Piezo2 (FAM38b) of 2,752 aas and 37 TMSs in a 4 x 9 + 1 TMS arrangement. It is the major transducer of mechanical force for touch sensation (Ranade et al. 2014) and is a rapidly adapting mechanically activated ion channel expressed in a subset of sensory neurons of the dorsal root ganglion and in cutaneous mechanoreceptors called Merkel cell neurite complexes. Ranade et al. 2014 showed that touch and pain are mediated by distinct receptors. Piezo2 mediates alloknesis (pathological sensations including itch of dry skin (Feng et al. 2018). In fact, PIEZO2 is a mechanosensitive cation channel that plays a key role in sensing touch, tactile pain, breathing and blood pressure. Wang et al. 2019 described the cryo-EM structure of mouse PIEZO2, which is a three-bladed, propeller-like trimer that comprises 114 TMSs (38 per protomer). TMSs 1-36 (TM1-36) are folded into nine tandem units of four transmembrane helices each to form the unusual non-planar blades. The three blades are collectively curved into a nano-dome of 28-nm diameter and 10-nm depth, with an extracellular cap-like structure embedded in the centre and a 9-nm-long intracellular beam connecting to the central pore. TMS38 and the C-terminal domain are surrounded by the anchor domain and TMS37, and they enclose the central pore with both transmembrane and cytoplasmic constriction sites. Structural comparison between PIEZO2 and its homologue PIEZO1 revealed that the transmembrane constriction site might act as a gate that is controlled by the cap domain (Wang et al. 2019). Up-regulation of Piezo2 in the pain afferent neurons following trigeminal nerve injury may play a role in the development of neuralgia (Liu et al. 2021). Altering expression of the genes encoding Kv1.1, Piezo2, and TRPA1 regulate the response of mechanosensitive muscle nociceptors (Nagaraja et al. 2021). Intrinsically disordered intracellular domains control key features of the mechanically-gated ion channel PIEZO2 (Verkest et al. 2022). Human cutaneous mechanoreceptors can perform mechanotransduction already during embryonic development (García-Mesa et al. 2022). Genetic alterations of Piezo2 have been reported in human cancer (Liu et al. 2022). Piezo2 transmembrane excitatory mechanosensitive ion channels have been identified as the principal mechanotransduction channels for proprioception (Sonkodi 2022). Mechanical distension/stretch in the colon provokes visceral hypersensitivity and pain. Xie et al. reported that mechanosensitive Piezo2 channels, expressed by TRPV1-lineage nociceptors, are involved in visceral mechanical nociception and hypersensitivity (Xie et al. 2023). Zhou et al. 2023 found that MyoD (myoblast determination)-family inhibitor proteins (MDFIC (246 aas and 2 - 3 C-terminal TMSs and MDFI ) are PIEZO1/2 interacting partners. These transcriptional regulators bind to PIEZO1/2 channels, regulating channel inactivation. Using single-particle cryoEM, the authors mapped the interaction site in MDFIC to a lipidated, C-terminal helix that inserts laterally into the PIEZO1 pore module. These Piezo-interacting proteins fit all the criteria for auxiliary subunits, contribute to explaining the vastly different gating kinetics of endogenous Piezo channels observed in many cell types, and elucidate mechanisms potentially involved in human lymphatic vascular disease (Zhou et al. 2023). PIEZO2 expression is an independent biomarker prognostic for gastric cancer and represents a potential therapeutic target (Zhang et al. 2024). Phosphatidic acid is an endogenous negative regulator of PIEZO2 channels and mechanical sensitivity (Gabrielle et al. 2024). TMC7, a non-mechanosensitive TMC (TC# 1.A.17.4.18)), inhibits Piezo2-dependent mechanosensation (West and Schneider 2024). |
Eukaryota | Metazoa, Chordata | PIEZO2 of Homo sapiens (Q9H5I5) + MDFIC or MDFI (Uniprot acc #s Q9P1T7 or Q99750), both of 246 aas with 2 - 3 C-terminal TMSs as auxillary proteins. |
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1.A.75.1.20 | Piezo homologue of 2888 aas and ~40 TMSs. |
Eukaryota | Ciliophora | Piezo of Pseudocohnilembus persalinus |
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1.A.75.1.21 | Piezo homologue of 2401 aas and ~ 38 TMSs. |
Eukaryota | Evosea | Piezo of Entamoeba histolytica |
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1.A.75.1.22 | Piezo2-like protein of 2811 aas and ~ 40 TMSs. |
Eukaryota | Piezo2 of Nannochloropsis gaditana |
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1.A.75.1.23 | Uncharacterized protein of 2710 aas and ~ 40 TMSs. |
Eukaryota | Oomycota | UP of Aphanomyces invadans |
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1.A.75.1.24 | Uncharacterized protein of 2121 aas and ~ 42 TMSs, possibly with 10 4 TMS repeats. |
Eukaryota | Parabasalia | UP of Tritrichomonas foetus |
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1.A.75.1.25 | Piezo-type mechanosensitive ion channel homolog isoform X1 of 2572 aas and ~38 TMSs with nine 2 + 1 + 1 TMS repeat units followed by 2 C-terminal TMSs that comprise the channel. It modulates vacuole morphology during tip growth (Radin et al. 2021). |
Eukaryota | Viridiplantae, Streptophyta | Piezo 1 of Physcomitrium patens (moss) |
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1.A.75.1.3 | Piezo mechanosensitive ion channel of 2760 aas and ~38 TMSs in a 4 x 9 + 2 TMS arrangement (Kim et al., 2012) |
Eukaryota | Metazoa, Arthropoda | Piezo (CG8486) of Drosophila melanogaster (Q9VLS3) |
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1.A.75.1.4 | Piezo protein homolog of 2462 aas and possibly 42 TMSs in an approximately 4 x 10 + 2 TMS arrangement. This piezo-like protein suppresses systemic movement of plant viruses in Arabidopsis thaliana (Zhang et al. 2019). It plays a role in root cap mechanotransduction (Fang et al. 2021) and modulates vacuole morphology during tip growth (Radin et al. 2021). Arabidopsis PIEZO1 localizes to the tonoplast and is required for vacuole tubulation in the tips of pollen tubes. . |
Eukaryota | Viridiplantae, Streptophyta | UP of Arabidodopsis thaliana (F4IN58) |
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1.A.75.1.5 | Piezo_RRas_bdg domain-containing protein of 2544 aas and ~ 40 TMSs. |
Eukaryota | Ciliophora | Piezo homolog of Paramecium tetraurelia (A0EF36) |
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1.A.75.1.6 | Piezo-like protein of 2724 aas and ~ 43 TMSs (Prole and Taylor 2013). |
Eukaryota | Euglenozoa | Piezo of Trypanosoma cruzi (Q4E330) |
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1.A.75.1.7 | Piezo homologue of 2382 aas and ~ 38 TMSs in a 4 x 9 + 2 TMS arrangement. |
Eukaryota | Metazoa, Nematoda | Piezo homologue of Ascaris suum (F1KQU6) |
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1.A.75.1.8 | Mechanosensitive piezo channel protein, isoform a, of 2438 aas. The C-terminal extracellular domain (before the last TMS) has a β-sandwich fold (Kamajaya et al. 2014). It coordinates multiple reproductive tissues to govern ovulation (Bai et al. 2020). |
Eukaryota | Metazoa, Nematoda | Piezo of Caenorhabditis elegans |
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1.A.75.1.9 | Piezo channel of 2013 aas and about 21 TMSs. |
Eukaryota | Metazoa, Platyhelminthes | Piezo of Schistosoma mansoni (Blood fluke) |
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1.A.76.1.1 | Magnesium transporter, MagT1; Ost3_Ost6; SLC58A1 (Goytain and Quamme, 2005; Schmitz et al., 2007; Zhou and Clapham, 2009; Gyimesi and Hediger 2022). As of 2018, the function of this protein as a Mg2+ transporter was under debate (Schäffers et al. 2018). This protein is of 335 aas with 5 TMSs in a 1 (N-terminal) + 2 + 2 (C-terninal) TMS arrangement. |
Eukaryota | Metazoa, Chordata | MagT1 of Homo sapiens (Q9H0U3) |
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1.A.76.1.10 | Ost3/Ost6 homologue of 334 aas and 5 TMSs |
Eukaryota | Viridiplantae, Chlorophyta | Ost3-like protein of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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1.A.76.1.11 | Uncharacterized protein of 277 aas |
Eukaryota | Foraminifera | UP of Reticulomyxa filosa |
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1.A.76.1.12 | Uncharacterized protein of 362 aas |
Eukaryota | Heterolobosea | UP of Naegleria gruberi (Amoeba) |
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1.A.76.1.13 | Uncharacterized protein of 328 aas and 7 (or 5) TMSs |
Eukaryota | Fungi, Ascomycota | UP of Tetrapisispora blattae (Yeast) (Kluyveromyces blattae) |
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1.A.76.1.14 | Mg2+ transporter, MagT1 homologue of 331 aas |
Eukaryota | Fungi, Ascomycota | MagT1 homologue of Pyronema omphalodes |
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1.A.76.1.2 | Mg2+ transporter; also called Tumor suppressor candidate 3 isoform a, Tusc3a (69% identity with MagT1) (Zhou and Clapham, 2009). It can transport Mg2+, Fe2+, Cu2+ and MnFe (Gyimesi and Hediger 2022). |
Eukaryota | Metazoa, Chordata | Tusc3a of Homo sapiens (Q13454) |
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1.A.76.1.3 | Magnesium transporter protein 1 (MagT1) with a thioredoxin domain (residues 50 - 150) and an Ost3/Ost6 domain (residues 160 - 310 with 4 TMSs). |
Eukaryota | Metazoa, Chordata | MagT1 of Danio rerio |
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1.A.76.1.4 | Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 3 |
Eukaryota | Evosea | Ost3 of Dictyostelium discoideum |
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1.A.76.1.5 | Ubiquitin conjugating enzyme of 345 aas with 4 C-terminal TMSs |
Eukaryota | Ciliophora | Ubiquitin conjugating enzyme of Oxytricha trifallax |
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1.A.76.1.7 | Putative magnesium transport protein of 354 aas and 4 C-terminal TMSs. |
Eukaryota | Ciliophora | MagT1 homologue of Albugo laibachii |
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1.A.76.1.8 | Glycosyl transferase, Ost3 of 350 aas and 4 TMSs. This protein is a subunit of the yeast oligosaccharyltransferase complex involved in N-glycosylation (Wild et al. 2018). It is not the catalytic subunit (see TC# 9.B.142.3.14). |
Eukaryota | Fungi, Ascomycota | Ost3 of Saccharomyces cerevisiae |
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1.A.76.1.9 | Ost6-like protein of 332 aas and 4 TMSs. |
Eukaryota | Fungi, Ascomycota | Ost6 of Saccharomyces cerevisiae (Baker's yeast) |
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1.A.76.2.1 | Oligosaccharyltransferase complex/magnesium transporter family protein of 173 aas and 3 or 4 TMSs. The proteins in this family are part of a complex of eight ER proteins that transfers core oligosaccharide from dolichol carrier to Asn-X-Ser/Thr motifs. This family includes both OST3 and OST6, each of which contains four predicted transmembrane helices. Disruption of OST3 and OST6 leads to a defect in the assembly of the complex. Hence, the function of these genes seems to be essential for recruiting a fully active complex necessary for efficient N-glycosylation. |
Eukaryota | Viridiplantae, Streptophyta | Uncharacterized protein of Arabidopsis thaliana (Mouse-ear cress) |
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1.A.76.2.10 | OstCL of 119 aas and 3 TMSs in a 1 + 2 TMS arrangement. |
Eukaryota | Metazoa, Chordata | OstCL of Homo sapiens |
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1.A.76.2.2 | Uncharacterized protein of 148 aas and 3 TMSs |
Eukaryota | Fornicata | UP of Giardia intestinalis (Giardia lamblia) |
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1.A.76.2.3 | Uncharacterized protein of 159 aas and 3 TMSs |
Eukaryota | Rhodophyta | UP of Cyanidioschyzon merolae |
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1.A.76.2.4 | Uncharacterized protein of 433 aas with 3 N-terminal TMSs. |
Eukaryota | Evosea | UP of Dictyostelium discoideum (Slime mold) |
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1.A.76.2.5 | Oligosaccharyl transferase complex subunit, EgrG of 144 aas and 3 TMSs. |
Eukaryota | Metazoa, Platyhelminthes | OST3 family member of Echinococcus granulosus (Hydatid tapeworm) |
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1.A.76.2.6 | OST3/OST6 superfamily protein of 158 aas and 3 TMSs. |
Eukaryota | Parabasalia | OST3 family protein of 158 aas |
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1.A.76.2.7 | OST3/OST6 Family protein of 159 aas and 3 TMSs. |
Eukaryota | Parabasalia | OST3 homologue of Trichomonas vaginalis |
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1.A.76.2.8 | Oligosaccharidyl transferase DS2 of 173 aas and 4 TMSs |
Eukaryota | Metazoa, Nematoda | DS2 of Loa loa (Eye worm) (Filaria loa) |
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1.A.76.2.9 | Oligosaccharidyl transferase, OstC of 149 aas and 3 TMSs in a 1 + 2 TMS arrangement. It may be involved in sperm membrane integrity (Illa et al. 2021). OSTA and OSTC are useful self-assessment tools for osteoporosis detection (Bui et al. 2022). |
Eukaryota | Metazoa, Chordata | OstC of Homo sapiens |
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1.A.77.1.1 | Inner membrane 40KD mitochondrial Ca2+ channel-forming uniporter, MCU or MICU2 (DUF607; 350 aas; coiled coil domain protein 109 A) (De Stefani et al., 2011; Drago et al., 2011). It functions with MICU1, an essential component of the system, as well as the gatekeeper for Ca2+ uptake (Mallilankaraman et al. 2012a; Mallilankaraman et al. 2012b). It contributes to metabolism-insulin secretion coupling in clonal pancreatic beta-cells (Alam et al. 2012). MCU-mediated Ca2+ uptake in beta cells is essential to establish a nutrient-induced mitochondrial pH gradient which is critical for sustained ATP synthesis and metabolism-secretion coupling in insulin-releasing cells (Quan et al. 2015). The mitochondrial calcium uniporter of pulmonary type 2 cells determines the severity of acute lung injury (Islam et al. 2022). Regulation of mitochondrial calcium uptake by the mitochondrial calcium uniporter complex is crucial for heart function. It has been demonstrated that mitochondrial calcium uptake (MICU)1 and MICU2, regulatory subunits of the complex, help maintain calcium homeostasis in cardiac mitochondria, provide potential targets for therapies aimed at improving mitochondrial function in heart disease (Ozkurede et al. 2024). |
Eukaryota | Metazoa, Chordata | MCU of Mus musculus (Q3UMR5) |
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1.A.77.1.10 | MCU homologue (355 aas; 2 TMSs) |
Bacteria | Chlorobiota | MCU homologue of Chlorobium phaeobacteroides (A1BIL6) |
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1.A.77.1.11 | Mitochondrial calcium uniporter, MCU, of 362 aas |
Eukaryota | Ciliophora | MCU of Tetrahymena thermophila |
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1.A.77.1.12 | The mitochondrial calcium uniporter regulatory subunit MCUb of 336 aas; part of the MCU complex (Sancak et al. 2013). MCU regulates procoagulant platelet formation (Kholmukhamedov et al. 2018) and interacts with the c-subunit of the mitochondrial ATPase (Huang and Docampo 2020). It functions in animals (but not in fungi or protozoans) with another protein, EMRE or SMDT1 of 107 aas (TC# 8.A.45.1.1) that interacts with and renders the channel functional (MacEwen et al. 2020). The mitochondrial calcium uniporter of pulmonary type 2 cells determines the severity of acute lung injury (Islam et al. 2022). Metal coordination complexes, particularly multinuclear ruthenium complexes, are the most widely investigated MCU inhibitors due to both their potent inhibitory activities as well as their longstanding use for this application (Huang and Wilson 2023). |
Eukaryota | Metazoa, Chordata | MCUb of Homo sapiens |
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1.A.77.1.13 | Mitochondrial calcium uniporter of 658 aas (Docampo et al. 2013). |
Eukaryota | MCU of Monosiga brevicollis |
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1.A.77.1.14 | Mitochondrial calcium uniporter of 297 aas. |
Eukaryota | Euglenozoa | MCU of Leishmania donovani |
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1.A.77.1.15 | MCU of 488 aas and 2 TMSs. The 3.8 Å cryoEM structure has been solved (Nguyen et al. 2018). The channel is a homotetramer with two-fold symmetry in its amino-terminal domain (NTD) that adopts a structure similar to that of human MCU. The NTD assembles as a dimer of dimers to form a tetrameric ring that connects to the transmembrane domain through an elongated coiled-coil domain. The ion-conducting pore domain maintains four-fold symmetry, with the selectivity filter positioned at the start of the pore-forming TM2 helix. The aspartate and glutamate sidechains of the conserved DIME motif are oriented towards the central axis and separated by one helical turn (Nguyen et al. 2018). |
Eukaryota | Fungi, Ascomycota | MCU of the fungus, Neosartorya fischeri |
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1.A.77.1.16 | Mitochondrial calcium uniporter protein, MCU, of 302 aas and 2 TMSs. It interacts with subunit c of the ATP synthase (Huang and Docampo 2020). |
Eukaryota | Euglenozoa | MCU of Trypanosoma cruzi |
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1.A.77.1.17 | CMU of 248 aas and 2 TMSs. It functions together with the EMRE regulatory protein (TC#8.A.45.1.6). MCU and EMRE form the minimal functional unit of the mitochondrial calcium uniporter complex in metazoans. Wang et al. 2020 functionally reconstituted an MCU-EMRE complex from the red flour beetle, Tribolium castaneum, and determined a cryo-EM structure of the complex at 3.5 Å resolution. They demonstrated Ca2+ uptake into proteoliposomes containing the purified complex. Uptake depended on EMRE as well as cardiolipin. The structure revealed a tetrameric channel with a single ion pore. EMRE was located at the periphery of the transmembrane domain and associates primarily with the first TMS of MCU. Coiled-coil and juxtamembrane domains within the matrix portion of the complex adopt markedly different conformations than in a structure of a human MCU-EMRE complex, suggesting that the structures represent different conformations of these functionally similar metazoan channels (Wang et al. 2020). |
Eukaryota | Metazoa, Arthropoda | Mcu of Tribolium castaneum |
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1.A.77.1.2 | MCU homologue of 338 aas and 2 TMSs. |
Eukaryota | Viridiplantae, Streptophyta | MCU homologue of Arabidopsis thaliana (Q1PE15) |
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1.A.77.1.3 | Algal MCU homologue (300 aas; 2 TMSs) |
Eukaryota | Viridiplantae, Chlorophyta | MCU homologue of Chlamydomonas reinhardtii (A8J6W0) |
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1.A.77.1.4 | Slime mold MCU homologue of 275 aas and 2 TMSs. The structure of the N-terminal domain (NTD) has been solved at 1.7 A resolution (Yuan et al. 2020). The oligomeric DdMCU-NTD contains four helices and two strands arranged in a fold that is completely different from the known structures of other MCU-NTD homologues. This domain may regulate channel activity (Yuan et al. 2020). |
Eukaryota | Evosea | MCU homologue of Dictyostellium discoideum (Q54LT0) |
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1.A.77.1.5 | Fungal MCU homologue of 493 aas and 2 TMS. The cryo-electron microscopy structure of the full-length MCU to an overall resolution of ~3.7 Å has been determined (Yoo et al. 2018). The structure reveals a tetrameric architecture, with the soluble and transmembrane domains adopting different symmetric arrangements within the channel. The conserved W-D-Phi-Phi-E-P-V-T-Y sequence motif of the MCU pore forms a selectivity filter comprising two acidic rings separated by one helical turn along the central axis of the channel pore (Yoo et al. 2018). |
Eukaryota | Fungi, Ascomycota | MCU homologue of Neurospora crassa (Q7S4I4) |
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1.A.77.1.6 | MCU homologue of 355 aas; 4 TMSs (2+2) (Docampo et al. 2013). |
Eukaryota | Euglenozoa | MCU homologue of Trypanosoma cruzi (E7KWU4) |
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1.A.77.1.7 | Mitochondrial Ca2+ Uniporter, a channel complex. MCU is a putative 5TMS protein (307 aas) with homology to MCU Ca2+/Mg2+ channels in the C-terminal 2TMS domain. The N-terminal domain is found only in Trypanosoma and Leishmania species. The TbMCU complex possesses four subunits, MCU (307 aas), MCUb (214 aas), MCUc (254 aas) and MCUd (249 aas)), present only in trypanosomatids and required for Ca2+ transport. These four subunits interact through their transmembrane helices to form hetero-oligomers in a ~380 KDa complex (Huang and Docampo 2018). |
Eukaryota | Euglenozoa | Channel homologues of Trypanosoma brucei |
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1.A.77.1.8 | Ciliate MCU homologue 362 aas; 2 TMSs |
Eukaryota | Ciliophora | MCU homologue of Paramecium tetraurelia (A0E7U6) |
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1.A.77.1.9 | MCU homologue (766 aas; 2 TMSs) |
Bacteria | Bacteroidota | MCU homologue of Cytophaga hutchinsonii (Q11Z39) |
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1.A.77.2.1 | Putative Mg2+ transporter, AtpZ |
Bacteria | Campylobacterota | AtpZ of Helicobacter pylori (Q1CUJ6) |
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1.A.77.2.10 | AtpZ homologue of 87 aas. |
Bacteria | Campylobacterota | AtpZ of Hippea maritima |
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1.A.77.2.11 | AtpZ homologue of 90 aas |
Bacteria | Campylobacterota | AtpZ of Campylobacter curvus |
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1.A.77.2.12 | AtpZ homologue of 60 aas |
Archaea | Euryarchaeota | AtpZ homologue of Methanothermococcus okinawensis |
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1.A.77.2.13 | AtpZ homologue of 80 aas |
Bacteria | Thermodesulfobacteriota | AtpZ of Geobacter metallireducens |
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1.A.77.2.14 | AtpZ homologue of 105 aas |
Bacteria | Pseudomonadota | AtpZ of Acidophilium multivorum |
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1.A.77.2.15 | AtpZ homologue of 96 aas |
Bacteria | Pseudomonadota | AtpZ of Tistrella mobilis |
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1.A.77.2.16 | Putative Mg2+ channel of 113 aas and 2 TMSs. Part of the F-type ATPase (Morales-Rios et al. 2015). |
Bacteria | Pseudomonadota | Magnesium channel of Paracoccus denitrificans |
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1.A.77.2.17 | Putative Mg2+ channel, AtpI, that functions with a Na+-transporting F-type ATPase (Soontharapirakkul et al. 2011). |
Bacteria | Cyanobacteriota | AtpI of Aphanothece halophytica |
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1.A.77.2.2 | AtpZ homologue (125 aas; 2 TMSs) |
Bacteria | Myxococcota | AtpZ homologue of Anaeromyxobacter sp. Fw109-5 (A7HIX1) |
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1.A.77.2.3 | AtpZ of 92 aas |
Bacteria | Thermodesulfobacteriota | AtpZ of Desulfovibrio vulgaris (A1VF64) |
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1.A.77.2.4 | AtpZ of 106 aas |
Bacteria | Chlorobiota | AtpZ of Chlorobium tepidum (Q8KGE5) |
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1.A.77.2.5 | AtpZ of 105 aas |
AtpZ of Rhodomicrobium vannielii (E3I7U2) |
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1.A.77.2.6 | AtpZ of 108 aas |
Bacteria | Pseudomonadota | AtpZ of Maricaulis maris (Q0AMJ5) |
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1.A.77.2.7 | ATP synthase protein Z of 114 aas |
Bacteria | Pseudomonadota | AtpZ of Rhodobacter capsulatus |
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1.A.77.2.8 | The Mg2+ uptake channel, AtpZ. Postulated to form homo- and/or hetero oligomers [(AtpZ)n-x (AtpI)x] (Hicks et al., 2003). The AtpI homologue (P22475) is in subfamily 1.A.77.3 and has TC# 1.A.77.3.1. |
Bacteria | Bacillota | The AtpZI Mg2+/Ca2+ channel of Bacillus pseudofirmus |
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1.A.77.2.9 | AtpZ of 112 aas.
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Archaea | Euryarchaeota | AtpI of Methanosarcina acetivorans (Q8TN54) |
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1.A.77.3.1 | AtpI of 133 aas, This protein is a part of a two component channel and as such is also listed with TC# 1.A.77.2.8. |
Bacteria | Bacillota | AtpI of Bacillus pseudofirmus |
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1.A.77.3.10 | AtpI homologue of 126 aas |
Bacteria | Pseudomonadota | AtpI of Ferrimonas balearica |
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1.A.77.3.11 | AtpI of 126 aas |
Bacteria | Pseudomonadota | AtpI of E. coli |
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1.A.77.3.12 | AtpI homologue of 185 aas |
Bacteria | Pseudomonadota | AtpI of Ralstonia solanacearum |
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1.A.77.3.13 | ATP synthase protein I | Bacteria | Mycoplasmatota | AtpI of Mycoplasma gallisepticum ) |
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1.A.77.3.14 | ATP synthase I, AtpI |
Bacteria | Bacillota | AtpI of Acetohalobium arabaticum |
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1.A.77.3.15 | ATP synthase subunit I |
Bacteria | Thermodesulfobacteriota | AtpI of Geobacter uraniireducens |
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1.A.77.3.16 | ATP synthase I |
Bacteria | Thermotogota | AtpI of Fervidobacterium pennivorans |
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1.A.77.3.17 | AtpI of the Na+ ATPase. Essential for assembly of the c-ring of the rotor (Brandt et al. 2013). |
Bacteria | Bacillota | AtpI of Acetobacterium woodii |
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1.A.77.3.18 | AtpI homologue of 122 aas and 4 TMSs |
Bacteria | Bacillota | AtpI homologue of Clostridium sticklandii |
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1.A.77.3.19 | AtpI homologue of 109 aas |
Bacteria | Thermotogota | AtpI of Thermatoga thermarum |
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1.A.77.3.2 | ATP synthase protein I | Bacteria | Bacillota | AtpI of Bacillus subtilis |
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1.A.77.3.20 | ATP synthase, subunit I of 117 aas and 4 TMSs |
Bacteria | Bacillota | AtpI of Staphylococcus aureus |
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1.A.77.3.21 | Bacteria | Cyanobacteriota | AtpI of Synechococcus sp. |
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1.A.77.3.22 | ATP snthase subunit I, AtpI of 147 aas |
Bacteria | Bacillota | AtpI of Halothermothrix orenii |
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1.A.77.3.23 | ATP synthase, subunit I, AtpI of 153 aas |
Bacteria | Actinomycetota | AtpI of Mycobacterium leprae |
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1.A.77.3.24 | AtpI of 255 aas and 4 TM |
Eukaryota | Rhodophyta | AtpI of Galdieria sulfuraria |
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1.A.77.3.25 | Putative AtpI of 122 aas and 4 TMSs |
Bacteria | Deferribacterota | AtpI of Denitrovibrio acetophilus |
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1.A.77.3.26 | Uncharacterized protein of 189 aas and 5 TMSs |
Bacteria | Myxococcota | UP of Anaeromyxobacter dehalogenans |
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1.A.77.3.27 | AtpI homologue of 133 aas |
Bacteria | Fusobacteriota | AtpI of Leptotrichia buccalis |
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1.A.77.3.28 | AtpI homologue of 126 aas |
Bacteria | Fusobacteriota | AtpI of Ilyobacter polytrophus |
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1.A.77.3.29 | AtpI homologue of 127 aas |
Bacteria | Fusobacteriota | AtpI of Propionigenium modestum |
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1.A.77.3.3 | ATP synthase subunit I |
Bacteria | Thermodesulfobacteriota | AtpI of Desulfococcus oleovorans |
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1.A.77.3.30 | AtpI homologue of 135 aas |
Bacteria | Fusobacteriota | AtpI of Sebaldella termitidis |
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1.A.77.3.31 | AtpI homologue of 164aas and 4 TMSs |
Bacteria | Mycoplasmatota | AtpI of Mycoplasma fermentans |
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1.A.77.3.32 | AtpI homologue of 150 aas |
Bacteria | Mycoplasmatota | AtpI of Mycoplasma arthritidis |
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1.A.77.3.33 | AtpI homologue of 161 aas. Immunogenic proteins have been evaluated as vaccine candidates against Mycoplasma synoviae (Zhang et al. 2023). |
Bacteria | Mycoplasmatota | AtpI of Mycoplasma synoviae |
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1.A.77.3.34 | AtpI of 140 aas and 4 TMSs |
Bacteria | Thermodesulfobacteriota | AtpI of Desulfotalea psychrophila |
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1.A.77.3.35 | Putative AtpI of 129 aas and 4 TMSs |
Bacteria | Bacillota | AtpI of Heliobacterium modesticaldum |
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1.A.77.3.36 | Putative AtpI of 139 aas and 4 TMSs |
Bacteria | Acidobacteriota | AtpI of Candidatus Koribacter versatilis |
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1.A.77.3.37 | Putative AtpI of 133 aas and 4 TMSs |
Bacteria | Thermodesulfobacteriota | AtpI of Desulfobacula toluolica |
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1.A.77.3.38 | Putative AtpI of 140 aas and 4 TMSs |
Bacteria | Thermodesulfobacteriota | AtpI of Syntrophus aciditrophicus |
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1.A.77.3.39 | Putative AtpI of 256 aas and 4 or 5 TMSs. The N-terminus may include a single TMS plus a hydrophilic domain before the C-terminal AtpI domain. |
Eukaryota | Rhodophyta | AtpI of Chondrus crispus |
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1.A.77.3.4 | ATP synthase protein I | Bacteria | Bacillota | AtpI of Bacillus megaterium |
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1.A.77.3.40 | AtpI of 156 aas and 4 TMSs |
Eukaryota | Cercozoa | AtpI of Paulinella chromatophora |
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1.A.77.3.41 | Putative AtpI of 119 aas and 4 TMSs |
Bacteria | Deferribacterota | AtpI of Deferribacter desulfuricans |
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1.A.77.3.42 | Putative AtpI of 138 aas and 4 TMSs |
Bacteria | Fibrobacteres/Acidobacteria group | AtpI of Granulicella tundricola |
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1.A.77.3.43 | Putative AtpI of 121 aas and 4 TMSs |
Bacteria | Nitrospirota | AtpI of Thermodesulfovibrio yellowstonii |
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1.A.77.3.44 | Putative AtpI of 160 aas and 4 TMSs |
Bacteria | Mycoplasmatota | AtpI of Mycoplasma mobile |
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1.A.77.3.45 | ATP synthase I-like protein, AtpI, of 385 aas amd 3 - 4 TMSs. |
Eukaryota | Viridiplantae, Chlorophyta | AtpI of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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1.A.77.3.5 | AtpI homologue |
Bacteria | Bacillota | AtpI homologue of Coprococcus catus |
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1.A.77.3.6 | AtpI homologue of 122aas and 4 TMSs |
Bacteria | Bacillota | AtpI homologue of Paenibacillus mucilaginosus |
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1.A.77.3.7 | ATP synthase protein I | Bacteria | Pseudomonadota | AtpI of Vibrio cholerae serotype O1 |
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1.A.77.3.8 | AtpI homologue of 150 aas |
Bacteria | Pseudomonadota | AtpI of Klebsiella pneumoniae |
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1.A.77.3.9 | AtpI homologue of 135 aas |
Bacteria | Pseudomonadota | AtpI of Pseudomonas putida |
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1.A.77.4.1 | Fusion protein with N-terminal 4 TMS AtpI domain and large soluble C-terminal α/β-hydrolase domain. |
Eukaryota | Rhodophyta | Fusion protein of Galdieria sulphuraria |
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1.A.77.4.2 | Fusion protein with N-terminal 4 TMS AtpI domain and large soluble C-terminal α/β-hydrolase domain. |
Eukaryota | Evosea | Fusion protein of Dictyostelium discoideum |
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1.A.77.4.3 | Fusion protein with N-terminal 4 TMS AtpI domain and large soluble C-terminal α/β-hydrolase domain. |
Eukaryota | Evosea | Fusion protein of Entamoeba histolytica |
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1.A.77.5.1 | AtpI homologue of 147 aas and 4 TMSs. Deletion of the gene encoding the ortholog, cg1360, affects ATP synthase function and enhances production of L-Valine in Corynebacterium glutamicum (Wang et al. 2019). |
Bacteria | Actinomycetota | AtpI of Corynebacterium diphtheriae |
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1.A.77.5.2 | AtpI homologue of 137 aas |
Bacteria | Actinomycetota | AtpI of Streptomyces avermitilis |
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1.A.77.5.3 | AtpI homologue of 145 aas |
Bacteria | Actinomycetota | AtpI of Frankia alni |
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1.A.77.5.4 | Putative AtpI of 177 aas and 4 TMSs |
Bacteria | Actinomycetota | AtpI of Saccharomonospora cyanea |
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1.A.77.5.5 | Putative ATP synthase protein I2 of 161 aas and 4 TMSs |
Bacteria | Actinomycetota | Putative reductase of Actinokineospora spheciospongiae |
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1.A.77.5.6 | Uncharacterized protein of 157 aas and 3-4 TMSs |
Bacteria | Actinomycetota | UP of Cellulomonas fimi |
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1.A.78.1.1 | Endosomal/Lysosomal K+ channel of 504 aas and 12 TMSs with two 6 TMS repeat units, KEL or TMEM175 (Cang et al. 2015). A mutation in the encoding gene is associated with Parkinson's disease (Jing et al. 2015; Tang et al. 2023). It forms a potassium-permeable leak-like channel, which regulates lumenal pH stability and is required for autophagosome-lysosome fusion (Lee et al. 2017). It also appears to be an H+ channel, and pathogenesis of PD is related to lysosomal dysfunction. There is a correlation between the lysosomal membrane protein TMEM175 and the risk of developing PD (Feng et al. 2024). TMEM175 plays a direct and critical role in lysosomal and mitochondrial functions as well as Parkinson's Disease (PD) pathogenesis (Jinn et al. 2017). The 3-D structures of the open and closed channels are known (Oh et al. 2020). Coding variants in TMEM175 which increase the propensity for Parkinson's disease, are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting glucocerebrosidase activity (Krohn et al. 2020). It constitutes the major lysosomal potassium channel (Lee et al. 2017) and is the pore-forming subunit of the LysoK(GF) complex, a complex activated by extracellular growth factors (Wie et al. 2021). The LysoK(GF) complex is composed of TMEM175 and AKT (AKT1, AKT2 or AKT3). In the complex, the TMEM175 channel is opened by conformational changes in AKT, leading to its activation (Wie et al. 2021). The lysoK(GF) complex is required to protect neurons against stress-induced damage. Hydrophobic gating, exhibited by TMEM175, is the process by which a nanopore may spontaneously dewet to form a "vapor lock" if the pore is sufficiently hydrophobic and/or narrow. This occurs without steric occlusion of the pore (Lynch et al. 2021). In addition to lysosomes, protein kinase B (PKB)-dependent regulation also influences TMEM175 currents in the plasma membrane (Pergel et al. 2021). Large-conductance Ca2+-activated K+ channel (BK) and transmembrane protein 175 (TMEM175) are the only two K+ channels known in lysosomes (Wu et al. 2022). Differential ion dehydration energetics explains selectivity in the non-canonical lysosomal K+channel, TMEM175 (Oh et al. 2022). 4-aminopyridine inhibits the lysosomal channel TMEM175 (Oh et al. 2022). TMEM175 is an evolutionarily distinct lysosomal cation channel whose mutation is associated with the development of Parkinson's disease. This protein regulates and changes in amount after cerebral ischemia (Zhang et al. 2023). The mechanism and therapeutic targets of the involvement of the lysosomal K+/proton channel TMEM175 in Parkinson's disease has been reported (Feng et al. 2024). This K+ channel in lysosomes becomes an H+ (hydrion) export channel with time (Feng et al. 2024). Selective inhibitors of the lysosomal Parkinson's Disease channel, TMEM175, have been discovered (Oh et al. 2024). These inhibitors are 2-phenylpyridin-4-ylamine (2-PPA), and AP-6. Cryo-EM structures of human TMEM175 bound to 2-PPA and AP-6 reveal that they act as pore blockers, binding at distinct sites in the pore and occluding the ion permeation pathway. Acute inhibition of TMEM175 by 2-PPA or AP-6 increases the level of lysosomal macromolecule catabolism, thereby accelerating macropinocytosis and other digestive processes (Oh et al. 2024). pH regulation of TMEM175, an endolysosomal cation channel, plays a role in Parkinson's Disease (Schulze et al. 2025). TMEM175 is both a K+ and an H+ channel (Schulze et al. 2025). |
Eukaryota | Metazoa, Chordata | KEL or TMEM175 of Homo sapiens |
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1.A.78.1.2 | TMEM175 of 506 aas and 12 TMSs |
Eukaryota | Metazoa, Chordata | TMEM175 of Takifugu rubripes (Japanese pufferfish) (Fugu rubripes) |
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1.A.78.1.3 | TMEM175 of 598 aas and 12 TMSs. |
Eukaryota | TMEM175 of Salpingoeca rosetta |
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1.A.78.2.1 | DUF211/TMEM175 of 206 aas and 6 TMSs. |
Bacteria | Bacteroidota | TMEM175 of Fibrella aestuarina |
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1.A.78.2.10 | TMEM175 lysosomal K+ channel of 203 aas and 6 TMSs. It's 3-d structure reveals a novel tetrameric arrangement (Lee et al. 2017). All six transmembrane helices of CmTMEM175 are tightly packed within each subunit without undergoing domain swapping. The highly conserved TM1 helix acts as the pore-lining inner helix, creating an hourglass-shaped ion permeation pathway in the channel tetramer. Three layers of hydrophobic residues on the carboxy-terminal half of the TM1 helices form a bottleneck along the ion conduction pathway and serve as the selectivity filter of the channel. Mutagenesis analysis suggests that the first layer of the highly conserved isoleucine residues in the filter is primarily responsible for channel selectivity (Lee et al. 2017). |
Bacteria | Cyanobacteriota | TMEM175 of Chamaesiphon minutus |
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1.A.78.2.11 | DUF1211 domain-containing protein of 161 aas and 5 TMSs |
Bacteria | Bacteroidota | DUF1211 protein of Hymenobacter psychrophilus |
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1.A.78.2.2 | PF06736/TMEM175 of 198 aas and 6 TMSs. |
Bacteria | Spirochaetota | TMEM175 of Leptospira inadai |
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1.A.78.2.3 | TMEM175 of 206 aas and 5 TMSs |
Bacteria | Actinomycetota | TMEM175 of Streptomyces collinus |
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1.A.78.2.4 | Uncharacterized protein of 216 aas and 6 TMSs |
Bacteria | Deinococcota | UP of Deinococcus radiodurans |
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1.A.78.2.5 | DUF1211/TMEM175 of 235 aas and 5 or 6 TMSs |
Bacteria | Pseudomonadota | TMEM175 of Azospirillum brasilense |
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1.A.78.2.6 | DUF1211 family member of 205 aas and 5 TMSs |
Archaea | Euryarchaeota | DUF1211 protein of Methanobacterium lacus |
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1.A.78.2.7 | Uncharacterized protein of 210 aas and 6 TMSs |
Archaea | Euryarchaeota | UP of Methanospirillum hungatei |
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1.A.78.2.8 | Uncharacterized protein of 195 aas and 6 TMSs. |
Bacteria | Bacillota | UP of Catellicoccus marimammalium |
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1.A.78.2.9 | TMEM175 homologue of 197 aas and 5 or 6 TMSs. It is a lysosomal K+ channel that is important for maintaining the membrane potential and pH stability of lysosomes. It contains two homologous copies of a 6 TMS domain, which has no sequence homology to the canonical tetrameric K+ channels and lacks the TVGYG selectivity filter motif found in these channels (Lee et al. 2017). The architecture represents a completely different fold from that of canonical K+ channels. All six transmembrane helices of CmTMEM175 are tightly packed within each subunit without undergoing domain swapping. The highly conserved TMS1 helix acts as the pore-lining inner helix, creating an hourglass-shaped ion permeation pathway in the channel tetramer. Three layers of hydrophobic residues on the carboxy-terminal half of the TMS1 form a bottleneck along the ion conduction pathway and serve as the selectivity filter. Mutagenesis analyses suggested that the first layer of the highly conserved isoleucine residues in the filter is primarily responsible for channel selectivity. Thus, the structure of CmTMEM175 represents a novel architecture of a tetrameric cation channel whose ion selectivity mechanism appears to be distinct from that of the classical K+ channel family (Lee et al. 2017). |
Cyanobacteriota | TMEM175 homologue of Chamaesiphon minutus |
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1.A.79.1.1 | The dsRNA transporter, SID-1 (Systematic RNA interference defective-1). Sid1 forms a gated transmembrane channel (Shih and Hunter 2011). It may function together with or be regulated by Sid-2, a metal-dependent nucleic acid binding protein (Q9GZC9) (McEwan et al. 2012), Sid-3, a tyrosyl protein kinase (Q10925), named Cdc-42-associated kinase, Ack, in mammals (Jose et al. 2012) and Sid-5 (Q19443) which co-localizes with RAB-7 (Q23146) and RLP-1 (Q11117). Endocytosis may play a role in dsRNA uptake. In Caenorhabditis elegans, inter-cellular transport of the small non-coding RNA causing systemic RNAi is mediated by the transmembrane protein SID1, encoded by the sid1 gene in the systemic RNAi defective (sid) loci. SID1 shares structural and sequence similarity with cholesterol uptake protein 1 (CHUP1) and is classified as a member of the ChUP family. Although systemic RNAi is not an evolutionarily conserved process, the sid gene products are found across the animal kingdom, suggesting the existence of other novel gene regulatory mechanisms mediated by small non-coding RNAs (Navratna et al. 2024). |
Eukaryota | Metazoa, Nematoda | SID-1 of Caenorhabditis elegans (AAF98593) |
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1.A.79.1.2 | The human SIDT1 protein (Duxbury et al. 2005; Pratt et al. 2012). This protein as well as SidT2 may be cholesterol transporters (Méndez-Acevedo et al. 2017), although they are annotated as RNA transporters, in accordance with several earlier publications. Morreover, SIDT1 localizes to endolysosomes and mediates double-stranded RNA transport into the cytoplasm (Nguyen et al. 2019). SIDT1 plays a key role in type I IFN responses to nucleic acids in plasmacytoid dendritic cells and mediates the pathogenesis of an imiquimod-induced psoriasis model (Morell et al. 2022). SIDT1-dependent absorption in the stomach mediates host uptake of dietary and orally administered microRNAs (Chen et al. 2021). The structure of the human systemic RNAi defective transmembrane protein 1 (hSIDT1) has revealed the conformational flexibility of its lipid binding domain (Navratna et al. 2023). Several subgroups of the family have been identified as cognate endopeptidases for four protein-sorting signals processed by a previously unknown machinery. Sorting signals with newly identified processing enzymes include MYXO-CTERM and three novel ones (Haft 2024). N-glycosylation is required for its functional role in SIDT1-mediated RNA uptake (Yang et al. 2024). The structure of recombinant human SIDT1 has been solved revealing that the extra-cytosolic domain of hSIDT1 adopts a double jelly roll fold, and the transmembrane domain exists as two modules - a flexible lipid binding domain and a rigid transmembrane domain core. These structural analyses provide insights into the inherent conformational dynamics within the lipid binding domain in ChUP family members (Navratna et al. 2024). Cryo-EM analysis revealed that human SID-1 transmembrane family member 1 dynamics underlie lipid hydrolytic activity (Hirano et al. 2024). Cryo-EM structures of human SID-1 reveal implications for their low-pH-dependent RNA transport activity (Zheng et al. 2024). New structure-dynamic clues underlie the regulatory diversity among tissue-specific NCX variants (Giladi et al. 2024).
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Eukaryota | Metazoa, Chordata | SIDT1 of Homo sapiens (Q9NXL6) |
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1.A.79.1.3 | Lysosomal systemic RNA interference defective protein-2, (systemic RNAi-defective (SID)) SidT2 of 832 aas and 12 TMSs in a 1 (N-terminal) + 1 (at residue 300) + 10 TMS arrangement. It increases the uptake of exogenous dsRNA and DNA (Aizawa et al. 2016). RNA and DNA are directly taken up by lysosomes in an ATP-dependent manner and degraded. SIDT2 has been reported to mediate RNA translocation during RNA autophagy and DNA translocation during DNA autophagy. Knockdown of Sidt2 inhibited, up to ~50%, total RNA degradation at the cellular level, independently of macroautophagy (Aizawa et al. 2016). RNA autophagy plays a role in constitutive cellular RNA degradation. SIDT2 also takes up single stranded oligonucleotides into cells (Takahashi et al. 2017). Contu et al. 2017 showed that three cytosolic YXXPhi motifs in SIDT2 are required for the lysosomal localization of SIDT2, and that SIDT2 interacts with adaptor protein complexes AP-1 and AP-2. On the other hand, Méndez-Acevedo et al. 2017 reported that this protein and SIDT1 transport cholesterol and not RNA. SIDT2 and RNautophagy promote tumor development (Nguyen et al. 2019). The cytosolic domain of SIDT2 carries an arginine-rich motif that binds to RNA/DNA and is important for the direct transport of nucleic acids into lysosomes (Hase et al. 2020). SIDT2 influences the three inflammatory signal pathways, eventually leading to damage of glomerular mesangial cells in mice (Sun et al. 2020). The variant rs1784042 of the SIDT2 gene is associated with the metabolic syndrome through Low HDL-c levels (León-Reyes et al. 2020). SidT2 enhances glucose uptake in peripheral tissues upon insulin stimulation (Xiong et al. 2020). The LIFR-AS1/miR-31-5p/SIDT2 axis modulated the development of papillary thyroid carcinoma (PTC) (Yi et al. 2021). The cryo-EM structures of human SIDT2 forms a tightly packed dimer with extensive interactions mediated by two previously uncharacterized extracellular/luminal beta-strand-rich domains and the unique transmembrane domain (TMD) (Qian et al. 2023). The TMD of each SIDT2 protomer contains eleven TMSs), and no discernible nucleic acid conduction pathway within the TMD, suggesting that it may act as a transporter. TM3-6 and TM9-11 form a large cavity with a putative catalytic zinc atom coordinated by three conserved histidine residues and one aspartate residue lying approximately 6 Å from the extracellular/luminal surface of the membrane. SIDT2 can hydrolyze C18 ceramide into sphingosine and fatty acid with a slow rate (Qian et al. 2023). SIDT2 inhibits phosphorothioate Aantisense oligonucleotide activity by regulating cellular localization of lysosomes (Zhao et al. 2023). SIDT2 is a player in cholesterol and lipoprotein metabolism in humans (León-Mimila et al. 2021). SIDT2 increases knockdown activity of gapmer antisense oligonucleotides (Kusumoto et al. 2025). |
Eukaryota | Metazoa, Chordata | SidT2 of Homo sapiens (Q8NBJ9) |
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1.A.79.1.4 | SidT2 dsRNA uptake channel of 856 aas and 12 or 13 TMSs. |
Eukaryota | Metazoa, Chordata | SidT2 of Siniperca chuatsi |
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1.A.79.1.5 |
The Cholesterol Uptake Protein ChUP-1 of 756 aas and 12 or 13 TMSs (Valdes et al., 2012). |
Eukaryota | Metazoa, Nematoda | ChUP-1 of Caenorhabditis elegans (Q9GYF0) |
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1.A.79.1.6 |
The ChUP-1 homologue, Sid1 |
Eukaryota | Evosea | ChUP-1 homologue of Dictyostelium discoideum (B0G177) |
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1.A.79.1.7 | Insect Sid-1 of 766 aas (Xu and Han 2008). |
Eukaryota | Metazoa, Arthropoda | Sid-1 of Aphis gossypii |
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1.A.79.1.8 | Sid-1 homologue of 718 aas |
Eukaryota | Metazoa, Nematoda | Sid-1 homologue of Caenorhabditis elegans |
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1.A.79.1.9 | Systemic RNA interference deficient-1 (Sid-1) transmembrane channel for the uptake of dsRNA, involving Sid-1-like proteins A and C, SilA and SilC (Cappelle et al. 2016). |
Eukaryota | Metazoa, Arthropoda | SilA/C of Leptinotarsa decemlineata (Colorado potato beetle) (Doryphora decemlineata) |
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1.A.79.2.1 | Prokaryotic Sid-1 homologue of 258 aas |
Bacteria | Pseudomonadota | Sid-1 homologue of Nitrosococcus watsoni |
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1.A.79.2.2 | Ceramidase domain-containing protein of 250 aas and 8 TMSs in a 1 + 2 + 4 + 1 TMS arrangement (common to other members of this family). |
Bacteria | Pseudomonadati, Pseudomonadota | Ceramidase domain-containing protein of Candidatus Thiodiazotropha endolucinida |
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1.A.79.2.3 | Ceramidase domain-containing protein (CDCP) of 270 aas and 8 TMSs in a 1 + 2 + 4 + 1 TMS arrangement. |
Bacteria | Pseudomonadati, Pseudomonadota | CDCP of Shewanella woodyi |
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1.A.79.2.4 | Alkaline phytoceramidase (AP) of 262 aas and 8 TMSs. |
Bacteria | Pseudomonadati, Nitrospinota | AP of Nitrospina gracilis |
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1.A.8.1.1 | Glycerol facilitator, GlpF. Transports various polyols with decreasing rates as size increases (Heller et al. 1980); also transports arsenite (As(III) and antimonite (Sb(III)) (Meng et al., 2004). Oligomerization may play a role in determining the rates of transport (Klein et al. 2019). AQP water permeability through GlpF can be regulated by lipid bilayer asymmetry and the transmembrane potential. The conserved Arg in the selectivity filter and positions and dynamics of multiple other pore lining residues modulate water passage through GlpF (Pluhackova et al. 2022). |
Bacteria | Pseudomonadota | GlpF of E. coli |
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1.A.8.1.2 | Aqp1 of 270 aas and 6 TMSs. Induced by NH3 but not CO2, but transports both gases. Aqp1 is found in the plasma membrae as well as the ER/chloroplast. Aqp1 may be involved in photoprotection. It may facilitate the efflux of NH3, preventing the uncoupling effect of high intracellular ammonia concentrations (Matsui et al. 2018). |
Eukaryota | Bacillariophyta | Aqp1 of Phaeodactylum tricornutum, a marine photoautotrophic diatoms |
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1.A.8.10.1 | Tonoplast intrinsic protein, TIPA or Tip3.1, of 268 aas and 6 TMSs. Phylogenetic distribution, structure, transport dynamics, gating mechanism, sub-cellular localization, tissue-specific expression, and co-expression of TIPs have been reviewed to define their versatile role in plants (Sudhakaran et al. 2021). Based on the phylogenetic distribution, TIPs are classified into five distinct groups with aromatic-arginine (Ar/R) selectivity filters, typical pore-morphology, and tissue-specific gene expression patterns. The tissue-specific expression of TIPs is conserved among diverse plant species, especially for TIP3s, which are expressed exclusively in seeds. The solute specificities of TIPs plays a role in physiological processes like stomatal movement and vacuolar sequestration as well as in alleviating environmental stress. TIPs also play a role in growth and developmental processes like radicle protrusion, anther dehiscence, seed germination, cell elongation, and expansion. The gating mechanism of TIPs regulates the solute flow in response to external signals, which helps to maintain the physiological functions of the cell (Sudhakaran et al. 2021). |
Eukaryota | Viridiplantae, Streptophyta | TIP of Arabidopsis thaliana (P26587) |
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1.A.8.10.10 | Aquaporin TIP2-1 (Delta-tonoplast intrinsic protein) (Delta-TIP) (Tonoplast intrinsic protein 2-1) (AtTIP2;1) (Daniels et al. 1996). Transports water and ammonia, and can be activated by mercury (Kirscht et al. 2016). The 3-d structure is known to 1.2Å resolution (Kirscht et al. 2016). It may participate in vacuolar compartmentation and detoxification of ammonium. |
Eukaryota | Viridiplantae, Streptophyta | TIP2-1 of Arabidopsis thaliana |
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1.A.8.10.11 | Probable aquaporin TIP-type alpha (Alpha TIP) (Tonoplast intrinsic protein alpha) | Eukaryota | Viridiplantae, Streptophyta | TIPA_PHAVU of Phaseolus vulgaris | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.8.10.12 | Aquaporin SIP2-1 (OsSIP2;1) (Small basic intrinsic protein 2-1) | Eukaryota | Viridiplantae, Streptophyta | SIP2-1 of Oryza sativa subsp. japonica | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.8.10.13 | Aquaporin | Eukaryota | Fungi, Microsporidia | AQP of Enterocytozoon bieneusi | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.8.10.14 | Uncharacterized protein of 295 aas and 6 TMSs. |
Eukaryota | Viridiplantae, Chlorophyta | UP of Volvox carteri |
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1.A.8.10.15 | The Aquaporin-8 (Aqp8) transporter is permeable to water, NH3, formamide and H2O2, and it is present in the inner membrane of mitochondria and the plasma membrane (Bienert et al., 2007; Saparov et al., 2007; Soria et al., 2010). Cholesterol, via sterol regulatory element-binding protein (SREBP) transcription factors, activates or represses genes involved in its hepatic biosynthetic pathway, and also modulates the expression of hepatocyte mitochondrial aquaporin-8 (mtAQP8), a channel that can function as peroxiporin by facilitating the transmembrane diffusion of H2O2. The peroxiporin, mtAQP8, plays a role in the SREBP-controlled hepatocyte cholesterogenesis (Danielli et al. 2019). Aquaporin-8 is important for cytokine-mediated toxicity in rat insulin-producing cells (Krüger et al. 2021). Aquaporin-8 ameliorates hepatic steatosis through the farnesoid X receptor in obese mice (Xiang et al. 2023). Aqp8 is a peroxyporin, transporting P2O2, which regulates oxidative stress responses (da Silva et al. 2024). |
Eukaryota | Metazoa, Chordata | Aqp8 of Homo sapiens (O94778) |
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1.A.8.10.16 | Aqp8a.1 of 260 aas and 6 TMSs. The spaciotemporal pattern of induction of three aquaporins during embyonic development in Zebrafish has been determined, and all three, Aqp8a.1, Aqp8a.2 and Aqp8b, show distictive patterns (Koun et al. 2016). |
Eukaryota | Metazoa, Chordata | Aqp8a.1 of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.A.8.10.17 | Aquaporin of 250 aas and 6 TMSs. It is a water channel required to facilitate the transport of water across membranes; it is involved in osmotolerance (Ghosh et al. 2006). |
Eukaryota | Fungi, Microsporidia | Aquaporin of Encephalitozoon cuniculi (Microsporidian parasite) |
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1.A.8.10.18 | Aqp0a of 263 aas and 6 TMSs. Zebrafish optical development requires regulated water permeability by Aquaporin 0 (Safrina et al. 2024). |
Eukaryota | Metazoa, Chordata | Aqp0a of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.A.8.10.2 | Tonoplast intrinsic protein-a (transports water, urea, glycerol and gases (CO2 and NH3) | Eukaryota | Viridiplantae, Streptophyta | TIPa of Nicotiana tabacum (Q9XG70) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.8.10.3 | Tonoplast intrinsic protein 1.1 of 251 aas and probably 6 TMSs. TIPs control water trade among cytosolic and vacuolar compartments and can also transport glycerol, ammonia, urea, hydrogen peroxide, metals/metalloids, and several amino acids (Liu et al. 2003). Additionally, TIPs, which can be responsive to nitrogen availability and salt sensitivity, are engaged with different abiotic stress responses and developmental processes like leaf expansion, root elongation and seed germination (Fan et al. 2023). TIPs of rice have also been studied (Balasaheb Karle et al. 2020). |
Eukaryota | Viridiplantae, Streptophyta | Tip1.1 of Arabidopsis thaliana (P25818) |
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1.A.8.10.4 | Vacuolar (tonoplast) NH3 channel, TIP2;3 (Loque et al., 2005). [Tip2;2 of wheat is also an NH3/H2O channel (Bertl and Kaldenhoff, 2007)]. | Eukaryota | Viridiplantae, Streptophyta | TIP2;3 of Arabidopsis thaliana (Q9FGL2) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.8.10.5 | Endoplasmic reticulum Small and Basic Intrinsic Protein; (SIP1;1) water channel (present in all plant tissues except seeds) (Ishikawa et al., 2005) May play a role in gas and water exchange between the plant and its environment via stromata (turgor-driven epidermal valves) and the hydathode pore (Pillitteri et al., 2008). |
Eukaryota | Viridiplantae, Streptophyta | SIP1;1 of Arabidopsis thaliana (Q9M8W5) |
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1.A.8.10.6 | The pollen-specific water/urea aquaporin, Tip1;3 (Soto et al. 2008) | Eukaryota | Viridiplantae, Streptophyta | Tip1;3 of Arabidopsis thaliana (O82598) |
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1.A.8.10.7 | The pollen-specific water/urea aquaporin. Tip5;1 (Soto et al. 2008) An aquaporin specifically targeted to pollen mitochondria; probably involved in nitrogen remobilization (Soto et al., 2010). |
Eukaryota | Viridiplantae, Streptophyta | Tip5;1 of Arabidopsis thaliana (Q9STX9) |
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1.A.8.10.8 | Aquaporin-B, AqpB of 294 aas and 6 TMSs. Tyr216 in loop D is a key residue in gating, possibly involving phosphorylation. Mutation of Tyr216 to aspartate or glutamate initiated water permeability. The truncated, permanently open AqpB yielded cells with reduced capability to cope with hypotonic stress (von Bülow et al. 2015). |
Eukaryota | Evosea | AqpB of Dictyostelium discoideum |
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1.A.8.10.9 | Aquaporin TIP1-2 (Gamma-tonoplast intrinsic protein 2) (Gamma-TIP2) (Salt stress-induced tonoplast intrinsic protein) (Tonoplast intrinsic protein 1-2) (AtTIP1;2) | Eukaryota | Viridiplantae, Streptophyta | TIP1-2 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.8.11.1 | Tonoplast intrinsic protein (ωTIP) | Eukaryota | Viridiplantae, Streptophyta | ωTIP of Pisum sativum (spP25794) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.8.11.10 | Pip2-4 of 291 aas with 6 TMSs. In tobacco plants, overexpression of the NtPIP2;4 gene can enhance drought resistance (Luo et al. 2025). |
Eukaryota | Viridiplantae, Streptophyta | Pip2-4 of Arabidopsis thaliana |
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1.A.8.11.2 | The plasma membrane aquaporin, NtAQP1 (H2O and CO2 permeable; important for photosynthesis, stomatal opening and leaf growth) (Uehlein et al., 2003; Uehlein et al., 2008) | Eukaryota | Viridiplantae, Streptophyta | NtAQP1 of Nicotiana tabacum (CAA04750) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.8.11.3 | Plasma membrane aquaporin 1, PIP1, PIP1;2, PIP1b, of 286 aas and 6 TMSs (Törnroth-Horsefield et al., 2006). Transports H2O, H2O2 (Dynowski et al., 2008), O2 and CO2 (Zwiazek et al. 2017). Forms active heterotetramers with PIP2;1 (1.A.8.11.4); down regulated under drought stress (Najafabadi et al., 2008); plays a role in salt tolerance (Li et al. 2018). Gated by H+, Ca2+, Mn2+ and Cd2+ (Verdoucq et al., 2008). The wheat orthologue has been described (Ayadi et al., 2011). 96% identical to PIP1;3. In Selaginella moellendorffii (Sm; spikemoss), SmPIP1;1 is retained in the ER while SmPIP2;1 is found in the plasma membrane but, upon co-expression, both isoforms are found in the plasma membrane as a heterotetramer, leading to a synergistic effect on water membrane permeability (Bienert et al. 2018). In some speices, PIP1 is inactive (e.g., in maize), but formation of a hetrotetramer with PIP2 allows transport (Vajpai et al. 2018). Transmembrane helices 2 and 3 determine the localization of plasma membrane PIPs (Wang et al. 2019). PIP1;2 from Malus domestica confers salt tolerance in transgenic Arabidopsis (Wang et al. 2022). The Pip1.1 and Pip1.2 of Brassica rapa mediate the uptake of neonicotinoid pesticides (Wan et al. 2024).
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Eukaryota | Viridiplantae, Streptophyta | PIP1.1 of Arabidopsis thaliana (P61837) |
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1.A.8.11.4 | Plasma membrane intrinsic protein 2a (forms active heterotetramers with PIP1;1 (TC# 1.A.8.11.3); down regulated under drought stress (Najafabadi et al., 2008). Transports H2O2 (Dynowski et al., 2008). The Mesembryanthemum crystallinum PIP2;1 orthologue is an aquaporin impermeable to urea and glycerol. It is positively regulated by PKA- and PKC- mediated phosphorylation (Amezcua-Romero et al., 2010). PIP1;1 and PIP2;2 (Q9ATM8) co-expression modulates the membrane water permeability in the halophyte Beta vulgaris storage root through a pH regulatory response, enhancing membrane versatility to adjust its water transfer capacity (Bellati et al., 2010). The wheat orthologue has been described (Ayadi et al., 2011). Inter-TMS interactions occurring both within and between monomers play crucial roles in tetramer formation, and assembly of tetramers is critical for their trafficking from the ER to the plasma membrane as well as water permeability (Yoo et al. 2016). This protein as well as 1.A.8.11.6 is possibly orthologous to spinach PIP1;2 for which the crystal structure is available (PDP# 4JC6) (Berny et al. 2016). Plays a role in drought and salt tolerance (Wang et al. 2015). PIP-type aqauporins may also transport CO2, boric acid, glycerol, arsenic and Na+ (Byrt et al. 2017). TMS2 and TMS3 are necessary and sufficient in AtPIP2 for its PM localization (Wang et al. 2019). Arabidopsis thaliana plasma membrane intrinsic protein (AtPIP2;1) is implicated in a salinity conditional influence on seed germination (Hoai et al., 2023; PMID 37277902). |
Eukaryota | Viridiplantae, Streptophyta | PIP2;1 of Arabidopsis thaliana (P43286) |
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1.A.8.11.5 | Probable aquaporin PIP2-6 (Plasma membrane intrinsic protein 2-6) (AtPIP2;6) (Plasma membrane intrinsic protein 2e) (PIP2e). In the radish (Raphaus sativus), there are 61 genes encoding aquaporins, and RsPIP2-6 is induced with high NaCl, and is involved in the salt stress response (Yi et al. 2022). The plasma membrane intrinsic protein OsPIP2;6 is involved in root-to-shoot arsenic translocation in rice (Oryza sativa L.) (Meselhy et al. 2024). |
Eukaryota | Viridiplantae, Streptophyta | PIP2-6 of Arabidopsis thaliana |
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1.A.8.11.6 | Aquaporin PIP2-8 (Plasma membrane intrinsic protein 2-8) (AtPIP2;8) (Plasma membrane intrinsic protein 3b) (PIP3b). This protein as well as 1.A.8.11.4 are possibly orthologous to spinach PIP1;2 for which the crystal structure is available (PDP# 4JC6) (Berny et al. 2016). |
Eukaryota | Viridiplantae, Streptophyta | PIP2-8 of Arabidopsis thaliana |
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1.A.8.11.7 | Aquaporin PIP2;5 (PIP2-5) of 285 aas. Transports water and hydrogen peroxide (H2O2) (Bienert et al. 2014; ). PIP1;2 doesn't transport H2O2. TMS3 contains an LxxA motif that targets the protein to the plasma membrane from the ER. While PIP2s are in the plasma mebrane, PIP1s are retained in the ER; this motif only partly explains the difference (Chevalier and Chaumont 2015). PIP1;2 AND PIP2;5 form homo- and heterotetramers (Berny et al. 2016). PIP2;6 is 85% identical, and Ytterbium, Yb3+, increases water flow in corn roots by activiating PIP2;6, PIP2;2 and TIP2;2 (Vorob'ev et al. 2019). Incubation with abscisic acid and the elicitor flg22 peptide induced the intracellular H2O2 accumulation in cells expressing ZmPIP2;5 (Ahmed et al. 2023). Sugarcane mosaic virus employs the 6K2 protein to impair ScPIP2; 4 transport of H2O2 to facilitate virus infection (Zhang et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | PIP2;5 of Zea mays |
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1.A.8.11.8 | Aqp2 of 297 aas and 6 TMSs. Induced by both NH3 and CO2, and transports both gases. Aqp2 is found in the plasma membrane and may be involved in photoprotection. It may facilitate the efflux of NH3, preventing the uncoupling effect of high intracellular ammonia concentrations (Matsui et al. 2018). |
Eukaryota | Bacillariophyta | Aqp2 of Phaeodactylum tricornutum, a marine photoautotrophic diatoms |
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1.A.8.11.9 | Water channel, Aqp2-3 or Aqp2;3 or PIP2C of 285 aas and 6 TMSs. Ectopic expression of CrPIP2;3, a plasma membrane intrinsic protein gene from the halophyte, Canavalia rosea, enhanced drought and salt-alkali stress tolerance in Arabidopsis (Zheng et al. 2021). The Arabidopsis ortholog is presented here. |
Eukaryota | Viridiplantae, Streptophyta | PIP2C of Arabidopsis thaliana |
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1.A.8.12.1 | Nodulin-26 aquaporin and glycerol facilitator, NIP (de Paula Santos Martins et al. 2015). Transports NH3 5-fold better than water in Hg2+-sensitive fashion (Hwang et al., 2010). |
Eukaryota | Viridiplantae, Streptophyta | Nodulin-26 of Glycine max (spP08995) |
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1.A.8.12.10 | Arsenite export pore, AqpS (Yang et al., 2005) | Bacteria | Pseudomonadota | AqpS of Sinorhizobium meliloti (CAC45655) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.8.12.11 | Uncharacterized MIP family protein of 274 aas and 6 TMSs. |
Eukaryota | Evosea | UP of Entamoeba histolytica |
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1.A.8.12.12 | Uncharacterized MIP family protein of 314 aas and 8 putative TMSs. The extra 2 non-homologous TMSs appear to be N-terminal. |
Eukaryota | Evosea | UP of Entamoeba histolytica |
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1.A.8.12.13 | Rice NIP2.1 (NIP2-1; NIP2;1) of 295 aas and 6 or 7 TMSs. It transports metaloids such as arsenous acid (arsenic) and silisic acid (silicon). The 3-D structure has been determined (Sharma et al. 2023). This protein is most similar to TC# 1.A.8.12.2 within TCDB. |
Eukaryota | Viridiplantae, Streptophyta | NIP2.1 of Zea mays |
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1.A.8.12.2 | The silicon (silicic acid) (undissociated form) transporter, Lsi1 (Ma et al., 2007a, b; Mitani et al., 2008). The barley orthologue Lsi1 (also called NIP2-1) is also a silicon (silicic acid) uptake channel (Chiba et al., 2009). Rice Lsi1 also transports arsenite and pentavalent mono and dimethyl arsenite (Li et al., 2009). In addition to silicon (Si), selenite (Se) uptake is mediated by Lsi1 (Zhao et al., 2010). Physicochemical and transcriptomic responses of Lactobacillus brevis JLD715 to sodium selenite have been reported (Yang et al. 2021). Many of the world's most important food crops such as rice, barley and maize accumulate silicon (Si) to high levels, resulting in better plant growth and crop yields (van den Berg et al. 2021). The first step in Si accumulation is the uptake of silicic acid by the roots, a process mediated by the NIP subfamily of aquaporins, also named metalloid porins. van den Berg et al. 2021 presented the X-ray crystal structure of the archetypal NIP family member from Oryza sativa (OsNIP2;1). The OsNIP2;1 channel is closed in the crystal structure by the cytoplasmic loop D, which is known to regulate channel opening in classical plant aquaporins. The structure reveals a novel, five-residue extracellular selectivity filter with a large diameter. Unbiased molecular dynamics simulations show a rapid opening of the channel to visualise how silicic acid interacts with the selectivity filter prior to transmembrane diffusion. These results may enable detailed structure-function studies of metalloid porins, including the basis of their substrate selectivity (van den Berg et al. 2021). Silicon (Si), the most abundant mineral element in the earth's crust, is taken up by plant roots in the form of silicic acid through Low silicon rice 1 (Lsi1). Lsi1 belongs to the Nodulin 26-like intrinsic protein subfamily and shows high selectivity for silicic acid. The crystal structure of rice Lsi1 at a resolution of 1.8 Å reveals transmembrane helical orientations different from other aquaporins, characterized by a unique, widely opened, and hydrophilic selectivity filter composed of five residues. Structural, functional, and theoretical investigations provided a solid basis for the Si uptake mechanism in plants (Saitoh et al. 2021). |
Eukaryota | Viridiplantae, Streptophyta | Lsi1 of Oryza sativa (Q6Z2T3) |
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1.A.8.12.3 | The boric acid channel protein, NIP5;1 (expressed in the root elongation zone and root hairs in response to boron deficiency) (Takano et al., 2006). Borate is an essential nutrient in plants. The ortholog in Brassica napus ( XP_013652160.1) is 301 aas in length with 6 TMSs and is 90% identical to the A. thaliana protein. Synthesis of the B. napus protein is induced in roots and shoots by a borate deficiency (Diehn et al. 2019). NIP2, 3, 4, 6 and 7 can also transport boric acid (Diehn et al. 2019). the grape ortholog can transport the same molecules (Sabir et al. 2020). |
Eukaryota | Viridiplantae, Streptophyta | NIP5;1 of Arabidopsis thaliana (NP_192776) |
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1.A.8.12.4 | The root-expressed MIP transporter of lactic acid, NIP2;1 (Nod26-like MIP-4; NLM4) (induced by water logging and anoxic stress; shows minimal water and glycerol transport). It may play a role in adaptation to lactic fermentaion under anaerobic stress (Choi and Roberts, 2007). Lactic acid transport is induced by anoxic stress (Choi and Roberts, 2007). | Eukaryota | Viridiplantae, Streptophyta | NIP2;1 of Arabidopsis thaliana (Q8W037) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.8.12.5 | The silicon (silicic acid) transporter, Nip2-2 (Nip2;2) (Mitani et al., 2008). Also transports arsenite (Li et al., 2009). |
Eukaryota | Viridiplantae, Streptophyta | Nip2-2 of Oryza sativa (Q67WJ8) |
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1.A.8.12.6 | Nip7;1 arsenite and borate channel (Isayenkov and Maathuis, 2008; Li et al., 2011) |
Eukaryota | Viridiplantae, Streptophyta | Nip7. 1 of Arabidopsis thaliana (Q8LAI1) |
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1.A.8.12.7 | Aquaporin NIP1-2 (NOD26-like intrinsic protein 1-2) (AtNIP1;2) (Nodulin-26-like major intrinsic protein 2) (NodLikeMip2) (Protein NLM2). Selectivity filters play roles in determining aluminum transport by AtNIP1;2 (Wang et al. 2021). |
Eukaryota | Viridiplantae, Streptophyta | NIP1-2 of Arabidopsis thaliana |
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1.A.8.12.8 | Aquaporin NIP1-1 (NOD26-like intrinsic protein 1-1) (AtNIP1;1) (Nodulin-26-like major intrinsic protein 1) (NodLikeMip1) (Protein NLM1). NIP-like aquaporins transport water, but also arsenic, boric acid, sliicon, glycerol, urea, lactic acid and ammonia (Mitani-Ueno et al. 2011; Hwang et al. 2010). The grape ortholog appears to transport the same molecules including water and glycerol, but also arsenate, borate, selenate and cadmium (Sabir et al. 2020). |
Eukaryota | Viridiplantae, Streptophyta | NIP1-1 of Arabidopsis thaliana |
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1.A.8.12.9 | Aquaporin NIP6-1 (NOD26-like intrinsic protein 6-1) (AtNIP6;1). The grape ortholog is impermeable to water, but permeable to glycerol (Sabir et al. 2020). |
Eukaryota | Viridiplantae, Streptophyta | NIP6-1 of Arabidopsis thaliana |
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1.A.8.13.1 | MIP family homologue | Archaea | Euryarchaeota | Orf of Archaeoglobus fulgidus, AE000782 (ID# AF1426) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.8.13.2 | Hg2+-inhibitable aquaporin, AqpM (transports both water and glycerol as well as CO2) (Kozono et al., 2003; Araya-Secchi et al., 2011). Its 3-d structure has been determined to 1.7 Å. In AqpM, isoleucine replaces a key histidine residue found in the lumen of water channels, which becomes a glycine residue in aquaglyceroporins. As a result of this and other side-chain substituents in the walls of the channel, the channel is intermediate in size and exhibits differentially tuned electrostatics when compared with the other subfamilies (Lee et al. 2005). |
Archaea | Euryarchaeota | AqpM of Methanothermobacter marburgensis |
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1.A.8.13.3 | Putative aquaporin, GlpF5, of 216 aas; probably transports water, glycerol and dihydroxyacetone (Bienert et al. 2013). |
Bacteria | Bacillota | GlpF5 of Lactobacillus plantarum |
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1.A.8.13.4 | Aquaporin, Aqp, of 222 aas and 6 TMSs. It functions in hydrogen peroxide (H2O2) export from the cell, relieving oxidative stress (Tong et al. 2019). It is an H2O2-inducible bacterial "peroxiporin". |
Bacteria | Bacillota | Aqp of Streptococcus oligofermentans or Streptococcus cristatus |
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1.A.8.13.5 | Aquaporin, Aqp9, of 231 aas and 6 TMSs. This protein co-localizes with the vacuolar proton pyrophosphatase to acidocalcisomes and the contractile vacuole complex (Montalvetti et al. 2004) which are involved in osmoregulation (Rohloff et al. 2004). Acidocalcisomes function as storage sites for cations and phosphorus, participate in PPi and poly P metabolism as well as volume regulation and are essential for virulence. A signalling pathway involving cyclic AMP generation is important for fusion of acidocalcisomes to the contractile vacuole complex, transference of aquaporin and volume regulation (Docampo et al. 2011). Hyperosmotic stress induces aquaporin-dependent cell shrinkage, polyphosphate synthesis, amino acid accumulation, and global gene expression changes in Trypanosoma cruzi (Li et al. 2011). Plasmodium spp. express a single AQP, Toxoplasma gondii two, while Trypanosoma cruzi and Leishamnia spp. encode up to five AQPs. Their AQPs are thought to import metabolic precursors and simultaneously to dispose of waste and to help parasites survive osmotic stress (Von Bülow and Beitz 2015). |
Eukaryota | Euglenozoa | Aqp9 of Trypanosoma cruzi |
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1.A.8.13.6 | Aquaporin of 214 aas and 6 TMSs in a 2 + 1 + 2 + 1 TMS arrangement. |
Bacteria | Bacteroidota | Aqp of Bacteroidia bacterium (subsurface metagenome) |
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1.A.8.14.1 | Putative aquaporin, Aqp2, with a large 300 residue amino terminal hydrophilic domain. The protein is of 603 aas and 7 TMSs in a 1 + 3 + 3 TMS arrangement. |
Eukaryota | Apicomplexa | Aqp2 of Plasmodium falciparum |
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1.A.8.14.2 | Erythrocyte membrane-associated antigen, putative, of 541 aas and 4 - 7 TMSs. |
Eukaryota | Apicomplexa | EMA of Plasmodium yoelii yoelii |
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1.A.8.14.3 | Erythrocyte membrane-associated antigen, putative, of 651 aas and 7 TMSs in a 1 + 3 + 3 TMS arrangement. |
Eukaryota | Apicomplexa | Aqp, putative, of Plasmodium yoelii yoelii |
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1.A.8.2.1 | Glycerol facilitator | Bacteria | Bacillota | GlpF of Bacillus subtilis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.8.2.10 | Aquaglyceroporin of 270 aas and 6 TMSs. |
Viruses | Bamfordvirae, Nucleocytoviricota | Aquaporin of Paramecium bursaria chlorella virus MT325 |
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1.A.8.2.11 | Lmo1539 of 272 aas and 7 possible TMSs. Lmo1539 is related to activation of the LiaR-mediated stress defense mechanism and is induced by treatment with nisin (TC# 1.C.20.1.1) (Pinilla et al. 2021). |
Bacteria | Bacillota | Lmo1539 of Listeria monocytogenes |
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1.A.8.2.12 | Aquaglyceroporin, AagP, of 298 aas and 6 TMSs. This protein transports water, glycerol and H2O2. It catalyzes H2O2 efflux during glycerol uptake and contributes to virulence in mice (Zhu et al. 2023). |
Bacteria | Bacillota | AagP of Streptococcus suis |
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1.A.8.2.2 | Mixed function glycerol facilitator/aquaporin, GlpF (Froger et al. 2001). |
Bacteria | Bacillota | GlpF of Lactococcus lactis |
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1.A.8.2.3 | Probable glycerol uptake facilitator protein | Bacteria | Mycoplasmatota | GlpF of Mycoplasma gallisepticum ) |
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1.A.8.2.4 | GlpF1; transports water, dihydroxyacetone and glycerol as well as D,L-lactic acid (Bienert et al. 2013). |
Bacteria | Bacillota | GlpF1 of Lactobacillus plantarum |
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1.A.8.2.5 | GlpF2. Transporter of water, dihydroxyacetone and glycerol (Bienert et al. 2013). |
Bacteria | Bacillota | GlpF2 of Lactobacillus plantarum |
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1.A.8.2.6 | GlpF3. Transports water, dihydroxyacetone and glycerol (Bienert et al. 2013). |
Bacteria | Bacillota | GlpF3 of Lactobacillus plantarum |
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1.A.8.2.7 | GlpF4. Transports water, dihydroxyacetone and glycerol as well as D,L-lactic acid (Bienert et al. 2013). |
Bacteria | Bacillota | GlpF4 of Lactobacillus plantarum |
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1.A.8.2.8 | Putative aquaporin, GlpF6. Probably transports water, glycerol and dihydroxyacetone (Bienert et al. 2013). |
Bacteria | Bacillota | GlpF6 of Lactobacillus plantarum |
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1.A.8.2.9 | Glycerol facilitator, GlpF, of 248 aas and 6 TMSs |
Bacteria | Bacteroidota | GlpF of Blattabacterium sp. subsp. Blattella germanica (strain Bge) (Blattella germanica symbiotic bacterium) |
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1.A.8.3.1 | Aquaporin Z water channel (aqpZ gene expression is under sigma S control; induced at the onset of stationary phase) (Mallo and Ashby, 2006). The high resolution 3-d structure is available (PDB 1RC2) revealing two re-entrant coil-helix domains from the selectivity filter (Savage et al. 2003). Coupled mutations enabled glycerol transport (Ping et al. 2018). |
Bacteria | Pseudomonadota | AqpZ of E. coli (P60844) |
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1.A.8.4.1 | Intracellular endoplasmic reticulum (ER)-localized Aquaporin 11 (Aqp11, AqpX1) water channel (important for the development of kidney proximal tubules; disruption produces neonatally fatal polycystic kidneys (Ishibashi 2006). Has a positively charged C-terminal amino acid cluster similar to the di-lysine motif (-KKXX) for ER retention (Nozaki et al., 2008)). In the horse, AQP3 and AQP11 are involved in the resilience of stallion sperm to withstand cryopreservation (Bonilla-Correal et al. 2017). |
Eukaryota | Metazoa, Chordata | Aqp11 of Homo sapiens (Q8NBQ7) |
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1.A.8.4.2 | Aquaporin-12A (AQP-12) of 295 aas and probably 7 TMSs with an extra N-terminal TMS. It bears a C-terminal KKXX-like ER retention sequence and is found intracelllularly (Ishibashi 2006). It is expressed in elevated amounts in exocrine glandular cells of the pancreas (Danielsson et al. 2014) but is also present in the nuclear envelope. A short perinuclear amphipathic α-helix in Apq12 promotes nuclear pore complex biogenesis (Zhang et al. 2021). |
Eukaryota | Metazoa, Chordata | AQP12A of Homo sapiens |
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1.A.8.4.3 | Aquaporin 10, Aqp10 of 259 aas and 6 TMSs |
Eukaryota | Metazoa, Nematoda | Aqp10 of Haemonchus contortus (Barber pole worm) |
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1.A.8.4.4 | Aquaporin of 263 aas and 7 TMSs (Stavang et al. 2015). |
Eukaryota | Metazoa, Arthropoda | Aquaporin of the salmon leach, Lepeophtheirus salmonis |
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1.A.8.4.5 | Aquaporin of 256 aas with 6 TMSs in a 3 (N-terminus) + 3 TMS (C-terminus) arrangement (Zhou et al. 2018). |
Eukaryota | Metazoa, Arthropoda | Aqp of Blomia tropicalis (mite) |
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1.A.8.4.6 | Aquaporin of 261 aas and 6 TMSs. Aquaporins may not play major roles in adapting to longterm survival in brackish water or they be regulated by non-transcriptional mechanisms like post-translational modifications (Misyura et al. 2020). |
Eukaryota | Metazoa, Arthropoda | Aqp of Aedes aegypti (Yellowfever mosquito) (Culex aegypti) |
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1.A.8.5.1 | FPS1 glycerol efflux facilitator. It is important for maintaining osmotic balance during mating-induced yeast cell fusion and for tolerating hypoosmotic shock; it also transports arsenite and antimonite). FPS1 is a homotetramer (Beese-Sims et al., 2011). It is important for osmo-adaptation by regulating intracellular glycerol levels during changes in external osmolarity. Upon high osmolarity conditions, yeast accumulate glycerol by increased production of the osmolyte and by restricting glycerol efflux through Fps1. The extended cytosolic termini of Fps1 contain short domains that are important for regulating glycerol flux through the channel (Hedfalk et al. 2004). The transmembrane core of the protein plays an equally important role (Geijer et al., 2012). The MAP kinase, Slt2, physically interacts with Fps1, and this interaction, dependent on phosphorylation of S537, regulates arsenite uptake (Ahmadpour et al. 2016). The N-terminal regulatory domain and the B-loop may interact in channel control (Karlgren et al. 2004). Fps1 resides in multi tetrameric clusters, and hyperosmotic and oxidative stress conditions cause Fps1 reorganization, and rapid exposure to hydrogen peroxide causes Fps1 degradation (Shashkova et al. 2021). Activation of the CWI pathway through high hydrostatic pressure, enhances glycerol efflux via Fps1 in Saccharomyces cerevisiae (see family 9.B.454 in TCDB). |
Eukaryota | Fungi, Ascomycota | FPS1 protein of Saccharomyces cerevisiae |
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1.A.8.5.2 | Fps1 hyperactive orthologue of the S. cerevisiae Fps1 (1.A.8.5.1) (Geijer et al., 2012). |
Eukaryota | Fungi, Ascomycota | Fps1 of Ashbya gossypii (Q75CI7) |
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1.A.8.6.1 | Aqy1, aquaporin (mediates H2O efflux during sporulation) (spore maturation) (Sidoux-Walter et al., 2004) | Eukaryota | Fungi, Ascomycota | Aqy1 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.8.6.2 | Aquaporin-2 Aqy2 (plays a role in reducing surface hydrophobicity promoting cell dispersion during starvation and reproduction) | Eukaryota | Fungi, Ascomycota | Aqy2 of Saccharomyces chevalieri | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.8.6.3 |
Aquaporin, Aqy1 (PIP2-7 7). The subangstron (0.88Å) structure is available (Kosinska Eriksson et al. 2013). the H-bond donor interactions of the NPA motif''s asparagine residues to passing water molecules are revealed. A polarized water-water H-bond configuration is observed within the channel. Four selectivity filter water positions are too closely spaced to be simultaneously occupied. Strongly correlated movements break the connectivity of selectivity filter water molecules to other water molecules within the channel, thereby preventing proton transport via a Grotthuss mechanism. |
Eukaryota | Fungi, Ascomycota | Aqy1 of Komagataella pastoris (Pichia pastoris) |
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1.A.8.6.4 | Water and CO2 permeable aquaporin, AQP1, of an edible mycorhizal fungus (desert truffles) (Navarro-Ródenas et al. 2012). |
Eukaryota | Fungi, Ascomycota | AQP1 of Terfezia claveryi |
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1.A.8.7.1 | Tobacco X-intrinsic protein (XIP1-1-β). Transports glycerol, urea and boric acid, but not water (Bienert et al., 2011). |
Eukaryota | Viridiplantae, Streptophyta | XIP1-1 of Nicotiana tomentosiformis (E3UN01) |
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1.A.8.7.2 | Potato X intrinsic protein, XIP1. Transports glycerol, urea and boric acid, but not water (Bienert et al., 2011). |
Eukaryota | Viridiplantae, Streptophyta | XIP1-1 of Solanum tuberosum (E3UMZ6) |
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1.A.8.7.3 | Morning glory XIP-1-1-α. Transports glycerol, urea and boric acid, but not water (Bienert et al., 2011). |
Eukaryota | Viridiplantae, Streptophyta | XIP1 of Ipomoea nil (E3UMZ5) |
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1.A.8.7.5 | Aquaporin F (AqpF) of 321 aas and 6 TMSs. It transports water and glycerol, but additionally transporters hydrogen peroxide (H2O2) for signaling purposes (Laothanachareon et al. 2023). It may be the only aquaporin capable of H2O2 transport and signalling. |
Eukaryota | Fungi, Ascomycota | AqpF of Aspergillus niger |
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1.A.8.8.1 | Aquaporin 1 (CO2-, O2-, H202- and nitrous oxide-permeable, water-selective, and monovalent cation (Li+. Na+ and K+) permeable) (Zwiazek et al. 2017; Varadaraj and Kumari 2020; Nourmohammadi et al. 2024). Aquaporin-1 tunes pain perception by interacting with Nav1.8 Na+ channels in dorsal root ganglion neurons (Zhang and Verkman, 2010). It is upregulated in skeletal muscle in muscular dystrophy (Au et al. 2008). AQP1 has been reported to first insert as a four-helical intermediate, where helices 2 and 4 are not inserted into the membrane. In a second step this intermediate is folded into a six-helical topology. During this process, the orientation of the third helix is inverted, and it can shift out the membrane core (Virkki et al. 2014). Its synthesis is regluated by Kruppel-like factor 2 (KLF2; Q9Y5W3) which also interacts directly with Aqp1 (Fontijn et al. 2015). A nanoscale ion pump has been derived artificially from Aqp1 (Decker et al. 2017). Mammalian AQP1 channels, activated by cyclic GMP, can carry non-selective monovalent cation currents, selectively blocked by arylsulfonamide compounds AqB007 (IC50 170 muM) and AqB011 (IC50 14 muM). Loop D-domain amino acids activate the channel for ion coductance (Kourghi et al. 2018). Water flux through AQP1s is inhibited by 1 - 10 mμM acetozolaminde (Gao et al. 2006). Aqp1 transports reactive oxygen and nitrogen species (RONS) which may induce oxidative stress in the cell interior. These RONS include both hydrophilic (H2O2 and OH) and hydrophobic (NO2 and NO) RONS (Yusupov et al. 2019). The position of the Arg-195 side chain shows a number of interactions for loop C (Dingwell et al. 2019). AQP1 play vital roles in cellular homeostasis at rest and during endurance running exercises (Rivera and Fahey 2019). AQP1 and AQP4 activities correlate with the severity of hydrocephalus induced by subarachnoid haemorrhage (Long et al. 2019). AQPs are related to osmoregulation and play a critical role in maturation, cryo-stability and motility activation in boar spermatozoa (Delgado-Bermúdez et al. 2019). In foetal kidney, AQP1 expression appeared in the apical and basolateral parts of cells, lining the proximal convoluted tubules and the descending limb of Henle's loop, then in the tubule pole of Bowman's capsule (Ráduly et al. 2019). Inhibition of aquaporin-1 prevents myocardial remodeling by blocking the transmembrane transport of hydrogen peroxide (Montiel et al. 2020). AQP1 Is up-regulated by hypoxia and leads to increased cell water permeability, motility, and migration in neuroblastoma (Huo et al. 2021). Aqp1 allows the transport of CO2 across membranes (Michenkova et al. 2021). Down-regulation of aquaporin-1 mediates a microglial phenotype switch affecting glioma growth (Hu et al. 2020). AQP1 expression is down-regulated following repeated exposure of UVB via MEK/ERK activation pathways, and this AQP1 reduction leads to changes of physiological functions in dermal fibroblasts (Kim et al. 2020). AQP1 and AQP7 are differentially regulated under hyperosmotic stress conditions, and AQP1 acts as an osmotic stress sensor and response factor (Aggeli et al. 2021). AQP1 plays a role in the pathogenesis of Wilms' tumor (Liu et al. 2023). Aquaporin-1 plays a role in cell proliferation, apoptosis, and pyroptosis of Wilms' tumor cells (Liu et al. 2024). AQP1 differentially orchestrates endothelial cell senescence (Shabanian et al. 2024). Aquaporin 1 aggravates lipopolysaccharide-induced macrophage polarization and pyroptosis (Wen and Ablimit 2024). Aqp1 transports cations such as K+ and Ca2+ (Nourmohammadi et al. 2024). AQP1 in the cytoplasm is a critical factor in breast cancer local invasion (Guo et al. 2023). A key gene encoding aquaporin 1 influences Wilms' tumor metastasis (Liu et al. 2023). Graphene quantum dots (GQDs) inhibit AQP1 water channels through the blockage of their openings (Du et al. 2024). Divalent cation blockers of AQP1, pH sensitivity of antagonists, and ion permeability of human AQP1 and 6 have been reported (Nourmohammadi et al. 2024). Optical monitoring with a lithium-sensitive photoswitchable probe in living cells independently demonstrated monovalent cation permeability of AQP1 channels (Nourmohammadi et al. 2024). Osmoregulation in response to salinity stress in the gills of the scalloped spiny lobster (Panulirus homarus) has been documented (Ran et al. 2024). AQP1 affects necroptosis by targeting RIPK1 in endothelial cells of atherosclerosis (Wang et al. 2025). |
Eukaryota | Metazoa, Chordata | Aquaporin 1 (AQP1) of Homo sapiens |
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1.A.8.8.10 | Water and urea transporting aquaporin (cockroach) (Herraiz et al., 2011). |
Eukaryota | Metazoa, Arthropoda | Aquaporin of Blatella germanica (G8YY04) |
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1.A.8.8.11 | Water channel, Aqp1; inhibited by HgCl2 and tetraethylammonium. Plays a role in water homeostasis during blood feeding and humidity adaptation of A. gambiae, a major mosquito vector of human malaria in Africa (Liu et al., 2011). |
Eukaryota | Metazoa, Arthropoda | Aqp1 of Anopheles gambiae (F2YNF6) |
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1.A.8.8.12 | Aquaporin, Aqp1 in the gall fly. Transports water but not glycerol or urea. Promotes freeze-tolerance (Philip et al., 2011). |
Eukaryota | Metazoa, Arthropoda | Aqp1 of Eurosta solidaginis (E4W5Y5) |
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1.A.8.8.13 | The Drosophila melanogaster integral protein, DRIP (Ishida et al., 2012). |
Eukaryota | Metazoa, Arthropoda | Aqp, DRIP of Drosophila melanogaster (Q9V5Z7) |
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1.A.8.8.14 | Lens fiber major intrinsic protein (MIP26) (MP26) | Eukaryota | Metazoa, Chordata | MIP26 of Rana pipiens |
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1.A.8.8.15 | Mercury-sensitive whitefly aquaporin-1 of the specialized filter chamber of the alimentary tract (Mathew et al. 2011). |
Eukaryota | Metazoa, Arthropoda | Aquaporin-1 of Bemisia tabaci |
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1.A.8.8.16 | Aquaporin-1 or Aquaporin1, Aqp1, of 258 aas and 6 TMSs. Three Aqp1 isoforms are differentially regluated by the function of the vasotocin (AVTR) and isotocin (ITR) receptors (Martos-Sitcha et al. 2015). Aqp1aa, one of two isoforms in teleosts, may play a role in spermatogenesis in Cynoglossus semilaevis (Guo et al. 2017). |
Eukaryota | Metazoa, Chordata | Aqp1 of Sparus aurata (Gilthead sea bream) |
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1.A.8.8.17 | Aquaporin-3, Aqp-3 of 271 aas. Transports water, glycerol, hydrogen peroxide and urea (Geadkaew et al. 2015). AQP3 induces the production of chemokines such as CCL24 and CCL22 through regulating the amount of cellular H2O2 in M2 polarized alveolar macrophages, implying a role of AQP3 in asthma (Ikezoe et al. 2016). |
Eukaryota | Metazoa, Platyhelminthes | Aqp3 of Opisthorchis viverrini (liver fluke) |
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1.A.8.8.18 | Aqp-x2 water channel in the luminal epithelium of urinary bladder cells and lungs. Responsive to Vasotocin (AVT) (Shibata et al. 2015). |
Eukaryota | Metazoa, Chordata | Aqp-x2 of Xenopus laevis |
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1.A.8.8.19 | Contractile vacuole aquaporin of 295 aas and 6 TMSs, Aqp. Shown to transport water, accounting for the high water permeability of the contractile vacuole (Nishihara et al. 2008). |
Eukaryota | Tubulinea | Aqp of Amoeba proteus (Amoeba) (Chaos diffluens) |
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1.A.8.8.2 | The lens fiber MIP aquaporin (Aqp0) of B. taurus (forms membrane junctions in vivo and double layered crystals in vitro that resemble the in vivo junctions). The water pore is closed in the in vitro structure (Gonen et al., 2004b). It interacts directly with the intracellular loop of connexin 45.6 via its C-terminal extension (Yu et al., 2005). Forms human cataract lens membranes (Buzhynskyy et al., 2007; Yang et al., 2011). A mutation that causes congenital dominant lens cataracts has been identified (Varadaraj et al. 2008). AqpO catalyzes Zn2+-modulated water permeability as a cooperative tetramer (Nemeth-Cahalan et al., 2007). It transports ascorbic acid (Nakazawa et al., 2011). The Detergent organization around solubilized aquaporin-0 using Small Angle X-ray Scattering has been reported (Berthaud et al., 2012). Aquaporin 0 (AQP0) in the eye lens is truncated by proteolytic cleavage during lens maturation. This truncated AQP0 is no longer a water channel (Berthaud et al. 2015). A mutation that causes congenital dominant lens cataracts has been identified (Varadaraj et al. 2008). Cataractogenesis in MIP mutants are probably caused by defects in MIP gene expression in mice (Takahashi et al. 2017). This may be caused by the ability of Aqp0 (as well as Aqp1 and Aqp5) to transport hydrogen peroxide (H2O2) which can cause cataracts (Varadaraj and Kumari 2020). An automated data processing and analysis pipeline for transmembrane proteins including Aqp0 in detergent solutions has been presented (Molodenskiy et al. 2020). EphA2 is required for normal Cx50 localization to the cell membrane, and conductance of lens fiber cells requires normal Eph-ephrin signaling and water channel (Aqp0) localization (Cheng et al. 2021). The local curvature of cellular membranes acts as a driving force for the targeting of membrane-associated proteins to specific membrane domains, as well as a sorting mechanism for transmembrane proteins, as demonstrated for Aqp0; AQP0 causes small negative curvature (Kluge et al. 2022). |
Eukaryota | Metazoa, Chordata | Major intrinsic protein (MIP or Aqp0) of Bos taurus |
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1.A.8.8.20 | Channel protein | Bacteria | Cyanobacteriota | Copper homeostasis protein (SmpX) of Synechococcus sp. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.8.8.21 | Aquaporin x5 of 273 aas and 6 TMSs, Aqp-x5. The sequence reveals a mercurial-sensitive cysteine and a putative phosphorylation motif site for protein kinase A at Ser-257 (Kubota et al. 2006). A swelling assay using Xenopus oocytes revealed that AQP-x5 facilitated water permeability. Expression of AQP-x5 mRNA was restricted to the skin, brain, lungs and testes. Immunofluorescence and immunoelectron microscopical studies using an anti-peptide antibody (ST-156) against the C-terminal region of the AQP-x5 protein revealed the presence of immunopositive cells in the skin, with the label predominately localized in the apical plasma membrane of the secretory cells of the small granular glands. These glands are unique both in being close to the epidermal layer of the skin and in containing mitochondria-rich cells with vacuolar H+-ATPase dispersed among its secretory cells. Results from immunohistochemical experiments on the mucous or seromucous glands of several other anurans verified this result (Kubota et al. 2006). |
Bacteria | Metazoa, Chordata | Aqp-x5 of Xenopus laevis (African clawed frog) |
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1.A.8.8.22 | Aqp-1A of 258 aas and 6 TMSs, DRIP1. Transports water but not glycerol or urea. Functions in water homeostasis in many tissues and stages of development (Lu et al. 2018). An aquaporin in the beet armyworm, Spodoptera exigua, (79% identical to the one in Chilo suppressalis, mediates cell shape change required for cellular immunity (Ahmed and Kim 2019). |
Eukaryota | Metazoa, Arthropoda | Aqp-1A of Chilo suppressalis (Asiatic rice borer moth) |
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1.A.8.8.23 | Aqp-2A of 269 aas and 6 TMSs, PRIP2. It transports water and urea but not glycerol or trehalose. It functions in water homeostasis in many tissues and stages of development (Lu et al. 2018). Its production in various tissues and stages of growth have been examined (Lu et al. 2021). |
Eukaryota | Metazoa, Arthropoda | Aqp-2A of Chilo suppressalis (Asiatic rice borer moth) |
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1.A.8.8.24 | Big brain-like protein of 309 aas and 6 probable TMSs, BibL1 (Lind et al. 2017). |
Eukaryota | Metazoa, Arthropoda | BibL1 of the euryhaline bay barnacle, Balanus improvisus (Darwin, 1854) (Amphibalanus improvisus) |
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1.A.8.8.25 | Aquaporin 1, AQP1, of 261 aas and 6 TMSs, which selectively transports water (Lind et al. 2017). |
Eukaryota | Metazoa, Arthropoda | AQP1 of the euryhaline bay barnacle Balanus improvisus (Darwin, 1854) (Amphibalanus improvisus) |
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1.A.8.8.26 | Aquaporin (Aqp) of 458 aas, 6 N-terminal TMSs and a 200 aa hydrophilic C-terminal domain. |
Eukaryota | Metazoa, Arthropoda | Aqp of Blomia tropicalis (mite) |
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1.A.8.8.27 | Aquaglyceroporin, Glp1, of 269 aas and 6 TMSs. Transports glycerol and water (Tsujimoto et al. 2017). |
Eukaryota | Metazoa, Arthropoda | Glp1 of Cimex lectularius (Bed bug) (Acanthia lectularia) |
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1.A.8.8.28 | Aquaporin-2, Aqp2, of 275 aas and 6 TMSs.It is subject to hyperosmotic stimulation in Chick Kidney (Sugiura et al. 2008). It is highly similar to the quail (Coturnix coturnix) ortholog which has been studied and shown to be a mercury-inhibited, vasotocin-sensitive water channel in the kidney (Yang et al. 2004). |
Eukaryota | Metazoa, Chordata | Aqp2 of Gallus gallus |
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1.A.8.8.29 | Aquaporin/glycerol transporter of 294 aas and 6 TMSs. Tandem duplication (TD) was the major mechanism of gene expansion in echinoderms and hemichordates, which, together with whole genome duplications (WGD) in the chordate lineage, continued to shape the genomic repertoires in craniates. Molecular phylogenies indicated that Aqp3-like and Aqp13-like channels were the probable stem subfamilies in craniates, with WGD generating Aqp9 and Aqp10 in gnathostomes but Aqp7 arising through TD in Osteichthyes (Yilmaz et al. 2020). |
Eukaryota | Metazoa, Hemichordata | Aqp of Saccoglossus kowalevskii (Acorn worm) |
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1.A.8.8.3 | The Big Brain, BIB aquaporin of 696 aas and 6 TMSs, transports ions by a channel mechanism involving E71 in TMS1) (Yool, 2007). BIB expressed in Xenopus oocytes is a monovalent cation channel modulated by tyrosine kinase signaling. BIB conductance shows voltage- and dose-dependent block by extracellular divalent cations Ca2+ and Ba2+ but not by Mg2+ in wild-type channels (Yanochko and Yool 2004). Site-directed mutagenesis of negatively charged glutamate (Glu274) and aspartate (Asp253) residues had no effect on divalent cation block, but mutation of Glu71 in the first TMS altered channel properties (Yanochko and Yool 2004). |
Eukaryota | Metazoa, Arthropoda | Big brain (BIB) of Drosophila melanogaster |
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1.A.8.8.30 | Aquaporin-A, AqpA of 249 aas and 6 TMSs. Aquaporins may not play major roles in adapting to longterm survival in brackish water or they be regulated by non-transcriptional mechanisms like post-translational modifications (Misyura et al. 2020). |
Eukaryota | Metazoa, Arthropoda | AqpA of Aedes aegypti (Yellowfever mosquito) (Culex aegypti) |
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1.A.8.8.31 | Aqp1 of 250 aas and 6 TMSs. Aqp1 localizes on the contractile vacuole complex in Paramecium multimicronucleatum (Ishida et al. 2021). |
Eukaryota | Ciliophora | Aqp1 of Paramecium multimicronucleatum |
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1.A.8.8.4 | Aqp6 aquaporin (also transports NO3- and other anions at acidic pH or in the presence of Hg2+) (Ikeda et al., 2002). AQP6 flicker rapidly between closed and open states. Two well conserved glycine residues: Gly-57 in TMS 2 and Gly-173 in TMS 5 reside at the contact point where the two helices cross. Mammalian orthologs of AQP6 have an asparagine residue (Asn-60) at the position corresponding to Gly-57 in Aqp6. Liu et al. 2005 showed that a single residue substitution (N60G in rat AQP6) eliminates anion permeability but increases water permeability. Chloride ions permeate through the pore corresponding to the central axis of the AQP6 homotetramer (Yamamoto et al. 2024). |
Eukaryota | Metazoa, Chordata | Aqp6 of Homo sapiens |
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1.A.8.8.5 |
Aquaporin-4 (AQP4) is the major water channel in the central nervous system and plays an important role in the brain's water balance, including edema formation and clearance. There are 6 splice variants; the shorter ones assemble into functional, tetrameric square arrays; the longer is palmitoylated on N-terminal cysteyl residues) (Suzuki et al., 2008). The longest, Aqp4e, has a novel N-terminal domain and forms a water channel in the plasma membrane although various shorter variants don't (Moe et al., 2008). AQP4, like AQP0 (1.A.8.8.2), forms water channels but also forms adhesive junctions (Engel et al., 2008) (causes cytotoxic brain swelling in mice (Yang et al., 2008)) Mice lacking Aqp4 have impaired olfactions (Lu et al., 2008). Aqp4 is down regulated in skeletal muscle in muscular dystrophy (Au et al. 2008). The crystal structure is known to 2.8 Å resolution (Tani et al., 2009). The structure reveals 8 water molecules in each of the four channels, supporting a hydrogen-bond isolation mechanism and explains its fast and selective water conduction and proton exclusion (Tani et al., 2009; Cui and Bastien, 2011). It is an important antigen in Neuromyelitis optica (NMO) patients (Kalluri et al., 2011). A connection has been made between AQP4-mediated fluid accumulation and post traumatic syringomyelia (Hemley et al. 2013). AQP4 has increased water permeability at low pH, and His95 is the pH-dependent gate (Kaptan et al. 2015). Also transports NH3 but not NH4+ (Assentoft et al. 2016). Cerebellar damage following status epilepticus involves down regulation of AQP4 expression (Tang et al. 2017). SUR1-TRPM4 and AQP4 form a complex to increase bulk water influx during astrocyte swelling (Stokum et al. 2017). A mutation, S111T, causes intellectual disability, hearing loss, and progressive gait dysfunction (Berland et al. 2018). As in humans, the chicken ortholog, Aqp4, is found in brain > kidney > stomach (Ramírez-Lorca et al. 2006). A Molecular Dynamics Investigation on Human AQP4 has been published (Marracino et al. 2018). AQP1 and AQP4 activities correlate with the severity of hydrocephalus induced by subarachnoid haemorrhage (Long et al. 2019). Di-lysine motif-like sequences formed by deleting the C-terminal domain of aquaporin-4 prevent its trafficking to the plasma membrane (Chau et al. 2021). Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation (Del Puerto et al. 2021). AQP4 expression is upregulated in cells exposed to dexamethasone, and SUMOylation [Small ubiquitin-like modifiers (SUMOs)] may participate in this regulation (Zhang et al. 2020). Simultaneous calmodulin binding to the N- and C-terminal cytoplasmic domains of aquaporin 4 has been demonstrated (Ishida et al. 2021). Aqp-4 plays a role in secondary pathological processes (spinal cord edema, glial scar formation, and inflammatory response) after spinal cord injury, SCI. Loss of AQP-4 is associated with reduced spinal edema and improved prognosis after SCI in mice, and downregulation of AQP-4 reduces glial scar formation and the inflammatory response after SCI (Pan et al. 2022). AQP4 contributes to the migration and proliferation of gliomas, and to their resistance to therapy. In glioma cell cultures, in both subcutaneous and orthotopic gliomas in rats, and in glioma tumours in patients, that transmembrane water-efflux rate is a sensitive biomarker of AQP4 expression (Jia et al. 2022). Aquaporin 4 is required for T cell receptor-mediated lymphocyte activation (Nicosia et al. 2023). Peripheral lung infections influence the blood brain barrier (BBB) water exchange, which appears to be mediated by endothelial dysfunction and is associated with an increase in perivascular AQP4 (Ohene et al. 2023). Trifluoperazine reduces apoptosis and inflammatory responses in traumatic brain injury by preventing the accumulation of Aquaporin4 on the surface of brain cells (Xing et al. 2023). Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke (Stokum et al. 2023). Aquaporin-4 expression and modulation may be important in a rat model of post-traumatic syringomyelia (Berliner et al. 2023). The Aqp4 water channel may be a drug target for Alzheimer's Disease (Silverglate et al. 2023). A series of 2,4,5-trisubstituted oxazoles 3a-j were synthesized by a Lewis acid mediated reaction of aroylmethylidene malonates with nitriles. In silico studies conducted using the protein data bank (PDB) structure 3gd8 for AQP4 revealed that compound 3a would serve as a suitable candidate to inhibit AQP4 in human lung cells (NCI-H460). In vitro studies demonstrated that compound 3a could effectively inhibit AQP4 and inflammatory cytokines in lung cells, and hence it may be considered as a viable drug candidate for the treatment of various lung diseases (Meenakshi et al. 2023). The effect of AQP4 and its palmitoylation on the permeability of exogenous reactive oxygen species has been considered (Cao et al. 2023). ORI-TRN-002 exhibits superior solubility and overcomes free fraction limitations compared to other reported AQP4 inhibitors, suggesting its potential as a promising anti-edema therapy for treating cerebral edema (Thormann et al. 2024). New biomarkers, such as aquaporin 4 have led to the identification of antigen-specific immune-mediated myelopathies and approved therapies to prevent disease progression (Levy 2024). AQP4 is upregulated in schizophrenia, and its inhibition attenuates MK-801-induced schizophrenia-like behaviors in mice (Nie et al. 2024). The roles of AQP4 expression and redistribution in the progression and treatment of glioma have been reviewed (Lan et al. 2024). AQP4 is expressed in the endfeet membranes of subpial and perivascular astrocytes and in the ependymal cells that line the ventricular system. The sporadic appearance of obstructive congenital hydrocephalus (OCHC) has been observed in the offspring of AQP4-/- mice (KO) due to stenosis of Silvio's aqueduct. The impact of aquaporin-4 and CD11c in microglia on the development of ependymal cells in the aqueduct has been studied (Mayo et al. 2024). |
Eukaryota | Metazoa, Chordata | AQP4 of Homo sapiens (P55087) |
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1.A.8.8.6 | Aqp1 water channel of the sleeping chironomid (functions in water removal during anhydrobiosis, Kikawada et al., 2008). | Eukaryota | Metazoa, Arthropoda | Aqp1 of Polypedilum vanderplanki |
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1.A.8.8.7 | Aqp2 water channel of the sleeping chironomid (functions in water homeostasis during anhydrobiosis (Kikawada et al., 2008). |
Eukaryota | Metazoa, Arthropoda | Aqp2 of Polypedilum vanderplanki (A5A7P0) |
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1.A.8.8.8 | Vasopressin-sensitive aquaporin-2 (Aqp2) in the apical membrane of the renal collecting duct (Fenton et al., 2008). Controls cell volume and thereby influences cell proliferation (Di Giusto et al. 2012). It plays a key role in concentrating urine. Water reabsorption is regulated by AQP2 trafficking between intracellular storage vesicles and the apical membrane. This process is tightly controlled by the pituitary hormone arginine vasopressin, and defective trafficking results in nephrogenic diabetes insipidus (NDI). The crystal structure of Aqp2 has been solved to 2.75 Å (Frick et al. 2014). In terrestrial vertebrates, AQP2 function is generally regulated by arginine-vasopressin to accomplish key functions in osmoregulation such as the maintenance of body water homeostasis by a cyclic AMP-independent mechanism (Olesen and Fenton 2017; Martos-Sitcha et al. 2015). AQP2 is expressed in the anterior vaginal wall and fibroblasts, and regulates the expression level of collagen I/III i, suggesting that AQP2 is associated with the pathogenesis of stress urinary incontinence through collagen metabolism during ECM remodeling (Zhang et al. 2017). As in humans, the chicken ortholog, Aqp2, is found only in the kidney (Ramírez-Lorca et al. 2006). AQP2 is critical in regulating urine concentrating ability. The expression and function of AQP2 are regulated by a series of transcriptional factors and post-transcriptional phosphorylation, ubiquitination, and glycosylation (He and Yang 2019). Mutation or functional deficiency of AQP2 leads to severe nephrogenic diabetes insipidus, and inhibition of various aquaporins leads to many water-related diseases such as, edema, cardiac arrest, and stroke. Maroli et al. 2019 reported on the molecular mechanisms of mycotoxin (citrinin, ochratoxin-A, and T-2 mycotoxin) inhibition of AQP2 and arginine vasopressin receptor 2 (AVPR2). Aquaporin-2 mutations cause Nephrogenic diabetes insipidus (Li et al. 2021). Meniere's disease is affected by dexamethasone which is a direct modulator of AQP2. The molecular mechanisms involved in dexamethasone binding to and its regulatory action upon AQP2 function have been described (Mom et al. 2022). Interaction of cortisol with aquaporin-2 modulates its water permeability (Mom et al. 2023). In the kidney collecting duct, arginine vasopressin-dependent trafficking of AQP2 fine-tunes reabsorption of water from pre-urine, allowing precise regulation of the final urine volume. Point mutations in the gene for AQP2 disturbs this process and leads to nephrogenic diabetes insipidus (NDI), wherein patients void large volumes of hypo-osmotic urine. In recessive NDI, mutants of AQP2 are retained in the endoplasmic reticulum due to misfolding. The structures allow interpretation of these results (Hagströmer et al. 2023). Differential regulation of autophagy on urine-concentrating capability occurs through modulating renal AQP2 expression (Xu et al. 2023). Aqp2 interacts with Ezrin (see 8.A.25.1.1 for a detailed description). In vivo treatment with calcilytic of Ca2+-sensitive receptors (CaSR ) knock-in mice ameliorates the renal phenotype reversing downregulation of the vasopressin-AQP2 pathway (Ranieri et al. 2024). The posttranslational modification ubiquitylation is a key regulator of AQP2 abundance and plasma membrane localization. Cullin-RING E3 ligases play a vital role in mediating some of the effects of vasopressin to increase AQP2 abundance and plasma membrane accumulation (Murali et al. 2024). There is a correlation between chronic subdural hematoma volume and serum AQP2 concentration, highlighting aquaporins' potential as clinical biomarkers (Czyżewski et al. 2024). |
Eukaryota | Metazoa, Chordata | Aqp2 of Homo sapiens (P41181) |
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1.A.8.8.9 | Aquaporin 5 (x-ray structure at 2.0 Å resolution (PDB# 3D9S) is available) (Horsefield et al., 2008). Aqp5 is a marker for proliferation and migration of human breast cancer cells (Jung et al., 2011). Plays a role in chronic obstructive pulmonary diseases (COPD) (Zhao et al. 2014). Its expression is regulated by androgens (Pust et al. 2015). As in humans, the chicken ortholog, Aqp5, is found in the intestine, the jejunum, ileum and colon (Ramírez-Lorca et al. 2006). Proteomic analyses of the ocular lens revealed palmitoylation (Wang and Schey 2018). Aquaporin 5 expression correlates with tumor multiplicity and vascular invasion in hepatocellular carcinoma (Vireak et al. 2019). The ability of Aqp5 (as well as Aqp0 and Aqp1) to transport hydrogen peroxide (H2O2) may cause cataracts in the eye (Varadaraj and Kumari 2020). AQP3 and AQP5 play important but different roles in spermatogenesis and sperm maturation in dogs (Mirabella et al. 2021). The up-regulation of AQP1, AQP3 and AQP5 in skin during summer season indicates roles in thermoregulation (Debbarma et al. 2020). Aqp5 interacts with TRPV4 (see 1.A.4.2.5 for the rat ortholog) (Kemény and Ducza 2022). AQP5 facilitates osmotically driven water flux across biological membranes as well as the movement of hydrogen peroxide and CO2. Various mechanisms dynamically regulate AQP5 expression, trafficking, and function. Besides fulfilling its primary water permeability function, AQP5 regulates downstream effectors (D'Agostino et al. 2023). Modulation of membrane trafficking of AQP5 in the lens in response to changes in zonular tension is mediated by TRPV1 (Petrova et al. 2023).Methazolamide reduces AQP5 mRNA expression and immune cell migration, and may be a drug for sepsis therapy (Rump et al. 2024). Aqp5 interacts with Ezrin (see 8.A.25.1.1). |
Eukaryota | Metazoa, Chordata | Aquaporin 5 of Homo sapiens (P55064) |
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1.A.8.9.1 | Aquaporin 3. 95% identical to the human orthologue. Poorly permeable to water, but more permeable to glycerol and arsenic trioxide (Palmgren et al. 2017). It is expressed in the plasma membrane of basal epidermal cells in the skin; loss of function prevents skin tumorigenesis and epidermal cell proliferation (Hara-Chikuma and Verkman, 2008). The human orthologue also transports both water and glycerol and is the predominant AQP in skin (Jungersted et al. 2013). It's function is necessary for normal proliferation of colon cancer cells due to glycerol uptake (Li et al. 2016). Aqp3 is implicated in cancer progression to the metastatic state as its function promotes cell migration and cell shape plasticity. Its synthesis is regulated by the AhR (aryl hydrocarbon (pollutant) receptor or dioxin receptor), a transcription factor triggered by environmental pollutants (Bui et al. 2016). Trefoil factor (TFF) peptides increase cell water permeability and induce prodcution of Aqp3 (Marchbank and Playford 2018). Although AQP3 and other similar transmembrane proteins do not themselves transport drugs, changes in their expression levels can cause changes in cell membrane fluidity, thus affecting drug absorption rates (Ikarashi et al. 2019). AQP3 levels are elevated in human endometrioid carcinoma (Watanabe et al. 2020). AQP3 and AQP5 play important roles in spermatogenesis and sperm maturation in dogs (Mirabella et al. 2021). AQP-1, 3 and 8 levels in amniotic fluid were measured in patients suffering from polyhydramnios. They were compared to the levels observed in control subjects, and their relationship with maternal factors and neonatal issues was analyzed. AQP-1, 3, 8 levels physiologically fluctuated, AQP-1 levels were the lowest and AQP-3 the highest, with a decrease at the end of pregnancy (Guibourdenche et al. 2021). The human ortholog, Aqp3 (Q92482) is 95% identical. It transports water, glycerol and urea, and is the blood group antigen, GIL (Roudier et al. 2002). Intra-endolymphatic sac steroids have regulatory effects on inner ear AQP-3 expression via the vestibular aqueduct and modulate the homeostasis of endolymphatic fluids (Kitahara et al. 2003).
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Eukaryota | Metazoa, Chordata | Aquaporin 3 of Rattus norvegicus (P47862) |
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1.A.8.9.10 | Aqp9 or Aqp-h9 of 294 aas. Takes up glycerol as well as water, and thereby contributes to freeze tolerance (Hirota et al. 2015). An almost identical orthologue, HC-9 in Dryophytes chrysoscelis (gray treefrog), similarly facilitates glycerol permeability. Both the transcriptional and translational levels of HC-9 change in response to thermal challenges, with a unique increase in liver during freezing and thawing (Stogsdill et al. 2017). |
Eukaryota | Metazoa, Chordata | Aqp9 of Hyla japonica |
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1.A.8.9.11 | Aqp1 of 304 aas and 6 TMSs; the most abundant transmembrane protein in the tegument of Schistosoma mansoni. This protein is expressed in all developmental stages and seems to be essential in parasite survival since it plays a crucial role in osmoregulation, nutrient transport and drug uptake (Figueiredo et al. 2014). |
Eukaryota | Metazoa, Platyhelminthes | Aqp1 of Schistosoma mansoni (Blood fluke) |
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1.A.8.9.12 | Basolateral Aqp3 of 292 aas and 6 TMSs in the frog urinary bladder (Shibata et al. 2015). |
Eukaryota | Metazoa, Chordata | Aqp3 of Xenopus laevis |
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1.A.8.9.13 | Aquaglycerolporin, Aqp (high permeability to ammonium, methylamine, glycerol and water) (Beitz et al., 2004) NH4+/NH3+CH3/glycerol/water transporter (Zeuthen et al., 2006). |
Eukaryota | Apicomplexa | Aqp of Plasmodium falciparum (CAC88373) |
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1.A.8.9.14 | Glycerolaquaporin 9, Aqp9 of 295 aas and 6 TMSs. Transports water, glycerol and arsenic trioxide, As2O3 (Palmgren et al. 2017) as well as urea and lactic acid (but not lactate) (Geistlinger et al. 2022). Primary APL cells express AQP9 significantly (2-3 logs) higher than other acute myeloid leukemia cells (AMLs), explaining their exquisite As2O3 sensitivity (Leung et al. 2007). AQP-7 and AQP-9-mediated glycerol transport in tanycyte cells may be under hormonal control to use glycerol as an energy source during the mouse estrus cycle (Yaba et al. 2017). It transports multiple neutral and ionic arsenic species including arsenic trioxide, monomethylarsenous acid (MAs(III)) and dimethylarsenic acid (DMA(V)). It also transports clinically relevant selenium species including monomethylselenic acid (MSeA), especially at acidic pH. FCCP, valinomycin and nigericin do not significantly inhibit MSeA uptake, but AQP9 also transport ionic selenite and lactate, with low efficiency compared with MSeA uptake. Selenite and lactate uptake is pH dependent and inhibited by FCCP and nigericin but not valinomycin. The selenite and lactate uptake via AQP9 can be inhibited by different lactate analogs. AQP9 transport of MSeA, selenite and lactate is inhibited by an AQP9 inhibitor, phloretin, and the AQP9 substrate, arsenite (As(III)) (Geng et al. 2017). The host aquaporin-9 is required for efficient Plasmodium falciparum sporozoite entry into human hepatocytes (Amanzougaghene et al. 2021). RG100204 is a direct blocker of the AQP9 channel (Florio et al. 2022). |
Eukaryota | Metazoa, Chordata | Aqp9 of Homo sapiens |
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1.A.8.9.15 | Aquaporin 9, Aqp9, small solute channel 1 of 296 aas and 6 TMSs (Wang and Ye 2016). |
Eukaryota | Metazoa, Platyhelminthes | Aqp9 of Echinococcus granulosus (Hydatid tapeworm) |
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1.A.8.9.16 | Water/glycerol aquaglyceroporin 2, AQP2, of 294 aas and 6 TMSs (Lind et al. 2017). |
Eukaryota | Metazoa, Arthropoda | AQP2 of the euryhaline bay barnacle, Balanus improvisus (Darwin, 1854) (Amphibalanus improvisus) |
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1.A.8.9.17 | Glycerol-aquaporin of 332 aas and 6 TMSs (Stavang et al. 2015). |
Eukaryota | Metazoa, Arthropoda | Aqp of the salmon leach, Lepeophtheirus salmonis |
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1.A.8.9.18 | Aquaporin of 341 aas and 7 TMSs (Ben Amira et al. 2018). |
Eukaryota | Fungi, Ascomycota | Aqp of Hypocrea atroviridis (Trichoderma atroviride) |
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1.A.8.9.19 | AQP2 (AQP9) of 312 aas and 6 TMSs; transports water, glycerol and urea as well as the drugs, melarsoprol and pentamidine (Schmidt et al. 2018). CCCP and gramicidin but not nigericin inhibit Trypanosoma brucei Aquaglyceroporins Aqp2 and Aqp3 at neutral pH (Petersen and Beitz 2020). |
Eukaryota | Euglenozoa | AQP2 of Trypanosoma brucei |
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1.A.8.9.2 |
Aquaporin-9 (Aqp9) (permeable to glycerol, urea, polyols, carbamides, purines, pyrmidines, nucleosides, monocarboxylates, pentavalent methylated arsenicals and the arsenic chemotherapeutic drug, trisenox (McDermott et al., 2009). It is poorly permeable to water and not permeable to β-hydroxybutyrate (Carbrey et al., 2003). (Regulated by CFTR and NHERF1 in response to cyclic AMP (Pietrement et al., 2008)) The 7 Å projection structure and a homology model revealed that pore-lining residues and the hydrophobic edge of the tripathic pore of GlpF (1.A.8.1.1) provide the basis for broad substrate specificity (Viadiu et al., 2007). It is important for urea transport in mouse hepatocytes (Jelen et al. 2012). Activation of the PPARα transcription factor results in reduction in the abundance of AQP9 in periportal hepatocytes, but its activation in the fed state directs glycerol into glycerolipid synthesis rather than into de novo synthesis of glucose (Lebeck et al. 2015). Azacytidine up-regulates AQP9 and enhances arsenic trioxide (As2O3)-mediated cytotoxicity in acute myeloid leukemia (AML) (Chau et al. 2015). Human Aqp9 transports hydrogen peroxide (HOOH) (Watanabe et al. 2016) and plays a role in certain types of cancer (Zheng et al. 2020). Human aquaporin 9 regulates Leydig cell steroidogenesis in diabetes (Kannan et al. 2022). |
Eukaryota | Metazoa, Chordata | Aqp9 of Rattus norvegicus (P56627) |
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1.A.8.9.20 | Aquaporin of 274 aas and 6 TMSs. See Zhou et al. 2018 for its identification. |
Eukaryota | Metazoa, Arthropoda | Aqp of Blomia tropicalis (mite) |
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1.A.8.9.21 | Aquaporin 3, Aqp3, of 304 aas and 6 TMSs. CCCP and gramicidin but not nigericin inhibit Trypanosoma brucei Aquaglyceroporins Aqp2 and Aqp3 at neutral pH (Petersen and Beitz 2020). |
Eukaryota | Euglenozoa | Aqp3 of Trypanosoma brucei |
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1.A.8.9.22 | Aquaporin-3-like protein, Aqp10b, of 374 aas and 6 TMSs (Santos et al. 2004). |
Eukaryota | Metazoa, Chordata | Aqp10b of Sparus aurata (gilthead seabream) |
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1.A.8.9.23 | Aqp3 of 294 aas and 6 TMSs (Mashini et al. 2022). |
Eukaryota | Metazoa, Cnidaria | Aqp3 of Exaiptasia diaphana |
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1.A.8.9.24 | Aqp3 of 292 aas and 6 TMSs. It is a water channel required to promote glycerol permeability and water transport across cell membranes (Roudier et al. 2002, Gotfryd et al. 2018). It acts as a glycerol transporter in skin and plays an important role in regulating the stratum corneum and epidermal glycerol content. It is involved in skin hydration, wound healing, and tumorigenesis, and it provides the kidney medullary collecting duct with high permeability to water, thereby permitting water to move in the direction of an osmotic gradient. It is slightly permeable to urea and H2O2, and may function as a water and urea exit mechanism in antidiuresis in collecting duct cells. It may play an important role in gastrointestinal tract water transport and in glycerol metabolism. Breast cancer cell invasion and metastasis are related to AQP3, which is the transmembrane transport channel for H2O2 molecules (Zhong et al. 2022). AQP3 plays a key role in cancer and metastasis. RoT inhibits human AQP3 activity with an IC50 in the micromolar range (22.8 ± 5.8 µM for water and 6.7 ± 3.0 µM for glycerol permeability inhibition). RoT blocks AQP3-glycerol permeation by establishing strong and stable interactions at the extracellular region of AQP3 pores (Paccetti-Alves et al. 2023). AQP3-mediated activation of the AMPK/SIRT1 signaling pathway curtails gallstone formation in mice by inhibiting inflammatory injury of gallbladder mucosal epithelial cells (Wang et al. 2023). The main subtype expressed in the epidermis and dermis is AQP3. AQPs exert certain physiological functions in the skin, such as the maintenance of normal shape, the regulation of body temperature, moisturization and hydration, anti-aging, damage repair and antigen presentation. The abnormal expression of AQPs in skin cells can lead to a variety of skin diseases (Liu et al. 2023). AQP3 promotes the invasion and metastasis in cervical cancer by regulating NOX4-derived H2O2 activation of the Syk/PI3K/Akt signaling axis. Aquaglyceroporin AQP3 is expressed in the mammalian lens (Petrova et al. 2024). Decreased AQP3 expression is associated with skin dryness, skin aging, psoriasis, and delayed wound healing (Filatov et al. 2024). The AQP3 gene is expressed in the mammalian lens (Petrova et al. 2024). |
Eukaryota | Metazoa, Chordata | Aqp3 of Homo sapiens |
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1.A.8.9.3 | Major aquaglyceroporin, LmAQP1: transports water, glycerol, methylglyoxal, trivalent metalloids such as arsenite and antimonite, dihydroxyacetone and sugar alcohols. Also takes up the activated form or the drug, pentostam. It localizes to the flagellum of the Leishmania promastigotes and is used to regulate volume in response to hypoosmotic stress; it functions in osmotaxis (Figarella et al., 2005; Gourbal et al, 2004). The first line treatment for cutaneous leishmaniasis is pentavalent antimony such as sodium stibogluconate (pentostam) and meglumine antimonite (glucantime), and both compounds are transported by LmAQP1 (Eslami et al. 2020). The mutation G133D in the Leishmania guyanensis AQP1 is highly destabilizing (Tunes et al. 2021). |
Eukaryota | Euglenozoa | Aqp1 of Leishmania major (Q6Q1Q6) |
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1.A.8.9.4 | Aquaporin 1 (permeable to water, glycerol, dihydroxyacetone and urea) (Uzcategui et al., 2004) |
Eukaryota | Euglenozoa | Aqp1 of Trypanosoma brucei (Q6ZXT4) |
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1.A.8.9.5 | Aquaporin 10 of 301 aas and 6 TMSs. Cell- and tissue-specific expression of AQP-0, AQP-3, and AQP-10 in the testis, efferent ducts, and epididymis has been demonstrated (Hermo et al. 2019). It is also present in keratinocytes and the stratum corneum (Jungersted et al. 2013). |
Eukaryota | Metazoa, Chordata | Aqp10 of Homo sapiens |
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1.A.8.9.6 | Glycerol/water/urea/arsenic trioxide-transporting channel protein, aqaporin 7 or Aqp7, but water is a poor substrate (Palmgren et al. 2017). Present in adipose tissue where it allows glycerol efflux. Defects result in increased accumulation of triglycerides, obesity and adult onset (type 2) diabetes (Lebeck 2014). It may be a drug target for anti-type 2 diabetes (Méndez-Giménez et al. 2018). AQP-7- and AQP-9-mediated glycerol transport in tanycyte cells may be under hormonal control to use glycerol as an energy source during the mouse estrus cycle (Yaba et al. 2017). It may also influence whole body energy metabolism (Iena and Lebeck 2018) including in the kidney (Schlosser et al. 2023). Aquaporin-7-mediated glycerol permeability is linked to human sperm motility in asthenozoospermia and during sperm capacitation (Ribeiro et al. 2023). AQP7 is also involved in the regulation of lipid synthesis, gluconeogenesis, and energy homeostasis, and it is intimately linked to a variety of diseases, such as obesity, type 2 diabetes mellitus, cardiovascular diseases, cancer, and inflammatory bowel disease (Liu et al. 2024). |
Eukaryota | Metazoa, Chordata | Aqp7 of Homo sapiens |
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1.A.8.9.7 | Glycerol facilitator, Yf1054c (70.5 kDa protein) (Oliveira et al., 2003) | Eukaryota | Fungi, Ascomycota | Yf1054c of Saccharomyces cerevisiae (P43549) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.8.9.8 | Glycerol uptake facilitator of 393 aas |
Eukaryota | Fungi, Ascomycota | Glycerol transporter of Cordyceps militaris (Caterpillar fungus) |
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1.A.8.9.9 | Aquaporin/glycerol facilitator of 294 aas and 6 TMSs. May play a role in freeze tolerance (Hirota et al. 2015). |
Eukaryota | Metazoa, Chordata | Aqp-9 of Xenopus tropicalis |
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1.A.81.1.1 | Low affinity Ca2+ influx system, Fig1p (Factor induced gene 1) (Muller et al., 2003; Ren et al., 2006) (298 aas; 4 TMSs). Involved in low affinity Ca2 influx during mating; required for membrane fusion during mating (Muller et al. 2003). |
Eukaryota | Fungi, Ascomycota | Fig1p of Saccharomyces cerevisiae (P38224) |
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1.A.81.2.1 | Low affinity Ca2+ channel of 4 putative TMSs, Fig1. Localizes to the membrane destined for fusion during mating (Yang et al. 2011). Facilitates Ca2 +entry in mating cells in preparation for cell fusion (Yang et al., 2011). |
Eukaryota | Fungi, Ascomycota | Fig1p of Candida albicans (Q59WR6) |
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1.A.81.3.1 | Low affinity Ca2+ influx (LACS) channel of the white head blight fungus; SUR7 superfamily. Required for normal growth and sexual development (Cavinder and Trail 2012). |
Eukaryota | Fungi, Ascomycota | Fig1 of Gibberella zeae (Fusarium graminearum (pseudograminearum)) |
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1.A.81.4.1 | Fig1 protein (317aas; 4TMSs). Essential for fruiting body formation and ascus development (Cavinder and Trail 2012). Predicted to be a low affinity Ca2+ transporter. Plays a role in fusion of asexual spores, and its absence yields calcium-dependent lysis. It may regulate aspects of membrane merger and repair during cell fusion (Palma-Guerrero et al. 2015). |
Eukaryota | Fungi, Ascomycota | Fig1 of Neurospora crassa (A7UX97) |
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1.A.81.4.2 | Uncharacterized protein of 278 aas and 4 TMSs in a 1 + 3 TMS arrangement. |
Eukaryota | Fungi, Ascomycota | UP of Botrytis tulipae |
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1.A.82.1.1 | Mechanotransduction channel complex of cochlear hair cells TMHS/LHFPL5 is encoded by the Lhfpl5 gene. The complex contains several proteins: the tetraspan membrane protein of hair cell stereocilia, (TMHS protein) or Lipoma HMGIC fusion partner-like 5 protein (LHFPL5) (Fettiplace 2016), the Protocadherin-15 protein, PCDH15, and the Tmc1 and Tmc2 proteins (TC# 1.A.17) (Xiong et al. 2012). TMHS and PCDH15 interact directly with Tmc1 and Tmc2, and these interactions are required for mechanotransduction (Maeda et al. 2014; Beurg et al. 2015). A primary function of Tmc1 may be calcium transport (Beurg et al. 2015). Hair cells express two molecularly and functionally distinct mechanotransduction channels with different subcellular distributions. One is activated by sound and is responsible for sensory transduction. This sensory transduction channel is expressed in hair cell stereocilia, and its activity is affected by mutations in the genes encoding the transmembrane proteins TMHS (this family), TMIE (TC family 8.A.116), TMC1 and TMC2 (family 1.A.17.4) (Wu et al. 2016). Thus, these 4 proteins may all be parts of a single channel complex. The other channel is the Piezo2 channel (TC# 1.A.75.1.2). TMHS is 68% identical to the human LHFPL3 protein (Q86UP9), and 62% identical to the human LHFPL4 protein (Q7Z7J7). The structure of protocadherin 15 with the tetraspan, LHFP5, has been determined (Ge et al. 2018). Deafness mutation D572N of TMC1 destabilizes TMC1 expression by disrupting LHFPL5 binding (Yu et al. 2020). |
Eukaryota | Metazoa, Chordata | The mechanotransduction channel complex of Homo sapiens: |
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1.A.82.1.2 | Lipoma HMGIC fusion partner-like 2 protein of 220 aas and 4 TMSs. The Human ortholog has UniProt acc # Q6ZUX7 with 228 aas and 85% identity with the mouse protein. |
Eukaryota | Metazoa, Chordata | Lipoma HMGIC fusion partner-like 2 protein of Mus musculus (Q8BGA2) |
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1.A.82.1.3 | Lipoma HMGIC fusion partner-like 2 protein, LHPL2 |
Eukaryota | Metazoa, Arthropoda | LHPL2 of Lepeophtheirus salmonis (salmon louse) |
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1.A.82.1.4 | Hypothetical protein of 299 aas |
Eukaryota | Metazoa, Arthropoda | HP of Daphnia pulex |
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1.A.82.1.5 | Uncharacterized protein of 218 aas and 4 TMSs. |
Eukaryota | Metazoa, Arthropoda | UP of Capitella teleta (Polychaete worm) |
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1.A.82.1.6 | The Lipoma HMGIC fusion partner, LHFP of 200 aas and 4 TMSs. Acts as a translocation partner of HMGIC in a lipoma (Petit et al. 1999). |
Eukaryota | Metazoa, Chordata | LHFP of Homo sapiens |
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1.A.82.1.7 | Tetraspan protein LHFPL4 or GARLH4 of 247 aas and 4 TMSs. It is a synapse-specific tetraspanin essential for inhibitory synapse function because it promotes cell-type specific targeting and clustering of synaptic GABA recpetors (Davenport et al. 2017; Han et al. 2020). |
Eukaryota | Metazoa, Chordata | LHFPL4 of Homo sapiens |
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1.A.82.1.8 | Uncharacterized protein of 618 aas and possibly 10 - 11 TMSs in a 1 + 2 + 1 + 1 +3 + 2 or 3 TMS arrangement. The N-terminal domain shows sequence similarity to members of TC# 1.A.82 while a central part shows similarity to members of TC# 9.B.422. |
Eukaryota | Metazoa, Rotifera | UP of Brachionus calyciflorus |
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1.A.83.1.1 | Viroporin VP2 |
Viruses | Polyomaviridae | VP2 of SV40 virus |
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1.A.83.1.2 | SV40 VP4 viroporin protein of 125 aas and 1 TMS (Raghava et al. 2011). It forms Ca2+-selective toroidal pores to disrupt membranes for viral particle release (Raghava et al. 2013; Scott and Griffin 2015). |
Viruses | Polyomaviridae | VP4 of Simian Virus 40 (SV40) |
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1.A.83.1.3 | VP2 protein of 240 aas and 1 TMS. |
Viruses | Shotokuvirae, Cossaviricota | VP2 of Pan troglodytes verus polyomavirus 1a |
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1.A.83.1.4 | VP3 protein of 190 aas and 1 TMS |
Shotokuvirae, Cossaviricota | VP3 of Chimpanzee polyomavirus |
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1.A.83.1.5 | The structure of the polyomavirus internal protein including a synthetic fragment of 18 aas in which the C-terminal sequence is derived from Vp2 of 319 aas and a 283 aa fragment of the major capsid protein Vp1, which has a full length of 384 aas, is known (1CN3), providing insight into their involvement in viral entry (Chen et al. 1998). The fragments of Vp1 and Vp2, present in this complex, are derived by proteolysis from two large full length proteins, Vp1 and Vp2 as noted above. These full length proteins are included here under TC# 1.A.83.1.5. There are multiple structures reported in PDB of the Vp1 protein: 1CN3, 1SID, 1SIE, 1VPN, 1VPS, 5CPZ, 5CQ0. |
Shotokuvirae, Cossaviricota | Vp2 of polyomavirus |
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1.A.83.1.6 | Minor capsid protein VP2/VP3 complex. Isoforms VP2 and VP3 are structural proteins that reside within the core of the capsid surrounded by 72 VP1 pentamers. They participate in host cell receptor binding together with VP1, the major capsid protein. Following virus endocytosis and trafficking to the endoplasmic reticulum, VP2 and VP3 form oligomers and integrate into the endoplasmic reticulum membrane. Heterooligomer VP2-VP3 may create a viroporin for transporting the viral genome across the ER membrane to the cytoplasm. Nuclear entry of the viral DNA involves the selective exposure and importin recognition of a VP2 or Vp3 nuclear localization signal (shared C-terminus). hey play a role in virion assembly within the nucleus, in particular through a DNA-binding domain located in the C-terminal region. N-terminal myristoylation suggests a scaffold function for virion assembly. |
Viruses | Shotokuvirae, Cossaviricota | VP2/VP3 of Budgerigar fledgling disease virus (BFPyV) (Aves polyomavirus 1) |
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1.A.84.1.1 | The human calcium homeostasis modulator protein 1, CALHM1 or FAM16C of 346 aas and 5 TMSs (Dreses-Werringloer et al. 2008). The P86L polymorphism increases Abeta levels and may influence Alzheimer's disease risk by interfering with CALHM1-mediated Ca2+ permeability (Dreses-Werringloer et al. 2008). The characteristics of this channel have been studied (Ma et al. 2012) and reviewed (Ma et al. 2015). Post-translational palmitoylation controls the voltage-gating and lipid raft association (Taruno et al. 2017). CALHM1 plays a role, complementary to PANX1 (TC#1.A.25.2.1), in ATP release and downstream ciliary beat frequency modulation following a mechanical stimulus in airway epithelial cells (Workman et al. 2017). CALHM1 is required for sensory perception of sweet, bitter and umami tastes. It is present in type II taste bud cells, where it plays a central role in taste perception by inducing ATP release from the cell with ATP acting as a neurotransmitter to activate afferent neural gustatory pathways. It acts both as a voltage-gated and calcium-activated ion channel mediating neuronal excitability in response to changes in extracellular Ca2+ concentration (Bhat et al. 2021). It has poor ion selectivity and forms a wide pore (around 14 Å) that mediates permeation of Ca2+, Na+ and K+, as well as monovalent anions. It acts as an activator of the ERK1 and ERK2 cascade and triggers endoplasmic reticulum stress by reducing the calcium content of the ER (Gallego-Sandín et al. 2011). It may indirectly control amyloid precursor protein (APP) proteolysis and aggregated amyloid-beta (Abeta) peptide levels in a Ca2+ dependent manner (Dreses-Werringloer et al. 2008). The ATP comes from unusually large mitochondria that are adjacent to clusters of CALHM1 channels in the plasma membrane (Romanov et al. 2018). Thus, neurotransmission does not rely on vesicle formation. Intramolecular disulfide bonds for biogenesis of CALHM1 ion channels are dispensable for voltage-dependent activation (Kwon et al. 2021). Intracellular Ca2+ oscillation frequency and amplitude modulation mediate epithelial apical and basolateral membranes crosstalk (Hassan et al. 2024).
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Eukaryota | Metazoa, Chordata | CALHM1 of Homo sapiens (Q8IU99) |
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1.A.84.1.10 | CALHM1 of 346 aas and 4 or 5 TMSs. A cryo-EM structure of full-length Ca2+-free CALHM1 from Danio rerio at an overall resolution of 3.1 Å has been published (Ren et al. 2020). The structure reveals an octameric architecture with a wide pore diameter of ~20 Å, presumably representing the active conformation. The structure is substantially different from that of the isoform CALHM2, which forms both undecameric hemichannels and gap junctions. The N-terminal small helix folds back to the pore and forms an antiparallel interaction with TMS 1. Structural analysis revealed that the extracellular loop 1 region within the dimer interface may contribute to oligomeric assembly. A positive potential belt inside the pore was identified that may modulate ion permeation (Ren et al. 2020). |
Eukaryota | Metazoa, Chordata | CALHM1 of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.A.84.1.2 | The human calcium homeostasis modulator protein 2, CALHM2 or FAM16B, of 323 aas and 4 or 5 TMSs. The structures and gating mechanism of CALHM2 have been reported (Choi et al. 2019). Cryo-EM structures in the Ca2+-free active or open state and in the ruthenium red (RUR)-bound inhibited state, have been solved at 2.7 Å resolution (see also Syrjanen et al. 2020 and Demura et al. 2020. Purified CALHM2 channels form both gap junctions and undecameric hemichannels. The protomer shows a mirrored arrangement of the TMSs (helices S1-S4) relative to other channels with a similar topology, such as connexins, innexins and volume-regulated anion channels. Upon binding to RUR, a contracted pore with notable conformational changes of the pore-lining helix S1 was observed, which swings nearly 60 degrees towards the pore axis from a vertical to a lifted position. Possibly a two-section gating mechanism is operative in which the S1 helix coarsely adjusts, and the N-terminal helix fine-tunes, the pore size (Choi et al. 2019). The Kilifish CALHM1 octameric structure reveals that the N-terminal helix forms the constriction site at the channel pore in the open state and modulates the ATP conductance. The CALHM2 undecamer and CLHM-1 nonamer structures show different oligomeric stoichiometries among CALHM homologs. The cryo-EM structures of a chimeric construct revealed that the intersubunit interactions in the transmembrane region and the TMS-intracellular domain linker define the oligomeric stoichiometry (Demura et al. 2020). |
Eukaryota | Metazoa, Chordata | CALHM2 of Homo sapiens (Q9HA72) |
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1.A.84.1.3 | The human calcium homeostasis modulator protein 3, CALHM3 or FAM26A, of 344 aas and 4 TMSs/ |
Eukaryota | Metazoa, Chordata | CALHM3 of Homo sapiens (Q86XJ0) |
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1.A.84.1.4 | Calcium homeostasis modulator 1 (CALHM1 or FAM26C) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability (Ma et al. 2015). CALHM1 (CALHM-1 or CLHM-1) is of 329 aas and exhibits 4 or 5 TMSs. This protein forms a protein complex, assembling into voltage-gated, Ca2+-sensitive, nonselective channels. These complexes contain an ion-conduction pore sufficiently wide to permit the passing of ATP molecules serving as neurotransmitters. Calcium homeostasis modulators (CALHMs/CLHMs) comprise a family of pore-forming protein complexes assembling into voltage-gated, Ca2+-sensitive, nonselective channels. These complexes contain an ion-conduction pore sufficiently wide to permit the passing of ATP molecules serving as neurotransmitters. Yang et al. 2020 and Demura et al. 2020 presented the structure of the Caenorhabditis elegans CLHM1 channel (1.A.84.1.4) in its open state, solved through single-particle cryo-EM at 3.7Å resolution. The transmembrane region of the channel structure of the dominant class shows an assembly of tenfold rotational symmetry in one layer, and its cytoplasmic region is involved in additional twofold symmetrical packing in a tail-to-tail manner. A series of amino acyl residues are critical for the regulation of the channel. presented the structure of the channel in its open state, solved through single-particle cryo-EM at 3.7Å resolution. The transmembrane region of the channel shows an assembly of tenfold rotational symmetry in one layer, and its cytoplasmic region is involved in additional twofold symmetrical packing in a tail-to-tail manner. A series of amino acyl residues are critical for regulation of the channel (Calcium homeostasis modulators (CALHMs/CLHMs) comprise a family of pore-forming protein complexes assembling into voltage-gated, Ca2+-sensitive, nonselective channels. These complexes contain an ion-conduction pore sufficiently wide to permit the passing of ATP molecules serving as neurotransmitters. Yang et al. 2020 presented the structure of the Caenorhabditis elegans CLHM1 channel (1.A.84.1.4) in its open state, solved through single-particle cryo-EM at 3.7Å resolution. The transmembrane region of the channel structure of the dominant class shows an assembly of tenfold rotational symmetry in one layer, and its cytoplasmic region is involved in additional twofold symmetrical packing in a tail-to-tail manner. A series of amino acyl residues are critical for regulation of the channel (Yang et al. 2020). |
Eukaryota | Metazoa, Nematoda | CALHM-1 of Caenorhabditis elegans (Q18593) |
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1.A.84.1.5 | CALHM4 or FAM26D of 314 aas and 4 TMSs |
Eukaryota | Metazoa, Chordata | FAM26D of Homo sapiens (Q5JW98) |
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1.A.84.1.6 | The CALHM6 or FAM26F channel protein of 315 aas and probably 5 TMSs. FAM26F (family with sequence similarity 26, member F) plays an important role in diverse immune responses (Malik et al. 2016). |
Eukaryota | Metazoa, Chordata | CALHM6 of Homo sapiens |
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1.A.84.1.7 | Calcium homeostasis modulators (CALHMs) are ATP release channels that play crucial roles in neurons including gustatory signaling and neuronal excitability. Pathologies of Alzheimer's disease and depression have been associated with the dysfunction of CALHMs (see TC# 1.A.84.1.1). CALHM5 structures, solved by cryoEM, showed an abnormally large pore channel structure assembled as an undecamer with four transmembrane helices (TMS1-TMS4), an N-terminal helix (NTH), an extracellular loop region and an intracellular C-terminal domain (CTD) that consists of three α-helices, CH1-3. The TMS1 and NTH were poorly defined among other CALHMs, but these regions were well defined in the CALHM5 channel structure (Bhat et al. 2021). |
Eukaryota | Metazoa, Chordata | CALHM5 of Homo sapiens |
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1.A.84.1.8 | Uncharacterized protein of 1457 aas with about 850 hydrophilic N-terminal aas and 8 C-terminal TMSs in a 4 + 4 arrangement. |
Eukaryota | Metazoa, Chordata | UP of Hirundo rustica rustica |
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1.A.84.1.9 | Killifish CALHM1 of 351 aas and 5 TMSs in a 2 + 2 + 1 TMS arrangement. The cryoEM structure has been determined to 2.66 Å resolution (Demura et al. 2020). The human CALHM-2 (CALMH2) and the C. elegans CLHM-1 (CLHM1) were also solved at lower resolution. The CALHM1 octameric structure reveals that the N-terminal helix forms the constriction site at the channel pore in the open state and modulates the ATP conductance. The CALHM2 undecamer and CLHM-1 nonamer structures show the different oligomeric stoichiometries among CALHM homologs. The cryo-EM structures of the chimeric construct revealed that the intersubunit interactions in the transmembrane region and the TMS-intracellular domain linker define the oligomeric stoichiometry (Demura et al. 2020). |
Eukaryota | Metazoa, Chordata | CALHM1 of Oryzias latipes (Japanese rice fish) (Japanese killifish) |
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1.A.84.2.1 | Sea anemone CALHM homologue |
Eukaryota | Metazoa, Cnidaria | CALHM homologue of Nematostella vectensis |
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1.A.84.2.2 | Uncharacterized protein of 304 aas and 4 TMSs. |
Eukaryota | Metazoa, Cnidaria | UP of Nematostella vectensis (Starlet sea anemone) |
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1.A.84.2.3 | Uncharacterized protein of 769 aas and 8 TMSs in a 4 + 4 TMS arrangement, with each 3 TMS unit followed by a hydrophilic region of about 180 aas. |
Eukaryota | Metazoa, Cnidaria | UP of Stylophora pistillata |
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1.A.84.2.4 | Calcium homeostasis modulator protein 5-like of 362 aas and 4 or 5 TMSs. |
Eukaryota | Metazoa, Cnidaria | CALHM protein of Actinia tenebrosa |
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1.A.84.2.5 | Uncharacterized protein of 356 aas and 4 or 5 TMSs. |
Eukaryota | Metazoa, Cnidaria | UP of Pocillopora damicornis |
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1.A.84.2.6 | Uncharacterized protein of 435 aas and 4 N-terminal TMSs (the FAM26 domain) followed by a hydrophilic region that shows sequence similarity with 9.B.96.1.1 (e-7). |
Eukaryota | Metazoa, Chordata | UP of Pelodiscus sinensis (Chinese soft-shelled turtle) |
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1.A.84.2.7 | Uncharacterized protein of 329 aas and 4 TMSs. |
Eukaryota | Metazoa, Cnidaria | UP of Henneguya salminicola |
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1.A.84.2.8 | Uncharacterized protein of 275 aas and 4 TM |
Eukaryota | Metazoa, Chordata | UP of Salmo trutta (river trout) |
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1.A.84.2.9 | Uncharacterized protein of 431 aas and 4 TMSs |
Eukaryota | Metazoa, Chordata | UP of Pygocentrus nattereri (red-bellied piranha) |
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1.A.84.3.1 | Uncharacterized protein of 328 aas and 4 TMSs |
Eukaryota | Metazoa, Chordata | UP of Sander lucioperca (pike-perch) |
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1.A.84.3.2 | Uncharacterized protein of 494 aas with 4 N-terminal TMSs and an long hydrophilic domain with one C-terminal TMS |
Eukaryota | Metazoa, Chordata | UP of Oryzias latipes (Japanese medaka) |
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1.A.84.3.3 | Uncharacterized protein of 268 aas and 4 TMSs |
Eukaryota | Metazoa, Chordata | UP of Archocentrus centrarchus (flier cichlid) |
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1.A.84.3.4 | Uncharacterized protein of 311 aas and 4 TMSs. |
Eukaryota | Metazoa, Chordata | UP of Anabas testudineus (climbing perch) |
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1.A.84.3.5 | Uncharacterized protein of 290 aas and 4 TMSs. |
Eukaryota | Metazoa, Chordata | UP of Astatotilapia calliptera (eastern happy) |
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1.A.84.3.6 | Uncharacterized protein of 332 aas and 4 N-terminal TMSs |
Eukaryota | Metazoa, Chordata | UP of Erpetoichthys calabaricus (reedfish) |
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1.A.84.4.1 | Uncharacterized protein of 312 aas and 4 TMSs |
Eukaryota | Metazoa, Mollusca | UP of Pomacea canaliculata |
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1.A.84.4.2 | Uncharacterized protein of 385 aas and 4 N-terminal TMSs. |
Eukaryota | Metazoa, Mollusca | UP of Pomacea canaliculata |
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1.A.84.4.3 | Uncharacterized protein of 278 aas and 4 TMSs. This protein shows substantial sequence similarity with TC#s 1.A.84.1.8, 1.7 and 1.5 (up to e-6). |
Eukaryota | Metazoa, Mollusca | UP of Pomacea canaliculata |
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1.A.85.1.1 | The human poliovirus 2B viroporin (from the polyprotein). The 97 residue 2B viroporin consists of residues 1031-1127 in the polyprotein. in vitro and in vivo translation-glycosylation compatible with the translocon-mediated insertion of the 2B product into the ER membrane as a double-spanning integral membrane protein with an N-/C-terminal cytoplasmic orientation has been reported (Agirre et al. 2008; Martínez-Gil et al. 2011). The in vitro translation of several truncated versions of the 2B protein suggests that the two hydrophobic regions cooperate to insert into the ER-derived microsomal membranes. 2B is specific for Ca2+ and plays a role in particle production and cell lysins (Scott and Griffin 2015). The 3A viroporin of poliovirus transports monovalent cations (Hyser and Estes 2015). It and the VP4 viroporin are encoded within the viral polyprotein of 2209 aas (P03300). |
Viruses | Orthornavirae, Pisuviricota | 2B viroporin of Human poliovirus 1 (Q9Q280) |
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1.A.85.1.2 | 2B protein (99 aas) derived from the polyprotein of human coxsackie virus (Patargias et al., 2009). It has specificy for Ca2+ and functions in particle production and cell lysis (Scott and Griffin 2015). |
Viruses | Orthornavirae, Pisuviricota | B2 capsid protein of the human coxsackie virus. (Q5MP79) |
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1.A.85.1.3 | Echovirus E30 polyprotein (128 aas; fragment). An intracellular (endomembrane) pore-forming peptide toxin which induces membrane permeability due to two consecutive hydrophobic segments that may form an α-helix-turn-α-helix hairpin membrane anchor that provides the basis for oligomeric pore formation (Sánchez-Martínez et al. 2012). This protein is derived from the Coxsackle virus B2 protein of 2187 aas (Q9YLG5) and may interact with a Ryanodine receptor (Schilling et al. 2013). |
Viruses | Orthornavirae, Pisuviricota | Polyprotein, including the 100 aa viroporin of human enterovirus (echovirus E30) |
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1.A.85.1.4 | Polyprotein of 2333 aas (includes the viroporin peptide, NS2B). Viroporin activity for the NS2B protein has been demonstrated (Ao et al. 2015). |
Viruses | Orthornavirae, Pisuviricota | Viroporin-containing polyprotein of foot-and-mouth disease virus |
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1.A.85.1.5 | Rat picornavirus 2B protein of 116 as and 2 TMSs, a membrane active peptide (Sánchez-Martínez et al. 2012). It has viroporin-like activity which affects the biological function of the membrane, regulates cell death, and affects the host immune response (Li et al. 2019). |
Viruses | Orthornavirae, Pisuviricota | 2B protein of rat picornavirus |
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1.A.85.1.6 | The genome polyprotein of 2292 aas encoding the viroporin of Encephalomyocarditis virus (Ito et al. 2012). |
Viruses | Orthornavirae, Pisuviricota | Polyprotein of Encephalomyocarditis virus |
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1.A.85.1.7 | Human rhinovirus 1A 2B protein of 2157 aas |
Viruses | Orthornavirae, Pisuviricota | 2B of human rhionvirus 1A |
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1.A.85.1.8 | The Viroporin, protein 2B, of 154 aas and 3 TMSs where TMS 2 provides the channel activity. Transports cations, Ca2+ and small molecules (Gladue et al. 2018). Present within the Polyprotein of 2332 aas. |
Viruses | Orthornavirae, Pisuviricota | Poly protein of foot-and-mouth disease virus (FMDV) |
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1.A.85.1.9 | Nonstructural protein, NS2B, partial of 122 aas and 2 TM |
Viruses | Orthornavirae, Pisuviricota | NS2B of Encephalomyocarditis virus |
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1.A.86.1.1 | The human papilloma virus type 16 (HPV16) L2 capsid protein of 99aas. It mediates virion endosomal escape and transport of the viral capsid to the nucleus (Bronnimann et al., 2013). Retromer (TC# 9.A.3 and 9.A.63) stabilizes transient membrane insertion of L2 capsid protein during retrograde entry of human papillomavirus (Xie et al. 2021). |
Viruses | Shotokuvirae, Cossaviricota | L2 of HPV16 (P03107) |
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1.A.86.1.2 | L2 protein of 187 aas of human papilloma virus (Campos 2017). |
Viruses | Shotokuvirae, Cossaviricota | L2 protein of human papilloma virus |
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1.A.86.1.3 | The L2 protein of 533 aas and 1 TMS. |
Viruses | Shotokuvirae, Cossaviricota | The L2 protein of Fulmarus glacialis papillomavirus 1 |
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1.A.86.1.4 | Late protein L2 of 155 aas. |
Bacteria | Chlamydiota | L2 of Chlamydia trachomatis |
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1.A.87.1.1 | Plant Ca2+ channel protein, Mid1 complementary activity 1, MCA1 (Iida et al. 2013). MCA1 and MCA2 each forms a homotetramer and exhibit Ca2+-permeable mechanosensitive channel activity. Both are single-pass type I transmembrane proteins with their N-termini located extracellularly and their C-termini located intracellularly. An EF hand-like motif, coiled-coil motif, and Plac8 motif may all be in the cytoplasm, suggesting that the activities of both channels can be regulated by intracellular Ca2+ and protein interactions (Kamano et al. 2015). However, hydropathy plots suggest that the Plac8 domain may be transmembrane with 3 TMSs. mca1 but not mca2 mutants show defects in root entry into hard agar, whereas mca2 but not mca1 mutants are defective in Ca2+ uptake in A. thaliana roots (Hamilton et al. 2015). Root growth reduction in response to mechanical stress involves MCA1 tgether with WDL5 (Q94C48) subject to ethylene-mediated regulation) and the co-receptor BAK1 (Q94F62) (Okamoto et al. 2021).
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Eukaryota | Viridiplantae, Streptophyta | MCA1 of Arabidopsis thaliana |
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1.A.87.1.2 | Plant Ca2+ channel protein, Mid1 complementary activity 2, MCA2 (Iida et al. 2013). Catalyzes mechanical stress-induced Ca2+ influx. It is tetrameric with a small transmembrane domain and a large cytoplasmic domain (Shigematsu et al. 2014). MCA1 and MCA2 both have their N-termini located extracellularly and their C-termini located intracellularly. An EF hand-like motif, coiled-coil motif, and Plac8 motif may all be in the cytoplasm, suggesting that the activities of both channels can be regulated by intracellular Ca2+ and protein interactions (Kamano et al. 2015). However hydropathy plots suggest that the Plac8 domain may be transmembrane with 3 TMSs. mca1 but not mca2 mutants show defects in root entry into hard agar, whereas mca2 but not mca1 mutants are defective in Ca2+ uptake in A. thaliana roots (Hamilton et al. 2015). |
Eukaryota | Viridiplantae, Streptophyta | MCA2 of Arabidopsis thaliana |
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1.A.87.1.3 | MCA1 isoform X2 of 377 aas with one N-terminal TMS and possibly 3 or 4 C-terminal TMSs. |
Eukaryota | Viridiplantae, Streptophyta | MCA1 of Solanum pennellii (Lycopersicon pennellii) |
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1.A.87.1.4 | PLAC8 family protein of 385 aas with MID1-complementing activity. |
Eukaryota | Viridiplantae, Streptophyta | PLAC8 family protein of Theobroma cacao |
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1.A.87.1.5 | Mid1 complementing activity 1 of 154 aa |
Eukaryota | Viridiplantae, Streptophyta | MCA1 of Vigna radiata |
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1.A.87.2.1 | Receptor protein kinase of 567 aas. The first 140 aas are homologous to the N-terminal domains of MCA1 and 2; residues 240 - 430 are homologous to ser/thr protein kinases of 9.A.15.1.1, 9.B.45.1.3 and 9.B.106.3.1. |
Eukaryota | Viridiplantae, Streptophyta | Receptor protein kinase of Zea mays |
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1.A.87.2.10 | Uncharacterized leucine-rich repeat domain-containing proteins of 387 aas and putative protein kinase of 399 aas, respectively, each with one TMS, the first of these proteins at the N-terminus, and the second near its C-terminus. These two proteins are most similar to different parts of the other proteins in TC subclass # 1.A.87.2. |
Bacteria | Thermodesulfobacteriota | UPs of Desulfosarcina alkanivorans |
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1.A.87.2.11 | Leucine-rich repeat (LRR) receptor-like serine/threonine-protein kinase, ERECTA, of 966 aas and 2 TMSs, one at the N-terminus of the protein, and one at residues 580 - 600. Oterh peaks of hydrophobicity may also be transmembrane. It is a receptor kinase that, together with ERL1 and ERL2,
regulates aerial architecture, including inflorescence (e.g. shoot
apical meristem-originating organ shape, elongation of the internode and
pedicels, and adaxial-abaxial polarity), and stomatal patterning (e.g.
density and clustering), probably by tuning cell division and expansion. It regulates canalization as well as cell wall composition and structure, and it confers resistance to the pathogenic bacteria Ralstonia solanacearum and
to the necrotrophic fungi Plectosphaerella cucumerina and Pythium
irregulare. It is required for callose deposition upon infection. (Torii et al. 1996). |
Eukaryota | Viridiplantae, Streptophyta | ERL2 of Arabidopsis thaliana |
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1.A.87.2.12 | Receptor-like kinase 1, RKL1, of 655 aas and 2 TMSs, one N-terminal and one centrally located. These receptor-like kinases directly regulate the functions of membrane transport proteins in plants (Li et al. 2022). |
Eukaryota | Viridiplantae, Streptophyta | RKL1 of Arabidopsis thaliana |
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1.A.87.2.13 | Transmembrane kinase receptor of 942 aas and 2 TMSs, one at the N-terminus of the protein and the second at residue 490 (Chang et al. 1992). It phosphorylates only serine and threonine residues (Schaller and Bleecker 1993) and is involved in auxin signal transduction and cell expansion as well as proliferation regulation (Dai et al. 2013). With ABP1, it is a cell surface auxin perception complex that activates ROP signaling pathways (Xu et al. 2014). It is required for auxin promotion of pavement cell interdigitation and promotes the formation of the ABP1-TMK1 protein complex (Xu et al. 2014). |
Eukaryota | Viridiplantae, Streptophyta | TMK1 of Arabidoopsis thaliana |
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1.A.87.2.14 | Nod-factor receptor 1a, NFR1, of 621 aas and about 6 TMSs in an estimated 2 + 1 + 1 + 1 + 1 TMS topology. This protein plus NFR5 constitutes the Lotus japonicus core receptor complex in root nodule symbiosis that initiates the cortical root nodule organogenesis program (Rübsam et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | NFR1 of Lotus japonicus |
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1.A.87.2.15 | Nod-factor receptor 5, NFR5, of 595 aas and about possibly 3 TMSs, one at the N-terminus, one at residue 250, and one at residue 470. This protein plus NFR1 (TC# 1.A.87.2.14) constitutes the Lotus japonicus core receptor complex in root nodule symbiosis that initiates the cortical root nodule organogenesis program (Rübsam et al. 2023).
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Eukaryota | Viridiplantae, Streptophyta | NFR5 of Lotus japonicus |
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1.A.87.2.16 | G-type lectin S-receptor-like serine/threonine-protein kinase, SRK, of 853 aas with possibly 4 TMSs, one at the N-terminus of the protein, and 3 more at residues 450, 580 and 710 (Zhou et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | SRK of Arabidopsis thaliana |
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1.A.87.2.17 | Pseudokinase (serine/threonine protein kinase), ZRK1, of 351 aas and 2 strongly hydrophobic TMSs (at residues 130 and 260) (Bi et al. 2021). |
Eukaryota | Viridiplantae, Streptophyta | ZRK1 of Arabidopsis thaliana |
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1.A.87.2.19 | Probable LRR receptor-like serine/threonine-protein kinase IRK of 964 aas and 2 or 3 TMSs, one at the N-terminus, one large peak at ~residues 610 - 640, and possibly one at the C-terminus of the protein. Distinct ADP-ribosylation factor-GTP exchange factors govern the opposite polarity of two receptor kinases, one of which is IRK, and the other is K0IN (Rodriguez-Furlan et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | IRK of Arabidopsis thaliana |
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1.A.87.2.2 | Protein kinase domain protein of 522 aas. |
Eukaryota | Viridiplantae, Streptophyta | PKD protein of Oryza sativa |
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1.A.87.2.3 | Receptor for extracellular ATP which functions in plant growth, development and stress responses; lectin receptor kinase 1.9; DORN1. Binds ATP with high affinity (46nM) and is required ofr ATP-induced calcium response, mitogen-activated protein kinase activation and normal gene expression (Choi et al. 2014). |
Eukaryota | Viridiplantae, Streptophyta | DORN1 of Arabidopsis thaliana |
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1.A.87.2.4 | GHR1 (GUARD CELL HYDROGEN PEROXIDE-RESISTANT 1) transmembrane receptor-like protein of 1053 aas and 1 - 3 TMSs. Regulates the SLAC1 protein (2.A.16.5.1) (Wang et al. 2017). The C-terminus shows extensive sequence similarity with members of this family, but the N-terminus shows similarity with members of family 3.A.20 (Leucine repeat proteins). |
Eukaryota | Viridiplantae, Streptophyta | GHR1 of Arabidopsis thaliana |
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1.A.87.2.5 | Uncharacterized protein with an ATP binding domain of 629 aas and 2 TMSs. |
Eukaryota | Viridiplantae, Streptophyta | UP of Arabidopsis thaliana |
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1.A.87.2.6 | Protein BRASSINOSTEROID INSENSITIVE 1, BRI1, of 1196 aas and 2 or 3 TMSs. Receptor with kinase activity
acting on both serine/threonine- and tyrosine-containing substrates. In response to brassinosteroid binding, it regulates a signaling cascade
involved in plant development, including expression of light- and
stress-regulated genes, promotion of cell elongation, normal leaf and
chloroplast senescence, and flowering. It binds brassinolide, and less
effectively, castasterone (Oh et al. 2009). |
Eukaryota | Viridiplantae, Streptophyta | BRI1 of Arabidopsis thaliana |
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1.A.87.2.9 | The phytosulfokine receptor, PSKR1, of 1008 aas with both a serine/threonine-protein kinase activity and a guanylate cyclase activity (Kwezi et al. 2011). In response to phytosulfokine binding, it activates a signaling cascade involved in plant cell differentiation, organogenesis, somatic embryogenesis, cellular proliferation and plant growth. It is also involved in plant immunity, with antagonistic effects on bacterial and fungal resistances (Mosher et al. 2013). CNGC17 and AHAs form a functional cation-translocating unit that is activated by PSKR1/BAK1 and possibly other BAK1/RLK complexes (Ladwig et al. 2015). PSKR is a transmembrane LRR-RLK family protein with a binding site for the small signalling peptide, phytosulfokine (PSK). There are 15 members in rice (Orysa sativa), induced under different conditions in different plant tissues (Nagar et al. 2020). PSKR1 and PSYR1 mediate a signaling pathway in response to two distinct ligands, which redundantly contribute to cellular proliferation and plant growth (Amano et al. 2007). |
Eukaryota | Viridiplantae, Streptophyta | PSKR1 of Arabidopsis thaliana (Mouse-ear cress) |
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1.A.87.3.1 | Plant cadmium resistance, PCR, protein of 164 aas. It shows homology to the C-terminal PLAC8 domain of MCA1 and 2. Strontium alleviates the growth inhibition and toxicity caused by cadmium in rice seedlings (Liu et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | Cadmium resistance protein of Solanum lycopersicum (Tomato) (Lycopersicon esculentum) |
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1.A.87.3.10 | Fruit-weight 2.2 protein of 197 aas and 3 TMSs. May be involved in Cd2+ resistance as well as translocation of Cd2+ from roots to shoots (Xiong et al. 2018). May form homooligomeric structures in the membrane. |
Eukaryota | Viridiplantae, Streptophyta | FWL protein of Medicago truncatula (Barrel medic) (Medicago tribuloides) |
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1.A.87.3.11 | Fruit-weight 2.2 protein of 161 aas and 4 TMSs. May be involved in Cd2+ resistance as well as translocation of Cd2+ from roots to shoots (Xiong et al. 2018). May form homooligomeric structures in the membrane. |
Eukaryota | Viridiplantae, Streptophyta | FWL protein of Medicago truncatula (Barrel medic) (Medicago tribuloides) |
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1.A.87.3.12 | Fruit Weight 2.2 (FW2.2) protein of 163 aas and possibly 3 TMSs. See family description for details (Beauchet et al. 2021).
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Eukaryota | Viridiplantae, Streptophyta | FW2.2 of Solanum lycopersicum (Tomato) (Lycopersicon esculentum) |
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1.A.87.3.13 | Protein PLANT CADMIUM RESISTANCE 10 of 190 aas and 2 (or 3) TMSs. It transports (expels) cadmium, lead and aluminum ions, thereby protecting the plant from these toxic cations for more appreciable growth (Guan et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | Cadmium resistance 10 protein of Populus euphratica (Euphrates poplar) |
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1.A.87.3.2 | Plant Cadmium Resistance (PCR) protein. This protein corresponds to the C-terminal PLAC8 domain of MCA1 (TC# 1.A.87.1.1) (Song et al., 2011). The plant cadmium resistance (PCR) gene family has been characterized in Brassica napus and one member, has been functionally analyzed: BnPCR10.1 is involved in cadmium and copper tolerance( (Liu et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | PLAC8 family protein of Arabidopsis thaliana |
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1.A.87.3.3 | Sea squirt membrane protein of 110 aas |
Eukaryota | Metazoa, Chordata | Membrane protein of Ciona intestinalis |
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1.A.87.3.4 | Uncharacterized protein of 161 aas |
Eukaryota | Viridiplantae, Streptophyta | UP of Capsella rubella |
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1.A.87.3.5 | Plant cadmium resistance 6 protein, CadR6, of 224 aas. |
Eukaryota | Viridiplantae, Streptophyta | CadR6 of Arabidopsis thaliana |
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1.A.87.3.6 | Uncharacterized protein of 186 aas |
Eukaryota | Viridiplantae, Streptophyta | UP of Glycine max |
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1.A.87.3.7 | Plant cadmium resistance 1 protein of 151 aas and 2 TMSs. PCR1. Involved in glutathione-independent cadmium resistance. Reduces cadmium uptake rather than activating efflux, but is not closely coupled to calcium transport (Song et al. 2011). |
Eukaryota | Viridiplantae, Streptophyta | PCR1 of Arabidopsis thaliana |
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1.A.87.3.8 | Plant cadmium resistance 2 (PCR2) protein. Zinc ion exporter (Song et al. 2010; Song et al. 2011). Involved in glutathione-independent cadmium resistance. Reduces cadmium uptake rather than activating efflux, but is not closely coupled to calcium transport. |
Eukaryota | Viridiplantae, Streptophyta | PCR2 of Arabidopsis thaliana |
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1.A.87.3.9 | FW2.2-like (FWL) protein of 180 aas and 2 or 3 TMSs. It is involved in plant and fruit development, and possibly in calcium transport (Libault and Stacey 2010). See family description for details about its possible functions in the tomato (Beauchet et al. 2021). |
Eukaryota | Viridiplantae, Streptophyta | FWL of Persea americanan (Avocado) |
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1.A.87.4.1 | Ubiquitin protein ligase with the first 250 aas homologous to MCA2. |
Eukaryota | Viridiplantae | Ubiquitin ligase of Physcomitrella patens |
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1.A.87.4.2 | U box containing protein 15 |
Eukaryota | Viridiplantae, Streptophyta | U box protein of Solanum lycopersicum (Tomato) (Lycopersicon esculentum) |
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1.A.87.5.1 | Protein kinase_Tyr of 657 aas with N-terminal domain similar to that of MCA1, with N-terminal TMS containing a conserved aspartyl residue. |
Eukaryota | Fungi, Basidiomycota | PKinase-Tyr of Phanerochaete carnosa |
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1.A.88.1.1 | K+ channel, Kch1 of 497 aas (Stefan et al. 2013). |
Eukaryota | Fungi, Ascomycota | Kch1 of Saccharomyes cerevisiae |
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1.A.88.1.2 | K+ channel Kch2/Pmp6 of 352 aas (Stefan et al. 2013). |
Eukaryota | Fungi, Ascomycota | Kch2 of Saccharomyces cerevisiae |
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1.A.88.1.3 | Kch homologue of 655 aa |
Eukaryota | Fungi, Ascomycota | Kch homologue of Candida maltosa |
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1.A.88.1.4 | Kch homologue of 1043 aas |
Eukaryota | Fungi, Ascomycota | Kch homologue of Aspergillus niger |
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1.A.88.1.5 | Vacuolar Kch homologue of 422 aas |
Eukaryota | Fungi, Basidiomycota | Kch of Cryptococcus (Filobasidiella) gattii (bacillisporus) |
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1.A.88.1.6 | Kch homologue of 1090 aas |
Eukaryota | Fungi, Ascomycota | Kch of Neurospora crassa |
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1.A.88.1.7 | Vacuolar Kch homologue of 527 aas |
Eukaryota | Fungi, Basidiomycota | Kch of Trichosporon asahii |
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1.A.88.1.8 | Kch homologue of 442 aas |
Eukaryota | Fungi, Ascomycota | Kch of Dekkera bruxellensis |
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1.A.88.1.9 | Kch homologue of 565 aas |
Eukaryota | Fungi, Ascomycota | Kch of Millerozyma (Pichia) farinosa (sorbitophila |
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1.A.89.1.1 | ORF4a viroporin of 133 aas and 3 TMSs (Zhang et al. 2013). |
Viruses | Orthornavirae, Pisuviricota | ORF4a of human coronavirus 229E |
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1.A.89.1.2 | Viroporin of 222 aas and 3 strongly hydrophobic TMSs in the N-terminal half of the protein followed by a region of moderate hydrophobicity in the C-terminal half. |
Viruses | Orthornavirae, Pisuviricota | Viroporin of human coronavirus NL63 |
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1.A.89.1.3 | Non structural protein 3c, a viroporin of 237 aas with 3 stronly hydrophobic TMSs in the N-terminal half of the protein and a broad region of moderate hydrophobicity in the second half. |
Viruses | Orthornavirae, Pisuviricota | Viroporin 3c of feline coronavirus UUF |
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1.A.89.1.4 | Viroporin ORF3-1 of 205 aas and 4 or more TMSs in a 3 + 1-3 TMS arrangement. |
Viruses | Orthornavirae, Pisuviricota | Orf3-1 viroporin of porcine respiratory coronavirus |
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1.A.89.1.5 | 3a protein of 152 aas and 3 or 4 TMSs |
Viruses | Orthornavirae, Pisuviricota | Protein 3a of Bat coronavirus |
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1.A.89.1.6 | ORF3 protein of 228 aas and 3 TMSs. |
Viruses | Orthornavirae, Pisuviricota | ORF3 of Chaerephon bat coronavirus/Kenya |
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1.A.9.1.1 | Nicotinic acetylcholine-activated cation-selective channel, pentameric α2βγδ (immature muscle) nα2βγδ (mature muscle), is activated by nicotine (Shen et al. 2022). A combination of symmetric and asymmetric motions opens the gate, and the asymmetric motion involves tilting of the TM2 helices (Szarecka et al. 2007). Acetylcholine receptor δ subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita (Brownlow et al., 2001; Webster et al., 2012). Residues in TMS2 and the cytoplasmic loop linking TMSs 3 and 4 influence conductance, selectivity, gating and desensitization (Peters et al., 2010). nAChR and TRPC channel proteins (1.A.4) mediate nicotine addiction in many animals from humans to worms (Feng et al., 2006). Cholesterol recognition motifs in transmembrane domains of the human nicotinic acetylcholine receptor have been identified (Baier et al., 2011). Allosteric modulators of the α4β2 subtype of neuronal nicotinic acetylcholine receptors, the dominant type in the brain, are numerous (Pandya and Yakel, 2011). α2β2 and α4β2 nicotinic acetylcholine receptors are inhibited by the β-amyloid(1-42) peptide (Pandya and Yakel, 2011b). The A272E mutation in the alpha7 subunit gives rise to spinosad insensitivity without affecting activation by acetylcholine (Puinean et al. 2012). Inhibited by general anaesthetics (Nury et al., 2011). The X-ray crystal structures of the extracellular domain of the monomeric state of human neuronal alpha9 nicotinic acetylcholine receptor (nAChR) and of its complexes with the antagonists methyllycaconitine and alpha-bungarotoxin have been determined at resolutions of 1.8 A, 1.7 A and 2.7 A, respectively (Zouridakis et al. 2014). Structurally similar allosteric modulators of α7 nAChR exhibit five different pharmacological effects (Gill-Thind et al. 2015). Mutations causing slow-channel myasthenia show that a valine ring in the channel is optimized for stabilizing gating (Shen et al. 2016). Quinoline derivatives act as agonists or antagonists depending on the type and subunit (Manetti et al. 2016). Conformational changes stabilize a twisted extracellular domain to promote transmembrane helix tilting, gate dilation, and the formation of a ""bubble"" that collapses to initiate ion conduction (Gupta et al. 2016). A high-affinity cholesterol-binding domain has been proposed for this and other ligand-gated ion channels (Di Scala et al. 2017). Positive allosteric modulators have been identified (Deba et al. 2018). Menthol stereoisomers exhibit fifferent effects on alpha4beta2 nAChR upregulation and dopamine neuron spontaneous firing (Henderson et al. 2019). Corticosteroids exert direct inhibitory action on the muscle-type AChR (Dworakowska et al. 2018). Both deltaL273F and epsilonL269F mutations impair channel gating by disrupting hydrophobic interactions with neighboring alpha-subunits. Differences in the extent of impairment of channel gating in delta and epsilon mutant receptors suggest unequal contributions of epsilon/alpha and delta/alpha subunit pairs to gating efficiency (Shen et al. 2019). Diffusion dynamics of the gangliosides, GM1s and AChRs is uniformly affected by the intracellular ATP level of a living muscle cell (He et al. 2020). M4, the outermost helix, is involved in opening of the alpha4beta2 nACh receptor (Mesoy and Lummis 2020). Cholesterol modulates the organization of the gammaM4 transmembrane domain of the muscle nicotinic acetylcholine receptor (de Almeida et al. 2004). Cryo-EM images showed that cholesterol segregates preferentially around the constituent ion channel of the receptor, interacting with specific sites in both leaflets of the bilayer. Cholesterol forms microdomains - bridges of rigid sterol groups that link one channel to the next (Unwin 2021). Desnitro-imidacloprid (DN-IMI) functionally affects human neurons similarly to the well-established neurotoxicant nicotine by triggering activation of alpha7 and several non-alpha7 nAChRs (Loser et al. 2021). The "lipid sensor" ability displayed by the outer ring of the M4 TMS and its modulatory role on nAChR function have been reviewed (Barrantes 2023). Anesthetic and two neuromuscular blockers act on muscle-type nicotinic receptors; the intravenous anesthetic etomidate binds at an intrasubunit site in the transmembrane domain and stabilizes a non-conducting, desensitized-like state of the channel (Goswami et al. 2023). The depolarizing neuromuscular blocker succinylcholine also stabilizes a desensitized channel but does so through binding to the classical neurotransmitter site. Rocuronium binds in this same neurotransmitter site but locks the receptor in a resting, non-conducting state. A novel binding site in the nicotinic acetylcholine receptor for MB327 can explain its allosteric modulation relevant for organophosphorus-poisoning treatment (Kaiser et al. 2023). A recombinant cellular model system for human muscle-type nicotinic acetylcholine receptor (alpha1(2)beta1deltaepsilon) has been presented (Brockmöller et al. 2023). AChR has 2 orthosteric sites (for neurotransmitters) in the extracellular domain linked to an allosteric site (a gate) in the transmembrane domain (Auerbach 2024). Escobar syndrome is a rare, autosomal recessive disorder that affects the musculoskeletal system and the skin. It is due to mutations in the CHRNG and TPM2 genes (Najjar et al. 2022). |
Eukaryota | Metazoa, Chordata | Acetylcholine receptors of Homo sapiens α2βγδ or ε |
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1.A.9.1.10 | The nicotinic acetylcholine receptor alpha 6 isoform 1 of 505 aas and 6 or 7 putative TMSs, with one N-terminal TMS, one C-terminal TMS, and 4 or 5 centrally located TMSs. 66% identical to TC# 1.A.9.1.6. A 3 aa deletion in the transmembrane domain causes resistance to spinosad, a macrocyclic lactone insecticide (Wang et al. 2016). Mutations in the orthologous α6 subunit of Rhyzopertha dominica (lesser grain borer; 81% identical to the moth protein) also gave rise to spanosad resistance (Wang et al. 2018). |
Eukaryota | Metazoa, Arthropoda | AcChR of Plutella xylostella (Diamondback moth) (Plutella maculipennis) |
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1.A.9.1.11 | Acetylcholine-activated cation-selective channel, alpha-type, Acr-16 of 504 aas and 6 putative TMSs. Four negative allosteric modulators of this channel in the parasite have been identified (Zheng et al. 2016). |
Eukaryota | Metazoa, Nematoda | Acr-16 of Ascaris suum (Pig roundworm) (Ascaris lumbricoides) |
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1.A.9.1.12 | Nicotinic acetylcholine receptor with three subunits, non-alpha subunit ShAR2beta of 545 aas, as well as two additional "non-alpha subunits of 714 and 736 aas, respectively, all with 6 TMSs, 1 N-terminal, 4 central, and 1 C-terminal (Bentley et al. 2007). |
Eukaryota | Metazoa, Platyhelminthes | Trimeric nAcChR of Schistosoma haematobium (Blood fluke) |
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1.A.9.1.13 | Neuronal acetylcholine receptor with two subunits, α- and β-subunits, Unc-63 (Lev7; 502 aas) and Acr-2 (575 aas), respectively. Probably acts in cholinergic motoneurons to regulate presynaptic neurotransmitter release, thereby ensuring normal level of excitation of cholinergic motoneurons during locomotion (Jospin et al. 2009). Involved in nAChR sensitivity to nicotine and levamisole (Culetto et al. 2004; Gottschalk et al. 2005). The AcChR subunits in C. elegans have been compared with those of parasitic nematodes (Holden-Dye et al. 2013). The Ascaris suum nicotinic acetylcholine receptor (nAChR) is modulated by compounds GSK575594A, diazepam and flumazenil (Stevanovic et al. 2021).
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Eukaryota | Metazoa, Nematoda | Neuronal AcChR of Caenorhabditis elegans |
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1.A.9.1.14 | Acetylcholine receptor with two subunits, α and β, Deg-3 (564 aas)and Acr-4 (548 aas). Subunits of the non-synaptic neuronal AChR, which may play a role in chemotaxis towards choline. After binding choline or acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane (Treinin et al. 1998; Yassin et al. 2001). |
Eukaryota | Metazoa, Nematoda | AcChR of Caenorhabditis elegans |
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1.A.9.1.15 | Acr-16 subunit of a levamisole-insensitive nicotinic receptor of 498 aas (Touroutine et al. 2005). C. elegans has 32 AcChR subunits, 22 of them of the alpha-type, and these are divided into at least five classes, DEG-3-like (9), ACR-16- like (11), UNC-8-like (3), UNC-38-like (3) and Unc-29-like (4) (Holden-Dye et al. 2013). |
Eukaryota | Metazoa, Nematoda | ACR-16 of Caenorhabditis elegans |
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1.A.9.1.16 | Beta-subunit (Unc-29; 493 aas) of a nicotinic AcChR. Non-alpha subunit of nAChR involved in nAChR sensitivity to nicotine and levasimole (Gottschalk et al. 2005). |
Eukaryota | Metazoa, Nematoda | UNC-29 of Caenorhabditis elegans |
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1.A.9.1.17 | Nicotinic acetylcholine receptor, Eat-2 (474 aas and 4 TMSs in a 3 + 1 arrangement)/Eat-18 in the MC
pharyngeal motor neuron involved in pharyngeal pumping. It plays a role in
the determination of life span, possibly via calorific restriction (McKay et al. 2004; Huang et al. 2004). Eat-18 may be the CRE-EAT-18 protein with TC# 8.A.47.1.3. |
Eukaryota | Metazoa, Nematoda | Eat2/Eat18 of Caernorhabditis elegans |
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1.A.9.1.18 | Neuronal acetylcholine receptor subunit alpha-5 of 429 aas and 4 apparent TMSs. It is part of an alpha-bungarotoxin binding acetylcholine receptor (Wu et al. 2005). |
Metazoa, Arthropoda | ACHA5 of Bactrocera dorsalis (oriental fruit fly) |
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1.A.9.1.19 | Acetyl choline binding protein, AchBP, of 229 aas, corresponding to the N-terminal extracellular domain of AcChRs. The crystal structure is known (Lin et al. 2016). It modulates synaptic transmission (Smit et al. 2001). This soluble protein has enhanced our understanding of the requirements for agonistic and antagonistic interactions at the ligand recognition site of the nAChRs. Camacho-Hernandez and Taylor 2020 have reviewed the potential and limitations of soluble surrogates, termed the AChBP family, in drug development. |
Eukaryota | Metazoa, Mollusca | AchBP of Lymnaea stagnalis (great pond snail) (Helix stagnalis) |
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1.A.9.1.2 | The nicotinic acetylcholine activated cation selective channel precursor, Acr-2 or Acr-3/Unc-38 (both β and α-type chains are required for activity; levamisole-gated; activity reduced by antagonists mecamylamine and d-tubocurarine) (Squire et al., 1995; Baylis et al., 1997). nAChR and TRPC channel proteins (1.A.4) mediate nicotine addiction in many animals from humans to worms (Feng et al., 2006). Functions at synapses in the nervous system and at neuromuscular junctions (Towers et al. 2006). Neonicottinoides affect worm behavior and development (Kudelska et al. 2017). C. elegans has a large number of nAcChR genes, only some of which are retained in parasitic nematodes (Holden-Dye et al. 2013). RIC-3 is an nAcChR chaparone (Treinin 2008). |
Eukaryota | Metazoa, Nematoda | Acr-2 or Acr-3/Unc-38 of Caenorhabditis elegans |
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1.A.9.1.20 | Nicotinic acetylcholine receptor, nAChR subunit type B of 527 aas and 4 TMSs (Jiao et al. 2019).
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Eukaryota | Metazoa, Mollusca | nAChR of Lymnaea stagnalis (Great pond snail) (Helix stagnalis) |
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1.A.9.1.21 | Nicotinic acetylcholine receptor, nAChR with 4 subunits, Alpha1, 2, and 3 as well as beta1. Bradysia odoriphaga is a destructive insect pest, damaging more than 30 crop species. Nicotinic acetylcholine receptors (nAChRs) mediating fast excitatory transmission in the central nervous systems in insects are the molecular targets of some economically important insecticides including imidacloprid, which has been widely used to control B. odoriphaga in China since 2013. Shan et al. 2020 cloned seven nAChR subunit genes from B. odoriphaga, including Boα1, Boα2, Boα3, Boα7, Boα8, Boβ1 and Boβ3. They resemble the Drosophila melanogaster nAChR alpha1 subunit, including an extracellular N-terminal domain containing six functional loops (loop A-F), a signature Cys-loop with two disulfide bond-forming cysteines separated by 13 amino acid residues, and four typical TMSs 1 - 4) in the C-terminal region. Four of these subunits are included in TCDB. The nicotinic acetylcholine receptor nAChR, is involved in immune regulation in pearl oysters (Pinctada fucata martensii). Neonicotinoids are selective modulators of insect nAChRs. These insecticides interact with the orthosteric sites of nAChRs, not only to activate nAChRs, but also to block the desensitizing component of nAChR responses. Recombinant vertebrate and insect/vertebrate hybrid nAChRs have been deployed to understand the mechanism of selectivity and diversity of neonicotinoid actions as well as to show that both alpha/alpha and alpha/non-alpha interfaces are involved in the interactions with neonicotinoids (Matsuda 2021).
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Eukaryota | Metazoa, Arthropoda | nAChR of Bradysia odoriphaga |
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1.A.9.1.22 | Alpha9/alpha10 (α9α10) neuronal acetylcholine receptor with the two subunits of 450 aas (α9; Chrna9 or NACHRA9) and 479 aas (α10; Chrna10 or NACHRA10). It is an ionotropic receptor with a probable role in the modulation of auditory stimuli. Agonist binding induces a conformation change that leads to the opening of an ion-conducting channel across the plasma membrane (Sgard et al. 2002, Zouridakis et al. 2014). The channel is permeable to a range of divalent cations including calcium, the influx of which may activate a potassium current which hyperpolarizes the cell membrane (Zouridakis et al. 2014). In the ear, this may lead to a reduction in basilar membrane motion, altering the activity of auditory nerve fibers and reducing the range of dynamic hearing. This may protect against acoustic trauma, and may also regulate keratinocyte adhesion (Nguyen et al. 2000). Hair cell alpha9alpha10 nicotinic acetylcholine receptor functional expression is regulated by ligand binding and deafness gene products (Gu et al. 2020). Auditory hair cells receive olivocochlear efferent innervation, which refines tonotopic mapping, improves sound discrimination, and mitigates acoustic trauma. The olivocochlear synapse involves α9α10nAChRs which assemble in hair cells only coincident with cholinergic innervation and do not express in recombinant mammalian cell lines. Genome-wide screening determined that assembly and surface expression of α9α10 require ligand binding. Ion channel function additionally demands an auxiliary subunit, which can be transmembrane inner ear (TMIE) or TMEM132e. Both of these single-pass transmembrane proteins are enriched in hair cells and underlie nonsyndromic human deafness. Inner hair cells from TMIE mutant mice show altered postsynaptic α9α10 function and retain α9α10-mediated transmission beyond the second postnatal week associated with abnormally persistent cholinergic innervation. Thus, the mechanism links cholinergic input with α9α10 assembly, identifies functions for human deafness genes TMIE/TMEM132e, and enables drug discovery for this elusive nAChR implicated in prevalent auditory disorders (Gu et al. 2020). Point mutations in the nicotinic receptor alpha1 subunit can be responsible for slow-channel myasthenia (Kudryavtsev et al. 2021).
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Eukaryota | Metazoa, Chordata | Alpha9/alpha10 (α9α10) neuronal acetylcholine receptor of Homo sapiens |
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1.A.9.1.23 | Fusion protein with an N-terminal kinase domain (residues 1 - 268; homologous and 37% identical to TC# 8.A.104.1.5) and a C-terminal acetylcholine receptor-α domain (residues 278 - 744, 45% identical to TC# 1.A.9.1.15) of C. elegans. These observations could reflect the presence of true fusion proteins, or they could be a result of sequencing errors. |
Eukaryota | Metazoa, Nematoda | Fusion protein of Halicephalobus sp. NKZ332
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1.A.9.1.24 | The neuronal acetylcholine receptor subunit alpha-5, CHRNA5 or NACHRA5, of 468 aas and 4 TMSs. After binding acetylcholine, this AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. This subunit is similar to the α4 subunit. It regulates vulnerability to alcohol, cocaine and tobacco use disorders (Haller et al. 2014). |
Eukaryota | Metazoa, Chordata | Acetylcholine receptor subunit α5 of Homo sapiens |
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1.A.9.1.3 | Nicotinic acetylcholine receptor β-1 subunit , Accβ1 (a target of insecticides (Yu et al., 2011; Tricoire-Leignel and Thany 2010)). |
Eukaryota | Metazoa, Arthropoda | Accβ1 of Apis cerana (F6JX92) |
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1.A.9.1.4 | Nicotinic acetylcholine receptor β-2 subunit, Accβ2 (a target of insecticides) |
Eukaryota | Metazoa, Arthropoda | Accβ2 of Apis cerana (F6JVF4) |
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1.A.9.1.5 | Acetylcholine receptor subunit alpha-type acr-5 | Eukaryota | Metazoa, Nematoda | Acr-5 of Caenorhabditis elegans |
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1.A.9.1.6 | The α4β2 nicotinic acetylcholine receptor. The NMR structure of the transmembrane domain and the multiple anaesthetic binding sites are known (Bondarenko et al., 2012). Mutations cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE; Díaz-Otero et al. 2000). Nicotinic receptors are important therapeutic targets for neuromuscular disease, addiction, epilepsy and for neuromuscular blocking agents used during surgery. This system contributes to cognitive functioning through interactions with multiple neurotransmitter systems and is implicated in various CNS disorders, i.e., schizophrenia and Alzheimer's disease. It provides an extra layer of molecular complexity by existing in two different stoichiometries determined by the subunit composition. By potentiating the action of an agonist through binding to an allosteric site, positive allosteric modulators can enhance cholinergic neurotransmission (Grupe et al. 2015). Most pentameric receptors are heteromeric. Morales-Perez et al. 2016 presented the X-ray crystallographic structure of the human α4β2 nicotinic receptor, the most abundant nicotinic subtype in the brain. The side chains of alpha4 L257 (9') and alpha4L264 (16') may beresponsible for the main constrictions in the transmembrane pore (Yu et al. 2019). Mechanistic steps for communication proceed (1) through a signal generated via loop C in the principal subunit, (2) transmitted gradually and cumulatively to loop F of the complementary subunit, and (3) to the TMSs through the M2-M3 linker (Oliveira et al. 2019). A genetic variant of the nicotinic receptor α4-subunit causes sleep-related hyperkinetic epilepsy via increased channel opening (Mazzaferro et al. 2022). |
Eukaryota | Metazoa, Chordata | α4β2 NAChR of Homo sapiens |
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1.A.9.1.7 | The alpha7 (α-7) nicotinic acetylcholine receptor (alpha-7 nAcChR) of 502 aas is encoded by the CHRNA7 gene. Acetylcholine binding induces conformational changes that result in open channel formation; opening is blocked by α-bungarotoxin. The protein is a homopentamer. It interacts with RIC3 for proper folding and assembly. The nAChR, but not the glycine receptor, GlyR, exhibits hydrophobic gating (Ivanov et al. 2007). Low resolution NMR structures with associated anesthetics have been reported (Bondarenko et al. 2013). Allosteric modulators exhibit up to 5 distinct pharmacological effects (Gill-Thind et al. 2015). Based on pore hydration and size, a high resolution structure for the channel in the open conformation has been proposed (Chiodo et al. 2015). Agonists reduce dyskinesias in both early- and later-stage Parkinson's disease (Zhang et al. 2015). Monoterpenes inhibit the alpha7 receptor in the order: carveol > thymoquinone > carvacrol > menthone > thymol > limonene > eugenole > pulegone = carvone = vanilin. Among the monoterpenes, carveol showed the highest potency (Lozon et al. 2016). A revised structural model has been proposed (Newcombe et al. 2017). In humans, exons 5-10 in CHRNA7 are duplicated and fused to the FAM7A genetic element, giving rise to the hybrid gene CHRFAM7A. Its product, dupalpha7, is a truncated subunit lacking part of the N-terminal extracellular ligand-binding domain and is associated with neurological disorders, including schizophrenia, and immunomodulation (Lasala et al. 2018). alpha7 and dupalpha7 subunits co-assemble into functional heteromeric receptors, in which at least two alpha7 subunits are required for channel opening. Dupalpha7's presence in the pentameric arrangement does not affect the duration of the potentiated events. Using an alpha7 subunit mutant, activation of (alpha7)2(dupalpha7)3 receptors occurs through ACh binding at the alpha7/alpha7 interfacial binding site (Lasala et al. 2018). B-973 is an efficacious type II positive allosteric modulator (PAM) of alpha7 nicotinic acetylcholine receptors that, like 4BP-TQS and its active isomer GAT107, is able to produce direct allosteric activation in addition to potentiation of orthosteric agonist activity, which identifies it as an ago-PAM (Quadri et al. 2018). DB04763, DB08122 and pefloxacin are antagonists (they are NAMs) while furosemide potentiated ACh responses (it is a Pam) (Smelt et al. 2018). At nM concentration, APPsα (amyloid precursor protein) is an allosteric activator of α7-nAChR, mediated by the C-terminal 16 amino acids (CTα16) (Korte 2019). At µM concentrations, Rice et al. 2019 identified the GABABR1a as a target of APPsα, binding the sushi 1 domain via a 17–amino acid sequence (17-mer). These receptors activate opposing downstream cascades. The intrasubunit cavity of the α7 AcChR is important for the activity of type II positive allosteric modulators while the ECD-TMD junction and intersubunit sites are probably important for the activity of type I positive allosteric modulators (Targowska-Duda et al. 2019). Flavonoids are positive allosteric modulators of alpha7 nicotinic receptors (Nielsen et al. 2019). Active and desensitized state conformations have been examined (Chiodo et al. 2018). Modulators are able to activate or deactivate a7 receptors via allosteric binding; they are called positive allosteric modulators (PAMs) or negative allosteric modulators (NAMs) (Al Rawashdah et al. 2019). Functional divergence related sites cluster in the ligand binding domain, the beta2-beta3 linker close to the N-terminal alpha-helix, the intracellular linkers between transmembrane domains, and the "transition zone" (Pan et al. 2019). A series of phosphonate-functionalized 1,2,3-triazoles are positive allosteric modulators of alpha7 nicotinic acetylcholine receptors (Nielsen et al. 2020). The E-1' --> A-1' substitution at the cytoplasmatic selectivity filter strongly affects sodium and chloride permeation in opposite directions, leading to a complete inversion of selectivity. Thus, structural determinants for the observed cationic-to-anionic inversion reveal a key role of the protonation state of residue rings far from the mutation, in the proximity of the hydrophobic channel gate (Cottone et al. 2020). Outer membrane mitochondrial nAChRs (e.g., α7 NAChR) regulate apoptosis-induced mitochondrial channel formation by modulating the interplay of apoptosis-related proteins (VDAC1 and Bax) in the mitochondrial outer membrane (Kalashnyk et al. 2020). PNU-120596, a positive allosteric modulator of mammalian alpha7 nicotinic acetylcholine receptor, increases the neuron response to alpha7 agonists while retarding desensitization (Vulfius et al. 2020). Differential interactions of resting, activated, and desensitized states of the alpha7 nicotinic acetylcholine receptor with lipidic modulators have been decumented (Zhuang et al. 2022). Structural elucidation of ivermectin binding to alpha7nAChR revealed the induced channel desensitization mechanism (Bondarenko et al. 2023). Enhancing effects of nicotine in the smooth muscle of the rabbit bladder possibly play roles in nicotines' effect, and the enhancing effect of nicotine on electrical field stimulation elicited contractile responses in isolated rabbit bladder straight muscle; the role of cannabinoid and vanilloid receptors have been discussed (İlhan et al. 2022). The α7 nAcChR is a key receptor in the cholinergic anti-inflammatory pathway, exerting an anti-depressant effect (Liu et al. 2023). α7-selective positive allosteric modulators (PAMs) bind to an inter-subunit site located in the transmembrane domain, but there are differing hypotheses about the site or sites at which allosteric agonists bind to α7 nAChRs. Available evidence supports the conclusion that direct allosteric activation by allosteric agonists occurs via the same inter-subunit transmembrane site that has been identified for several alpha7-selective PAMs (Sanders and Millar 2023). DM506 (3-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole fumarate), a derivative of ibogamine, inhibits α7 and α9-α10 nicotinic acetylcholine receptors by different allosteric mechanisms (Tae et al. 2023). Side groups convert the alpha7 nicotinic receptor agonist ether quinuclidine into a type I positive allosteric modulator. Ligand 6 is a novel type I positive allosteric modulator (PAM-I) of alpha7 nAChR (Viscarra et al. 2023). |
Eukaryota | Metazoa, Chordata | The homomeric α7 acetylcholine receptor of Homo sapiens |
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1.A.9.1.8 | Nicotinic receptor, nAChRalpha7, of 560 aas and 5 TMSs. The beta-amyloid protein (TC# 1.C.50.1.1) can activate the nAChRalpha7 receptor (Hassan et al. 2019). |
Eukaryota | Metazoa, Arthropoda | Nicotinic receptor, nAChRalpha7, of Drosophila melanogaster |
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1.A.9.1.9 | The cation-selective pentameric nicotinic acetylcholine receptor, nAChR, with α (461 aas; P02710), β (493 aas; P02712), γ (506 aas; P02714) and δ (522 aas; P02718) subunits. The transmembrane domain of the uncoupled nAChR adopts a conformation distinct from that of the resting or desensitized state (Sun et al. 2016). Studies with this receptor have been reviewed (Unwin 2013). Many small molecules interact with nAChRs including d-tubocurarine, snake venom protein α-bungarotoxin (α-Bgt), and α-conotoxins, neurotoxic peptides from Conus snails. Various more recently discovered compounds of different structural classes also interact with nAChRs including the low-molecular weight alkaloids, pibocin, varacin and makaluvamines C and G. 6-Bromohypaphorine from the mollusk Hermissenda crassicornis does not bind to Torpedo nAChR but behaves as an agonist on human α7 nAChR (Kudryavtsev et al. 2015). Dimethylaniline mimics the low potency and non-competitive actions of lidocaine on nAChRs, as opposed to the high potency and voltage-dependent block by lidocaine (Alberola-Die et al. 2016). Cholesterol is a potent modulator of the Torpedo nAChR (Baenziger et al. 2017). Cholesterol may play a mechanical role by conferring local rigidity to the membrane so that there is productive coupling between the extracellular and membrane domains, leading to opening of the channel (Unwin 2017). 11beta-(p-azidotetrafluorobenzoyloxy)allopregnanolone (F4N3Bzoxy-AP), a general anesthetic, a photoreactive allopregnanolone analog and a potent GABAAR PAM,was used to characterize steroid binding sites in the Torpedo nAChR in its native membrane environment (Yu et al. 2019). The steroid-binding site in the nAChR ion channel was identified, and additional steroid-binding sites could also be occupied by other lipophilic nAChR antagonists. Structural features of the αM4 TMS determine how lipid dependent changes in alphaM4 structure may ultimately modify nAChR function (Thompson et al. 2020). The positive allosteric modulators (PAMs) of the alpha7 nicotinic receptor, N-(5-Cl-2-hydroxyphenyl)-N'-[2-Cl-5-(trifluoromethyl)phenyl]-urea (NS-1738) and (E)-3-(furan-2-yl)-N-(p-tolyl)-acrylamide (PAM-2) potentiate the alpha1beta2gamma2L GABA(A) receptor through interactions with the classic anesthetic binding sites located at intersubunit interfaces in the transmembrane domain of the receptor. Pierce et al. 2023 employed mutational analysis to investigate the involvement and contributions made by the individual intersubunit interfaces to receptor modulation by NS-1738 and PAM-2. They showed that mutations to each of the anesthetic-binding intersubunit interfaces (beta+/alpha-, alpha+/beta-, and gamma+/beta-), as well as the orphan alpha+/gamma- interface, modify receptor potentiation by NS-1738 and PAM-2. Mutations to any single interface can fully abolish potentiation by the alpha7-PAMs (Pierce et al. 2023). |
Eukaryota | Metazoa, Chordata | nAChR of Tetronarce californica (Pacific electric ray) (Torpedo californica) |
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1.A.9.10.1 | Cyc-loop anion ligand-gated receptor of 453 aas and 6 TMSs, LIC1 (Mukherjee 2015). |
Eukaryota | Viridiplantae, Chlorophyta | LIC1 of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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1.A.9.10.2 | Uncharacterized ligand-gated ion channel of 539 aas and 4 TMSs. |
Eukaryota | Viridiplantae, Chlorophyta | Uncharacterized LIC of Chlorella variabilis (Green alga) |
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1.A.9.2.1 | Serotonin (5-hydroxytryptamine)-activated cation-selective receptor/channel, 5-HT3R. Residues in TMS2 and the cytoplasmic loop linking TMSs 3 and 4 influence conductance, selectivity, gating and desensitization (Peters et al., 2010; McKinnon et al., 2011). Resveratrol enhances ion currents (Lee et al., 2011). Rings of charge within the extracellular vestibule influence ion permeation (Livesey et al., 2011). Based on the 3-d structure, serotonin binding first induces distinct conformational fluctuations at the side chain of W156 in the highly conserved ligand-binding cage, followed by tilting-twisting movements of the extracellular domain which couple to the transmembrane TM2 helices, opening the hydrophobic gate at L260 and forming a continuous transmembrane water pathway (Yuan et al. 2016). There are 5 isoforms of 5-HT3A which include 5-HT3AB, 5-HT3AC, 5-HT3AD, and 5-HT3AE, all of which have similar but distinct pharmacological profiles compared to those of 5-HT3A receptors (Price et al. 2017). Trans-3-(4-methoxyphenyl)-N-(pentan-3-yl)acrylamide (TMPPAA) is a potent agonist with behavior different from that of 5-HT (Gasiorek et al. 2016). Two serotonin-bound structures of the full-length 5-HT3A receptor in distinct conformations reveal the mechanism underlying channel activation (Basak et al. 2018). The trans-cis isomerization of a proline at the interface between the extracellular and transmembrane domain may be the switch between closed and open states of the channel (Crnjar et al. 2019). SR 57227A is the most commonly used 5-HT3 receptor agonist with the ability to cross the blood brain barrier (Nakamura et al. 2019). Picrotoxin antagonizes serotonin (5-HT)3 receptors in a subunit-dependent fashon (Das and Dillon 2005). It interacts directly with the chaparone protein, Ric-3, (TC# 8.A.71.1.1) (Pirayesh et al. 2019). A nanopore based on the 5-HT3 receptor channel (see TC# 1.A.9.2.1) responds to an electric field than induces wetting of the hydrophobic gate (Klesse et al. 2020). Cholesterol content in the membrane promotes key lipid-protein interactions (Crnjar and Molteni 2021). Triple arginines are molecular determinants for pentameric assembly of the intracellular domain of 5-HT3A receptors (Pandhare et al. 2019). Five different subunits of the human serotonin (5-HT3) receptor exist and these are present in both central and peripheral systems. Different subunits alter the efficacy of 5-HT3 receptor antagonists used to treat diarrhoea predominant-irritable bowel syndrome, chemotherapy induced nausea and vomiting and depression. Cells transfected with either fluorescent protein tagged A or A and C subunits generate whole cell currents in response to 5-HT. The A and C subunits associate forming AC heteromer complexes at or near the cell surface, and a proportion can also form A or C homomers. Both A homomers and AC heteromers contribute to whole cell currents in response to 5-HT with minimal contribution from C homomers (Abad et al. 2020). It is a biomarker for endometriosis (EM), a common gynecological disorder that often leads to irregular menstruation and infertility (Jiang et al. 2022).Perić et al. 2022 have summarized information on the location of the components of the serotonin system in the human placenta, their regulation, function, and alterations in pathological pregnancies. Molecular dynamics refinement of open state serotonin 5-HT(3A) receptor structures have been reported (Li et al. 2023). The structures of tetrameric forms of the serotonin-gated 5-HT3A receptor ion channel have been determined (Introini et al. 2024). The tetrameric structures have near-symmetric transmembrane domains, but asymmetric extracellular domains, and can bind serotonin. The cryo-EM structures were used to decipher the assembly pathway of pentameric 5-HT3R and suggest a potential functional role for the tetrameric receptors (Introini et al. 2024). |
Eukaryota | Metazoa, Chordata | Serotonin (5HT3) receptor (5HT3R) of Homo sapiens (P46098) |
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1.A.9.2.2 | The heteromeric serotonin 5HT3A receptor (Hanna et al., 2000). The influences of serotonin on single neurons, neural networks, and cortical circuits in the prefrontal cortex (PFC) of the rat is where the effects of serotonin have been most thoroughly studied (Puig and Gulledge 2011). |
Eukaryota | Metazoa, Chordata | The 5HT3A/5HT3B receptor of Rattus norvegicus |
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1.A.9.2.3 | The 5-hydroxytryptamine (serotonin) receptor-3A receptor/cation-selective ion channel, 5-HT3AR, of 454 aas. The channel is activated by the binding of serotonin to an extracellular orthosteric site, located at the interface of two adjacent receptor subunits. A variety of compounds modulate agonist-evoked responses of 5-HT3ARs and other Cys-loop receptors by binding to distinct allosteric sites (Lansdell et al. 2014). Alternative intersubunit pathways may exist for ion translocation at the interface between the extracellular and the transmembrane domains, in addition to the one along the channel main axis. An arginine triplet located in the intracellular domain may determine the characteristic low conductance properties of the channel (Di Maio et al. 2015). The 12 Å resolution structure of the protein in a lipid bilayer (cryo EM) reveals topological features (Kudryashev et al. 2016). A chimeric receptor consisting of the extracellular domain of the 5-HT3A receptor and the transmembrane domain of a prokaryotic homologue, ELIC has been constructed (Price and Lummis 2018). The resulting receptor responds to 5-HT. Partial agonists and competitive antagonists activate and inhibit the chimera. Examination of a range of receptor modulators including ethanol, thymol, 5-hydroxyindole, and 5-chloroindole suggest that these compounds act via the transmembrane domain, except for 5-hydroxyindole, which can compete with 5-HT at the orthosteric binding site (Price and Lummis 2018). The receptor has 4 TMSs, M1 - M4, and Y441 in M4 interacts with D238 in M1, W459 in M4 interacts with F144 in the Cys loop, and D434 in M4 interacts with R251 in M2 according to the residue numbering system of Mesoy et al. 2019. This suggests that M4 helicies in LIC receptors interact with other parts of these receptors differently. Amino acid residues involved in agonist binding, linked to channel gating, that are proximal to the transmembrane domain for halothane modulation have been identified (Kim et al. 2009). Microsecond-timescale simulations suggest 5-HT mediates preactivation of the 5-HT3A serotonin receptor (Guros et al. 2019). Minimal structural rearrangement of the cytoplasmic pore occur during activation (Panicker et al. 2004). The intracellular domain starts with a short loop after the third TMS, followed by a short alpha-helical segment, a large unstructured loop, and finally, the membrane-associated MA-helix that continues into the last TMS (Stuebler and Jansen 2020). The MA-helices from all five subunits form the extension of the transmembrane ion channel and shape what has been described as a "closed vestibule," with the lateral portals obstructed by loops and their cytosolic ends forming a tight hydrophobic constriction. Although conformational changes associated with gating promote cross-linking for I409C/R410C, which in turn decreases channel currents, cross-linking of L402C/L403C is functionally silent in macroscopic currents. These results support the hypothesis that concerted conformational changes open the lateral portals for ion conduction, rendering ion conduction through the vertical portal unlikely (Stuebler and Jansen 2020). |
Eukaryota | Metazoa, Chordata | 5HT3AR of Homo sapiens |
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1.A.9.2.4 | Zinc-activated ligand-gated cation channel of 412 aas and 5 TMSs, ZACN; ZAC. Zac displays potencies and efficacies in the rank orders of H+>Cu2+>Zn2+ and H+>Zn2+>Cu2+, respectively. ZAC appears to be non-selectively permeable to monovalent cations, whereas Ca2+ and Mg2+ inhibit the channel (Trattnig et al. 2016). ZAC is an atypical cys-loop receptor in terms of its identified agonists and channel characteristics, but its signal transduction seems to undergo similar conformational transitions as those in other members of the family (Madjroh et al. 2021). N-(thiazol-2-yl)-benzamide analogs comprise a class of selective antagonists of ZAC (Madjroh et al. 2021). It transports monovalent cations (Lu et al. 2025). |
Eukaryota | Metazoa, Chordata | Zac of Homo sapiens |
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1.A.9.2.5 | The 5-hydroxytryptamine (serotonin) receptor 3B, HTR3B, of 441 aas and 4 or 5 TMSs in a 1 (N-terminal) + 2 or 3 (residues 240 - 320) + 1 TMS (C-terminal). This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor is a ligand-gated ion channel, which when activated, causes fast, depolarizing responses. It is a cation-specific, but otherwise relatively nonselective, ion channel (Kelley et al. 2003). The MX helix on the cytoplasmic side of the membrane can modulate the function of the receptor, and its interactions with membrane lipids play a major role (Mocatta et al. 2022). |
Eukaryota | Metazoa, Chordata | 5HT3B receptor of Homo sapiens |
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1.A.9.2.6 | Zinc-activated ligand-gated ion channel isoform X1, ZACN-X1, of 662 aas and 11 TMSs in a 4 + 1 + 3 + 1 TMS arrangement. The first 4 TMSs (about residues 1 - 244) are homologous to residues 153 - 398 in the opioid receptor (TC# 9.A.14.13.18) while most of the rest of the protein is homologous to TC# 1.A.9.2.4 (residues ~191 - 662). This latter region shows a 3 + 1 TMS arrangement as is true for most members of the LIC family proteins. |
Eukaryota | Metazoa, Chordata | ZACN-X1 of Odocoileus virginianus texanus |
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1.A.9.3.1 | Adult strychnine-sensitive glycine-inhibited chloride (anion selective) heteropentameric channel (GlyR; GLRA1) consisting of α1- and β-subunits (Cascio, 2004; Sivilotti, 2010). Ivermectin potentiates glycine-induced channel activation (Wang and Lynch, 2012). Molecular sites for the positive allosteric modulation of glycine receptors by endocannabinoids have been identified (Yévenes and Zeilhofer, 2011). Different subunits contribute asymmetrically to channel conductances via residues in the extracellular domain (Moroni et al., 2011; Xiong et al., 2012). Dominant and recessive mutations in GLRA1 are the major causes of hyperekplexia or startle disease (Gimenez et al., 2012). Open channel 3-d structures are known (Mowrey et al. 2013). Desensitization is regulated by interactions between the second and third transmembrane segments which affect the ion channel lumen near its intracellular end. The GABAAR and GlyR pore blocker, picrotoxin (TC# 8.C.1), prevents desensitization (Gielen et al. 2015). The x-ray structure of the α1 GlyR transmembrane domain has been reported (Moraga-Cid et al. 2015), and residue S296 in hGlyR-alpha1 is involved in potentiation by Delta(9)-tetrahydrocannabinol (THC) (Wells et al. 2015). The structure has also been elucidated by cryo EM (Du et al. 2015) and by x-ray crystalography (Huang et al. 2015). The latter presented a 3.0 A X-ray structure of the human glycine receptor-alpha3 homopentamer in complex with the high affinity, high-specificity antagonist, strychnine. The structure allowed exploration of the molecular recognition of antagonists. Comparisons with previous structures revealed a mechanism for antagonist-induced inactivation of Cys-loop receptors, involving an expansion of the orthosteric binding site in the extracellular domain that is coupled to closure of the ion pore in the transmembrane domain. The GlyR beta8-beta9 loop is an essential regulator of conformational rearrangements during ion channel opening and closing (Schaefer et al. 2017). Association of GlyR with the anchoring protein, gephyrin (Q9NQX3), is due to a hydrophobic interaction formed by Phe 330 of gephyrin and Phe 398 and Ile 400 of the GlyR beta-loop (Kim et al. 2006). Alcohols and volatile anesthetics enhance the function of inhibitory glycine receptors (GlyRs) by binding to a single anaesthetic binding site (Roberts et al. 2006). Aromatic residues in the GlyR M1, M3 and M4 α-helices are essential for receptor function (Tang and Lummis 2018). The neurological disorder, startle disease, is caused by glycinergic dysfunction, mainly due to missense mutations in genes encoding GlyR subunits (GLRA1 and GLRB). Another neurological disease with a phenotype similar to startle disease is a special form of stiff-person syndrome (SPS), which is most probably due to the development of GlyR autoantibodies (Schaefer et al. 2018). GlyRs can be modulated by positive allosteric modulators (PAMs) that target the extracellular, transmembrane and intracellular domains (Lara et al. 2019). Mutations in GLRA1 give rise to hyperekplexia (Milenkovic et al. 2018). Neurosteroid binding sites of GABAARs are conserved in the GlyRs (Alvarez and Pecci 2019). The intracellular domain of homomeric glycine receptors modulates agonist efficacy (Ivica et al. 2020). Inhibitory glycinergic transmission in the adult spinal cord is primarily mediated by glycine receptors (GlyRs) containing the alpha1 subunit. Alpha1ins, a longer alpha1 variant with 8 amino acids inserted into the intracellular large loop between TMSs 3 and 4, is expressed in the dorsal horn of the spinal cord, distributed at inhibitory synapses, and it is engaged in negative control over nociceptive signal transduction. Activation of metabotropic glutamate receptor 5 (mGluR5; TC# 9.A.14.7.1) specifically suppressed alpha1ins-mediated glycinergic transmission and evoked pain sensitization. Extracellular signal-regulated kinase (ERK) was critical for mGluR5 to inhibit alpha1ins. By binding to a D-docking site created by the 8-amino-acid insert ERK catalyzed alpha1ins phosphorylation at Ser380, which favored alpha1ins ubiquitination at Lys379 and led to alpha1ins endocytosis. Disruption of the ERK interaction with alpha1ins blocked Ser380 phosphorylation, potentiated glycinergic synaptic currents, and alleviated inflammatory and neuropathic pain (Zhang et al. 2019). The startle disease mutation (αS270T) affects the opening state for activation of presynaptic homomeric GlyRs, as well as postsynaptic heteromeric GlyRs, but the former are affected more. Both respond to glycine less efficiently (Wu et al. 2020). Cannabinoids exert therapeutic effects on several diseases such as chronic pain and startle disease by targeting glycine receptors (GlyRs). They target a serine residue at position 296 in the third TMS of the alpha1/alpha3 GlyR on the outside of the channel at the lipid interface where cholesterol concentrates. GlyRs are associated with cholesterol/caveolin-rich domains. and cholesterol reduction significantly inhibits cannabinoid potentiation of glycine-activated currents (Yao et al. 2020). Residues involved in glucose sensitivity of recombinant human glycine receptors have been identified (Hussein et al. 2020). Lipid-protein interactions are dependent on the receptor state, suggesting that lipids may regulate the receptor's conformational dynamics ((Dämgen and Biggin 2021)). Some protein-lipid interactions occur at a site at the communication interface between the extracellular and transmembrane domain, and in the active state, cholesterol can bind to the binding site of the positive allosteric modulator, ivermectin (Dämgen and Biggin 2021). An intracellular domain determines the agonist specificity (Ivica et al. 2021). The general anesthetic etomidate and fenamate mefenamic acid oppositely affect GABAAR and GlyR. These drugs potentiated GABAARs but blocked GlyRs (Rossokhin 2020). Alpha 1 glycine receptors are strongly inhibited by two flavanoids, quercetin and naringenin (Breitinger et al. 2021). The glycine receptor beta-subunit A455P variant occurs in a family affected by hyperekplexia syndrome (Aboheimed et al. 2022). Evidence for distinct roles of conserved proline residues in GlyR has been presented (Lummis and Dougherty 2022). Cannabinoids in general, and THC in particular, modulate pain perception via GlyR with possible clinical applications (Alvarez and Alves 2022). A set of functionally essential but differentially charged amino-acid residues in the transmembrane domain of the alpha1 and beta subunits explains asymmetric activation. These findings point to a gating mechanism that is distinct from homomeric receptors but more compatible with heteromeric GlyRs, being clustered at synapses through beta subunit-scaffolding protein interactions (Liu and Wang 2023). Such a mechanism provides a foundation for understanding how gating of the Cys-loop receptor members diverge to accommodate a specific physiological environment. Gallagher et al. 2022 reviewed the structural basis for how current compounds cause positive allosteric modulation of glycine receptors and discusses their therapeutic potential as analgesics. Gibbs et al. 2023 demonstrated distinct compositional and conformational properties of α1βGlyR. A glycine-elicited conformational change precedes pore opening. Low concentrations of glycine, partial agonists or specific mixtures of glycine and strychnine trigger weakly activating the channel (Shi et al. 2023). Molecular dynamic simulations of a partial agonist bound-closed Cryo-EM structure reveal a highly dynamic nature: a marked structural flexibility at both the extracellular-transmembrane interface and the orthosteric site, generating docking properties. A progressive propagating transition towards channel opening highlights structural plasticity within the mechanism of action of allosteric effectors (Shi et al. 2023). The spatiotemporal expression pattern of the GlyR alpha4 subunit has been studied, and the results suggest that glycinergic signaling modulates social, startle, and anxiety-like behaviors in mice (Darwish et al. 2023). Human alpha1beta GlyR is a major Cys-loop receptor that mediates inhibitory neurotransmission in the central nervous system of adults. Glycine binding induces cooperative and symmetric structural rearrangements in the neurotransmitter-binding extracellular domain but asymmetrical pore dilation in the transmembrane domain. SA symmetric response in the extracellular domain is consistent with electrophysiological data showing cooperative glycine activation and contribution from both alpha1 and beta subunits. A set of functionally essential but differentially charged amino acid residues in the transmembrane domain of the alpha1 and beta subunits explains asymmetric activation (Liu and Wang 2023). Modelling and molecular dynamics predict the structure and interactions of the glycine receptor intracellular domain (Thompson et al. 2023). Multiple cannabinoid-binding sites are present for the allosteric regulation of GlyR (Bartocci et al. 2024). |
Eukaryota | Metazoa, Chordata | Glycine receptor of heteromeric α1/ β-subunit channels (GlyR) of Homo sapiens |
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1.A.9.3.2 | Photoreceptor in large monopolar cells (LMCs) histamine-gated chloride channel, HclA (Ort) (forms homomers, and heteromers with HclB; homomers resemble native LMC receptors (Pantazis et al., 2008)). hclA mutations lead to defects in the visual system, neurologic disorders and changed responsiveness to neurotoxins (Iovchev et al. 2006).
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Eukaryota | Metazoa, Arthropoda | HclA of Drosophila melanogaster (A1KYB4) |
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1.A.9.3.3 | Photoreceptor LMC histamine-gated chloride channel HclB (HisCl1) (forms homomers as well as heteromers with HclA; homomers and heteromers are more sensitive to histamine but with smaller conductance that of HclA (Pantazis et al., 2008)). | Eukaryota | Metazoa, Arthropoda | HclB of Drosophila melanogaster (NP_731632) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.9.3.4 | Glutamate receptor of 552 aas, GluCl-2 (Lynagh et al. 2014). |
Eukaryota | Metazoa, Platyhelminthes | GluCl-2 of Schistosoma mansoni (Blood fluke) |
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1.A.9.3.5 | The low-affinity serotonin receptor, Lgc-40; also gated by choline and acetylcholine (Ringstad et al., 2009). | Eukaryota | Metazoa, Nematoda | Lgc-40 of Caenorhabditis elegans (Q22741) |
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1.A.9.3.6 | Glycine receptor, GlyR or GlyREM with two subunits, Glra4a (subunit GlyRα; 459 aas) and Glra4b (subunit Glrb or GlyRβ; 498 aas). These subunits are about 80% identical to the human subunits (TC# 1.A.9.3.1). Agonists include glycine, β-alanine, GABA and taurine (Ivica et al. 2021). Intracellular loop domains (ICD) in part determine the agonist specificity and efficiency (Ivica et al. 2021). Lateral fenestrations between subunits in the extracellular domain provide the main translocation pathway for chloride ions to enter/exit a central water-filled vestibule at the entrance of the transmembrane channel (Cerdan et al. 2022). |
Eukaryota | Metazoa, Chordata | GlyRα/GlyRβ of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.A.9.3.7 | Histamine-gated chloride channel 2 (HACl2) of 425 aas and 4 TMSs. HACls mediate fast inhibitory neurotransmission in invertebrate nervous systems and have important roles in light reception, color processing, temperature preference and light-dark cycles. The fall armyworm, Spodoptera frugiperda is a primary destructive pest of grain and row crops (Yin et al. 2021). Histamine (HA) and gamma-aminobutyric acid (GABA) activated inward currents when SfHACls were singly or collectively expressed with different ratios in Xenopus laevis oocytes. These channels were ~2000-fold more sensitive to HA than to GABA. They were anion-selective channels that were highly dependent on changes in external chloride concentrations, but insensitive to changes in external sodium concentrations. The insecticides abamectin (ABM) and emamectin benzoate (EB) also activated these channels (Yin et al. 2021). |
Eukaryota | Metazoa, Arthropoda | HACl of Spodoptera frugiperda (fall armyworm) |
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1.A.9.4.1 | Glutamate-inhibited chloride (anion-selective) channel, CIα chain. This protein is 98% identical to the ortholog in Musca domestica (the house fly). Fluralaner (Bravecto) is an isoxazoline ectoparasiticide which potently inhibits GABA-gated chloride channels (GABACls) and less potently glutamate-gated chloride channels (GluCls) in insects. The amino acid, Leu315, in Musca GluCls is important in determining the selectivity of fluralaner and ivermectin which react in opposite ways (Nakata et al. 2017). Fipronil is a GABA-gated chloride channel blocker (Pfaff et al. 2021). The differential response to avermectin of Caligus rogercresseyi GluCl subunits, which are highly conserved in the Northern hemisphere sea louse Lepeophtheirus salmonis, could have an influence on the response of these parasites to treatment with macrocyclic lactones (Tribiños et al. 2023). |
Eukaryota | Metazoa, Arthropoda | Glutamate receptor CIα chain of Drosophila melanogaster |
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1.A.9.4.2 | Glutamate-gated chloride channel (GluClα or Glc-1) (α-subunits when mutated confer resistance to the antiparisitic drug, avermectin (ivermectin) (Dent et al., 2000)). A naturally occurring 4-aa deletion in the ligand binding domain of Glc-1 confers resistance to avermectin (Ghosh et al., 2012). Several 3-d structures are known (3RIF; Hibbs and Gouaux, 2011). Ivermectin (avermectin; IVM), an anthelmintic drug, inhibits neuronal activity and muscular contractility in arthropods and nematodes, activating glutamate-gated chloride channels at nanomolar concentrations (Lynagh and Lynch, 2012; Calimet et al. 2013; Degani-Katzav et al. 2017). Ivermectin resistance has been studied in Haemonchus contortus (the Barber pole worm) leading to the conclusion that mutations to ivermectin resistance affected the intrinsic properties of the receptor with no specific effect on IVM binding (Atif et al. 2017). Glutamate binding triggers a rapidly reversible current in heteromeric channels formed by Glc-1 and Glc-2, while the anti-helmintic drug ivermectin and other avermectins trigger a permanently open channel configuration. Channels containing only Glc-1 are activated by ivermectin, but not by glutamate alon, and Glutamate binding triggers a rapidly reversible current in heteromeric channels formed by Glc-1 and Glc-2, while the anti-helmintic drug ivermectin and other avermectins including ibotenate trigger a permanently open channel configuration. Channels containing only Glc-1 are activated by ivermectin, but not by glutamate alone. The channel is blocked by picrotoxin and flufenamic acid (Cully et al. 1994; Das and Dillon 2005). A database of glutamate-gated chloride (GluCl) subunits across 125 nematode species reveals patterns of gene accretion and sequence diversification (O'Halloran 2022). The gene encoding this protein is expressed at varying levels in response to the presence of ivermectin (Dube et al. 2023). |
Eukaryota | Metazoa, Nematoda | GluCl of Caenorhabditis elegans |
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1.A.9.4.3 | Glutamate-gated chloride channel, GluC1 or Glc-4 (Yamaguchi et al., 2012). Ivermectin, an anthelminthic drug, inhibits neuronal activity and muscular contractility in arthropods and nematodes, activating glutamate-gated chloride channels at nanomolar concentrations (Lynagh and Lynch, 2012; Zemkova et al. 2014). Mutations in GluCl associated with field ivermectin-resistant head lice have been identified (Amanzougaghene et al. 2018). |
Eukaryota | Metazoa, Nematoda | GluC1 of Haemonchus contortus (P91730) |
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1.A.9.4.4 | Glc-4 (GluC1) glutamate receptor of 500 aas. The x-ray structure of several states including two apo states have been solved, revealing the gating mechanism of cys-loop receptors (Althoff et al. 2014). Ligand-induced conformational gating has been proposed (Yoluk et al. 2015). Effects of L-glutamate, ivermectin, ethanol and anesthetics have been examined (Heusser et al. 2016). |
Eukaryota | Metazoa, Nematoda | Glc-4/GluC1 of Caenorhabditis elegans |
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1.A.9.4.5 | Glutamate-gated chloride channel of 448 aas, GluCl. A point mutation, A309V in TMS 3, renders the protein and the organism > 11,000-fold resistant to abamectin, an insecticide of this moth, which is a global pest of cruciferous vegetables (Wang et al. 2015). Both A309V and G315E mutations contribute to target-site resistance to abamectin (Wang et al. 2017). Fluralaner (Bravecto) is an isoxazoline ectoparasiticide which potently inhibits GABA-gated chloride channels (GABACls) and less potently glutamate-gated chloride channels (GluCls) in insects. The amino acid, Leu315, in Musca (fly) GluCls is important in determining the selectivity of fluralaner and ivermectin which react in opposite ways (Nakata et al. 2017).
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Eukaryota | Metazoa, Arthropoda | GluCl of Plutella xylostella (Diamondback moth) (Plutella maculipennis) |
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1.A.9.4.6 | Glutamate-gated chloride channel exon 3c variant of 447 aas and 5 TMSs. Okaramines produced by Penicillium simplicissimum AK-40 activate l-glutamate-gated chloride channels (GluCls) and thus paralyze insects. The B. mori GluCl containing the L319F mutation retained its sensitivity to l-glutamate, but responses to ivermectin were reduced and those to okaramine B were completely eliminated (Furutani et al. 2017). |
Eukaryota | Metazoa, Arthropoda | GluCl of Bombyx mori (Silk moth) |
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1.A.9.4.7 | Ligand-gated ion channel, Lgc-34 of 390 aas and 4 TMSs. IGDB-2, an Ig/FNIII protein, binds LGC-34 to control sensory compartment morphogenesis (Wang et al. 2017). |
Eukaryota | Metazoa, Nematoda | LGC-34 of Caenorhabditis elegans |
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1.A.9.5.1 | γ-Aminobutyric acid (GABA)-inhibited chloride channel, GABARA1 or GABAAR. The major central endocannabinoid, 2-arachidonoyl glycerol (2-AG), directly acts at GABA(A) receptors. It potentiates the receptor at low GABA concentrations (Sigel et al., 2011). Hydrophobic anions potently and uncompetitively antagonize GABA (A) receptor function (Chisari et al., 2011). Regulated by neurosteroids; activated by pregnenolone and allopregnenalone (Costa et al., 2012). Different subunits contribute asymmetrically to channel conductances via residues in the extracellular domain (Moroni et al., 2011). Potentiated by general anaesthetics (Nury et al., 2011). Direct physical coupling between the GABA-A receptor and the KCC2 chloride transporter underlies ionic plasticity in cerebellar purkinje neurons in response to brain-derived neurotrophic factor (BDNF) (Huang et al. 2013). GABA type A receptors, the brain's major inhibitory neurotransmitter receptors, are the targets for many general anesthetics, including volatile anesthetics, etomidate, propofol, and barbiturates. Anesthetics usually bind at intersubunit sites (Chiara et al. 2013). Etomidate and propofol are potent general anesthetics that act via GABAA receptor allosteric co-agonist sites located at transmembrane beta+/alpha- inter-subunit interfaces. In heteromeric receptors, betaN265 (M2-15') on beta2 and beta3 subunits are important determinants of sensitivity to these drugs (Stewart et al. 2014). A P302L mutation in the gamma2 (γ2) subunit (Dravet syndrome in humans) of the mouse when expressed with the α1 and β3 subunits, produced a 90% decrease in conductance due to slow activation and enhance desensitization. It shifted the channel to a low-conductance state by reshaping the hour-glass-like pore cavity during transitions between closed, open, and desensitized states (Hernandez et al. 2017). Numerous postive and negative allosteric modulators have been identified (Maldifassi et al. 2016). Crystal structures of neurosteroids bound to alpha homopentameric GABAARs have revealed binding to five equivalent sites (Alvarez and Pecci 2018). Masiulis et al. 2019 reported high-resolution cryo-EM structures in which the full-length human alpha1beta3gamma2L GABAA receptor in lipid nanodiscs is bound to (1) the channel-blocker picrotoxin, (2) the competitive antagonist bicuculline, (3) the agonist GABA, and (4 AND 5) the classical benzodiazepines alprazolam and diazepam. They described the binding modes and mechanistic effects of these ligands, the closed and desensitized states of the GABAA receptor gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding region and the transmembrane, pore-forming region (Masiulis et al. 2019). Rare variants in the ε-subunit have been identified in patients with a wide spectrum of epileptic phenotypes (Markus et al. 2020). Many (but not all) sedative-hypnotics are capable of positively modulating the GABAA receptor by binding within a common set of hydrophobic cavities (McGrath et al. 2020). Isoflurane binds to a site within the transmembrane domains of the receptor and suggest functional similarity between the GABA(A) alpha-1, -2, and -3 subunits (Schofield and Harrison 2005). Mutations ain the M2 and M3 TMSs of the GABAARs alpha1 and beta2 subunits affect late gating transitions including opening/closing and desensitization (Terejko et al. 2021). The distance between an alpha1beta3gamma2L GABA type A receptor residue and the drug, etomidate, when bound in the transmembrane beta+/alpha- interface, has been determined (Fantasia et al. 2021). There is a binding site in the beta(+)alpha(-) interface for the anesthetic, propofol (Borghese et al. 2021). Delta selective compound 2 (DS2; 4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridin-3-yl]benzamide) is widely used to study selective actions mediated by delta-subunit-containing GABAA receptors. The molecular determinants responsible for positive modulation by DS2 have been identified (Falk-Petersen et al. 2021). Two high-resolution structures of GABAA receptors in complex with zolpidem, a positive allosteric modulator and heavily prescribed hypnotic, and DMCM, a negative allosteric modulator with convulsant and anxiogenic properties. These two drugs share the extracellular benzodiazepine site at the alpha/gamma subunit interface and two transmembrane sites at beta/alpha interfaces. Structural analyses reveal a basis for the subtype selectivity of zolpidem that underlies its clinical success (Zhu et al. 2022). Molecular dynamics simulations provided insight into how DMCM switches from a negative to a positive modulator as a function of binding site occupancy (Zhu et al. 2022). Avermectin-imidazo[1,2-a]pyridine hybrids are potent GABAA receptor modulators (Volkova et al. 2022). Clptm1 is a target for suppressing epileptic seizures by regulating GABA(A) R-mediated inhibitory synaptic transmission in a PTZ-induced epilepsy model (Zhang et al. 2023). The allosteric modulation of α1β3γ2 GABA(A) receptors by farnesol through neurosteroid sites has been characterized (Gc et al. 2023). Chloride ion dysregulation in epileptogenic neuronal networks has been reviewed (Weiss 2023). Mutation of valine 53 at the interface between extracellular and transmembrane domains of the beta(2) principal subunit affects the GABA(A) receptor gating has beeen examined (Kłopotowski et al. 2023). Acrylamide-derived modulators of the GABA(A) receptor have been described (Arias et al. 2023). Resting-state alterations in behavioral variant frontotemporal dementia are related to the distribution of monoamine and GABA neurotransmitter systems (Hahn et al. 2024). Paralogous epilepsy-associated GABAA receptor variants have clinical implications and the mechanisms, and potential pitfalls have been reviewed (Kan et al. 2024). |
Eukaryota | Metazoa, Chordata | GABA receptor of Rattus norvegicus |
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1.A.9.5.10 | GABA gated chloride channel of 537 aas and 4 TMSs, GABA or Rdl. The tropical cattle tick, Rhipicephalus microplus, is one of the most damaging parasites that affects cattle in tropical and subtropical regions in the world. Tick resistance to acaricides is dispersed worldwide, and a number of associated mutations in target site genes have been described. Phenylpyrazole (e.g., fipronil) and cyclodiene (e.g., lindane, dieldrin) insecticides both have the same mode of action, blocking the GABA-gated chloride channel encoded by the GABA-Cl gene. A conserved mutation, rdl (resistance to dieldrin) is found across a number of arthropods resistant to cyclodienes and phenylpyrazoles. In ticks, the mutation T290L, was identified in the second transmembrane (TMS2) domain of the GABA-gated chloride channel of Australian cattle tick populations that are resistant to dieldrin, but other mutations giving rise to resistance have been described. Cross-resistance between fipronil and lindane was reported in R. microplus populations (Castro Janer et al. 2019). |
Eukaryota | Metazoa, Arthropoda | Rdl of Rhipicephalus microplus (Cattle tick) (Boophilus microplus) |
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1.A.9.5.11 | The Rdl (RDL) GABA receptor of 606 aas and 4 TMSs. Amino acids important for function have been identified (Nakao and Banba 2020). Shisa reduces the sensitivity of the homomeric RDL channel to GABA in the two-spotted spider mite, Tetranychus urticae Koch (Zhan et al. 2023). External amino acid residues of insect GABA receptor channels dictate the action of the isoxazoline ectoparasiticide, fluralaner (Asahi et al. 2023). Fluralaner was the first isoxazoline ectoparasiticide developed to protect companion animals from fleas and ticks. Conserved external aas of insect GABAR channels play a critical role in the antagonistic effect of fluralaner (Asahi et al. 2023). |
Eukaryota | Metazoa, Arthropoda | Rd1 GABA receptor of Drosophila melanogaster |
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1.A.9.5.12 | γ-aminobutyric acid (GABA)-gated cation channel, EXP-1 | Eukaryota | Metazoa, Nematoda | EXP-1 in Caenorhabditis elegans | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.9.5.13 | γ-aminobutyric acid (GABA) receptor subunit beta of 499 aas and 4 TMSs, one N-terminal, one C-terminal, and two plus a central P-loop, near the C-terminal end of the protein. GABA, an inhibitory neurotransmitter, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel. PNU-120596, a positive allosteric modulator of mammalian alpha7 nicotinic acetylcholine receptor, is a negative modulator of ligand-gated chloride-selective channels of the gastropod, Lymnaea stagnalis (Vulfius et al. 2020).
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Eukaryota | Metazoa, Mollusca | GABA recptor of Lymnaea stagnalis (Great pond snail) (Helix stagnalis) |
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1.A.9.5.14 | GABAAR beta subunit of 474 aas and 4 TMSs in a 3 + 1 TMS arrangement. γ-aminobutyric acid type A receptors (GABAARs) are ligand gated channels mediating inhibition in the central nervous system. Garifulina et al. 2022 identified a previouly undescribed function of beta-subunit homomers as proton-gated anion channels. Mutation of a single H267A in beta3 subunits completely abolished channel activation by protons. In molecular dynamic simulations of the beta3 crystal structure, protonation of H267 increased the formation of hydrogen bonds between H267 and E270 of the adjacent subunit, leading to a pore stabilising ring formation and accumulation of Cl- within the transmembrane pore. Conversion of these residues in proton insensitive rho1 subunits transfered proton-dependent gating, thus highlighting the role of this interaction in proton sensitivity. Activation of chloride and bicarbonate currents at physiological pH, and kinetic studies, suggest a physiological role in neuronal and non-neuronal tissues that express beta subunits, and thus they are potential novel drug target (Garifulina et al. 2022). Residues in the 1st TMS are important for GABAArho receptor function (Crowther et al. 2022).
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Eukaryotes | Metazoa, Chordata | Beta subunit of Homo sapiens |
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1.A.9.5.15 | Gamma-aminobutyric acid receptor subunit alpha-5, GABRA5, of 462 aas and 4 TMSs in a 3 + 1 C-terminal arrangement. It is a ligand-gated chloride channel subunit which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain (Butler et al. 2018, Hernandez et al. 2019). It may be involved in GABA-A receptor assembly, and GABA-A receptor immobilization and accumulation by gephyrin at the synapse (Hernandez et al. 2019). Ablation of Gabra5 influences corticosterone levels and anxiety-like behavior in mice (Syding et al. 2023). |
Eukaryota | Metazoa, Chordata | GABRA5 of Homo sapiens |
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1.A.9.5.16 | Gamma-aminobutyric acid receptor subunit alpha-1 (GABAAR1) of 455 aas and 4 TMSs. GABA(A)Rs are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including anaesthetics, sedatives, hypnotics and antidepressants (Sun et al. 2023). GABA(A)Rs mediate rapid inhibitory transmission. They are ligand-gated chloride ion channel proteins and exist in about a dozen or more heteropentameric subtypes exhibiting variable age and brain regional localization and thus participation in differing brain functions and diseases. GABA(A)Rs are also subject to modulation by several chemotypes of allosteric ligands that help define structure and function, including subtype definition (Olsen 2015). The channel blocker picrotoxin identified a noncompetitive channel blocker site in GABA(A)Rs. This ligand site is located in the transmembrane channel pore, whereas the GABA agonist site is in the extracellular domain at subunit interfaces, a site useful for low energy coupled conformational changes of the functional channel domain. Two classes of pharmacologically important allosteric modulatory ligand binding sites reside in the extracellular domain at modified agonist sites at other subunit interfaces: the benzodiazepine site and the high-affinity, relevant to intoxication, ethanol site. The benzodiazepine site is specific for certain GABA(A)R subtypes, mainly synaptic, while the ethanol site is found at a modified benzodiazepine site on different, extrasynaptic subtypes. In the transmembrane domain are allosteric modulatory ligand sites for diverse chemotypes of general anesthetics: the volatile and intravenous agents, barbiturates, etomidate, propofol, long-chain alcohols, and neurosteroids (Olsen 2015). The last are endogenous positive allosteric modulators. X-ray crystal structures of prokaryotic and invertebrate pentameric ligand-gated ion channels, and the mammalian GABA(A)R protein, allow homology modeling of GABA(A)R subtypes with the various ligand sites located to suggest the structure and function of these proteins and their pharmacological modulation. Our understanding of GABA(A)R pharmacology has been hindered by the vast number of pentameric assemblies that can be derived from 19 different subunits and the lack of structural knowledge of clinically relevant receptors. Sun et al. 2023 isolated native murine GABA(A)R assemblies containing the widely expressed alpha1 subunit and elucidated their structures in complex with drugs used to treat insomnia (zolpidem (ZOL) and flurazepam) and postpartum depression (the neurosteroid allopregnanolone (APG)). Using cryo-EM analysis, three major structural populations in the brain were revealed: the canonical alpha1beta2gamma2 receptor containing two alpha1 subunits, and two assemblies containing one alpha1 and either an alpha2 or alpha3 subunit, in which the single alpha1-containing receptors feature a more compact arrangement between the transmembrane and extracellular domains. APG is bound at the transmembrane alpha/beta subunit interface, even when not added to the sample, revealing an important role for endogenous neurosteroids in modulating native GABA(A)Rs. Together with structurally engaged lipids, neurosteroids produce global conformational changes throughout the receptor that modify the ion channel pore and the binding sites for GABA and insomnia medications. The data revealed the major alpha1-containing GABA(A)R assemblies, bound with endogenous neurosteroids, thus defining a structural landscape from which subtype-specific drugs can be developed (Sun et al. 2023). A QSAR model demonstrated robustness and a high degree of predictability. Moreover, specific molecular fragments were identified that exerted both positive and negative effects on binding activity. This discovery paves the way for the swift prediction of binding activity for emerging benzodiazepines (Antović et al. 2023). |
Eukaryota | Metazoa, Chordata | GABAAR1 of Mus musculus |
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1.A.9.5.17 | Gamma-aminobutyric acid receptor subunit, GABRA4 or GABAAR, of 554 aas and 4 TMSs (Sente et al. 2022). Alpha subunit of the heteropentameric ligand-gated chloride channel
gated by gamma-aminobutyric acid (GABA), a major inhibitory
neurotransmitter in the brain. GABA-gated
chloride channels, also named GABA(A) receptors (GABAAR), consist of
five subunits arranged around a central pore and contain GABA active
binding site(s) located at the alpha and beta subunit interface(s). When
activated by GABA, GABAARs selectively allow the flow of chloride
anions across the cell membrane down their electrochemical gradient. GABAARs
containing alpha-4 are predominantly extrasynaptic, contributing to
tonic inhibition in dentate granule cells and thalamic relay neurons. |
Eukaryota | Metazoa, Chordata | GABRA4 of Homo sapiens |
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1.A.9.5.2 | γ-Aminobutyric acid (GABA)-inhibited Cl- channel, type A (α-, β- γ-subunit precursors), GABRA2 or GABAAR2, regulated by GABA receptor accessory protein, GABARAP (Luu et al., 2006) and FRMD7 (TC# 8.A.25.1.5) (Jiang et al. 2020). A mutation in the GABAA receptor alpha 1 subunit, linked to human epilepsy, affects channel gating properties (Fisher 2004). The anti-convulsant stiripentol acts directly on the GABA(A) receptor as a positive allosteric modulator (Fisher 2009). The major central endocannabinoid, 2-arachidonoyl glycerol (2-AG), also directly acts at GABA(A) receptors to potentiate the receptor at low GABA concentrations (Sigel et al., 2011). The recpetor is also allosterically regulated by neurosteroids via TMS1 of the beta subunit (Baker et al. 2010). General anesthetic binding site(s) have been identified (Chiara et al., 2012; Woll et al. 2018). Hydrophobic anions potently and uncompetitively antagonize GABA (A) receptor function (Chisari et al., 2011). Regulated by neurosteroids; activated by pregnenolone and allopregnenalone (Costa et al., 2012). Allopregnanolone and its synthetic analog alphaxalone are GABAAR positive allosteric modulators (Yu et al. 2019). Different subunits contribute asymmetrically to channel conductances via residues in the extracellular domain (Moroni et al., 2011). Potentiated by general anaesthetics (Nury et al., 2011). Both the alpha and beta subunits are important for activation by alcohols and anaesthetics (McCracken et al. 2010). Direct physical coupling between the GABA-A receptor (of 4 TMSs) and the KCC2 chloride transporter underlies ionic plasticity in cerebellar purkinje neurons in response to brain-derived neurotrophic factor (BDNF) (Huang et al. 2013). An anesthetic binding site has been identified (Franks 2015). Desensitization is regulated by interactions between the second and third transmembrane segments which affect the ion channel lumen near its intracellular end. The GABAAR and GlyR pore blocker, picrotoxin (TC# 8.C.1), prevents desensitization (Gielen et al. 2015). The mechanism of action of methaqualone (2-methyl-3-O-tolyl-4(3H)-quinazolinone, Quaalude(R)), a sedative-hypnotic and recreational drug. Methaqualone is a positive allosteric modulator (PAM) at human alpha1,2,3,5beta2,3gamma2S GABAA receptors (GABAARs) expressed, whereas it displays diverse functionalities at the alpha4,6beta1,2,3delta GABAAR subtypes, ranging from inactivity (alpha4beta1delta), through negative (alpha6beta1delta) or positive allosteric modulation (alpha4beta2delta, alpha6beta2,3delta), to superagonism (alpha4beta3delta) (Hammer et al. 2015). The thyroid hormone L-3,5,3'-triiodothyronine (T3) inhibits GABAA receptors at micromolar concentrations and has common features with neurosteroids such as allopregnanolone (ALLOP). Westergard et al. 2015 used functional experiments on alpha2beta1gamma2 GABAA receptors to detect competitive interactions between T3 and an agonist (ivermectin, IVM) with a crystallographically determined binding site at subunit interfaces in the transmembrane domain of a homologous receptor (glutamate-gated chloride channel, GluCl). T3 and ALLOP showed competitive effects, supporting the presence of a T3 and ALLOP binding site at one or more subunit interfaces. Residues in the beta3 subunit, at or near the etomidate/propofol binding site(s), form part of the valerenic acid modulator binding pocket (Luger et al. 2015). IV general anesthetics, including propofol, etomidate, alphaxalone, and barbiturates, enhance GABAA receptor activation. These anesthetics bind in transmembrane pockets between subunits of typical synaptic GABAA receptors (Forman and Miller 2016). Carisoprodol can directly gate and allosterically modulate type A GABA (GABAA) receptors (Kumar et al. 2017). The former sedative-hypnotic and recreational drug methaqualone (Quaalude) is a moderately potent, non-selective positive allosteric modulator of GABAA receptors (GABAARs) (Hammer et al. 2015). A methaqualone analog, 2-phenyl-3-(p-tolyl)quinazolin-4(3H)-one (PPTQ) exhibits intrinsic activity at micromolar concentrations and potentiates the GABA-evoked signaling at concentrations down to the low-nanomolar range (Madjroh et al. 2018). The PPTQ binding site is allosterically linked with sites targeted by neurosteroids and barbiturates. Anesthetic pharmacophore binding has been studied (Fahrenbach and Bertaccini 2018). GABAA receptors are modulated via several sites by GABA, benzodiazepines, ethanol, neurosteroids and anaesthetics among others. Amundarain et al. 2018 presented a model of the alpha1beta2gamma2 subtype GABAA receptor in the APO state and in complex with selected ligands, including agonists, antagonists and allosteric modulators. Sites in TMSs 2 and 3 are important for alcohol-induced conformational changes (Jung and Harris 2006). Many anesthetics and neurosteroids act through binding to the GABAAR transmembrane domainnad x-ray structures have revealed how α-xalone, a neurosteroid anaesthetic, binds and influences potentiation, activation and desensitization (Chen et al. 2018). AA29504 is an allosteric agonist and positive allosteric modulator of GABAA receptors (Olander et al. 2018). Allosteric shift analysis in mutant α1β3γ2L GABAA receptors indicates selectivity and cross-talk among intersubunit transmembrane anesthetic sites (Szabo et al. 2019). Several epilepsy-causing mutations have been identified in the genes of the α1, β3, and γ2 subunits comprising the GABAA receptor (Absalom et al. 2019). Constituents of the GABAA receptor include a transmembrane GARLH/LHFPL protein (TC# 1.A.82.1.7) and the inhibitory synaptic protein, neuroligin 2 (TC# 8.A.117.1.1) (Tomita 2019). GABAA receptors containing mutant alpha5 and alpha1 subunits all had reduced cell surface and total cell expression with altered endoplasmic reticulum processing, impaired synaptic clustering, reduced GABAA receptor function and decreased GABA binding potency. Thus, GABRA5 is a causative gene for early onset epileptic encephalopathy (Hernandez et al. 2019). Mutations at Gln242 or Trp246 that eliminate neurosteroid effects do not eliminate neurosteroid binding within the intersubunit site, but significantly alter the preferred orientation of the neurosteroid (Sugasawa et al. 2019). Binding sites and interactions of propanidid and AZD3043 within GABAAR have been identified (Wang et al. 2018). Clptm1 limits GABAAR forward trafficking from the ER to the plasma membrane, and it regulates inhibitory homeostatic plasticity (Ge et al. 2018). The mechanisms of potentiation and inhibition of GABAA receptors by non-steroidal anti-inflammatory drugs, niflumic and mefenamic acids, have been described (Rossokhin et al. 2019). GABAARs are targets for important classes of clinical agents (e.g., anxiolytics, anticonvulsants, and general anesthetics) that act as positive allosteric modulators (PAMs). PAMs bind selectively to a single intersubunit site in the GABAAR transmembrane domain (Jayakar et al. 2019). The gamma2 subunit is required for clustering of these receptors, for recruitment of the submembrane scaffold protein gephyrin to postsynaptic sites, and for postsynaptic function of GABAergic inhibitory synapses (Alldred et al. 2005). The fourth TMS of the gamma2 subunit is required for postsynaptic clustering, but both the major cytoplasmic loop and the fourth transmembrane domain contribute to efficient recruitment of gephyrin to postsynaptic receptor clusters and are essential for restoration of miniature IPSCs (Alldred et al. 2005). Oligomerization and cell surface expression of recombinant GABAA receptors tagged in the delta subunit have been examined (Oflaz et al. 2019). The isoxazoline ectoparasiticide, fluralaner, exerts antiparasitic effects by inhibiting the function of GABARs, but substitutions of Gly333 in TMS3 led to substantial reductions in the sensitivity to fluralaner (Yamato et al. 2020). A potent photoreactive general anesthetic with novel binding site selectivity for GABAA receptors has been identified (Shalabi et al. 2020). GABAA receptor neurosteroid binding sites have been reviewed (Alvarez et al. 2019). Missense variants in GABRA2 are associated with early infantile epileptic encephalopathy (EIEE) as well as other disorders (Sanchis-Juan et al. 2020). Elevin novel molecules, identified using reinforcement learning, showed positive allosteric modulation, with two showing 50% activation in the low micromolar range (Michaeli et al. 2020). GABAA Receptor ligands interact with binding sites in the transmembrane domain and in the extracellular domain (Iorio et al. 2020). Many (but not all) sedative-hypnotics are capable of positively modulating the GABAA receptor by binding within a common set of hydrophobic cavities (McGrath et al. 2020). Allopregnanolone (3alpha5alpha-P), pregnanolone), and their synthetic derivatives are potent positive allosteric modulators (PAMs) of GABAA receptors with in vivo anesthetic, anxiolytic, and anti-convulsant effects. Photoaffinity labeling procedures have been used to identify an intersubunit steroid-binding site in heteromeric GABA type A (GABAA) receptors (Jayakar et al. 2020). Diazepam binds to etomidate binding sites in the transmembrane receptor domain giving rise to antagonism (McGrath et al. 2020). The alpha1 subunit histidine 55 at the interface between the extracellular and transmembrane domains affects preactivation and desensitization of the GABAA receptor (Kaczor et al. 2021). Coordinated downregulation of KCC2 and the GABAA receptor contributes to inhibitory dysfunction during seizure induction (Wan et al. 2020). Loss of GABAergic inhibition provides a mechanism underlying GABRB2-associated neurodevelopmental disorders (El Achkar et al. 2021). GABAAR binds the anaesthetic, Propofol, to induced conformational changes (Yuan et al. 2021). Methaqualone (2-methyl-3-(o-tolyl)-quinazolin-4(3H)-one, MTQ) is a moderately potent positive allosteric modulator (PAM) of GABAA receptors (GABAARs). Several additional potent GABAAR PAMs include 2,3-diphenylquinazolin-4(3H)-one (PPQ), 3-(2-chlorophenyl)-2-phenylquinazolin-4(3H)-one (Cl-PPQ), and others (Wang et al. 2020). Interfacial binding sites for cholesterol on GABAA receptors compete with neurosteroids (Lee 2021). GABAAR is inhibited by L-type calcium channel blockers (Das et al. 2004). In in vivo studies, Stigmasterol (0.5-3.0 mg/kg, i.p.) exerted significant anxiolytic and anticonvulsant effects in an identical manner to allopregnanolone, indicating the involvement of a GABAergic mechanism. Thus, GABAA receptors are subject to anxiolytic and anticonvulsant activities of stigmasterol. Thus, stigmasterol is a candidate steroidal drug for the treatment of neurological disorders due to its positive modulation of GABA receptors (Karim et al. 2021). Sesquiterpenes and sesquiterpenoids harbor modulatory allosteric properties that affect inhibitoryGABAA receptors (Janzen et al. 2021). High-dose benzodiazepines positively modulate GABAA receptors via a flumazenil-insensitive mechanism (Wang et al. 2021). Benzodiazepine binding to transmembrane anaesthetic binding sites of the GABAA receptor can produce positive or negative modulation manifesting as decreases or increases in locomotion, respectively. Selectivity for these sites may contribute to the distinct GABAA receptor and behavioural actions of different benzodiazepines, particularly at high anaesthetic concentrations (McGrath et al. 2021). (+)-Catharanthine potentiates the GABAA receptor by binding to a transmembrane site at the beta(+)/alpha(-) interface near the TMS2-TMS3 loop (Arias et al. 2022). Diazepam derivatives are allosteric modulators of GABAA receptor alpha1beta2gamma2 subtypes (Djebaili et al. 2022). α1 proline 277 residues regulate GABAAR gating through M2-M3 loop interactions in the interfacial region (Kaczor et al. 2022). Regulated assembly and neurosteroid modulation constrain GABA(A) receptor pharmacology in vivo (Sun et al. 2023). Pathogenic variants of the human GABRA1 gene are associated with epilepsy (Arslan 2023). Resting-state alterations in behavioral variant frontotemporal dementia are related to the distribution of monoamine and GABA neurotransmitter systems (Hahn et al. 2024). GABA-A receptor changes underpin the antidepressant response to ketamine (Sumner et al. 2024). Structural insights into GABAA receptor potentiation by Quaalude have been reported (Chojnacka et al. 2024). Opening of a GABAA receptor occurs through the αβ interface (Haloi et al. 2025). |
Eukaryota | Metazoa, Chordata | GABA type A receptor of Homo sapiens (α-/β-/γ-subunits + GABARAP) |
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1.A.9.5.3 | Gamma-aminobutyric acid (GABA) receptor alpha 2 subunit of 499 aas. It's structure and sites of glycosylation and phsophorylation have been identified (Zuo et al. 2013). Isocycloseram is a "GABA-gated chloride channel allosteric modulator (Blythe et al. 2022). |
Eukaryota | Metazoa, Arthropoda | Gamma-aminobutyric receptor alpha 2 subunit of Spodoptera litura (Asian cotton leafworm) |
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1.A.9.5.4 | The GABA receptor consisting of α1, β3, and γ2 subunits. Heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as the histamine receptor and mediates cellular responses to histamine. Functions as a receptor for diazepines and various anesthetics, such as pentobarbital which bind to separate allosteric effector binding sites. Functions as ligand-gated chloride channel (Jayakar et al. 2015). GABRA1 mutations are associated with familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy, idiopathic familial generalized epilepsy, infantile spasms and Dravet syndrome. Thus, GABRA1 mutations are associated with infantile epilepsy including early onset epileptic encephalopathies including Ohtahara syndrome and West syndrome (Kodera et al. 2016). A variant of GABRA1 (A332V) causes increased sensitivity for GABA and alterred desensitization (Steudle et al. 2020). Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (Johannesen et al. 2021). The patho-mechanism and precision medicine approach in GABRA1-related disorders have been discussed (Musto et al. 2023). Receptor desensitization of gain-of-function GABRB3 variants correlates with clinical severity (Lin et al. 2023). GABRG2 mutations cause genetic epilepsy with febrile seizures: the structures. The roles, and molecular genetics have been described (Li et al. 2024). |
Eukaryota | Metazoa, Chordata | GABA Receptor subunits α1/β3/γ2 of Homo sapiens |
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1.A.9.5.5 | Human GABA-A (hGABA-A) rho1 receptor of 479 aas and 4 TMSs. The guanidine compound, amiloride, antagonized the heteromeric GABA-A, glycine, and nicotinic acetylcholine receptors, but it exhibits characteristics consistent with a positive allosteric modulator for the hGABA-A rho1 receptor (Snell and Gonzales 2016). Picrotoxinin binds to both GABAA-rho1 and -rho2 in the homomeric channels, but to GABAA-rho2 with 10x higher affinity (Naffaa and Samad 2016). The inhibitory site for ethanol in GABAA rho1 receptors regulates acute functional tolerance to moderate ethanol intoxication. Low sensitivity to alcohol intoxication is linked to risk for the development of alcohol dependence in humans (Blednov et al. 2017). Positive and negative allosteric modulators of GABAA receptors have been reviewed (Olsen 2018). A single amino acid change within the ion-channel domain accelerates desensitization and increases taurine agonism (Martínez-Torres and Miledi 2013). |
Eukaryota | Metazoa, Chordata | GABA-A rho1 receptor of Homo sapiens |
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1.A.9.5.6 | Gamma-aminobutyric acid receptor, LCCH3 (β) of 496 aas and 4 TMSs/ GRD of 686 aas and 4 TMSs. LCCH3 combines with the ligand-gated ion channel subunit, GRD, to form cation-selective GABA-gated ion channels. The heteromultimeric receptor is activated by GABA (EC50=4.5 microm), muscimol (EC50=4.8 microm) and trans-4-aminocrotonic acid (EC50=104.5 microm), and partially by cis-4-aminocrotonic acid (EC50=106.3 microm). Picrotoxin effectively blocked the GABA-gated channel (IC50=0.25 microm), but bicuculline, TPMTA, dieldrin and lindane did not. The benzodiazepines flunitrazepam and diazepam did not potentiate the GABA-evoked current (Gisselmann et al. 2004). The system has been partially characterized from the small brown planthopper, Laodelphax striatellus (Fallen), a major insect pest of crop systems in East Asia (Wei et al. 2017). Isocycloseram is a "GABA-gated chloride channel allosteric modulator (Blythe et al. 2022). A GABA-gated chloride channel mutation (Rdl) induces cholinergic physiological compensation resulting in cross resistance in Drosophila melanogaster (Xie et al. 2024). |
Eukaryota | Metazoa, Arthropoda | LCCH3/GRD/RDL of Drosophila melanogaster (Fruit fly) |
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1.A.9.5.7 | GABA(A) receptor subunit alpha-3 of 492 aas and 4 TMSs, GABRA3. GABAA receptor subunits have been linked to a spectrum of benign to severe epileptic disorders. A loss of function presents a major pathomechanism. Loss increases the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern (Niturad et al. 2017). GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel. |
Eukaryota | Metazoa, Chordata | GABRA3 of Homo sapiens |
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1.A.9.5.8 | Rice stem borer GABA recpetor of 496 aas and 4 TMSs. Insect GABAR is a major targets of insecticides. cDNAs (CsRDL1A and CsRDL2S) encoding the two isoforms of RDL subunits were cloned from the rice stem borer Chilo suppressalis. Transcripts of both genes demonstrated similar expression patterns in different tissues and developmental stages, although CsRDL2S was approximately 2-fold more abundant than CsRDL1A throughout all development stages. Electrophysiological results using a two-electrode voltage clamp demonstrated that GABA activated currents in oocytes injected with both cRNAs. The EC50 value of GABA in activating currents was smaller in oocytes co-injected with CsRDL1A and CsRDL2S than in oocytes injected singly. The IC50 value of the insecticide fluralaner in inhibiting GABA responses was smaller in oocytes co-injected with different cRNAs than in oocytes injected singly. Co-injection also changed the potency of the insecticide dieldrin in oocytes injected singly. Thus, heteromeric GABARs were formed by the co-injections of CsRDL1A and CsRDL2S in oocytes. Although the presence of Ser at the 2'-position in the second TMS was responsible for the insensitivity of GABARs to dieldrin, this amino acid did not affect the potencies of the insecticides fipronil and fluralaner. Thus, C. suppressalis may adapt to insecticide pressure by regulating the expression levels of CsRDL1A and CsRDL2S and the composition of both subunits in GABARs. Neuroligin 3 from the common cutworm enhances the GABA-induced current of a recombinant SlRDL1 channel (Wang et al. 2021). GABA receptor channels are blocked by the ectoparasiticide, fluralaner (Kono et al. 2022). |
Eukaryota | Metazoa, Arthropoda | GABAR of Chilo suppressalis (Asiatic rice borer moth) |
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1.A.9.5.9 | GabaA1 receptor of 459 aas and 4 TMSs. 87% identical to the human homologue (TC# 1.A.9.5.4). Insecticides, abamectin, dieldrin, fluralaner and fipronil strongly inhibited GABA-induced inward current >50% at 10-6 M, while alpha-endosulfan, flufiprole and ethiprole inhibited <50% (Huang et al. 2018). Flumazenil-insensitive benzodiazepine binding sites in GABAA receptors contribute to benzodiazepine-induced immobility in zebrafish larvae (Cao et al. 2019). Delta selective compound 2 (DS2; 4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridin-3-yl]benzamide) is widely used to study selective actions mediated by delta-subunit-containing GABAA receptors. The molecular determinants responsible for positive modulation by DS2 have been identified (Falk-Petersen et al. 2021). |
Eukaryota | Metazoa, Chordata | GabaA1 receptor of Danio rerio (Zebrafish) |
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1.A.9.6.1 | Homomeric serotonin (5-HT)-gated chloride channel, (controlling locomotion) MOD-1 (Menard et al., 2005) | Eukaryota | Metazoa, Nematoda | 5-HT-gated chloride channel, MOD-1 in Caernorhabditis elegans | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.A.9.6.2 | The high affinity dopamine receptor chloride channel, Lgc-53 (Ringstad et al., 2009). | Eukaryota | Metazoa, Nematoda | Lgc-53 of Caenorhabditis elegans (Q2PJ95) |
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1.A.9.6.3 | The high affinity tyramine (amine-gated) chloride channel receptor, Lgc-55 (Ringstad et al., 2009). Activated by amphetamines (Safratowich et al. 2013). |
Eukaryota | Metazoa, Nematoda | Lgc-55 of Caenorhabditis elegans (Q9TVI7) |
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1.A.9.8.1 | The prokaryotic H+-gated ion channel, GlvI or GLIC (Bocquet et al., 2007), solved at 2.9 Å resolution in the open pentameric state (3EHZ_E) (Bocquet et al., 2009; Corringer et al. 2010). The basis for ion selectivity has been reported (Fritsch et al., 2011). Two stage tilting of the pore lining helices results in channel opening and closing (Zhu and Hummer, 2010). The mechanical work of opening the pore is performed primarily on the M2-M3 loop. Strong interactions of this short and conserved loop with the extracellular domain are therefore crucial to couple ligand binding to channel opening. The H+-activated GLIC has an extracellular domain between TMSs M3 and M4 but lacks the intracellular domain (ICD) which is a distinct folding domain (Goyal et al., 2011). The structural basis for alcohol modulation of GLIC has been reported (Howard et al., 2011). The structure of the M2 TMS indicates that the charge selectivity filter is in the cytoplasmic half of the channel (Parikh et al. 2011). Below pH 5.0, GLIC desensitizes on a time scale of minutes. During activation, the extracellular hydrophobic region undergoes changes involving outward translational movement, away from the pore axis, leading to an increase in pore diameter. The lower end of M2 remains relatively immobile (Velisetty et al., 2012). During desensitization, the intervening polar residues in the middle of M2 move closer to form a solvent-occluded barrier and thereby reveal the location of a distinct desensitization gate. In comparison to the crystal structure of GLIC, the structural dynamics of the channel in a membrane environment suggest a more loosely packed conformation with water-accessible intrasubunit vestibules penetrating from the extracellular end all the way to the middle of M2 in the closed-state (Velisetty et al. 2012). Pore opening and closing is well understood (Zhu and Hummer 2010). X-ray structures of general anaesthetics bound to GLIC revealed a common general-anaesthetic binding site, which pre-exists in the apo-structure in the upper part of the transmembrane domain of each protomer (Nury et al., 2011). Large blockers bind in the center of the membrane, but divalent transition metal ions bind to the narrow intracellular pore entry (Hilf et al., 2010). Alcohols and anaesthetics induce structural changes and activate ligand-gated ion channels of the LIC family by binding in intersubunit cavities (Sauguet et al. 2013; Ghosh et al. 2013). Gating at pH 4 has been visualized by x-ray crystallography (Gonzalez-Gutierrez et al. 2013) Site-directed spin labeling and x-ray analyses have revealed gating transition motions and mechanisms that distinguish active from desensitized states (Dellisanti et al. 2013; Sauguet et al. 2013). Gating involves major rearrangements of the interfacial loops (Velisetty et al. 2014). A single point mutation can change the effect of an anesthetic (desfurane; chloroform) from an inhibitor to a potentiator (Brömstrup et al. 2013). An interhelix hydrogen bond involving His234 is important for stabilization of the open state (Rienzo et al. 2014). The outermost M4 TMS makes distinct contributions to the maturation and gating of the related GLIC and ELIC homologs, suggesting that they exhibit divergent mechanisms of channel function (Hénault et al. 2015). The same allosteric network may underlie the actions of various anesthetics, regardless of binding site (Joseph and Mincer 2016). GLIC and ELIC (TC# 1.A.9.9.1) may represent distinct transmembrane domain archetypes (Therien and Baenziger 2017). Arcario et al. 2017 have demonstrated an anesthetic binding site in GLIC which is accessed through a membrane-embedded tunnel. The anesthetic interacts with a previously known site, resulting in conformational changes that produce a non-conductive state of the channel (Arcario et al. 2017). The gating mechanism has been studied (Lev et al. 2017). R-Ketamine inhibits members of the LIC family, and the structural and dynamics basis for the assymetric inhibitory modulation of ketamine has been revealed (Ion et al. 2017). Residue E35 has been identified as a key proton-sensing residue, as neutralization of its side chain carboxylate stabilizes the active state. Thus, proton activation occurs allosterically at the level of multiple loci with a key contribution of the coupling interface between the extracellular and transmembrane domains (Nemecz et al. 2017). General anesthetics can allosterically favor closed channels by binding in the pore or favor open channels via various subsites in the transmembrane domain (Fourati et al. 2018). GLIC's gating by protonation proceeds by making use of loop F, already known as an allosteric site in other pLGICs, instead of the classic orthosteric site (Hu et al. 2018). Binding of fentanyl to its binding site within GLIC results in conformational changes that inhibit conduction through the channel (Faulkner et al. 2019). This channel and others have been studied by high-speed atomic force microscopy (HS-AFM) which has made it possible to characterized the conformational dynamics of single unlabeled transmembrane channels and transporters (Heath and Scheuring 2019). Pentameric ligand-gated ion channels undergo subtle conformational cycling to control electrochemical signal transduction. Lycksell et al. 2021 used small-angle neutron scattering (SANS) to probe ambient solution-phase properties of GLIC under resting and activating conditions. Resting-state GLIC was the best-fit crystal structure to SANS curves, with no evidence for divergent mechanisms. Thus, the findings demonstrate state-dependent changes in a pentameric ion channel by SANS. A 3-state model has been proposed; mutations at the subunit interface in the extracellular domain (ECD) principally alter pre-activation, while mutations in the lower ECD and the transmembrane domain principally alter activation. Propofol alters both transitions (Lefebvre et al. 2021). Cryo-EM structures of GLIC under three pH conditions showed that decreased pH is associated with improved resolution and side chain rearrangements at the subunit/domain interface, particularly involving functionally important residues in the beta1-beta2 and M2-M3 loops. Molecular dynamics simulations substantiated flexibility in the closed-channel extracellular domains relative to the transmembrane ones and supported electrostatic remodeling around E35 and E243 in proton-induced gating. Exploration of secondary cryo-EM classes further indicated a low-pH population with an expanded pore (Rovšnik et al. 2021). Polyunsaturated fatty acids (PUFAs) inhibit pentameric ligand-gated ion channels (pLGICs) by selectively binding to a single site in the outer transmembrane domain of ELIC (Dietzen et al. 2022). Bupropion is an atypical antidepressant and smoking cessation drug which causes adverse effects such as insomnia, irritability, and anxiety. Bupropion inhibits dopamine and norepinephrine reuptake transporters and eukaryotic cation-conducting pentameric ligand-gated ion channels (pLGICs), such as nicotinic acetylcholine (nACh) and serotonin type 3A (5-HT3A) receptors, at clinically relevant concentrations. Pirayesh et al. 2023 examined the inhibitory potency of bupropion in this GLIC). Bupropion inhibited proton- induced currents in GLIC with an inhibitory potency of 14.9 +/- 2.0 muM, comparable to clinically attainable concentrations previously shown to also modulate eukaryotic pLGICs. Using single amino acid substitutions in GLIC and two-electrode voltage-clamp recordings, a binding site for bupropion in the lower third of the first TMS M1 at residue T214. The side chain of M1 T214 together with additional residues of M1 and also of M3 of the adjacent subunit have previously been shown to contribute to binding of other lipophilic molecules like allopregnanolone and pregnanolone (Pirayesh et al. 2023). Bupropion is an atypical antidepressant and smoking cessation drug that causes adverse effects such as insomnia, irritability, and anxiety. It inhibits dopamine and norepinephrine reuptake transporters and eukaryotic cation-conducting pentameric ligand-gated ion channels, such as nicotinic acetylcholine and serotonin type 3A receptors, at clinically relevant concentrations. Do et al. 2024 demonstrated that bupropion also inhibits a prokaryotic homolog of pentameric ligand-gated ion channels, the Gloeobacter violaceus ligand-gated ion channel (GLIC). |
Bacteria | Cyanobacteriota | GlvI or GLIC of Gloeobacter violaceus (Q7NDN8) |
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1.A.9.8.2 | Uncharacterized ligand-gated ion channel of 343 aas and 4 C-terminal TMSs. |
Bacteria | Cyanobacteriota | LIC family protein of Lyngbya aestuarii |
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1.A.9.8.3 | Ligand-gated ion channel of 312 aas and 5 TMSs, one N-terminal and 4 C-terminal (Jaiteh et al. 2016). |
Archaea | Nitrososphaerota | LIC of Thaumarchaeota archaeon N4 |
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1.A.9.8.4 | Uncharacterized ligand-gated ion channel of 351 aas and 4 TMSs. |
Bacteria | Pseudomonadota | UP of Francisella cf. novicida |
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1.A.9.9.1 | The bacterial pentameric Cys-loop ligand-gated ion channel (Erwinia chrysanthemi ligand-gated ion channel), ELIC. A 3.3 Å resolution structure is available (Hilf and Dutzler, 2008; Corringer et al., 2010). X-ray analyses have identified three distinct binding sites for anaesthetics, one in the channel, one at the end of a TMS, and one in a hydrophobic pocket of the extracellular domain (Spurny et al. 2013). Motions involving desensitization have been defined (Dellisanti et al. 2013). Simulations indicate the similarities with and differences between the Acetylcholine receptor (Cheng et al. 2009). This family includes members with very divergent properties (Gonzalez-Gutierrez and Grosman 2015). Cysteamine is an agonist for ELIC (Hénault and Baenziger 2016). X-ray structures and functional measurements support a pore-blocking mechanism for the inhibitory action of short-chain alcohols which bind to the TMSs (Chen et al. 2016). GLIC (TC# 1.A.9.8.1) and ELIC may represent distinct transmembrane domain archetypes (Therien and Baenziger 2017), and both bind hopenoids at the mamalian cholesterol binding site (Barrantes and Fantini 2016). A high-resolution structure of ELIC in a lipid-bound state has revealed a phospholipid binding site at the lower half of pore-forming transmembrane helices M1 and M4 and at a nearby site for neurosteroids, cholesterol or general anesthetics (Hénault et al. 2019). This site is shaped by an M4-helix kink and a Trp-Arg-Pro triad that is highly conserved in eukaryote GABAA/C and glycine receptors. M4 is intrinsically flexible, and M4 deletions or disruptions of the lipid-binding site accelerate desensitization, suggesting that lipid interactions shape the agonist response (Hénault et al. 2019). 1-Palmitoyl-2-oleoyl phosphatidylglycerol (POPG) stabilizes the open state of ELIC relative to the desensitized state by direct binding to specific sites (Tong et al. 2019). The nicotinic acetylcholine receptor from the Torpedo electric organ, when reconstituted in membranes formed by zwitterionic phospholipids alone, exposure to agonist fails to elicit ion-flux activity, and ELIC has a similar lipid sensitivity. Structures of ELIC in palmitoyl-oleoyl-phosphatidylcholine- (POPC-) only nanodiscs in both the unliganded (4.1-Å resolution) and agonist-bound (3.3 Å) states using single-particle cryoEM have been solved (Kumar et al. 2020). The largest differences occur at the level of loop C - at the agonist-binding sites - and the loops at the interface between the extracellular and transmembrane domains (ECD and TMD, respectively). The transmembrane pore is occluded similarly in both structures. POPC-only membranes prevent ECD-TMD coupling so that the "conformational wave" of liganded-receptor gating takes place in the ECD and the interfacial M2-M3 linker, but fails to penetrate the membrane and propagate into the TMD. The higher affinity for agonists, characteristic of the open- and desensitized-channel conformations, results from the tighter confinement of the ligand to its binding site; this limits the ligand's fluctuations, and thus delays its escape into bulk solvent (Kumar et al. 2020). |
Bacteria | Pseudomonadota | ELIC of Dickeya chrysanthemi (Pectobacterium chrysanthemi) (Erwinia chrysanthemi) |
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1.A.9.9.2 | Cys-loop ligand-gated pentameric cation channel of 320 aas and 4 C-terminal TMSs sTeLIC (Hu et al. 2018); from a bacterial endosymbiont of Tevnia jerichonana (vent Tica). 28% identical to ELIC (TC# 1.A.9.9.1). The crystal structure has been determined in a wide open state, revealing a cavity for modulation. It is gated by alkaline pH. Two charged restriction rings are present in the vestibule. Functional characterization shows sTeLIC to be a cationic channel activated at alkaline pH. It is inhibited by divalent cations, but not by quaternary ammonium ions such as tetramethylammonium. Hu et al. 2018 also found that sTeLIC is allosterically potentiated by the aromatic amino acids, Phe and Trp, as well as their derivatives, such as 4-bromo-cinnamate, whose cocrystal structure reveals a vestibular binding site equivalent to, but more deeply buried than, the one already described for benzodiazepines in ELIC. The channel is regulated by a semi-conserved cationic-lipid binding site, where the residue involved is the tryptophan, W206 (Sridhar et al. 2021). |
Bacteria | Pseudomonadota | sTeLIC of a γ-proteobacterial endosymbiont of Tevnia jerichonana (vent Tica) |
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1.A.9.9.3 | X-ray structures of CLIC of 680 aas and 1N-terminal and 4 C-terminal TMSs with a large N-terminal hydrophilic domain (NTD) from a Desulfofustis deltaproteobacterium have been solved. The protein includes a periplasmic NTD fused to the conventional ligand-binding domain (LBD) (Hu et al. 2020). The NTD consists of two jelly-roll domains interacting across each subunit interface. Binding of Ca2+ at the LBD subunit interface is associated with a closed transmembrane pore, with resolved monovalent cations intracellular to the hydrophobic gate. Accordingly, DeCLIC-injected oocytes conducted currents only upon depletion of extracellular Ca2+. DeCLIC crystallized in the absence of Ca2+ with a wide-open pore and remodeled periplasmic domains, including increased contacts between the NTD and classic LBD agonist-binding sites. Functional, structural, and dynamical properties of DeCLIC paralleled those of sTeLIC, a pLGIC from another symbiotic prokaryote. Based on these DeCLIC structures, the previous structure of bacterial ELIC (the first high-resolution structure of a pLGIC) should be reclassified as a "locally closed" conformation. Structures of DeCLIC in multiple conformations illustrate dramatic conformational state transitions and diverse regulatory mechanisms available to ion channels in pLGICs, particularly involving Ca2+ modulation and periplasmic NTDs (Hu et al. 2020). Ligand-binding affinities are insensitive to binding-site occupancy, and mutations in residues in the transmembrane domain are unlikely to affect the channel's affinities for ligands that bind to the extracellular domain (Godellas and Grosman 2022). Cation-selective pLGICs contain a long helical extension (MA) of one of the transmembrane helices. The MA helix affects both the membrane expression of, and ion conductance levels through, these pLGICs. In fact, the MA helix Is important for receptor assembly and function in the alpha4beta2 nACh receptor (Fricska et al. 2023). |
Bacteria | Thermodesulfobacteriota | CLIC or pLGIC of Desulfofustis deltaproteobacterium |
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1.A.90.1.1 | The small hydrophobic (SH) viroporin protein of 179 aas. Has properties of a viroporin and modulates viral fusogenic activity (Masante et al. 2014). |
Viruses | Orthornavirae, Negarnaviricota | The SH viroporin protein of human metapneumovirus (HMPV) . |
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1.A.90.1.2 | Human metapneumovirus small hydrophobic (SH) protein of 177 aas and 1 TMS. |
Viruses | Orthornavirae, Negarnaviricota | SH protein of the human metapneumovirus |
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1.A.90.1.3 |
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Viruses | Orthornavirae, Negarnaviricota | SH protein of avian metapneumovirus |
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1.A.91.1.1 | The plasmodial three-component surface broad specificity anion channel complex. One component is PSAC (Clag3.2, Clag3/2, RhopH1, of 1416 aas and at least two putative TMSs, one N-terminal and one C-terminal (residues 1199 to 1223)). The latter is an amphipathic α-helix thought to form the channel in the multisubunit complex (Sharma et al. 2015). CLAG3 undergoes hetero-association, and its expression determines the channel phenotype quantitatively, leading to host erythrocyte permeability to ions and nutrients (Gupta et al. 2018). The isoforms traffic to and insert in the host membrane while remaining associated with two unrelated parasite proteins, RhopH2 (CLAG3.2 of 1414 aas (B0M163) and RhopH3 (CLAG3.3 (B0M0W2) of 897 aas and up to 4 TMSs, one N-terminal and up to three centrally located. Both the channel phenotypes and molecular changes are consistent with a multiprotein complex that forms the nutrient pore, supporting direct involvement of the CLAG3 protein in channel formation (Gupta et al. 2018). Inhibitors potentially useful theraputically at 5 μM concentrations include PRT1-20 and ISPA-28. Their use suggested that there may be two routes of nutrient entry via the PSAC (Pain et al. 2016). Reviewed by Meier et al. 2018. Malaria parasites use a soluble RhopH complex for erythrocyte invasion and an integral membrane channel form for nutrient uptake (Schureck et al. 2021). (See family description for more details.) The kinetics of CLAG3.2 insertion into the erythrocyte membrane has been studied (Shao et al. 2022). Ion channel proteins in P. falciparum have been reviewed (Desai 2024). |
Eukaryota | Apicomplexa | PSAC (Clag3.2) of Plasmodium falciparum |
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1.A.91.1.2 | Uncharacterized protein of 1454 aas and 2 or 3 TMSs (N- and C-terminal). |
Eukaryota | Apicomplexa | UP of Theileria orientalis |
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1.A.91.1.3 | Rhoptry neck protein, Ron2, of 1350 aas and 2 TMSs, N- and C-terminal. |
Eukaryota | Apicomplexa | Ron2 of Babesia divergens |
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1.A.91.1.4 | Rhoptry neck protein 2-like protein 2 (Precursor), related, of 1275 aas and 3 TMSs, 1 N-terminal, and two C-terminal. |
Eukaryota | Apicomplexa | Ron2 of Eimeria brunetti |
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1.A.91.1.5 | Uncharacteerized protein of 1462 aas and 3 TMSs, one N-terminal, and two C-terminal. |
Eukaryota | Apicomplexa | UP of Hammondia hammondi |
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1.A.92.1.1 | Scylla serrata reovirus of 323 aas and 2 N-terminal TMSs, p35 or VP10, encoded by the S10 gene. This proposed viroporin seems to transport ions in a channel-type mechanism (Zhang et al. 2015). This putative viroporin interacts with host proteins (Yuan et al. 2017). |
Viruses | Orthornavirae, Duplornaviricota | p35 of Scylla serrata reovirus |
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1.A.92.1.2 | Uncharaterized protein of 323 aas and 2 or 3 N-terminal TMSs. |
Viruses | Orthornavirae, Duplornaviricota | UP of Eriocheir sinensis reovirus |
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1.A.92.1.3 | VP10 of 340 aas and 2 or 3 N-terminal TMSs. This protein is 73% identical to 1.A.92.1.2. |
Viruses | Orthornavirae, Duplornaviricota | VP10 of Eriocheir sinensis reovirus |
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1.A.93.1.1 | Viroporin, NS3, of 229 aas and 2 TMSs (Han and Harty 2004) with N-terminal coiled-coil domains that may promote oligomeric pore formation (Chacko et al. 2015). |
Viruses | Orthornavirae, Duplornaviricota | NS3 of BlueTongue Virus |
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1.A.93.1.2 | NS3 of 217 aas and 2 TMSs. |
Viruses | Orthornavirae, Duplornaviricota | NS3 of African horse sickness virus |
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1.A.93.1.3 | NS3 of 264 aas and 2 TMSs. |
Viruses | Orthornavirae, Duplornaviricota | NS3 of Umatilla virus |
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1.A.93.1.4 | Non-structural protein, NS3 or Nsp3, of 251 aas and 2 TMSs. |
Viruses | Orthornavirae, Duplornaviricota | Nsp3 of Mobuck virus |
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1.A.93.2.1 | NS3 of 171 aas and 2 TMSs. |
Viruses | Orthornavirae, Duplornaviricota | NS3 of Great Island virus |
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1.A.94.1.1 | Non-structural glycoprotein 4, NSP4 or enterotoxin, of 175 aas and 2 TMSs (Hyser et al. 2012). A pentatmeric structure of a 53 aas NSP4 fragment has been solved (3MIW). NSP4 viroporin is involved in activation. It increases the endoplasmic reticulum (ER) permeability, resulting in decreased ER calcium stores and activation of plasma membrane (PM) calcium influx channels, ultimately causing the elevation in cytoplasmic calcium (Hyser et al. 2013). It activates ER calcium store-operated calcium entry (Hyser et al. 2013). NSP4 VPD is a Ca2+/Ba2+-conducting cation-selective viroporin that transports monovalent and divalent cations equally well (Pham et al. 2017). It may be involved in particle production (Scott and Griffin 2015). |
Viruses | Orthornavirae, Duplornaviricota | NSP4 of Rotavirus A |
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1.A.94.1.2 | NSP4 of 169 aas and 2 TMSs |
Viruses | Orthornavirae, Duplornaviricota | NSP4 of Avian rotavirus A |
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1.A.94.1.3 | NSP4 of 169 aas and 2 TMSs |
Viruses | Orthornavirae, Duplornaviricota | NSP4 of chicken rotavirus |
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1.A.94.1.4 | Rotavirus NSP4 of 170 aas and 2 TMSs. |
Viruses | Orthornavirae, Duplornaviricota | NSP4 of Rotavirus A |
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1.A.95.1.1 | Alpha1 protein of 88 aas and 1 TMS |
Viruses | Orthornavirae, Negarnaviricota | α1 protein of Bovine ephemeral fever virus (BEFV) |
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1.A.95.1.2 | Alpha1 protein of 105 aas and 1 TMS |
Viruses | Orthornavirae, Negarnaviricota | α1 protein of Kimberley virus |
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1.A.95.1.3 | Alpha1 homologue of 85 aas and 1 TMS |
Viruses | Orthornavirae, Negarnaviricota | α1 protein of Iriri virus |
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1.A.95.1.5 | Alpha1 protein of 91 aas and 1 TMS |
Viruses | Orthornavirae, Negarnaviricota | α1 protein homologue of Curionopolis virus |
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1.A.95.1.7 | Alpha1 homologue of 88 aas and 1 TMS |
Viruses | Orthornavirae, Negarnaviricota | α1 protein of Berrimah virus |
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1.A.95.2.4 | Uncharacterized protein, U3, of 109 aas and 1 or 2 TMSs. |
Viruses | Orthornavirae, Negarnaviricota | U3 of Tibrogargan virus (TIBV) |
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1.A.95.2.5 | Uncharacterized protein of 120 aas and 1 or 2 TMSs |
Viruses | Orthornavirae, Negarnaviricota | UP of Hart Park virus |
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1.A.96.1.1 | Agnoprotein viroporin of 71 aas and 1 TMS (Suzuki et al. 2010). It is cation-selective, capable of Ca2+ accomodation, and is involved in particle production (Scott and Griffin 2015). |
Viruses | Shotokuvirae, Cossaviricota | Agnoprotein of human polyoma JC virus |
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1.A.96.1.2 | Agnoprotein of 90 aas and 2 TMSs. |
Viruses | Polyomaviridae | Agnoprotein of Simian virus 40 (SV40) |
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1.A.96.1.3 | Agnoprotein of 68 aas and 1 TMS |
Viruses | Shotokuvirae, Cossaviricota | Agnoprotein of Yellow baboon polyomavirus 2 |
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1.A.97.1.1 | The E5 viroporin protein of 83 aas and 3 TMSs (Wetherill et al. 2012). It forms hexameric channels with TMS2 lining the pore, creating a water column through which ions and small molecules, including H+, can pass fairly non-specifically (Mahato and Fischer 2016). A "snapshot" structure of the putative open pore of the protein bundle suggested the proposed low channel selectivity (Mahato and Fischer 2016). The protein is involved in signalling and protein trafficking. Its gene may be an oncogene (Scott and Griffin 2015).The protein also interacts with the fourth TMS of the 16 kDa c subunit of the human vacuolar H+-ATPase (Mahato and Fischer 2018). |
Viruses | Shotokuvirae, Cossaviricota | E5 protein of high-risk human papillomavirus (cervical cancer-causing) type 16 (HPV16) |
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1.A.97.1.2 | Human papillomavirus type 82 E5 protein of 84 aas and 3 TMSs. |
Viruses | Shotokuvirae, Cossaviricota | E5 of human papillomavirus type 82 |
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1.A.97.1.3 | Human papillomavirus type 39 E5 protein of 72 aas and 2 TMSs. |
Viruses | Shotokuvirae, Cossaviricota | E5 protein of human papillomavirus type 39 |
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1.A.97.1.4 | Common chimpanzee papillomavirus 1 E5 protein of 94 aas and 3 TMSs |
Viruses | Shotokuvirae, Cossaviricota | E5 protein of the common chimpanzee papillomavirus 1 |
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1.A.97.1.5 | Human papillomavirus type 6 E5a protein of 91 aas and 3 TMSs. |
Viruses | Shotokuvirae, Cossaviricota | E5a protein of human papillomavirus type 6 |
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1.A.98.1.1 | HTLV-1 P13 viroporin of 87 aas. Transports K+ (Hyser and Estes 2015). Large protein conformation changes occur upon transitioning from the soluble to the membrane-bound state. p13(II)-assisted transport of K+ suggests an involvement in the control of the transmembrane potential (Georgieva et al. 2020). |
Viruses | Pararnavirae, Artverviricota | P13 of Human T-cell leukemia (lymphotropic) virus type-1 (C6L855) |
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1.A.98.1.2 | The Tax protein of 58 aas. |
Viruses | Pararnavirae, Artverviricota | Tax of Human T-cell leukemia virus 3 (HTLV-3) (Human T-lymphotropic virus 3) |
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1.A.98.1.3 | p30 protein of 177 aas and 1 or 2 TMSs |
Viruses | Pararnavirae, Artverviricota | p30 protein of Human T-cell leukemia virus type I |
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1.A.99.1.1 | The avian infectious bronchitis virus envelope small membrane protein E of 108 aas and 2 TMSs. IBV E functions as a viroporin and plays a role in virus budding, possibly by altering membrane morphology at the virus assembly site (Pendleton and Machamer 2008). It also mediates ER stress and thereby modulates virion release, apoptosis, viral fitness, and pathogenesis (Li et al. 2019). |
Viruses | Orthornavirae, Pisuviricota | The E protein of avian infectious bronchitis virus |
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1.A.99.1.2 | Small envelope membrane protein E of 65 aas and 2 TMSs |
Viruses | Orthornavirae, Pisuviricota | E protein of Turkey enteric coronavirus (TCoV) (TCV) |
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1.A.99.1.3 | Small membrane envelope (E) protein of 95 aas and 1 or 2 TMSs |
Viruses | Orthornavirae, Pisuviricota | E protein of Beluga Whale coronavirus SW1 |
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1.B.1.1.1 | OmpF general porin. OmpF can deliver peptides of >6 KDa (epitopes) including protamine, through the pore lumen from the periplasm to the outside (Housden et al., 2010; Ghale et al. 2014). For cephalosporin antibiotics, the interaction strength series is ceftriaxone > cefpirome > ceftazidime (Lovelle et al. 2011). An unfolded protein such as colicin E9 can thread through OmpF from the outside to reach the periplasm (Housden et al. 2013). Polynucleotides can pass through OmpF (Hadi-Alijanvand and Rouhani 2015). LPS influences the movement of bulk ions (K+ and Cl-), but the ion selectivity of OmpF is mainly affected by bulk ion concentrations (Patel et al. 2016). OMPs such as OmpF cluster into islands that restrict their lateral mobility, while IMPs generally diffuse throughout the cell. Rassam et al. 2018 demonstrated that when transient, energy-dependent transmembrane connections are formed, IMPs become subjugated by the inherent organisation of OMPs, and that such connections impact IMP function. They showed that while establishing a translocon for import, colicin ColE9 sequesters the IMPs of the proton motive force (PMF)-linked Tol-Pal complex into islands mirroring those of colicin-bound OMPs. Through this imposed organisation, the bacteriocin subverts the outer-membrane stabilizing role of Tol-Pal, blocking its recruitment to cell division sites and slowing membrane constriction. The ordering of IMPs by OMPs via an energised inter-membrane bridge represents an emerging functional paradigm in cell envelope biology (Rassam et al. 2018). Colicin E9 (ColE9) disordered regions exploit OmpF for direction-specific binding, which ensures the constrained presentation of an activating signal within the bacterial periplasm (Housden et al. 2018). Anionic lipid binding can prevent closure of OmpF channels, thereby increasing access of antibiotics that use porin-mediated pathways (Liko et al. 2018). OmpF may be the major route of D-lactate/D-3-hydroxybutyrate oligo-ester secretion (Utsunomia et al. 2017). Lipid Headgroup Charge and Acyl Chain Composition Modulate Closure of the channel (Perini et al. 2019). Piperacillin, tazobactam, ampicillin and sulbactam interact strongly with OmpF, and may be transported (Wang et al. 2019). Gating kinetics are governed by lipid characteristics so that each stage of a sequential closure is different from the previous one, probably because of intra- or intermonomeric rearrangements (Perini et al. 2019). OmpF transports fosfomycin (Golla et al. 2019) and bacteriocins into cells. Polypeptide transport/binding processes generate an essentially irreversible, hook-like assembly that constrains an import activating peptide epitope between two subunits of the OmpF trimer (Lee et al. 2020). Physical properties of bacterial porins (OmpF and OmpC) match environmental conditionsof induction (Milenkovic et al. 2023). Enrofloxacin caused blockage of ion current through OmpF, depending on the side of addition to the assymetic bilayer containing lipopolysaccharide and the transmembrane voltage applied (Donoghue et al. 2023). OmpF homologs are OmpK35 of Klebsiella pneumoniae and OmpE35 of Enterobacteria cloacae, and these porins transport ciprofloxacin (Acharya et al. 2024). OmpC and OmpF outer membrane porins of Escherichia coli and Salmonella enterica form bona fide amyloids (Belousov et al. 2023). Mechanisms of ciprofloxacin translocation through OmpF and other major diffusion channels of the ESKAPE pathogens Klebsiella pneumoniae and Enterobacter cloacae have been elucidated (Acharya et al. 2024). |
Bacteria | Pseudomonadota | OmpF of E. coli (P02931) |
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1.B.1.1.10 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Dickeya dadantii |
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1.B.1.1.11 | Porin OmpPst1. Transports carbapenem antibiotics imipenem will slow flux and meropenem with rapid flux in a reconsituted ion conductance system (Bajaj et al. 2012). |
Bacteria | Pseudomonadota | OmpPst1 of Providencia stuartii |
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1.B.1.1.12 | High conductance Omp35 (OmpK35; OmpF) porin. Expression levels are important for beta-lactam/cephalosporin resistance (Bornet et al. 2004). 95% identical to the Klebsiella pneumoniae orthologue, OmpK35 (Taherpour and Hashemi 2013). In K. pneumoniae, colistin-based combination therapy with a carbapenem and/or tigecycline was associated with significantly decreased mortality rates due in part to synergistic induction of porins K35 and K36 (Stein et al. 2015). They influence imipenem susceptibility as well (Wassef et al. 2015). These two porins play roles in conferring carbapenem resistance in K. pneumoniae (Hamzaoui et al. 2018; Ye et al. 2018). Loss of a single porin (OmpK35 or OmpK36 (TC# 1.B.1.1.19) in Klebsiella pneumoniae is paired with reductions in capsule, increased LPS, and up-regulated transcription of compensatory porin genes, but loss of both porins resulted in an increase in capsule production. Loss of OmpK35 alone or dual porin loss was further associated with reduced oxidative burst by macrophages and increased ability of the bacteria to survive phagocytic killing (Brunson et al. 2019). |
Bacteria | Pseudomonadota | Omp35 of Enterobacter (Aerobacter) aerogenes |
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1.B.1.1.13 | Omp36 (OmpC) porin of 375 aas (Dé et al. 2001; Bornet et al. 2004). Mutations affect beta-lactam and carbapenem (imipenem) sensitivity (Pavez et al. 2016). |
Bacteria | Pseudomonadota | Omp36 of Enterobacter (Aerobacter) aerogenes |
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1.B.1.1.14 | Major voltage-independent outer membrane porin, OmpH (Chevalier et al. 1993). A 3D model was obtained using in silico modeling. OmpH is probably a homotrimeric, 16 stranded, β-barrel porin involved in the non-specific transport of small, hydrophilic molecules, serving osmoregulatory functions (Ganguly et al. 2015). |
Bacteria | Pseudomonadota | OmpH of Pasteurella multocida |
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1.B.1.1.15 | OmpU porin (cation-selective; PK/PCl = 14; bile salt inducible) (low permeability to bile) (Simonet et al., 2003). OmpU influences sensitivities to β-lactam antibiotics and sodium deoxycholate induction of biofilm formation and growth on large sugars (Pagel et al., 2007). The effective pore radus is 0.55 nm which increases with acidic pH but decreases with increasing ionic strength (Duret and Delcour 2010). OmpU induces target animal cell death after it inserts into host mitochondrial membranes (Gupta et al. 2015). The high resolution structures of OmpT and OmpU, the two major porins in V. cholerae, have been determined, and both have unusual constrictions that create narrower barriers for small-molecule permeation and change the internal electric fields of the channels (Pathania et al. 2018). Vibrio cholerae OmpU activates dendritic cells via TLR2 and the NLRP3 inflammasome (Dhar et al. 2023). Four conserved domains in OmpU are linked with resistance to bile and host-derived antimicrobial peptides. Mutant strains for these domains exhibit differential susceptibility patterns to these and other antimicrobials. A mutant strain in which the four domains of the clinical allele were exchanged for those of a sensitive strain exhibits a resistance profile closer to a porin deletion mutant. Finally, using phenotypic microarrays, novel functions of OmpU and their connection with allelic variability were uncovered (Grant et al. 2023). |
Bacteria | Pseudomonadota | OmpU of Vibrio cholerae |
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1.B.1.1.16 | OmpC of 367 aas (Vostrikova et al. 2013). |
Bacteria | Pseudomonadota | OmpC of Yersinia enterocolitica |
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1.B.1.1.17 | OmpF of 243 aas (Vostrikova et al. 2013). |
Bacteria | Pseudomonadota | OmpF of Yersinia enterocolitica |
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1.B.1.1.18 | Putative porin of 381 aas |
Bacteria | Pseudomonadota | PP of Klebsiella pneumoniae |
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1.B.1.1.19 | Outer membrane porin, KpnO, OmpCKP or OmpK36 of 367 aas. Loss causes increased drug (e.g., carbapenem and imipenem, but not colistin) resistance (Wassef et al. 2015, Jasim et al. 2018) decreased virulence and increased susceptibility to gastrointestinal stress (García-Sureda et al. 2011; Srinivasan et al. 2012). Expression is under PhoBR control. Porin deficiency is a widespread phenomenon, probably accounting for elevated ertapenem resistance (Wise et al. 2018). Loss of OmpK36 gives rise to carbapenem resistance (i.e., meropenem resistance) (Pal et al. 2019). |
Bacteria | Pseudomonadota | KpnO of Klebsiella pneumoniae |
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1.B.1.1.2 | PhoE phosphoporin. The 3-d structure is available (PDB#1PHO) |
Bacteria | Pseudomonadota | PhoE of E. coli |
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1.B.1.1.20 | Outer membrane porin 1, OmpPst1 or Omp-Pst1. Transports beta lactams with decreased efficiency in the order of ertapenem > cefepime > cefoxitin (Tran et al. 2010). 93% identical in sequence to 1.B.1.1.11. Voltage-gating of this porin and porin 2 (TC# 1.B.1.1.24) from the same organism have been analyzed (Song et al. 2015). Facing channels are open in any two adjacent porin structures, suggesting that dimers and trimers not only promote cell-to-cell contact but also contribute to intercellular communication (El-Khatib et al. 2018). |
Bacteria | Pseudomonadota | OmpPst1 of Providencia stuartii |
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1.B.1.1.21 | Outer membrane non-specific porin, OmpN or OmpS2, under the control of SoxS, and coregulated with the ydbK gene encoding pyruvate:flavodoxin oxidoreductase which plays a role in protection against oxidative stress (Prilipov et al. 1998; Fàbrega et al. 2012). MicC sRNA acts together with the σE envelope stress response pathway to control OmpN levels in response to β-lactam antibiotics (Dam et al. 2017). |
Bacteria | Pseudomonadota | OmpN of E. coli |
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1.B.1.1.22 | Outer membrane porin of 383 aas, OmpS2. Activated by OmpR and LeuO (Fernández-Mora et al. 2004). |
Bacteria | Pseudomonadota | OmpS2 of Salmonella typhi |
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1.B.1.1.23 | Outer membrane trimeric porin, OmpY (also called OmpN or OmpC2) of 360 aas. The effects of the length of loop L2 on function and stability have been studied (Solov'eva et al. 2017). |
Bacteria | Pseudomonadota | OmpY of Yersinia pseudotuberculosis |
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1.B.1.1.24 | Porin 2 (Omp-Pst2 or OmpPst2) of 365 aas. Voltage gating is observed for Omp-Pst2, where the binding of cations in-between L3 and the barrel wall results in exposing a conserved aromatic residue in the channel lumen, thereby halting ion permeation. Comparison of Omp-Pst1 (TC# 1.B.1.1.20) with Omp-Pst2 suggested that their differing sensitivities to voltage is encoded in the hydrogen-bonding network anchoring L3 onto the barrel wall. The strength of this network governs the probability of cations binding behind L3. That Omp-Pst2 gating is observed only when ions flow against the electrostatic potential gradient of the channel suggests a possible role for this porin in the regulation of charge distribution across the outer membrane and bacterial homeostasis (Song et al. 2015). |
Bacteria | Pseudomonadota | OmpPst2 of Providenica stuartii |
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1.B.1.1.25 | Anion-selective, voltage-sensitive porin, VCA_1008, of 331 aas with a pore exclusion limit of 6.9 nm (Goulart et al. 2015). |
Bacteria | Pseudomonadota | VCA_1008 of Vibrio cholerae |
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1.B.1.1.26 | The mature outer membrane protein, OmpC of 342 aas. Elicits an immune response (Yadav et al. 2016). |
Bacteria | Pseudomonadota | OmpC of Aeromonas hydrophila |
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1.B.1.1.27 | Outer membrane porin, OmpS1 of 394 aas. mutants defective for OmpS1 are attenuated for virulence in mice (Rodríguez-Morales et al. 2006). |
Bacteria | Pseudomonadota | OmpS1 in Salmonella enterica serovar Typhi |
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1.B.1.1.28 | OmpF of 364 aas and 1 N-terminal TMS. It has an abnormally high closing potential possibly due to charged residues and intramolecular bonds (Chistyulin et al. 2019). |
Bacteria | Pseudomonadota | OmpF of Yersinia ruckeri |
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1.B.1.1.29 | Outer membrane porin, OmpE36, of 369 aas and 1 N-terminal TMS. It is 90% identical to Omp36 (TC# 1.B.1.1.13). Divalent cations, especially Ca2+, stabilize its binding to LPS molecules (Kesireddy et al. 2019). |
Bacteria | Pseudomonadota | OmpE36 of Klebsiella aerogenes (Enterobacter aerogenes) |
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1.B.1.1.3 | OmpC general porin. Expression of OmpC and OmpF is reciprocally regulated by the EnvZ/OmpR sensor kinase/response regulator system (Egger et al. 1997). Mutants isolated from patients with MDR E. coli, resistant to several antibiotics, showed decreased permeability to these antibiotics (Lou et al. 2011). The diffusion route of the fluoroquinolone, enrofloxacin, through the OmpC porin has been reported (Prajapati et al. 2018). This system also transports azithromycin (Luo et al. 2024). |
Bacteria | Pseudomonadota | OmpC of E. coli |
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1.B.1.1.30 | OmpU of 337 aas. OmpU is recognized by Toll-Like receptors in monocytes and macrophages for the induction of proinflammatory responses (Gulati et al. 2019). |
Bacteria | Pseudomonadota | OmpU of Vibrio parahaemolyticus |
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1.B.1.1.31 | OmpC of 384 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadati, Pseudomonadota | OmpC of Enterobacter hormaechei |
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1.B.1.1.32 | Outer membrane porin, OmpN or OmpK37 of 374 aas and 1 N-terminal TMS. It was found to have higher mutability as a distinguishing feature which makes it an important protein in monitoring the evolving resistances in microorganisms |
None | Pseudomonadati, Pseudomonadota | OmpN of Klebsiella pneumoniae |
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1.B.1.1.4 |
Weakly anion-selective NmpC (OmpD) porin (Prilipov et al. 1998). Transports methyl benzyl viologen, ceftriaxone and hydrogen peroxide in Salmonella species (Hu et al. 2011; Calderón et al. 2010). |
Bacteria | Pseudomonadota | NmpC of E. coli |
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1.B.1.1.5 | LC (lysogenic conversion) porin. Can replace OmpC and OmpF and is therefore probably non-selective (Fralick et al. 1990). Synthesis is subject to catabolite repression mediated by the cyclicAMP receptor protein, CRP (Blasband and Schnaitman 1987).
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Viruses | Heunggongvirae, Uroviricota | LC porin of phage PA-2 |
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1.B.1.1.6 | Major outer membrane porin, OpnP. Probably orthologous to the E. coli OmpF. Expression of the opnP gene is activated by EnvZ and regulated by temperatur (Forst et al. 1995; Forst and Tabatabai 1997). |
Bacteria | Pseudomonadota | OpnP of Xenorhabdus nematophilus |
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1.B.1.1.7 | ComP porin. A virulence factor essential for cytotoxicity and apoptosis by this enteric pathogen (Tsugawa et al., 2008) |
Bacteria | Pseudomonadota | ComP of Plesiomonas shigelloides (A0JCJ5) |
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1.B.1.1.8 | Trimeric 16 TMS non-specific porin, Omp-EA (Elazer et al., 2007) | Bacteria | Pseudomonadota | Omp-EA of Erwinia amylovora (A0RZH5) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.1.1.9 | OmpU porin (weakly cation-selective; expression is induced by bile salts; OmpU mediates bile salt resistance) (Wang et al., 2003). This protein is 65% identical to OmpU of Vibrio alginolyticus which is involved in iron balance (Lv et al. 2020). |
Bacteria | Pseudomonadota | OmpU of Listonella (Vibrio) anguillarum (Q8GD13) |
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1.B.1.10.1 | Legiobactin receptor, LbtU of 361 aas with one N-terminal TMS and 16 predicted beta-strands (Chatfield et al., 2011). |
Bacteria | Pseudomonadota | LbtU of Legionella pneumoniae (E2JEY3) |
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1.B.1.11.1 | Putative porin (based on homology) of 375 aas |
Bacteria | Campylobacterota | Putative porin of Helicobacter hepaticus |
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1.B.1.12.1 | Porin of 194 aas and 10 transmembrane β-strands, Omp1X (Park et al. 2014). |
Bacteria | Pseudomonadota | Porin of Xanthomonas oryzae |
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1.B.1.2.1 | Omp25 of 255 aas. Associates with CarO (Siroy et al. 2005). |
Bacteria | Pseudomonadota | Omp25 of Acidetobacter baumannii |
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1.B.1.2.2 | Putative porin of 251 aas |
Bacteria | Pseudomonadota | PP of Shewanella piezotolerans |
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1.B.1.2.3 | Putative porin of 306 aas |
Bacteria | Pseudomonadota | PP of Colwellia psychrerythraea (Vibrio psychroerythus) |
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1.B.1.2.4 | Outer membrane porin, Omp33 or Omp33-36. This protein is a virulence factor and induces apoptosis in the host (Rumbo et al. 2014; Smani et al. 2013). It is involved in carbapenem resistance and is highly polymorphic (Novović et al. 2018). |
Bacteria | Pseudomonadota | Omp33-36 of Acinetobacter baumannii |
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1.B.1.3.1 | Omp2 porin. Several differing sequences for this protein can be found in GenBank. The one with acc# P46025 is 80% identical to the one listed here in TCDB. It may transport β-lactams and novobiocin (Zwama et al. 2019). |
Bacteria | Pseudomonadota | Omp2 of Haemophilus influenzae |
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1.B.1.3.2 | OmpP2 porin (transports NAD and NMN; transport Km=5 mM; may also serve as a general diffusion porin) (Andersen et al., 2003). Its solute transport activity with size exclusion limit has been described (Kattner et al. 2015). |
Bacteria | Pseudomonadota | OmpP2 of Haemophilus influenzae (Q48217) |
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1.B.1.3.3 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Haemophilus parainfluenzae |
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1.B.1.3.4 | Putative porin |
Bacteria | Pseudomonadota | Putaive porin of Neisseria sp. |
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1.B.1.4.1 | Omp porin | Bacteria | Pseudomonadota | Omp porin of Bordetella pertussis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.1.4.2 | Phthalate porin, OphP (Chang et al. 2009). | Bacteria | Pseudomonadota | OphP of Burkholderia capacia (C0LZS0) |
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1.B.1.4.3 | Porin of 38 KDa,Omp38 in Burkholderia pseudomallei, the causative agent of melioidosis, an infectious disease of animals and humans. MDR can be due to mutations in Omp38. Ion current blockages of reconstituted Omp38 by seven antimicrobial agents occurred in a concentration-dependent manner with the translocation on-rate following the order: norfloxacin>ertapenem>ceftazidime>cefepime>imipenem>meropenem>penicillin G (Suginta et al. 2011). Also allows transport of neutral sugars and numerous antimicrobial agents including cephalosporin and carbapenem (Aunkham et al. 2014). |
Bacteria | Pseudomonadota | Omp38 of Burkholderia pseudomallei |
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1.B.1.4.4 | Outer membrane porin of 353 aas (Brunen et al. 1991). |
Bacteria | Pseudomonadota | OMP of Acidovorax delafieldii |
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1.B.1.4.5 | Porin-like protein |
Bacteria | Chlorobiota | Porin of Chlorobium phaeobacteroides |
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1.B.1.4.6 | Putative porin of 248 aas |
Bacteria | Pseudomonadota | PP of Burkholderia cepacia (T0ET67) |
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1.B.1.4.7 | Outer membrane porin, OMPNK8 of 380 aas. Probably involved in transport of and chemotaxis toward β-ketoadipate; encoded by a gene (orf1) on a megaplasmid (pNK8) that carries the gene cluster (orf1-tfdT-CDEF), encoding chlorocatechol-degrading enzymes. orf1 is induced by the presence of 3-chlorobenzoate as is the tfd operon (Yamamoto-Tamura et al. 2015). |
Bacteria | Pseudomonadota | OMPNK8 of Burkholderia sp. NK8 |
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1.B.1.4.8 | Outer membrane porin of 394 aas and 16 predicted beta strands, isolated from an endosymbiont of a trypanosomatid protozoan (Andrade et al. 2011). |
Bacteria | Pseudomonadota | Porin of an endosymbiont of Crithidia deanei |
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1.B.1.4.9 | OmpQ porin of 364 aas |
Bacteria | Pseudomonadota | OmpQ of Bordetella parapertussis |
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1.B.1.5.1 | Oma1 porin (Class 1) (Tanabe et al., 2010) |
Bacteria | Pseudomonadota | Oma1 of Neisseria gonorrhoeae |
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1.B.1.5.2 | PorA porin, cation selective at pH > 6; anion selective at pH < 4 (a continuum electrodiffusion model accounts for the results) (Cervera et al., 2008). Both PorA and PorB have been used for vaccine development (Whiting et al. 2019). |
Bacteria | Pseudomonadota | PorA of Neisseria meningitidis |
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1.B.1.5.3 | Major outer membrane protein IB (OMB) (slightly cation-selective porin) | Bacteria | Pseudomonadota | OMB of Neisseria sicca | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.1.5.4 |
PorB porin (Song et al. 1998; Tanabe et al., 2010). The 2.3 Å structure has been determined by x-ray crystallography. There are three putative solute translocation pathways through the channel pore: One pathway transports anions nonselectively, one tranports cations nonselectively, and one facilitates the specific uptake of sugars (Kattner et al. 2012). Regulated by ATP binding (Tanabe et al., 2010). Exhibits voltage-dependent closure (Jadhav et al. 2013). Its unique solute transport activity with size exclusion limit has been described (Kattner et al. 2015). The β-lactam antibiotic ampicillin binds to PorB (Bartsch et al. 2019). Recombination in loop regions between pathogenic and non-pathogenic Neisseria spp. has been observed, suggested a mechanism for developing variation in drug resistance (Manoharan-Basil et al. 2023). Gonococcal PorB is a multifaceted modulator of host immune responses (Jones et al. 2024). |
Bacteria | Pseudomonadota | PorB porin of Neisseria meningitidis |
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1.B.1.5.6 | Porin of 434 aas amd 1 N-terminal TMS. |
Bacteria | Acidobacteriota | Porin of Holophaga foetida |
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1.B.1.6.1 | Anion-selective porin protein 32, Omp32. The structure is known to 1.5 Å resolution (Zachariae et al. 2006). |
Bacteria | Pseudomonadota | Porin protein 32 of Comamonas (Delftia) acidovorans |
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1.B.1.6.2 | Outer membrane porin of 304 aas (Brunen et al. 1991). |
Bacteria | Pseudomonadota | OMP of Acidovorax delafieldii |
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1.B.1.6.3 | Outer membrane porin of 319 aas (Brunen et al. 1991). |
Bacteria | Pseudomonadota | OMP of Acidovorax delafieldii |
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1.B.1.6.4 | Outer membrane porin of 313 aas |
Bacteria | Chrysiogenota | Porin of Desulfurispirillum indicum |
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1.B.1.7.1 | Chitoporin, ChiP of 366 aas and 1 N-terminal TMS. Its synthesis is induced by (GlcNAcn, n = 2-6, but not by GlcNAc or other sugars. A nulll mutant did not grow on GlcNAc3 and transported a nonmetabolizable analogue of GlcNAc2 at a reduced rate. (Keyhani et al., 2000). |
Bacteria | Pseudomonadota | ChiP of Vibrio furnissii |
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1.B.1.7.2 | Sugar-specific chitoporin of 375 aas, ChiP. The best substrate is chitohexose, but ChiP transports a variety of chitooligosaccharides. Trp136 is important for the binding affinity for chitohexaose (Chumjan et al. 2015). X-ray crystal structures of ChiP from V. harveyi in the presence and absence of chito-oligosaccharides have been solved (Aunkham et al. 2018). Structures without bound sugar reveal a trimeric assembly with an unprecedented closing of the transport pore by the N-terminus of a neighboring subunit. Substrate binding ejects the pore plug to open the transport channel.The structures explain the exceptional affinity of ChiP for chito-oligosaccharides and point to an important role of the N-terminal gate in substrate transport (Aunkham et al. 2018). Hydrogen-bonds contribute to sugar permeation (Chumjan et al. 2019). This protein is 90% identical to the chitoporin of the Vibrio campbellii chitoporin (Aunkham et al. 2020). The C2 entity of chitosugars is crucial for the molecular selectivity of the Vibrio campbellii chitoporin (Suginta et al. 2021). |
Bacteria | Pseudomonadota | ChiP of Vibrio harveyi |
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1.B.1.8.1 | Low ion selective porin (PK/PCl = 4), OmpT (high permeability to bile) (Simonet et al., 2003). OmpT has an effective radius of 0.43nm, and acidic pH, high ionic strength, or exposure to polyethyleneglycol stabilizes a less conductive state (Duret & Delcour, 2010). It binds the biofilm matrix protein, Bap1, which influences antimicrobial peptide (polymyxin B and LL-37) resistance (Duperthuy et al. 2013). The high resolution structures of OmpT and OmpU, the two major porins in V. cholerae, have been determined, and both have unusual constrictions that create narrower barriers for small-molecule permeation and change the internal electric fields of the channels (Pathania et al. 2018). |
Bacteria | Pseudomonadota | OmpT of Vibrio cholerae (AAC28105) |
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1.B.1.8.2 | Putative uncharacterized protein | Bacteria | Spirochaetota | Tresu_2327 of Treponema succinifaciens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.1.8.3 | Porin-like protein H (37 kDa outer membrane protein) | Bacteria | Pseudomonadota | ompH of Photobacterium profundum ) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.1.8.4 | OmpT of 322 aas and 1 N-terminal TMS. OmpT is a promising vaccine candidate against V. ichthyoenteri infections in fish (Tang et al. 2019). |
Bacteria | Pseudomonadota | OmpT of Vibrio ichthyoenteri |
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1.B.1.9.1 | The outer membrane porin, M35 (Easton et al., 2005) | Bacteria | Pseudomonadota | M35 of Moraxella catarrhalis (AAX99225) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.1.9.2 | Major porin of 369 aas, involved in anaerobic respiration, positively regulated by both CRP and FNR, OmpS38 or Omp35 (Gao et al. 2015). |
Bacteria | Pseudomonadota | OmpS38 of Shewanella oneidensis |
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1.B.10.1.1 | Nucleoside-specific channel forming protein, Tsx (Benz et al. 1988). |
Bacteria | Pseudomonadota | Tsx of E. coli (P0A927) |
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1.B.10.2.1 | Outer membrane protein phage receptor | Bacteria | Pseudomonadota | OmpK of Vibrio parahaemolyticus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.10.2.2 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Pseudomonas aeruginosa |
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1.B.10.2.3 | Tsx porin homologue |
Bacteria | Pseudomonadota | Tsx porin family of Pseudomonas aeruginosa |
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1.B.10.2.4 | Uncharacterized protein of 256 aas |
Bacteria | Pseudomonadota | UP of Psychrobacter cryohalolentis |
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1.B.10.2.5 | Tsx homologue of 296 aas |
Bacteria | Pseudomonadota | Tsx homologue of Photorhabdus temperata |
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1.B.10.2.6 | Tsx homologue of 262 aas |
Bacteria | Verrucomicrobiota | Tsx homologue of Coraliomargarita akajimensis |
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1.B.10.3.1 | Tsx porin family member |
Bacteria | Pseudomonadota | Tsx porin family member of E. coli |
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1.B.10.3.2 | Uncharacterized porin of 226 aas |
Bacteria | Pseudomonadota | UP of Vibrio cholerae |
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1.B.11.1.1 | Type κ fimbrial usher, FacD | Bacteria | Pseudomonadota | FacD of E. coli (P06970) |
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1.B.11.1.2 | Type κ fimbrial usher, AfrB | Bacteria | Pseudomonadota | AfrB of E. coli (Q07686) |
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1.B.11.2.1 | Type π fimbrial usher, PapC. The crystal structure of the PapC usher translocation domain has been solved (Daniels and Normark, 2008; Remaut et al., 2008). The crystal structure of the full-length PapC usher in complex with its cognate PapDG chaperone-subunit complex in a pre-activation state has been solved. This elucidated the molecular details of how the usher is specifically engaged by allosteric interactions with its substrate, preceding activation, and how the usher facilitates the transfer of subunits from the amino-terminal periplasmic domain to the CTDs during pilus assembly (Omattage et al. 2018). |
Bacteria | Pseudomonadota | PapC of E. coli (P07110) |
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1.B.11.2.2 | Uncharacterized outer membrane usher protein YbgQ |
Bacteria | Pseudomonadota | YbgQ of Escherichia coli |
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1.B.11.3.1 | Type γ fimbrial usher, FimC | Bacteria | Pseudomonadota | FimC of Bordetella pertussis (P33410) |
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1.B.11.3.10 | Outer membrane usher protein FasD |
Bacteria | Pseudomonadota | FasD of E. coli |
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1.B.11.3.11 | Fimbrial usher, YehB of 826 aas. |
Bacteria | Pseudomonadota | YehB of E. coli |
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1.B.11.3.2 | The outer membrane usher protein, MrkC precursor (for type III fimbriae) (Burmolle et al., 2008) | Bacteria | Pseudomonadota | MrkC precursor of Bordetella pertussis (P21647) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.11.3.3 |
Type γ4 fimbrial usher, HtrE or EcpC. Functions with EcpD to assemble the E. coli common pilus, and extracellular fiber-like structure that plays a role in early biofilm formation and host cell recognition (Garnett et al. 2012). |
Bacteria | Pseudomonadota | HtrE of E. coli (P33129) |
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1.B.11.3.4 | Type γ3 fimbrial usher, CssD | Bacteria | Pseudomonadota | CssD of E. coli (P53513) |
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1.B.11.3.5 | Type γ1 fimbrial usher, YcbS | Bacteria | Pseudomonadota | YcbS of E. coli (Q8CVM4) |
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1.B.11.3.6 | Type γ2 fimbrial usher, YraJ | Bacteria | Pseudomonadota | YraJ of E. coli (P42915) |
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1.B.11.3.7 | Usher protein, CupB3 (POTRA domain containing P-usher) [Dual function in secreting fimbril subunits and cell surface adhesin, CupB5 (Q9HWU6) which is homologous to members of the AT1 and AT2 families (1.B.12 and 1.B.40)] (Ruer et al., 2008). | Bacteria | Pseudomonadota | CupB3 Usher of Pseudomonas aeruginosa (Q9HWU4) |
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1.B.11.3.8 | Usher, Caf1A, important for F1 antigen assembly |
Bacteria | Pseudomonadota | Caf1A of Yersinia pestis (P26949) |
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1.B.11.3.9 | Fimbial usher protein, FimD |
Bacteria | Pseudomonadota | FimD of E. coli (P30130) |
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1.B.11.4.1 | Type α fimbrial usher, CfaC | Bacteria | Pseudomonadota | CfaC of E. coli (P25733) |
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1.B.11.5.1 | Type β fimbrial usher, YhcD | Bacteria | Pseudomonadota | YhcD of E. coli (P45420) |
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1.B.11.6.1 | Type σ fimbrial usher, CsuD | Bacteria | Pseudomonadota | CsuD of Acinetobacter baumannii (Q6XBY3) |
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1.B.11.6.2 | Fimbrial usher protein |
Bacteria | Myxococcota | FUP of Myxococcus xanthus |
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1.B.11.6.3 | Fimbrial usher, PapC |
Bacteria | Spirochaetota | PapC homologue of Spirochaeta africana |
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1.B.11.6.4 | Fimbrial usher protein of 892 aas (Nuccio and Bäumler 2007). |
Bacteria | Cyanobacteriota | Fimbrial usher protein of Synechocystis sp. |
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1.B.11.7.1 | Fimbrial O.M. usher protein (760aas) | Bacteria | Pseudomonadota | Usher protein of Burkholderia multivorans (A9AQJ0) |
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1.B.11.8.1 | Fimbrial usher protein of 729 aas (Nuccio and Bäumler, 2007). Note: Deinococcus radiodurans has an envelope with two membranes; the outer membrane lacks lipopolysaccharide. |
Bacteria | Deinococcota | Fimbrial usher protein of Deinococcus radiodurans |
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1.B.12.1.1 | Autotransporter of adhesin involved in diffuse adherence, AidA (Charbonneau and Mourez, 2007). Heptosylated on 16 ser and thr residues which is required for adhesion (Charbonneau et al., 2007). | Bacteria | Pseudomonadota | AidA of E. coli | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.12.1.10 | PmpF of 1034 aas (Vasilevsky et al. 2016). |
Bacteria | Chlamydiota | PmpF of Chlamydia trachomatis |
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1.B.12.1.2 | Autoexporter of virulence factor G, VirG or IcsA | Bacteria | Pseudomonadota | VirG of Shigella flexneri | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.12.1.3 | The MisL autotransporter/fibronectin binding protein; expression of misL is regulated by MisT (Tükel et al., 2007) |
Bacteria | Pseudomonadota | MisL of Salmonella typhimurium (AAD16954) |
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1.B.12.1.4 | Putative autotransporter, YcbB; YuaO of 1758 aas. |
Bacteria | Pseudomonadota | YuaO of E. coli K12 |
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1.B.12.1.5 | Biofilm adhesin autotransporter of 1250 aas, YfaL (Berry et al. 2009). |
Bacteria | Pseudomonadota | YfaL of E. coli |
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1.B.12.1.6 | Autotransporter of 1349 aas, EhaA, involved in autoaggregation, biofilm formation and adhesion to epithelial cells (Wells et al. 2008). |
Bacteria | Pseudomonadota | EhaA of E. coli O157 |
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1.B.12.1.7 | Autotransporter PmpA of 975 aas (Vasilevsky et al. 2016). |
Bacteria | Chlamydiota | PmpA of Chlamydia trachomatis |
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1.B.12.1.8 | PmpB of 1754 aas (Vasilevsky et al. 2016) |
Bacteria | Chlamydiota | PmpB of Chlamydia trachomatis |
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1.B.12.1.9 | PmpD of 1531 aas (Vasilevsky et al. 2016). |
Bacteria | Chlamydiota | PmpD of Chlamydia trachomatis |
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1.B.12.10.1 | The Campylobacter adhesion protein, CapA (Ashgar et al., 2007) | Bacteria | Campylobacterota | CapA of Campylobacter jejuni (Q0PAN9) |
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1.B.12.11.1 | The outer membrane acid phosphatase autotransporter, MapA (940 aas) (Hoopman et al., 2008) | Bacteria | Pseudomonadota | MapA of Moraxella catarrhalis (A9XED4) |
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1.B.12.12.1 | The acidic repeat AT protein, ARP (1441 aas) (Litwin et al., 2007) (shows N-terminal sequence similarity to 1.B.12.2.3 and C-terminal similarity to 1.B.12.8.2). | Bacteria | Pseudomonadota | Arp of Bartonella henselae (Q6G2D1) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.12.12.4 | Uncharacterized opacity protein or related surface antigen of 398 aas and 1 N-terminal TMS. |
Bacteria | Planctomycetota | UP of Candidatus Brocadiaceae bacterium |
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1.B.12.13.1 | Surface antigen, Sca2; required for intracellular actin based motility in Rickettsia (Kleba et al., 2010). |
Bacteria | Pseudomonadota | Sca2 of Rickettsia rickettsii (Q3L8P4) |
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1.B.12.13.2 | Autotransporter, OmpA |
Bacteria | Pseudomonadota | OmpA of Rickettsia sp. p1A (B5A5W2) |
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1.B.12.13.3 | Autotransporter, OmpB |
Bacteria | Pseudomonadota | OmpB of Rickettsia helvetica (F1CET6) |
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1.B.12.2.1 | Autoexporter of pertactin, Ptt of 910 aas with a C-terminal β-barrel domain which has been crystalized (Zhu et al. 2007). It is a bacterial adhesin and vaccine target which influences the duration of B. pertussis infections but does not otherwise affect the disease (Vodzak et al. 2016). |
Bacteria | Pseudomonadota | Ptt of Bordetella pertussis |
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1.B.12.2.2 | Autoexporter of tracheal colonization factor | Bacteria | Pseudomonadota | TcfA of Bordetella pertussis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.12.2.3 | Autoexporter of Bordetella resistance to killing proteins | Bacteria | Pseudomonadota | BrkA of Bordetella pertussis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.12.2.4 | Autotransporter-1 family member |
Bacteria | Bacillota | Autotransporter-1 of Selenomonas sputigena |
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1.B.12.2.5 | Autotransporter, BapC of 909 aas with an established transmembrane β-barrel and a long α-structured passenger domain (Riaz et al. 2015). |
Bacteria | Pseudomonadota | BapC of Bordetella pertussis |
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1.B.12.2.6 | Putative autotransporter of 955 aas |
Bacteria | Pseudomonadota | Autotransporter of E. coli |
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1.B.12.2.7 | Autotransporter of 980 aas, EhaB, involved in biofilm formation as well as adhesion to collagen I and laminin (Wells et al. 2008). |
Bacteria | Pseudomonadota | EhaB of E. coli |
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1.B.12.3.1 | Autoexporter of IgA protease | Bacteria | Pseudomonadota | IgA protease of Neisseria gonorrhoeae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.12.3.2 | Autoexporter of adhesion and penetration protein |
Bacteria | Pseudomonadota | Hap of Haemophilus influenzae |
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1.B.12.3.3 | Autotransporter/adhesin of 912 aas and 1 N-terminal TMS, Aae. Aae mediates A. actinomycetemcomitans adhesion to epithelial cells and may be involved in biofilm formation and interaction with adsorbed salivary proteins (Nunes et al. 2017). |
Bacteria | Pseudomonadota | Aae of Aggregatibacter actinomycetemcomitans (Actinobacillus actinomycetemcomitans) (Haemophilus actinomycetemcomitans) |
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1.B.12.4.1 | Autoexporter of EPEC-secreted protein C | Bacteria | Pseudomonadota | EspC of E. coli | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.12.4.2 | Autoexporter of temperature-sensitive hemagglutinin, a hemoglobin binding protease, Tsh/Hbp (1377 aas) (Jong and Luirink, 2008; Peterson et al., 2006). The pore of the Hbp TD is largely obstructed, but a variant that lacked one amino acid residue from the N-terminus showed the opening and closing of a channel comparable to what was reported for the TD of NalP. Hbp is processed by an autocatalytic intramolecular mechanism resulting in the stable docking of the α-helical plug in the barrel. |
Bacteria | Pseudomonadota | Tsh/Hbp of E. coli |
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1.B.12.4.3 | Autotransporter of serine protease, EspP (with long N-terminal leader that prevents improper folding in the periplasm) (Szabady et al., 2005; Ieva et al., 2008). Energy for export is provided by the folding of the C-terminal domain (Peterson et al., 2010). |
Bacteria | Pseudomonadota | EspP of E. coli (NP_052685) |
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1.B.12.4.4 | Autotransporter-1, Pet (serine protease; 1295 aas)) (Eslava et al., 1998; Leyton et al., 2010). The first stage of autotransporter folding determines whether subsequent translocation can deliver the N-terminal domain to its functional form on the bacterial cell surface. Paired conserved glycine-aromatic 'mortise and tenon' motifs join neighbouring beta-strands in the C-terminal barrel domain, and mutations within these motifs slow the rate and extent of passenger domain translocation to the surface of bacterial cell (Leyton et al. 2014). |
Bacteria | Pseudomonadota | Pet of E. coli (O68900) |
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1.B.12.4.5 | Autotransporter-1, Pic (serine protease;1372 aas) (Henderson et al., 1999). |
Bacteria | Pseudomonadota | Pic of E. coli (Q7BS42) |
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1.B.12.4.6 | Autotransporter-1, Sat (Serine protease; 1295 aas) (Guyer et al., 2000). |
Bacteria | Pseudomonadota | Sat of E. coli (Q8FDW4) |
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1.B.12.4.7 | Vacuolating Autotransporter-1, Vat (1376 aas; protease; pertactin-like passenger domain; virulence factor) |
Bacteria | Pseudomonadota | Vat of E. coli (A1A7W8) |
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1.B.12.5.1 | Autoexporter of serine protease | Bacteria | Pseudomonadota | Ssp of Serratia marcescens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.12.5.10 | Autotransporter, YapE of 1072 aas (Lawrenz et al. 2013). |
Bacteria | Pseudomonadota | YapE of Yersinia pestis |
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1.B.12.5.11 | Autotransporter outer membrane beta-barrel domain-containing protein of 2358 aa |
Bacteria | Pseudomonadota | Autotransporter outer membrane beta-barrel domain-containing protein of Burkholderia cepacia |
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1.B.12.5.2 | The Azorhizobial autotransporter AoaA, required for N- fixing activity of stem nodules (Suzuki et al., 2008). | Bacteria | Pseudomonadota | AoaA of Azorhizobium caulinodans (A8IBA8) |
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1.B.12.5.3 | The cytotoxin/agglutinin AT-1 protein, Pta (Alamuri and Mobley, 2008). | Bacteria | Pseudomonadota | Pta of Proteus mirabilis (B4F2I9) |
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1.B.12.5.4 | Autotransporter-1, ShdA (2035 aas) (Kingsley et al., 2003). |
Bacteria | Pseudomonadota | ShdA of Salmonella enterica (Q9XCJ4) |
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1.B.12.5.5 | Autotransporter-1, BigA (1953 aas) (Lauri et al. 2011). |
Bacteria | Pseudomonadota | BigA of Salmonella typhimurium (P25927) |
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1.B.12.5.6 | Autotransporter essential for virulence and biofilm formation of 1242 aas, Pfa1. The passenger domain is a serine protease, cytotoxic to cultured fish cells (Hu et al. 2009). |
Bacteria | Pseudomonadota | Pfa1 of Pseudomonas fluorescens |
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1.B.12.5.7 | Putative autotransporter of 886 aas |
Bacteria | Pseudomonadota | AT of Bordetella pertussis |
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1.B.12.5.8 | Autotransporter of 1128 aas |
Bacteria | Pseudomonadota | AT of Chromobacterium vioalceum |
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1.B.12.5.9 | Autoexporter of lipase/esterase, EstA | Bacteria | Pseudomonadota | EstA of Pseudomonas aeruginosa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.12.7.1 | Autoexporter of Helicobacter surface ring protein | Bacteria | Campylobacterota | Hsr of Helicobacter mustelae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.12.8.1 | Putative autotransporter of 736 aas |
Bacteria | Pseudomonadota | AT of Yersina pestis |
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1.B.12.8.2 | Fluffing protein (Flu) or antigen-43 (Ag-43; Ag43; also called YeeQ and YzzX). Processed proteolytically to the α- (soluble) and β- (membrane anchored) subunits; determines colony morphology and autoaggregation of E. coli K12 and many pathogenic strains (Henderson et al., 1997; Klemm et al. 2006). May function in autotransporter processing. |
Bacteria | Pseudomonadota | Flu of E. coli |
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1.B.12.8.3 | Autotransporter-1, TibA (989 aas; an Adhesin/Invasin associated with some enterotoxigenic E. coli) (Lindenthal and Elsinghorst et al., 1999; Klemm et al. 2006). |
Bacteria | Pseudomonadota | TibA of E. coli (Q9XD84) |
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1.B.12.8.4 | Putative outer membrane autotransporter, YnaI, of 863 aas and one N-terminal TMS. |
Bacteria | Pseudomonadota | YnaI of E. coli |
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1.B.12.9.1 | Autotransporter of N-terminal protease passenger domain that cleaves surface-localized virulence factors. The 3-d structure is known (Oomen et al., 2004). The crystal structure of the NalP translocator domain revealed a 12 β-stranded transmembrane beta-barrel containing a central alpha-helix. The transmembrane beta-barrel is stable even in the absence of the alpha-helix. Removal of the helix results in an influx of water into the pore region, suggesting the helix acts as a 'plug' (Khalid and Sansom 2006). The dimensions of the pore fluctuate, but the NalP monomer is sufficient for the transport of the passenger domain in an unfolded or extended conformation (Khalid and Sansom 2006). NalP is subject to phase variation (Oldfield et al. 2013). |
Bacteria | Pseudomonadota | pNalP of Neisseria meningitidis (AAN71715) |
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1.B.12.9.2 | The serine protease autotransporter, SphB1 | Bacteria | Pseudomonadota | SphB1 of Bordetella pertussis (Q7W0C9) |
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1.B.13.1.1 | Alginate export porin, AEP or AlgE (Rehm et al. 1994). A monomeric 18 stranded beta-barrel that is part of a multicomponent, two membrane, envelope-spanning complex that includes AlgK, AlgX and Alg44 (Rehman and Rehm 2013). |
Bacteria | Pseudomonadota | AlgE of Pseudomonas aeruginosa |
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1.B.13.1.2 | Porin, AlgE (AlgJ) |
Bacteria | Pseudomonadota | Porin of Azotobacter vinelandii |
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1.B.13.1.3 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Burkholderiales bacterium |
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1.B.13.1.4 | Putative porin |
Bacteria | Aquificota | Putative porin of Thermovibrio ammonificans |
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1.B.13.1.5 | Putative porin |
Bacteria | Campylobacterota | Putative porin of Nitratiruptor sp. SB155-2 |
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1.B.13.1.6 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of E. coli |
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1.B.13.1.7 | Alginate export porin of 460 aas. May also export neutral lipids such as triacylglycerols, wax esters, and polyhydroxyalkanoates (Manilla-Pérez et al. 2010). |
Bacteria | Pseudomonadota | AlgE of Alcanivorax borkumensis |
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1.B.13.2.1 | Putative porin |
Bacteria | Spirochaetota | Putative porin of Turneriella parva |
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1.B.13.2.2 | Putative porin of 536 aas |
Bacteria | Spirochaetota | Putative porin of Turneriella parva |
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1.B.13.3.1 | Putative porin |
Bacteria | Verrucomicrobiota | Putative porin of Pedosphaera parvula |
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1.B.13.3.2 | Putative porin of 455 aas |
Bacteria | Bacteroidota | Putative porin of Flavobacterium johnsoniae |
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1.B.13.3.3 | Putative porin |
Bacteria | Acidobacteriota | Putative porin of Solibacter usitatus |
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1.B.13.3.4 | Putative porin of 447 aas |
Bacteria | Pseudomonadota | Putative porin of Brucella abortus |
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1.B.13.3.5 | PF13372 domain protein of 609 aas |
Bacteria | Spirochaetota | PF13372 domain protein of Leptspira interrogans |
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1.B.14.1.1 | FhuE ferric-coprogen receptor of 729 aas and 1 N-terminal TMS. It is required for the uptake of Fe3+ via coprogen, ferrioxamine B, and rhodotorulic acid (Hantke 1983). The crystal structure of FhuE in complex with coprogen was determined, providing a structural basis to explain its selective promiscuity (Grinter and Lithgow 2019). The structural data, in combination with functional analysis, showed that FhuE has evolved to specifically engage with planar siderophores. A potential evolutionary driver, and a critical consequence of this selectivity, is that it allows FhuE to exclude antibiotics that mimic nonplanar hydroxamate siderophores. These toxic molecules could otherwise cross the outer membrane barrier through a Trojan horse mechanism (Grinter and Lithgow 2019). |
Bacteria | Pseudomonadota | FhuE of E. coli |
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1.B.14.1.10 | The outer membrane ferrioxamine/desferrioxamine receptor, FoxA(1) (most like TC# 1.B.14.1.4 and 9) (Wei et al., 2007) | Bacteria | Pseudomonadota | FoxA(1) of Nitrosomonas europaea (Q82VI7) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.1.11 | The outer membrane ferric-anguibactin receptor/transporter, FatA (Lopez and Crosa, 2007) | Bacteria | Pseudomonadota | FatA of Vibrio anguillarum (P11461) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.1.12 | FecA ferric-citrate receptor (PA3901) (Marshall et al., 2009) (62% identical to the E. coli FecA). | Bacteria | Pseudomonadota | FecA of Pseudomonas aeruginosa (Q9HXB2) |
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1.B.14.1.13 | CfrA ferric receptor (Carswell et al., 2008). | Bacteria | Campylobacterota | CfrA of Campylobacter jejuni (A3ZKG8) |
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1.B.14.1.14 | Ferric-pseudobactin 358 receptor | Bacteria | Pseudomonadota | PupA of Pseudomonas putida |
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1.B.14.1.15 | Ferrichrome receptor FcuA | Bacteria | Pseudomonadota | FcuA of Yersinia enterocolitica | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.1.16 | Probable TonB-dependent receptor BfrD (Virulence-associated outer membrane protein Vir-90) | Bacteria | Pseudomonadota | BfrD of Bordetella pertussis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.1.17 |
Ferrioxamine receptor, FoxA. Transports a variety of Ferrioxamine B analogues (Kornreich-Leshem et al. 2005). |
Bacteria | Pseudomonadota | FoxA of Yersinia enterocolitica |
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1.B.14.1.18 | TonB-dependent receptor (Bhat et al. 2011). |
Bacteria | Myxococcota | TonB-dependent receptor of Myxococcus xanthus |
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1.B.14.1.19 | TonB-dependent receptor |
Bacteria | Myxococcota | TonB-dependent receptor of Myxococcus xanthus |
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1.B.14.1.2 | FhuA ferrichrome (also albomycin and rifamycin; Colicin M; Microcin J25; Phage T5) receptor (transports phage T1, T5 and φ80 DNA across the outer membrane, dependent on DcrA (SdaC; TC #2.A.42.2.1) and DcrB) (Forms a complex with and acts with TonB and FhuD (the periplasmic binding receptor (3.A.1.14.3) to deliver siderophore to FhuD (Carter et al., 2006; Braun et al., 2009)). Deletion of the 160-residue cork domain and five large extracellular loops converted this non-conductive, monomeric, 22-stranded beta-barrel protein into a large-conductance protein pore (Wolfe et al. 2015). FhuA and its various applications indicate that it is a versatile building block to generate hybrid catalysts and materials (Sauer et al. 2023). |
Bacteria | Pseudomonadota | FhuA of E. coli |
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1.B.14.1.20 | The iron-citrate receptor/transporter, FecA. TonB mediates both signaling and transport by unfolding portions of the transporter (Mokdad et al. 2012). The ferric citrate regulator, FecR, is translocated across the bacterial inner membrane via a unique Twin-arginine transport dependent mechanism (Passmore et al. 2020). |
Bacteria | Pseudomonadota | FecA of E. coli |
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1.B.14.1.21 | Ferrioxamine receptor |
Bacteria | Pseudomonadota | Ferrioxamine receptor of Pseudovibrio sp. JE062 |
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1.B.14.1.22 | FepA ferri-enterobactin (also Colicins B and D) receptor for the 37 aas disulfide-containing K+ channel toxin, BgK (Braud et al., 2004). Functions by a "ball and chain" mechanism; The transport process involves expulsion of the N-terminal globular domain from the C-terminal beta-barrel (Ma et al. 2007). Conformational rearrangements occur in the N-terminus of FepA during FeEnt transport, but disengagement of the N-domain, out of the rigid channel suggests that it remains within the transmembrane pore as FeEnt enters the periplasm (Majumdar et al. 2020). |
Bacteria | Pseudomonadota | FepA of E. coli |
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1.B.14.1.23 | OMR of 938 aas |
Bacteria | Myxococcota | OMR of Myxococcus xanthus |
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1.B.14.1.24 | Putative TonB-dependent siderophore receptor, Sde_3611 |
Bacteria | Pseudomonadota | Sde3611 of Saccharophagus degradans |
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1.B.14.1.25 | Nickel uptake receptor/channel of 724 aas (Benoit et al. 2013). |
Bacteria | Campylobacterota | HH0418 of Helicobacter hepaticus |
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1.B.14.1.26 | Iron siderophore (ferripyoverdine) receptor and importer, FpvA of 808 aas (Ye et al. 2014). The crystal structure of FpvA has been solved at 3.6 Å resolution. It is folded in two domains: a transmembrane 22-stranded beta-barrel domain occluded by an N-terminal domain containing a mixed four-stranded beta-sheet (the plug). The beta-strands of the barrel are connected by long extracellular loops and short periplasmic turns (Cobessi et al. 2005). |
Bacteria | Pseudomonadota | FpvA of Pseudomonas aeruginosa |
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1.B.14.1.27 | Iron(III) dicitrate transport protein, FecA1: iron dicitrate uptake receptor of 767 aas. Regulated by the ferric uptake regulator transcription factor, Fur (van Vliet et al. 2002) in response to iron availability (Danielli et al. 2009). Involved in iron deficiency anemia in children (Kato et al. 2017). |
Bacteria | Campylobacterota | FecA1 of Helicobacter pylori |
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1.B.14.1.28 | FecA3 of 843 aas. Probable receptor for nickel. Shows 50% identiy with TC# 1.B.14.1.27. Repressed by nickel in the medium, mediated by NikR (Danielli et al. 2009). NikR seems to interact in an asymmetric mode with the fecA3 target to repress its transcription (Romagnoli et al. 2011). |
Bacteria | Campylobacterota | FecA3 of Helicobacter pylori |
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1.B.14.1.29 | Iron-deficiency-induced (2x) iron siderophore uptake outer membrane receptor, FhuA, of 828 aas and 1 N-terminal TMS (Qiu et al. 2018). |
Bacteria | Cyanobacteriota | FhuA of Synechocystis sp. (strain PCC 6803 / Kazusa) |
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1.B.14.1.3 | Ferric enterobactin (also ferricorynebactin) receptor, IroN |
Bacteria | Pseudomonadota | IroN of Salmonella typhimurium |
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1.B.14.1.30 | Outer membrand iron siderophore uptake receptor of 853 aas and 1 N-terminal TMS, Slr1490. |
Bacteria | Cyanobacteriota | Slr1490 of Synechocystis sp. (strain PCC 6803 / Kazusa) |
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1.B.14.1.31 | Outer membrane porin, PiuA, of 753 aas. A deficiency of this iron transporter, PiuA in P. aeruginosa, caused 16-fold increases in cefiderocol resistance, suggesting that it contribute to the permeation of cefiderocol into the cell (Ito et al. 2018). |
Bacteria | Pseudomonadota | PiuA of Pseudomonas aeruginosa |
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1.B.14.1.32 | Catechol iron-siderophore uptake system, IrgA, an iron-regulated outer membrane virulence protein, of 652 aas and 1 N-terminal TMS (Wyckoff et al. 2015). It is involved in the initial step of iron uptake by
binding ferric vibriobactin, an iron chelatin siderophore that allows
V. cholerae to extract iron from the environment and takes up linear enterobactin derivatives (Wyckoff et al. 2015). |
Bacteria | Pseudomonadota | IrgA of Vibrio cholerae |
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1.B.14.1.33 | Heme/hemin outer membrane TonB-related receptor of 708 aas, Tlr (Slakeski et al. 2000). |
Bacteria | Bacteroidota | Tlr of Porphyromonas gingivalis |
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1.B.14.1.4 | CirA Fe3+-catecholate receptor. Serves as the receptor for the TonB- and proton-dependent uptake of the E. coli bacteriocin, Microcin L (MccL) (Morin et al., 2011). CirA is also the translocator for colicin Ia (Jakes and Finkelstein, 2010). Plays roles in cefiderocol and ceftazidime resistance (Ito et al. 2018). Genotypic evolution of Klebsiella pneumoniae sequence type 512 during Ceftazidime/Avibactam, Meropenem/Vaborbactam, and Cefiderocol treatment. This occurred through plasmid loss, outer membrane porin alteration, and a nonsense mutation in the cirA siderophore gene, resulting in high levels of cefiderocol resistance (Arcari et al. 2023). |
Bacteria | Pseudomonadota | CirA of E. coli |
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1.B.14.1.5 | PfeA ferric enterobactin receptor | Bacteria | Pseudomonadota | PfeA of Pseudomonas aeruginosa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.1.6 | Ferripyoverdine/pyocin S3 receptor, FpvA (Adams et al., 2006; Nader et al., 2007; Schalk et al., 2009; Nader et al., 2011) |
Bacteria | Pseudomonadota | FpvA of Pseudomonas aeruginosa |
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1.B.14.1.7 | Iron malleobactin receptor, FmtA (Alice et al., 2006) | Bacteria | Pseudomonadota | FmtA of Burkholderia pseudomallei (EBA51007) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.1.8 | The Ferripyochelin receptor, FptA (Michel et al., 2007). In addition to Fe3+, FptA takes up Co2+, Ga3+, and Ni2+ at low rates (Braud et al., 2009). The high resolution 3-d structure of FptA (2.0 Å) bound to iron-pyochelin has been solved (Cobessi et al. 2005). The pyochelin molecule provides atetra-dentate coordination of iron. The structure is typical of the TonB-dependent receptor/transporter superfamily. |
Bacteria | Pseudomonadota | FptA of Pseudomonas aeruginosa (P42512) |
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1.B.14.1.9 | Ferric-catecholate siderophore (dihydroxybenzoylserine, dihydroxybenzoate) uptake receptor, Fiu or YbiL (Hantke, 1990; Curtis et al., 1988). Plays roles in cefiderocol and ceftazidime resistance (Ito et al. 2018). It can also transport catechol-substituted cephalosporins and is a receptor for microcins M, H47 and E492 (Patzer et al. 2003; Destoumieux-Garzón et al. 2006). |
Bacteria | Pseudomonadota | Fiu of E. coli (P75780) |
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1.B.14.10.1 | Heme/hemoglobin receptor, HmuR (also binds the Cu2+, Zn2+ and Fe2+ derivatives of protoporphyrin IX). Functions with the O.M. heme binding lipoprotein, HmuY (AAQ66587; Olczak et al., 2007). | Bacteria | Bacteroidota | HmuR of Porphyromonas gingivalis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.10.2 | TonB-dependent receptor |
Bacteria | Myxococcota | TonB receptor of Myxococcus xanthus |
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1.B.14.10.3 | TonB-dependent receptor |
Bacteria | Myxococcota | TonB recpetor of Myxocuccus xanthus |
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1.B.14.10.4 | Putative TonB-dependent receptor |
Bacteria | Cyanobacteriota | OMR of Gloeobacter violaceus |
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1.B.14.10.5 | Probable TonB-dependent long chain alkane receptor of 699 aas (Gregson et al. 2018). |
Bacteria | Pseudomonadota | TonB-dependent receptor of Thalassolituus oleivorans |
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1.B.14.10.6 | Cobalt cation concentration sensitive Btu-like system, Btu1, of 698 aas and 1 N-terminal TMS. It facilitates cobalamin uptake in Anabaena sp. PCC 7120 (Graf et al. 2024). The regulation by cobalt and cobalamin as well as their uptakes are described for Anabaena sp. PCC 7120, a model filamentous heterocyst-forming cyanobacterium. Anabaena contains at least three cobalamin riboswitches in its genome, for one of which the functionality was confirmed (Graf et al. 2024). Two outer membrane-localized cobalamin TonB-dependent transporters, namely BtuB1 and BtuB2, were identified. BtuB2 is important for fast uptake of cobalamin under conditions with low external cobalt, whereas BtuB1 appears to function in cobalamin uptake under conditions of sufficient cobalt supply. While the general function is comparable, the specific function of the two genes differs and mutants thereof show distinct phenotypes. The uptake of cobalamin depends further on the TonB and a BtuFCD machinery, as mutants of tonB3 and btuD show reduced cobalamin uptake rates. |
Bacteria | Cyanobacteriota | BtuB1 of Anabaena sp. PCC 7120 |
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1.B.14.11.1 | The Nickel (Ni2+) receptor (FrpB4; Hp1512) of 877 aas. Energized by the TonB/ExbBD complex (Schauer et al., 2007). Capable of binding both haem and haemoglobin but shows greater affinity for haem. The mRNA levels of frpB1 were repressed by iron and lightly modulated by haem or haemoglobin. Overexpression of the frpB1 gene supported cellular growth when haem or haemoglobin were supplied as the only iron source (Carrizo-Chávez et al. 2012). |
Bacteria | Campylobacterota | FrpB4 of Helicobacter pylori (Q9ZJA8) |
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1.B.14.12.1 | The TonB-dependent maltooligosaccharide OM receptor/porin, MalA (Lohmiller et al., 2008). | Bacteria | Pseudomonadota | MalA of Caulobacter crescentus (Q9A608) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.12.2 | The N-acetyl glucosamine/chitin oligosaccharide OM receptor porin, NagA (Eisenbeis et al., 2008). | Bacteria | Pseudomonadota | NagA of Caulobacter crescentus (Q9AAZ6) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.12.3 | TonB-dependent receptor |
Bacteria | Myxococcota | TonB-dependent receptor of Myxococcus xanthus |
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1.B.14.13.1 | TonB-dependent receptor of 763 aas |
Bacteria | Pseudomonadota | Receptor of Xanthomonas campestris |
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1.B.14.14.1 | The thiamine receptor (BT2390) (energized by TonB/ExbBD) (Rodionov et al. 2002). |
Bacteria | Bacteroidota | BT2390 of Bacteroides thetaiotaomicron (Q8A552) |
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1.B.14.15.1 | Putative porin of the DUF4289 family; 655 aas and 32 putative transmembrane beta strands. |
Bacteria | Bacteroidota | PP of Psychroflexus torquis |
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1.B.14.15.2 | Putative porin of 776 aas |
Bacteria | Bacteroidota | PP of Provotella ruminicola |
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1.B.14.15.3 | Putative porin of 631 aas |
Bacteria | Bacteroidota | PP of Amoebophilus asiaticus |
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1.B.14.15.4 | Putative DUF4289 family porin of 687 aas |
Bacteria | Bacteroidota | PP of Niastella koreensis |
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1.B.14.15.5 | Putative porin of 627 aas |
Bacteria | Ignavibacteriota | PP of Melioribacter roseus |
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1.B.14.15.6 | Putative porin of 650 aas |
Bacteria | Ignavibacteriota | PP of Ignavibacterium album |
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1.B.14.15.7 | Putative porin of 621 aas |
Bacteria | Bacteroidota | PP of Cryptocercus punctulatus |
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1.B.14.16.1 | DUF940 homologue of 720 aas, one signal sequence and 30 putative β-strands. Homologous to proteins designated YmcA, WbfB and YjbH. |
Bacteria | Chlamydiota | DUF940 homologue of Protochlamydia amoebophila |
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1.B.14.16.10 | Putative LPS exporter receptor, OtuG. It's gene is in a cluster with several LPS biosynthetic enzymes. |
Bacteria | Pseudomonadota | OtuG of Vibrio parahaemolyticus |
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1.B.14.16.11 | OMR of 698 aas and 1 N-terminal TMS, GlfD or YmcA. Probably involved in capsular polysaccharide export (Peleg et al. 2005). |
Bacteria | Pseudomonadota | GlfD of E. coli |
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1.B.14.16.2 | DUF940 homologue of 953 aas, one N-terminal signal sequence and 30 putative beta strands. |
Bacteria | Pseudomonadota | DUF940 homologue of Chromobacterium violaceum |
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1.B.14.16.3 | DUF940 homologue of 689 aas, one N-terminal signal sequence and 28 putative TM β-strands. |
Bacteria | Pseudomonadota | DUF940 homologue of Psychromonas ingrahamii |
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1.B.14.16.4 | DUF940 homologue of 940 aas, one N-terminal signal sequence and 32 putative TM β-strands. |
Bacteria | Pseudomonadota | DUF940 homologue of E. coli |
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1.B.14.16.5 | DUF940 homologue of 716 aas with one N-terminal signal sequence and 27 putative beta strands. |
Bacteria | Chlamydiota | DUF940 homologue of Parachlamydia acanthamoebae |
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1.B.14.16.6 | DUF940 homologue of 718 aas, an N-terminal signal sequence and 33 putative beta strands. |
Bacteria | Pseudomonadota | DUF940 homologue of Photobacterium angustum |
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1.B.14.16.7 | Putative polysaccharide exporter of 690 aas and 34 predicted TMSs, WbfB. Encoded in a gene cluster with polysaccharide biosynthetic enzymes and a putative periplasmic polysaccharide export protein. |
Bacteria | Thermodesulfobacteriota | Putative OMR concerned with polysaccharide export of Syntrophus aciditrophicus |
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1.B.14.16.8 | Putative polysaccharide/glycolipid/glycoprotein export receptor of 736 aas and 30 predicted β-strands, WbfB. The gene encoding this protein is in a cluster with UDP-N-acetyl D-quinovosamine -4 epimerase. |
Bacteria | Pseudomonadota | Putative exporter of Vibrio anguillarum |
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1.B.14.16.9 | Putative lipopolysaccharide export receptor, WbfB. It is encoded in a gene cluster with LPS biosynthetic genes. |
Bacteria | Pseudomonadota | WbfB of Vibrio parahaemolyticus |
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1.B.14.17.1 | Uncharacterized protein of 922 aas |
Bacteria | Bacteroidota | UP of Dyadobacter fermentans |
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1.B.14.17.2 | Putative Planctomycetes OMR of 799 aas |
Bacteria | Planctomycetota | Putative OMR of Planctomyces brasiliensis |
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1.B.14.17.3 | Putative Planctomycetes OMR of 1101 aas |
Bacteria | Planctomycetota | Putative OMR of Isosphaera pallida |
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1.B.14.17.4 | Uncharacterized protein of 1055 aas |
Bacteria | Lentisphaerota | UP of Lentisphaera araneosa |
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1.B.14.18.1 | Putative Verucomicrobial OMP of 676 aas |
Bacteria | Verrucomicrobiota | Putative OMR of Optutus terrae |
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1.B.14.18.2 | Uncharacterized OM channel superfamily member of 791 aas |
Bacteria | Verrucomicrobiota | UP of Pedosphaera parvula |
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1.B.14.19.1 | Putative TonB-dpenedent receptor of 790 aas, YddB. It is encoded by a gene adjacent to the YddA-encoding gene (TC# 3.A.1.203.11). YddA is a probable fatty acid exporter. the yddB gene is adjacent to a gene encoding a putative Zn2+ protease, PqqL. |
Bacteria | Pseudomonadota | YddB of E. coli |
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1.B.14.19.2 | TonB-dependent receptor of 843 aas. |
Bacteria | Pseudomonadota | Receptor of Rhodobacter capsulatus |
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1.B.14.19.3 | TonB-dependent receptor/transporter of 834 aas. |
Bacteria | Verrucomicrobiota | Receptor of Verrucomicrobiaceae bacterium |
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1.B.14.2.1 | HmbR Hemoglobin receptor |
Bacteria | Pseudomonadota | HmbR of Neisseria meningitidis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.2.10 | Heme transporter BhuA (Brucella heme uptake protein A) | Bacteria | Pseudomonadota | BhuA of Brucella abortus |
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1.B.14.2.11 | Heme/hemopexin utilization protein C | Bacteria | Pseudomonadota | HxuC of Haemophilus influenzae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.2.12 |
The transferrin receptor/lipoprotein complex, TbpAB (TbpA receptor, 912aas; TbpB lipoprotein, 625aas). The plug domain can fold independently of the beta-barrel, but extracellular loops of the beta-barrel are required for ferritin binding (Oke et al. 2004). |
Bacteria | Pseudomonadota | TbpAB of Haemophilus influenzae |
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1.B.14.2.13 |
Hemoglobin receptor, HgbA. Residues for hemoglobin binding and utilization differ (Fusco et al. 2013). |
Bacteria | Pseudomonadota | HgbA of Haemophilus ducreyi |
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1.B.14.2.14 | Heme/hemoglobin receptor of 660 aas and 22 C-terminal β-strands with an N-terminal "plug" domain, ShuA. The 3-d structure is known to 2.6 Å resolution, revealing the histidyl residues in the barrel and plug that can interact with heme (Cobessi et al. 2010). |
Bacteria | Pseudomonadota | ShuA of Shigella dysenteriae |
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1.B.14.2.15 | Uncharacterized outer membrane receptor, probably for iron transport. |
Bacteria | Pseudomonadota | OMR of Xanthomonas oryzae |
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1.B.14.2.16 | Transferrin binding protein A, TbpA of 914 aas. A 3-D model revealed a narrow channel through the entire length of the protein. The spatial arrangement of external loops, and their relevance to the mechanism of iron translocation is presented (Oakhill et al. 2005). |
Bacteria | Pseudomonadota | TbpA of Neisseria meningitidis |
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1.B.14.2.17 | The iron-catechol siderophore uptake/receptor, VctA, of 659 aas. Linear enterobactin derivatives are substrates, but it also transports the synthetic siderophore MECAM [1,3,5-N,N',N″-tris-(2,3-dihydroxybenzoyl)-triaminomethylbenzene] (Wyckoff et al. 2015). |
Bacteria | Pseudomonadota | VctA of Virbio cholerae |
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1.B.14.2.2 | HemR Heme (Hemin) receptor | Bacteria | Pseudomonadota | HemR of Yersinia enterocolitica | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.2.3 | HpuAB hemoglobin-haptoglobin receptor; porphyrin transporter (HpuA=lipoprotein; HpuB=OMR porin). Surface exposed loops in the gonococcal HpuB transporter are important for hemoglobin binding and utilization (Awate et al. 2023). |
Bacteria | Pseudomonadota | HpuAB of Neisseria meningitidis |
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1.B.14.2.4 | Lactoferrin receptor (A=OMR porin; B=lipoprotein), LbpAB or IroAB. This two-component system extracts iron from the host glycoproteins lactoferrin and transferrin. Homologous iron-transport systems consist of a membrane-bound transporter and an accessory lipoprotein. The crystal structure of the N-terminal domain (N-lobe) of the accessory lipoprotein, lactoferrin-binding protein B (LbpB) is homologous to the structures of the accessory lipoproteins, transferrin-binding protein B (TbpB) and LbpB from the bovine pathogen Moraxella bovis. Docking the LbpB with lactoferrin reveals extensive binding interactions with the N1 subdomain of lactoferrin. The nature of the interaction precludes apolactoferrin from binding LbpB, ensuring the specificity for iron-loaded lactoferrin, safeguarding proper delivery of iron-bound lactoferrin to the transporter LbpA. The structure also reveals a possible secondary role for LbpB in protecting the bacteria from host defences. Following proteolytic digestion of lactoferrin, a cationic peptide derived from the N-terminus is released. This peptide, called lactoferricin, exhibits potent antimicrobial effects. The docked model of LbpB with lactoferrin reveals that LbpB interacts extensively with the N-terminal lactoferricin region (Brooks et al. 2014). |
Bacteria | Pseudomonadota | LbpAB of Neisseria meningitidis |
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1.B.14.2.5 | TbpA single component transferrin receptor | Bacteria | Pseudomonadota | TbpA of Pasteurella multocida | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.2.6 | HugA heme receptor/porin | Bacteria | Pseudomonadota | HugA of Plesiomonas shigelloides (Q93SS7) |
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1.B.14.2.7 | Hemin (Heme)-binding receptor, ShmR (also transports the toxic heme analog, gallium protoporphyrin) (Amarelle et al., 2008). |
Bacteria | Pseudomonadota | ShmR of Sinorhizobium meliloti (Q92N43) |
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1.B.14.2.8 | The heme-iron (from hemin and hemoglobin) utilization receptor, BhuR (Brickman et al., 2006; Vanderpool and Armstrong, 2004). |
Bacteria | Pseudomonadota | BhuR of Bordetella pertussis (Q7VSQ4) |
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1.B.14.2.9 | Probable TonB-dependent receptor NMB0964 | Bacteria | Pseudomonadota | Y964 of Neisseria meningitidis MC58 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.3.1 | BtuB cobalamin receptor (also transports phage C1 DNA across the outer membrane). Two Ca2+ binding sites in BtuB mediate cobalamine binding (Cadieux et al., 2007). Cobalamine uptake into the periplasm is reversible, but efflux is pmf-independent (Cadieux et al., 2007). The 3-d structure is available (PDB#1NQE). The Ton box and the extracellular substrate binding site are allosterically coupled (bidirectional), and TonB binding may initiate a partial round of transport (Sikora et al. 2016). Substrate binding to the extracellular surface of the protein triggers the unfolding of an energy coupling motif at the periplasmic surface. Thus, substrate binding reduces the interaction free energy between certain residues, thereby triggering the unfolding of the energy coupling motif (Lukasik et al. 2007). Multiple extracellular loops contribute to substrate binding and transport by BtuB (Fuller-Schaefer and Kadner 2005). |
Bacteria | Pseudomonadota | BtuB of E. coli |
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1.B.14.3.2 | TonB-dependent receptor (Bhat et al. 2011). |
Bacteria | Myxococcota | TonB-dependent receptor of Myxococcus xanthus |
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1.B.14.3.3 | TonB-dependent receptor (Bhat et al. 2011). |
Bacteria | Myxococcota | TonB receptor of Myxococcus xanthus |
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1.B.14.3.4 | TonB-dependent receptor (Bhat et al. 2011). |
Bacteria | Myxococcota | TonB-dependent receptor of Myxococcus xanthus |
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1.B.14.3.5 | TonB-dependent receptor (Bhat et al. 2011). |
Bacteria | Myxococcota | TonB-dependent receptor of Myxococcus xanthus |
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1.B.14.3.6 | Probable siderophore-specific outer membrane receptor of 869 aas, MxcH |
Bacteria | Myxococcota | MxcH of Stigmatella aurantiaca |
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1.B.14.3.7 | TonB-dependent receptor |
Bacteria | Pseudomonadota | OMR of Shewanella oneidensis |
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1.B.14.4.1 | Cu2+-transporting, Cu2+-regulated outer membrane protein C, OprC (Yoneyama and Nakae 1996). OprC impairs host defense by increasing the quorum-sensing-mediated virulence of P. aeruginosa (Gao et al. 2020). |
Bacteria | Pseudomonadota | OprC of Pseudomonas aeruginosa |
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1.B.14.4.2 | Cu2+-transporting, outer membrane protein, NosA | Bacteria | Pseudomonadota | NosA of Pseudomonas stutzeri | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.4.3 | TonB-dependent receptor/channel for substrate uptake across the outer membrane of 656 aas |
Bacteria | Pseudomonadota | Receptor of E. coli |
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1.B.14.5.1 | HasR receptor-HasA haemophore heme receptor complex (HasA, an extracellular heme binding protein, binds one heme and transfers it directly to HasR, which uses HasB (2.C.1.1.2) (a TonB homologue) instead of TonB (2.C.1.1.1) for energization) (Benevides-Matos et al., 2008; Izadi-Pruneyre et al., 2006; Lefèvre et al., 2008; Benevides-Matos and Biville, 2010). A signaling domain in HasR interacts with a partially unfolded periplasmic domain of an antisigma factor, HasS, to control transcription by an ECF sigma factor (Malki et al. 2014). The HasR domain responsible for signal transfer is highly flexible in two stages of signaling, extends into the periplasm at about 70 to 90 A from the HasR beta-barrel and exhibits local conformational changes in response to the arrival of signaling activators (Wojtowicz et al. 2016). Studies revealed a previously unidentified network of HasR-HasB protein-protein interactions in the periplasm (Somboon et al. 2024). |
Bacteria | Pseudomonadota | HasR-HasA of Serratia marcescens |
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1.B.14.5.2 | The heme receptor HxuC (PA1302) serves as a pyocin M4 (Colicin M-type; PaeM4) target at the cellular surface. |
Bacteria | Pseudomonadota | HxuC of Pseudomonas aeruginosa |
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1.B.14.6.1 | SusC receptor/porin for maltooligosaccharides (up to maltoheptaose). Forms a complex with and functions with SusD porin (TC# 8.A.46.1.1) as well as SusE and SusF porins (TC#s 1.B.38.1.1 and 1.2) as well as the SusG α-amylase (TC#8.A.9.1.3). These proteins are all involved in starch utilization (Shipman et al. 2000; Reeves et al. 1997; Cho and Salyers 2001; Foley et al. 2018). |
Bacteria | Bacteroidota | SusC of Bacteroides thetaiotaomicron |
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1.B.14.6.10 | DUF4480 putative OMR of 835 aas. |
Bacteria | Bacteroidota | OMR of Capnocytophaga canimorsus |
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1.B.14.6.11 | OMR (DUF4480) of 976 aas |
Bacteria | Bacteroidota | OMR of Zobellia galactanivorans |
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1.B.14.6.12 | OMR (DUF4480) of 775 aas |
Bacteria | Bacteroidota | OMR of Saprospira grandis |
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1.B.14.6.13 | SusC homologue of 940 aas. Functions with SusD homolgoue TC# 8.A.46.1.2. |
Bacteria | Bacteroidota | SusC homologue of Bacteroides thetaiotaomicron |
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1.B.14.6.14 | Putative porin of 830 aas and 16 predicted TMSs. The β-barrel domain is the N-terminal ~250 aas which corresponds to the DUF4480 or Peptidase M14NE family in Pfam. The large hydrophilic C-terminal domain is of unknown function. |
Bacteria | Bacteroidota | Putative porin of Aequorivita sublithincola |
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1.B.14.6.15 | TonB-dependent collagenase (proteinase) of 1047 aas (Bhattacharya et al. 2017). The primary pathogen of the Great Barrier Reef sponge, Rhopaloeides odorabile, identified as a unique strain (NW4327) of Pseudoalteromonas agarivorans. It produces collagenases which degrade R. odorabile skeletal fibers. |
Bacteria | Proteobacteria | Collagenase of Pseudoalteromonas agarivolans NW4327 (a marine sponge parasite) |
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1.B.14.6.16 | Possible Iron receptor, RagA of 1036 aas. Its gene forms part of a small operon which may have arisen via horizontal gene transfer into the genome. The 55 kDa antigen (RagB; TC# 8.A.46.3.5), encoded within the same operon, may act in concert at the surface of the bacterium to facilitate active transport, mediated through the periplasmic spanning protein, TonB (Curtis et al. 1999). The genetic and functional diversity of Porphyromonas gingivalis survival factor, RagAB have been studied (Montz et al. 2025). |
Bacteria | Bacteroidota | RagAB of Porphyromonas gingivalis |
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1.B.14.6.17 | SusC of 1041 aas and 1 N-terminal TMS (Joglekar et al. 2018). |
Bacteria | Bacteroidota | SusC of Bacteroides thetaiotaomicron |
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1.B.14.6.18 | TonB-dependent receptor/transporter of 909 aas |
Bacteria | Acidobacteriota | Receptor of Granulicella mallensis |
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1.B.14.6.2 | The Omp200 porin complex (consists of Omp121 [an OMR family member] and Omp71 [a protein nonhomologous to other proteins in the databases]) | Bacteria | Bacteroidota | Omp121/Omp71 complex of Bacteroides fragilis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.6.3 | Outer membrane porin required for intercellular signalling via C-signal (CsgA), Oar (Bhat et al. 2011). |
Bacteria | Myxococcota | Oar of Myxococcus xanthus |
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1.B.14.6.4 | TonB-dependent outer membrane porin/receptor, Oar |
Bacteria | Pseudomonadota | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.6.5 | TonB-dependent outer membrane receptor of 792 aas. |
Bacteria | Bacteroidota | TonB receptor of Bacteroides caccae |
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1.B.14.6.6 | TonB-dependent receptor of 970 aas |
Bacteria | Spirochaetota | TonB receptor of Leptospira interrogans |
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1.B.14.6.7 | TonB-dependent receptor |
Bacteria | Bacteroidota | TonB receptor of Pedobacter heparinus |
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1.B.14.6.8 | Putative OMR (DUF4480) of 709 aas and one N-terminal TMS. The first 120 residues show sequence similarity with TC#1.B.14.6.2. |
Bacteria | Bacteroidota | Putative OMR of Bacteroides fragilis |
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1.B.14.6.9 | Putative OMR (DUF4480) of 828 aas, and N-terminal TMS and 32 predicted TM β-strands. |
Bacteria | Bacteroidota | Putative OMR of Croceibacter atlanticus |
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1.B.14.7.1 | CjrC outer membrane receptor of 753 aas. It is iron and temperature regulated, and functions with CjrB, a distant TonB homologue (TC# 2.C.1.1.3). Together these two proteins are required for uptake of colicin J in Shigella and enteroinvasive E. coli strains (Smajs and Weinstock 2001). |
Bacteria | Pseudomonadota | CjrC of E. coli |
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1.B.14.7.2 | Probable TonB-dependent receptor NMB1497 |
Bacteria | Pseudomonadota | NMB1497 of Neisseria meningitidis |
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1.B.14.7.3 | Probable TonB-dependent receptor HI_1217 |
Bacteria | Pseudomonadota | HI_1217 of Haemophilus influenzae |
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1.B.14.8.1 | Putative salicin/arbutin (aromatic β-glucoside) receptor, SalC | Bacteria | Pseudomonadota | SalC of Azospirillum irakense | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.8.2 | The iron (Fe3+) · pyridine-2,6-bis(thiocarboxylic acid) (PDTC) receptor, PdtK. Functions with the MFS carrier, PdtE (TC #2.A.1.55.1) (Leach and Lewis, 2006). | Bacteria | Pseudomonadota | PdtK of Pseudomonas putida (ABC68350) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.8.3 | Vibriobactin receptor, VuiA or VuuA of 687 aas and 1 N-terminal TMS. There is conserved, global coordinate iron regulation in V. cholerae by the Fur transcription factor, responsive to iron (Butterton et al. 1992). V. cholerae synthesizes and uses the catechol siderophore vibriobactin and also uses siderophores secreted by other species, including enterobactin produced by E. coli (Wyckoff et al. 2015). ViuB, a putative V. cholerae siderophore-interacting protein (SIP), functionally substituted for the E. coli ferric reductase YqjH, which promotes the release of iron from the siderophore in the bacterial cytoplasm. In V. cholerae, ViuB is required for the use of vibriobactin but is not required for the use of MECAM, fluvibactin, ferrichrome, or the linear derivatives of enterobactin, all substrates of ViuA (Wyckoff et al. 2015). |
Bacteria | Pseudomonadota | ViuA of Vibrio cholerae serotype O1 |
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1.B.14.8.4 | The thiamine receptor (SO2715) (energized by TonB/ExbBD) (Rodionov et al. 2002) |
Bacteria | Pseudomonadota | SO2715 of Shewanella oneidensis (Q8EDM8) |
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1.B.14.8.5 | TonB-dependent receptor of 726 aas. |
Bacteria | Pseudomonadota | Receptor of Colwellia psychrerythraea |
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1.B.14.8.6 | The (thio)quinolobactin receptor, QbsI, of 669 aa |
Bacteria | Pseudomonadota | QbsI of Pseudomonas fluorescens |
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1.B.14.8.7 | FyuA Fe3+-yersiniabactin and pesticin (Psn; a bacteriocin) receptor and uptake protein of 673 aas. It contributes to biofilm formation and infection (Hancock et al., 2008). It is similar to FrpA, an outer membrane protein involved in piscibactin secretion in Vibrio anguillarum (Lages et al. 2022). |
Bacteria | Pseudomonadota | FyuA of Yersinia enterocolitica (P0C2M9) |
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1.B.14.9.1 | RhtA Rhizobactin 1021 (siderophore) receptor/porin | Bacteria | Pseudomonadota | RhtA of Sinorhizobium meliloti | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.9.2 | Acr ferric achromobactin (hydroxycarboxylate siderophore) receptor/porin (Franza et al., 2005) | Bacteria | Pseudomonadota | Acr of Erwinia chrysanthemi (AAL14566) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.9.3 | The ferric ferrichrome/aerobactin receptor/porin, IutA (Forman et al., 2007) |
Bacteria | Pseudomonadota | IutA of Yersinia pestis (Q7CGN6) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.14.9.4 | Putative TonB-dependent heme receptor |
Bacteria | Campylobacterota | TonB-dependent heme receptor of Campylobacter jejuni |
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1.B.14.9.5 | TonB-dependent receptor of 700 aas, YncD, a probable iron transporter/receptor in the outer membrane. Deletion of the orthologous yncD genes in Salmonella strains leads to attenuated strains, potentially useful for vaccine development (Xiong et al. 2012; Xiong et al. 2015). Its synthesis is depressed by inclusion of high glucose concentrations in the medium (Yang et al. 2011). YncD is a receptor for a T1-like Escherichia coli phage named vB_EcoS_IME347 (IME347) (Li et al. 2018). |
Bacteria | Pseudomonadota | YncD of E. coli |
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1.B.14.9.6 | SchT (IutA) is capable of using dihydroxamate xenosiderophores, either ferric schizokinen (FeSK) or a siderophore of the filamentous cyanobacterium Anabaena variabilis ATCC 29413 (SAV), as the sole source of iron in a TonB-dependent manner (Obando S et al. 2018). Functions with the ABC uptake system having the TC# 3.A.1.14.24. |
Bacteria | Cyanobacteriota | SchT of Synechocystis sp. PCC 6803 |
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1.B.15.1.1 | Raffinose porin, RafY | Bacteria | Pseudomonadota | RafY of E. coli | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.15.1.2 | Putative glycoporin |
Bacteria | Pseudomonadota | Putative porin of Vibrio shilonii |
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1.B.15.1.3 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Polaromonas naphthalenivorans |
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1.B.15.1.4 | Putative porin of 374 aas |
Bacteria | Proteobacteria | Putative porin of Vibrio harveyi |
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1.B.15.1.5 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Pychromonas ingrahamii |
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1.B.16.1.1 | Short chain amide porin, FmdC | Bacteria | Pseudomonadota | FmdC of Methylophilus methylotrophus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.16.1.10 | Phosphate-selective porin |
Bacteria | Nitrospirota | Porin of Thioflavicoccus mobilis |
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1.B.16.1.11 | Putative porin |
Bacteria | Thermodesulfobacteriota | Putative porin of Thermodesulfobacterium sp. (strain OPB45) |
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1.B.16.1.2 | Outer membrane porin FmdC or ExtI of 406 aas and 1 N-terminal TMS. The expression level of the extI gene did not respond to changes in osmolality and phosphate starvation.The only change due to an extI deficiency was a decreased ability to reduce selenite and tellurite (Jahan et al. 2018). This porin is responsible for the uptake of selenite and plays a role in the subcellular localization of the rhodanese-like lipoprotein, ExtH (Q748R1) (Jahan et al. 2019). |
Bacteria | Thermodesulfobacteriota | ExtI of Geobacter sulfurreducens |
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1.B.16.1.3 |
Outer membrane porin (Bhat et al. 2011). |
Bacteria | Myxococcota | TonB-dependent receptor of Myxococcus xanthus |
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1.B.16.1.4 | Putative outer membrane porin |
Bacteria | Myxococcota | OMP of Anaeromyxobacter dehalogenans |
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1.B.16.1.5 | Short chain amide porin |
Bacteria | Aquificota | Amide porin of Hydrogenobaculum sp. HO |
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1.B.16.1.6 | Phosphate-selective porin O/P |
Bacteria | Thermodesulfobacteriota | Porin of Thermodesulfobacterium geofontis |
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1.B.16.1.7 | Phosphate-selective porin |
Bacteria | Aquificota | Porin of Thermocrinis albus |
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1.B.16.1.8 | Phosphate-selective porin O/P |
Bacteria | Chrysiogenota | Omp O/P of Desulfurispirillum indicum |
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1.B.16.1.9 | Uncharacterized protein of 428 aas |
Bacteria | Gemmatimonadota | UP of Gemmatimonas aurantiaca |
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1.B.16.2.1 | Putative porin O |
Bacteria | Bacteroidota | Porin O of Flavobacterium indicum |
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1.B.16.2.2 | Putative porin of 451 aas |
Bacteria | Spirochaetota | Putative porin of Leptospira biflexa |
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1.B.16.2.3 | Putative porin O/P of 413 aas. |
Bacteria | Thermodesulfobacteriota | Porin O/P of Geobacter sp. |
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1.B.16.2.4 | Phosphate-selective porin O/P of 421 aas |
Bacteria | Acidobacteriota | Porin of Holophaga foetida |
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1.B.16.2.5 | Putative porin |
Bacteria | Acidobacteriota | Porin of Terriglobus roseus |
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1.B.16.2.6 | Phosphate-specific porin O/P |
Bacteria | Aquificota | Porin of Aquifex aeolicus |
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1.B.16.2.7 | Anion-selective porin of 581 aas |
Bacteria | Nitrospirota | Porin of Candidatus Nitrospira defluvii |
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1.B.16.2.8 | Putative porin of 579 aas |
Bacteria | Planctomycetota | Porin of Rhodopirellula baltica |
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1.B.162.1.1 | Cap15, chains A and B, of 131 aas, have been solved and revealed a compact 8 stranded β-barrel. It allows the bacteria to disrupt the inner membrane to protect itself from the virus (see family description) (Duncan-Lowey et al. 2021). It resembles the short soluble region of about 160 aas between TMSs 2 and 3 in the K+ channel with a Uniprot ID of F7Q1W9 and a TC# of 1.A.1.2.39. |
Bacteria | Pseudomonadota | Cap15 of Haloplasma contractile |
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1.B.162.1.10 | Uncharacterized protein of 255 aas and 3 N-terminal TMSs. |
Bacteria | Bacteroidota | UP of Kordia antarctica |
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1.B.162.1.2 | pancortin-3 of 198 aas and 2 or 3 N-terminal TMSs. |
Bacteria | Pseudomonadota | Pancortin-3 of E. coli |
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1.B.162.1.3 | Uncharacterized protein of 183 aas and 3 TMSs, 2 at the N-terminus of the protein and one in the middle of the protein. |
Bacteria | Mycoplasmatota | UP of Acholeplasmatales bacterium (gut metagenome) |
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1.B.162.1.4 | Uncharacterized protein of 196 aas with two N-terminal TMSs. |
Bacteria | Bacteroidota | UP of Sunxiuqinia elliptica |
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1.B.162.1.5 | Uncharacterized protein of 225 aas and 2 N-terminal TMSs. |
Bacteria | Pseudomonadota | UP of Blastomonas natatoria |
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1.B.162.1.6 | Uncharacterized protein of 205 aas and 2 N-terminal TMSs. |
Bacteria | Pseudomonadota | UP of Methylobacterium sp. WL116 |
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1.B.162.1.7 | Uncharacterized protein with two N-terminal TMSs. |
Bacteria | Pseudomonadota | UP of Thalassospira xiamenensis |
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1.B.162.1.8 | Uncharacterized protein of 228 aas and 2 or 3 TMSs. |
Bacteria | Pseudomonadota | UP of Zoogloea oleivorans |
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1.B.162.1.9 | Uncharacterized protein of 250 aas and 2 or 3 TMSs. |
Bacteria | Planctomycetota | UP of Tautonia marina |
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1.B.163.1.1 | Mycolic acid outer membrane porin, PorA(2) of 374 aas and 2 hydrophobic peaks at its N- and C-termini. The protein forms pores that are slightly cation-selective. |
Bacteria | Actinomycetota | PorA of Corynebacterium amycolatum |
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1.B.163.1.2 | DUF3068 PorA porin of 364 aas and two TMSs, N- and C-terminal. |
Bacteria | Actinomycetota | PorA of Corynebacterium diphtheriae |
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1.B.163.1.3 | DUF3068 domain-containing protein, PorA, of 331 aas and 2 N- and C-terminal TMSs. |
Bacteria | Actinomycetota | PorA(2) of Streptomyces inusitatus |
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1.B.163.1.4 | PorA of 340 aas and 2 TMSs. |
Bacteria | Actinomycetota | PorA of Actinoallomurus bryophytorum |
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1.B.163.1.5 | DUF3068 domain-containing protein, PorA(2) of 359 aas with 2 TMSs. |
Bacteria | Actinomycetota | PorA(2) of Nocardiopsis potens |
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1.B.163.1.6 | Porin PorA family protein of 363 aas and 2 TMSs. |
Bacteria | Actinomycetota | PorA of Catenulispora pinistramenti |
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1.B.163.1.7 | DUF3068 domain-containing protein of 321 aas and 2 TM |
Bacteria | Actinomycetota | DUF3068 domain protein of Nonomuraea glycinis |
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1.B.163.1.8 | PorA of 391 aas and 2 TMSs, N- and C-terminal (Piselli et al. 2022). |
Bacteria | Actinomycetota | PorA of Rhodococcus ruber |
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1.B.163.1.9 | PgfA (MSMEG_0317), a periplasmic protein, interacts with trehalose monomycolate (TMM) and MmpL3 (TC# 2.A.6.5.6). It is a key determinant of polar growth and cell envelope composition in mycobacteria, and the LamA-mediated recruitment of this protein to one side of the cell is a required step in the establishment of cellular asymmetry (Gupta et al. 2022). |
Bacteria | Actinomycetota | PgfA of Mycolicibacterium smegmatis (Mycobacterium smegmatis; mycobacterium phlei) |
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1.B.164.1.1 | The nutrient outer membrane channel, CpnT, of 846 aas and 1 N=terminal TMS and possibly two more TMSs at about residues 220 and 270. It can be mutated to serve as a Ca2+ channel and promote cell death (D'Elia and Weinrauch 2023). |
Bacteria | Actinomycetota | CpnT of Mycobacterium tuberculosis |
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1.B.164.1.2 | Uncharacterized protein of 426 aas with two putative TMSs, one N-terminal and one at residues 250. Only the first domain, the outer membrane channel domain, presumably specific for nutrients, is present, not the toxin domain which is the C-terminal domain of CpnT (TC#1.B.164.1.1). |
Bacteria | Actinomycetota | UP of Nocardia araoensis |
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1.B.164.1.3 | Uncharacterized protein of 475 aas and 2 or possibly 3 TMSs, one at the N-terminus, one at about residue 220, and possibly a third (with less hydrophobicity) at about residue 270. |
Bacteria | Actinomycetota | UP of Gordonia rubripertincta |
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1.B.164.1.4 | Uncharacterized protein of 475 aas and 2 or 3 TMSs, one at the N-terminus of the protein and one or two are residues 320 - 370. |
Bacteria | Actinomycetota | UP of Streptomyces tanashiensis |
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1.B.164.1.5 | Uncharacterized protein of 1362 aas with 2 strongly hydrophobic putative TMSs between residues 270 and 320, followed by 4 more putative TMSs of much lower hydrophobicity between residues 340 and 430. |
Bacteria | Actinomycetota | UP of Microbacterium sp. GCS4 |
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1.B.164.1.6 | Uncharacterized protein of 496 aas and posibly 2 TMSs + several smaller hydrophobicity peaks that could be TMSs. |
Bacteria | Pseudomonadota | UP of Vibrio cholerae |
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1.B.164.1.7 | Uncharacterized protein of 499 aas and 4 putative TMSs between residues 240 and 330. |
Bacteria | Actinomycetota | UP of Aeromicrobium sp. (soil metagenome) |
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1.B.164.1.8 | Colicin D domain-containing protein of 453 aas and 2 TMSs between residues 160 and 320. |
Bacteria | Actinomycetota | UP of Saccharopolyspora erythraea |
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1.B.165.1.1 | AvrE (DspE) of 1838 aas and a beta (β) structure after secretion from the bacteriial cytoplasm via a type III protein secretion system (TC# 3.A.6) into the host cell and insertion into the plasma membrane of the plant cell where it transports metabolites, water and small molecules such as fluorescene dyes (Nomura et al. 2023). DspE in Xenopus oocytes resulted in inward and outward currents, permeability to water and osmolarity-dependent oocyte swelling and bursting. Liposome reconstitution confirmed that the DspE channel alone is sufficient to allow the passage of small molecules such as fluorescein dye. Targeted screening of chemical blockers based on the predicted pore size (15-20 Å) of the DspE channel identified polyamidoamine dendrimers as inhibitors of the DspE/AvrE channels. Notably, polyamidoamines broadly inhibit AvrE and DspE virulence activities in Xenopus oocytes and during E. amylovora and P. syringae infections. |
Bacteria | Pseudomonadota | AvrE of Erwinia amylovora |
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1.B.165.1.2 | AvrE of 1795 aas with a beta (β) structure; it inserts into the plant cell membrane after secretion from the bacterium via the type III secretion system (TC# 3.A.6) to form pores (Nomura et al. 2023). |
Bacteria | Pseudomonadota | AvrE of Pseudomonas syringae |
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1.B.165.1.3 | AvrE-family type 3 secretion system effector of 1625 aas. |
Bacteria | Pseudomonadota | AvrE homolog of Dickeya chrysanthemi (Pectobacterium chrysanthemi) |
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1.B.165.1.4 | AvrE-family type 3 secretion system effector of 1839 aa |
Bacteria | Pseudomonadota | AvrE of Mixta calida |
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1.B.165.1.5 | DspE-family type 3 secretion system effector of 1829 aas. |
Bacteria | Pseudomonadota | DspE of Pantoea agglomerans pv. gypsophilae (Erwinia herbicola) |
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1.B.165.1.6 | AvrE-family type 3 secretion system effector of 1829 aa |
Bacteria | Pseudomonadota | AvrE homolog of Brenneria goodwinii |
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1.B.165.1.7 | Type III effector protein AvrE1 of 1437 aa |
Bacteria | Pseudomonadota | AvrE of Pseudomonas orientalis |
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1.B.165.1.8 | AvrE-family type 3 secretion system effector of 1889 aa |
Bacteria | Pseudomonadota | AvrE homolog of Pseudomonas quasicaspiana |
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1.B.165.1.9 | Averulence protein, DspE of 1614 aas. |
Bacteria | Pseudomonadota | DspE (DspA) of Pectobacterium atrosepticum (Erwinia carotovora subsp. atroseptica)
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1.B.166.1.2 | FlxA-like family protein of 419 aas with 1 N-terminal TMS and a β-barrel structure.
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Bacteria | Pseudomonadota | FlxA-like protein of Cysteiniphilum bacterium |
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1.B.166.1.3 | DUF3573 domain-containing protein of 468 aas with one N-terminal TMS. |
Bacteria | Pseudomonadota | DUF3573 protein of Francisellaceae bacterium |
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1.B.166.1.4 | LbtU family siderophore porin of 417 aas with 1 N-terminal TMS. |
Bacteria | Pseudomonadota | LbtU of Thiotrichales bacterium |
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1.B.166.1.5 | LbtU family siderophore porin of 511 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | LbtU of Methylococcales bacterium |
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1.B.167.1.1 | The TiME tube protein in the outer membrane of M. smegmatis. It is of 198 aas in length. The 3.d structure is known (see family description). |
None | Bacillati, Actinomycetota | Time of Mycobacterium (Mycolicibacterium) smegmatis |
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1.B.167.1.2 | The TiME tube protein in the outer membrane of M. tuberculosis. It is of 214 aas in length (See family description for details). |
None | Bacillati, Actinomycetota | TiME protein of Mycobacterium tuberculosis |
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1.B.167.1.3 | PknH-like extracellular domain-containing protein of 209 aas and 1 N-terminal TMS. |
None | Bacillati, Actinomycetota | PknH-like protein of Segniliparus rugosus |
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1.B.167.1.4 | PknH-like extracellular domain-containing protein of 252 aas and 1 N-terminal TMS. |
None | Bacillati, Actinomycetota | PknH-like protein of Segniliparus rugosus |
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1.B.167.1.5 | Uncharacterized protein of 234 aas and 1 N-terminal TMS. |
None | Bacillati, Actinomycetota | UP of Mycolicibacterium thermoresistibile |
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1.B.167.1.6 | Uncharacterized protein of 203 aas and 1 N-terminal TMS. |
None | Bacillati, Actinomycetota | UP of Mycolicibacterium paratuberculosis |
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1.B.17.1.1 | TolC outer membrane exporter of hemolysin, drugs, siderophores such as enterobactin, etc. (Bleuel et al., 2005). The 3-d structure is available (PDB#1EK9). The three monomers form a continuous channel, and each monomer contributes 4 β-strands to the 12 stranded β-barrel (Koronakis et al. 2000). The Salmonella enterica subspecies Typhi homologue is the ST50 antigen (G4C2H4) used in tests for typhoid fever, and a 2.98 Å resolution structure revealed a trimer that forms an alpha-helical tunnel and a beta-barrel transmembrane channel traversing the periplasmic space and outer membrane, respectively (Guan et al. 2015). K. pneumoniae TolC plays a role in resistance towards most antibiotics, suggesting that it can interact with the AcrB efflux pump (Iyer et al. 2019). β-lactam drug efflux is mediated by TolC (Kantarcioglu et al. 2024). Molecular dynamics simulations of drug-free TolC reveal essential movements and key residues involved in TolC opening. A whole-gene-saturation mutagenesis assay, mutating each TolC residue and measuring fitness effects under β-lactam selection, was performed, and it was shown the TolC-mediated efflux of three antibiotics: oxacillin, piperacillin, and carbenicillin. Steered molecular dynamics simulations identify general and drug-specific efflux mechanisms, revealing key positions at TolC's periplasmic entry affecting efflux motions (Kantarcioglu et al. 2024). |
Bacteria | Pseudomonadota | TolC of E. coli |
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1.B.17.1.2 | PrtF outer membrane exporter of proteases | Bacteria | Pseudomonadota | PrtF of Erwinia chrysanthemi | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.17.1.3 | The OMF, EexF (functions with ABC exporter, EexD (TC# 3.A.1.110.10) and MFP EexE (TC# 8.A.1.3.3)) (Gimmestad et al., 2006). |
Bacteria | Pseudomonadota | EexF of Azotobacter vinelandii (C1DS86) |
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1.B.17.1.4 | TolC of Sinorhizobium meliloti (affects secretion of proteins, polysaccharide, and multiple drugs (Cosme et al., 2008)) | Bacteria | Pseudomonadota | TolC of Sinorhizobium meliloti (Q92Q38) |
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1.B.17.1.5 | Putative outer membrane factor of 420 aas |
Bacteria | Chlamydiota | Outer membrane factor of Parachlamydia acanthamoebae |
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1.B.17.1.6 | Uncharacterized protein of 425 aas with an N-terminal TMS. |
Bacteria | Bdellovibrionota | UP of Bdellovibrio exovorus |
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1.B.17.1.7 | Outer membrane protein of 462 aas and 1 N-terminal TMS |
Bacteria | Bdellovibrionota | OMP of Bdellovibrio bacteriovorus |
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1.B.17.2.1 | CnrC outer membrane exporter of Ni2+ and Co2+. Functions with TC# 2.A.6.1.1 and 8.A.1.2.1. |
Bacteria | Pseudomonadota | CnrC of Alcaligenes eutrophus |
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1.B.17.2.10 | Putative ABC-type glycolipid export outer membrane factor, HgdD, of 483 aas (Hahn et al., 2012). |
Bacteria | Cyanobacteriota | HgdD of Thermosynechococcus sp. NK55a. |
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1.B.17.2.11 | Uncharacterized OMF protein of 485 aas and 1 N-terminlal TMS. |
Bacteria | Bdellovibrionota | UP of Bdellovibrio bacteriovorus |
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1.B.17.2.2 | CzcC outer membrane exporter of Co2+, Cd2+, Zn2+. Functions with CzcAB (2.A.6.1.2). |
Bacteria | Pseudomonadota | CzcC of Alcaligenes eutrophus |
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1.B.17.2.3 | CyaE outer membrane exporter of cyclolysin | Bacteria | Pseudomonadota | CyaE of Bordetella pertussis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.17.2.4 | Outer membrane efflux protein of the OEP or OMF family |
Bacteria | Myxococcota | OEP of Myxococcus xanthus |
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1.B.17.2.5 | Outer membrane efflux protein |
Bacteria | Bacillota | Outer membrane efflux protein of Selenomonas sputigena |
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1.B.17.2.6 | Outer membrane efflux porin, Oep |
Bacteria | Myxococcota | Oep of Myxococcus xanthus |
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1.B.17.2.7 |
Outer membrane efflux porin, Oep (OMF family) |
Bacteria | Myxococcota | Oep of Myxococcus xanthus |
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1.B.17.2.8 | Outer membrane efflux porin (Bhat et al. 2011). |
Bacteria | Myxococcota | Oep of Myxococcus xanthus |
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1.B.17.2.9 | Outer membrane efflux protein, Oep |
Bacteria | Myxococcota | Oep of Myxococcus xanthus |
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1.B.17.3.1 | NodT2 outer membrane exporter of lipooligosaccharides | Bacteria | Pseudomonadota | NodT2 of Rhizobium leguminosarum | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.17.3.10 | Outer membrane factor of 478 aas, MdtQ (YohG). Involved in resistance to puromycin, acriflavin and tetraphenylarsonium chloride (Sulavik et al. 2001). |
Bacteria | Pseudomonadota | MdtQ of E. coli |
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1.B.17.3.11 | TolC-like outer membrane factor protein, TdeA of 457 aas, required for leukotoxin and drug export (Crosby and Kachlany 2007). Functions with the MFP, LtxD (TC# 8.A.1.3.4) and the ABC exporter (TC# 3.A.1.109.8). |
Bacteria | Pseudomonadota | TdeA of Aggregatibacter (Actinobacillus; Haemophilus) actinomycetemcomitans |
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1.B.17.3.12 | The OMR, SilC, of 490 aas. Francisella tularensis, the causative agent of tularemia, contains three paralogs of OMRs, two, termed as TolC and FtlC, are important for tularemia pathogenesis. The third OM protein SilC, is homologous to the silver cation efflux protein of other bacteria. SilC is encoded in an operon encoding an Emr-type multi-drug efflux pump of F. tularensis. A ΔsilC mutant exhibited increased sensitivity towards antibiotics, oxidants and silver as well as diminished intramacrophage growth and attenuated virulence in mice. TolC and EmrA1 contribute to Francisella novicida multidrug resistance and modulation of host cell death (Kopping et al. 2024). |
Bacteria | Pseudomonadota | SilC of Francisella tularensis |
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1.B.17.3.13 | Multidrug resistance protein in the Outer Membrane Factor (OMF) Family of 490 aas and 1 N-terminal TMS (Hasan et al. 2024). |
Bacteria | Pseudomonadota | OMF family protein of Vandammella animalimorsus |
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1.B.17.3.2 | FusA outer membrane exporter of fusaric acid | Bacteria | Pseudomonadota | FusA of Burkholderia cepacia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.17.3.3 | OpcM outer membrane exporter of multiple drugs | Bacteria | Pseudomonadota | OpcM of Burkholderia cepacia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.17.3.4 | SilC outer membrane exporter of silver ion, Ag+ | Bacteria | Pseudomonadota | SilC of Salmonella typhimurium | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.17.3.5 | CusC outer membrane exporter of copper ion, Cu+, and silver ion Ag+. The crystal structure of CusC is known (Lei et al. 2013) providing evidnce concerning the folding mechanism giving rise to the channel. |
Bacteria | Pseudomonadota | CusC (YlcB) of E. coli |
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1.B.17.3.6 | VceC outer membrane exporter of drugs (Federici et al., 2005) | Bacteria | Pseudomonadota | VceC of Vibrio cholerae (A6XV56) |
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1.B.17.3.7 | HI1462 outer membrane, low conductance, anion-selective exporter (selectivity is due to an arginine residue at the tunnel entrance). (Polleichtner and Anderson, 2006) | Bacteria | Pseudomonadota | HI1462 of Haemophilus influenzae (P45217) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.17.3.8 | Chromosomal NodTch (orthologous to 1.B.17.3.1) (478 aas) required for cell survival (Hernandez-Mendoza et al., 2007). |
Bacteria | Pseudomonadota | NodTch of Rhizobium etli (B3PY75) |
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1.B.17.3.9 | MdtP (acts with MdtO (TC# 2.A.85.6.1) and MdtN (TC# 8.A.1.1.3)) (Sulavik et al., 2001). |
Bacteria | Pseudomonadota | MdtP of E. coli (P32714) |
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1.B.17.4.1 | Outer membrane factor of 459 aas. May function with an ABC exporter (A0LKG3/A0LKG4) and a membrane fusion protein (A0LKG1) (based on genomic context). |
Bacteria | Thermodesulfobacteriota | OMF of Syntrophobacter fumaroxidans |
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1.B.18.1.1 | OMA protein component of a PST-type exopolysaccharide export system (outer membrane porin constituent) | Bacteria | Pseudomonadota | ExoF of Rhizobium meliloti | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.18.1.2 | OMA protein component of an ABC-type group 2 capsular polysaccharide (polysialic acid) export system (outer membrane porin constituent) | Bacteria | Pseudomonadota | KpsD of E. coli | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.18.2.1 | OMA protein component of an ABC-type Vi polysaccharide antigen export system, VexA (functions with VexBCD, 3.A.1.101.2) (Hashimoto et al., 1993) | Bacteria | Pseudomonadota | VexA of Salmonella typhi (Q04976) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.18.2.2 | OMA component of exopolysaccharide exporter, PssN (outer membrane lipoprotein, oriented toward the periplasm; predominantly of β-structure, but with some α-structure) (Marczak et al., 2006). | Bacteria | Pseudomonadota | PssN of Rhizobium leguminosarum (Q27SU9) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.18.2.3 | Capsular polysialate exporter component, CtrA. OMA of 3.A.1.101.3 (functions with 3.A.1.101.3 (ABC) and 8.B.4.2.1 (MPA2)) (Larue et al., 2011) |
Bacteria | Pseudomonadota | CtrA of Neisseria meningitidis (Q547A8) |
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1.B.18.2.4 | The OMA capsular polysaccharide exporter of 394 aas, BexD (Kroll et al. 1990). |
Bacteria | Pseudomonadota | BexD of Haemophilus influenzae |
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1.B.18.3.1 | OMA component of the group 1 K30 capsular polysaccharide, colanic acid, export system, Wza (Reid and Whitfield, 2005) (outer membrane porin constituent). The 3-d structure of the Wza/Wzc complex has been solved by Collins et al. (2007). It spans the periplasm, comprising a central constituent for complex formation. The x-ray structure shows an integral outer membrane transmembrane α-helical barrel with a large central cavity, similar to the secretin protein, PilQ (1.B.22.2.1) (Collins and Derrick, 2007). Wza is an octameric α-helical outer membrane channel that directly exports nascent capsular polysaccharide chains through the Wza portal (Nickerson et al. 2014). Peptides based on the C-terminal D4 domain of Wza form transmembrane, ion conducting α-helical barrels. The helix barrel contains eight D4 peptides arranged in parallel (Mahendran et al. 2017). |
Bacteria | Pseudomonadota | Wza of E. coli (P0A930) |
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1.B.18.3.2 | The OMA protein component of a PST-type exopolysaccharide exporter (EpsE; TC# 2.A.66.2.11) (Huang and Schell, 1995) | Bacteria | Pseudomonadota | EpsA of Ralstonia solanacearum (Q45407) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.18.3.3 |
The Wza protein, an OMA homologue. May functions with an α-glycosyl transferase, RemC (A5FNG2) which shows limited sequence similarity to the cytoplasmic domain of 2.A.38.4.5, and the Wzc tyrosine protein kinase (8.A.3.3.4) (Shrivastava et al. 2012). |
Bacteria | Bacteroidota | Wza of Flavobactrerium johnsoniae |
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1.B.18.3.4 | Outer membrane polysaccharide-specific porin, Wza of 348 aas. |
Bacteria | Chlamydiota | Wza of Parachlamydia acanthamoebae |
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1.B.18.3.5 | Polysaccharide transmembrane transporter of 741 aas. |
Bacteria | Cyanobacteriota | PS exporter of Oscillatoria acuminata |
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1.B.18.3.6 | Polysaccharide exporter of 680 aas |
Bacteria | Planctomycetota | PS exporter of Rhodopirellula sallentina |
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1.B.18.3.7 | The outer membrane exo-polysaccharide (xanthan) exporter, GumB of 286 aas (Bianco et al. 2014). |
Bacteria | Pseudomonadota | GumB of Xanthomonas campestris |
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1.B.18.3.8 | Outer membrane auxillary lipoprotein of 698 aas and 1 N-terminal TMS, GlfD or YmcA. Probably involved in capsular polysaccharide export (Peleg et al. 2005; Cuthbertson et al. 2009; Nadler et al. 2012). |
Bacteria | Pseudomonadota | GlfD of E. coli |
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1.B.18.3.9 | Outer membrane polysaccharide biosynthesis/export protein, Opx, EpsY or MXAN_7417 of 219 aas and 1 N-terminal TMS. The gene encoding this protein is adjacent to EpsZ (MXAN_7415; TC# 9.B.18.1.6), an exopolysaccharide biosynthetic protein, and Wzx (MXAN_7416; TC# 2.A.66.12.12), a polysaccharide cytoplasmic membrane flippase (Pérez-Burgos et al. 2020). |
Bacteria | Myxococcota | Opx of Myxococcus xanthus |
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1.B.19.1.1 | Cation-selective, glucose-inducible glucose-transporting porin (also transports glycerol, mannitol, fructose, maltose, pentoses, etc.) (Adewoye and Worobec 1999). |
Bacteria | Pseudomonadota | OprB porin of Pseudomonas aeruginosa |
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1.B.19.1.2 | The quorum sensing acyl homoserine lactone porin, OprB | Bacteria | Pseudomonadota | OprB of Burkholderia pseudomallei (EBA45175) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.19.1.3 | Carbohydrate-selective porin OprB (Shrivastava et al., 2011). The high resolution 3-d structure reveals a 16 β-TMS barrel with a constriction explaining the preference of this porin for monosaccharides over disaccharides (van den Berg 2012). |
Bacteria | Pseudomonadota | OprB of Pseudomonas putida (B0KPQ1) |
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1.B.19.1.4 | OprB homologue |
Bacteria | Cyanobacteriota | OprB homologue of Prochlorococcus marinus (A2CB33) |
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1.B.19.1.5 | OprB homologue |
Bacteria | Pseudomonadota | OprB homologue of Rhodomicrobium vannielii (E3I261) |
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1.B.19.1.6 | OprB homologue |
Bacteria | Planctomycetota | OprB homologue of Planctoymyces maris (A6C291) |
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1.B.19.1.7 | OprB homologue |
Bacteria | Planctomycetota | OprB homologue of Rhodopirellula baltica |
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1.B.19.1.8 | Putative porin OprB |
Bacteria | Acidobacteriota | OprB of Acidobacterium capsulatum |
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1.B.19.1.9 | Porin of 425 aas, OprB, required for virulence and biofilm formation (Ficarra et al. 2016). It is a sugar-selective porin (Bae et al. 2018). |
Bacteria | Pseudomonadota | OprB of Xanthomonas citri pv. mangiferaeindicae |
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1.B.2.1.1 | MomP (Omp1) major general porin (transports many small molecules including sugars and amino acids). A transport mechanism and antigenic properties have been studied for the closely related C. pneumoniae protein (Atanu et al. 2013). The ortholog of this protein in Clamydia abortus is likely to be part of the outer membrane complex (COMC) used as a potential vaccine candidate against ovine enzootic abortion (Longbottom et al. 2019). |
Bacteria | Chlamydiota | Omp1 of Chlamydia psittaci |
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1.B.2.1.2 | Major outer membrance protein MomP (OmpA, Omp1, Omp1L2) of 394 aas; 1 N-terminal TMS Rodríguez-Marañón et al., 2002). This protein is covalently linked to two other cys-rich proteins via disulfide bonds, OmcA (Omp2A; Omp3) with 88 aas and 1 N-terminal TMS, and OmcB (Omp2, Omp2B) with 547 aas and 1 N-terminal TMS. Together these proteins comprise the Chlamydial outer membrane complex (COMC) (Findlay et al. 2005). MOMP is the most suitable substitute for whole cell targets for vaccine production, and its delivery as a combined systemic and mucosal vaccine is most effective (Phillips et al. 2019). It is also a drug target (Sadhasivam et al. 2019). The efficacy of a novel affitoxin targeting MOMP against Chlamydia trachomatis in vitro and in vivo has been reported (Li et al. 2024). |
Bacteria | Chlamydiota | MomP of Chlamydia trachomatis with two auxiliary proteins, OmcA and OmcB |
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1.B.2.1.3 | Outer membrane porin, OmpA-A of 259 aas. This protein may be C-terminally truncated since it is substantially smaller than most of the other members of this family. |
Bacteria | Chlamydiota | OmpA-A of Simkania negevensis |
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1.B.2.1.4 | PorB dicarboxylate-specific porin (Kubo and Stephens 2001). Mutations in porB can give rise to tetracycline resistance (). |
Bacteria | Chlamydiota | PorB of Chlamydia trachomatis |
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1.B.2.1.5 | Uncharacterized protein of 299 aas and 1 N-terminal TMS. May be C-terminally truncated. |
Bacteria | Myxococcota | UP of Deltaproteobacteria bacterium |
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1.B.2.1.6 | Uncharacterized protein of 271 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of Thiohalophilus thiocyanatoxydans |
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1.B.2.1.7 | Uncharacterized protein of 230 aas and 1 N-terminal TMS |
Bacteria | Candidatus Omnitrophota | UP of Candidatus Omnitrophica bacterium |
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1.B.2.1.8 | Uncharacterized protein of 325 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of unclassified Thioalkalivibrio |
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1.B.20.1.1 | Outer membrane toxin channel protein, ShlB | Bacteria | Pseudomonadota | ShlB of Serratia marcescens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.20.1.10 | Outer
membrane protein component of a toxin-immunity protein module, which
functions as a cellular contact-dependent growth inhibition (CDI)
system. CdiB is of 584 aas and possibly two TMSs, one N-terminal, and one C-terminal. CDI modules allow bacteria to communicate with and inhibit the
growth of closely related neighboring bacteria in a contact-dependent
fashion. CdiB is required for secretion and assembly of the
CdiA toxin protein. Expression
of the cdiAIB locus in B. thailandensis confers protection against
other bacteria carrying the locus; growth inhibition requires cellular
contact (Nikolakakis et al. 2012). The 3-d structures of two such systems have been determined (see family description) (Guerin et al. 2020). |
Bacteria | Pseudomonadota | CdiB2 of Burkholderia pseudomallei |
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1.B.20.1.11 | CdiB (FhaC) of 562 aas and one N-terminal TMS. |
Bacteria | Pseudomonadota | CdiB of Yersinia pestis |
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1.B.20.1.12 | CdiB of 579 aas and one N-terminal α-TMS. The 3-D structure has been determined (see family description) (Guerin et al. 2020). |
Bacteria | Pseudomonadota | CdiB of Acinetobacter baumannii |
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1.B.20.1.2 | Outer membrane hemolysin secretion protein, HpmA | Bacteria | Pseudomonadota | HpmA of Proteus mirabilis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.20.1.3 | Outer membrane transporter essential for contact-dependent growth inhibition, CdiB, of 588 aas and possibly two TMSs, one N-terminal and one near the C-terminus (Q3YL97). It exports the protein toxin, CdiA (AAZ57198) (Aoki et al., 2005). It mediates contact-dependent growth inhibition (CDI), a phenomenon by which bacterial cell growth is regulated by direct cell-to-cell contact. The CdiA/CdiB two-partner secretion system appears to play a direct role (Aoki et al. 2008). The 3-d structure of this secretion system and one other have been determined (Guerin et al. 2020). |
Bacteria | Pseudomonadota | CdiB of E. coli (AAZ57197) |
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1.B.20.1.4 | The outer membrane haemolysin-like OptA exporter, OptB (OptA, AAG55657, resembles Alveicin B, 1.C.75.1.1) (Choi et al., 2007). Choi and Bernstein (2010) have demonstrated that BpaA is secreted in a two step process, and the C-terminus of OtpA enters the OtpB pore before the N-terminus. |
Bacteria | Pseudomonadota | OptB of E. coli (Q8XAN8) |
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1.B.20.1.5 | The HrpA/HrpB TPS adhesin system (HrpB = HecB) (Schmitt et al., 2007) |
Bacteria | Pseudomonadota | HecB of Neisseria meningitidis (Q9JY22) |
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1.B.20.1.6 | Outer membrane hemagglutinin secretion protein, FhaC. Functionally important conserved motifs have been identified (Delattre et al., 2010). The x-ray structure reveals a beta-barrel pore obstructed by two structural elements conserved in all two partner secretion systems, an N-terminal α-helix and an extracellular loop. FhaC goes from the closed to the open state in the presence of the filamentous haemagglutinin adhesin, FHA. The N-terminal α-helix is displaced into the periplasm during FHA secretion (Guérin et al. 2014). With two POTRA domains in the periplasm, a transmembrane beta barrel and a large loop harboring a functionally important motif, FhaC epitomizes the conserved features of the superfamily (Jacob-Dubuisson et al. 2009). The conserved secretion domain of FHA interacts with the POTRA domains, specific extracellular loops and strands of FhaC and the inner beta-barrel surface. The interaction map indicates a funnel-like pathway, with conformationally flexible FHA entering the channel in a non-exclusive manner and exiting along a four-stranded beta-sheet at the surface of the FhaC barrel. This sheet of FhaC guides the secretion domain of FHA along discrete steps of translocation and folding (Baud et al. 2014). The membrane-proximal POTRA domain exists in several conformations, and the binding of FHA displaces this equilibrium (Guérin et al. 2015). TpsB (Two Partner Secretion) transporters belong to the Omp85 or OMPPI superfamily, whose members catalyze protein insertion into, or translocation across membranes. They are composed of a transmembrane β barrel preceded by two periplasmic POTRA domains that bind the incoming protein substrate. Sicoli et al. 2022 detected minor states in heterogeneous populations, identifying transient conformers of FhaC. This revealed substantial, spontaneous conformational changes on a slow time scale, with parts of the POTRA2 domain approaching the lipid bilayer and the protein's surface loops. An amphipathic POTRA2 β hairpin inserts into the β barrel, and these motions enlarge the channel to initiate substrate secretion. This shows how TpsB transporters mediate protein secretion without the need for cofactors, by utilizing intrinsic protein dynamics (Sicoli et al. 2022). |
Bacteria | Pseudomonadota | FhaC of Bordetella pertussis (P35077) |
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1.B.20.1.7 | Portra domain containing ShlB-type family protein of 354 aas and 2 α-TMSs, one N-terminal and one C-terminal. |
Bacteria | Pseudomonadota | ShlB-type protein of E. coli |
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1.B.20.1.8 | Hemolysin activator protein, ExlB of 570 aas. Exports the exotoxin, ExlA (TC# 1.C.73.1.1) (Elsen et al. 2014; Basso et al. 2017). |
Bacteria | Pseudomonadota | ExlB of Pseudomonas aeruginosa |
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1.B.20.1.9 | Outer membrane exporter of the ChlA exotoxin, ChlB, of 566 aas (Brumbach et al. 2007). |
Bacteria | Pseudomonadota | ChlB of Chromobacterium violaceum |
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1.B.20.2.1 | Hypothetical protein of 579 aas |
Bacteria | Pseudomonadota | HP of Erythrobacter litoralis |
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1.B.20.2.2 | The ShlB/FhaC/HecB family hemolysin secretion/activation protein of 555 aas. |
Bacteria | Pseudomonadota | Cytotoxin of Cupriavidus taiwanensis |
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1.B.20.2.3 | Putative type Vb secretion system, beta-barrel domain proteinof 584 aas. |
Bacteria | Pseudomonadota | cytotoxin exporter of Bradyrhizobium japonicum |
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1.B.20.3.1 | Heme-hemopexin utilization protein B precursor | Bacteria | Pseudomonadota | Hxb2 of Haemophilus influenzae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.20.3.2 | HMW1B outer membrane exporter, required for secretion of HMW1A and HMW2A adhesins (exhibit a twin pore dimeric structure) (Li et al., 2007) and forms a large-conductance channel (Duret et al., 2008). The protein has a modular three domain structure: an N-terminal membrane domain, a central periplasmic domain and a C-terminal membrane anchor domain that oligomerizes and forms a pore (Surana et al. 2006). The periplasmic domain is required for secretion. |
Bacteria | Pseudomonadota | HMW1B of Haemophilus influenzae (Q4QJR3) |
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1.B.20.3.3 | EtpB, a functionally asymmetric pore with three conductance states (Meli et al., 2009). |
Bacteria | Pseudomonadota | EtpB of E. coli (Q29XT8) |
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1.B.20.3.4 | The BpaB outer membrane channel protein. Exports BpaA (Brown et al., 2004). BpaA is very large (~530kDa) and contains 3 repeats, each ~700aas in length. |
Bacteria | Pseudomonadota | BpaB of Burkholderia pseudomallei (Q6Y659) |
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1.B.20.3.5 | Hypothetical protein of 576 aas |
Bacteria | Chlorobiota | HP of Chlorobium chlorochromatii |
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1.B.20.3.6 | Two component virulence-related protein exporter, PdtB of 544 aas. Exports the PdtA adhesin (4180 aas; Q9I5N6) to the cell surface for processing (Faure et al. 2014). |
Bacteria | Pseudomonadota | PdtB of Pseudomonas aeruginosa |
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1.B.20.3.7 | Uncharacterized protein of 455 aas and 1 N-terminal TMS. |
Bacteria | Cyanobacteriota | UP of Oscillatoriales cyanobacterium |
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1.B.20.4.1 | Pore-forming outer membrane constituent CptB of 441 aas, of an export system for cytotoxic, CptA (TC# 1.C.75.1.8) (Gentile et al. 2020). |
Bacteria | Fusobacteriota | CptB of Sneathia amnii |
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1.B.20.4.2 | Uncharacterized protein of 497 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of Phocoenobacter uteri |
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1.B.21.1.1 | Non-specific, 14 β-stranded monomeric OmpG porin (Conlan et al. 2000). pH-induced conformational changes of OmpG have been studied after reconstitution in native E. coli lipids (Mari et al., 2010). Encoded by a gene in a gene cluster also encoding an ABC sugar uptake system (TC# 3.A.1.1.46), a glucosyl hydrolase and two oxidoreductases. Therefore it's phsiological function may be glucoside uptake. At neutral/high pH, the channel is open and permeable to substrates of size up to 900Da. At acidic pH, loop L6 folds across the channel and blocks the pore. The channel blockage at acidic pH appears to be triggered by the protonation of a histidine pair on neighboring β-strands, which repel one another, resulting in the rearrangement of loop L6 and channel closure (Köster et al. 2015). Crystallization and analysis by electron microscopy and X-ray crystallography revealed the fundamental mechanisms essential for channel activity. A 28 aa extension has been added to the 14 β-TMS barrel to make a 16 β-TMS barrel with normal activity and stability but differing pH sensitivity (Korkmaz et al. 2015). A minimized OmpG porin of only 220 aas still exhibits gating, but it was 5-fold less frequent than in native OmpG. The residual gating of the minimal pore is independent of L6 rearrangements and involves narrowing of the ion conductance pathway, most probably driven by global stretching-flexing deformations of the membrane-embedded β-barrel (Grosse et al. 2014). pH-dependent gating is controlled by an electrostatic interaction network formed between the gating loop and charged residues in the lumen (Perez-Rathke et al. 2018). 3-d structures of the protein in lipid bilayers have been solved (Retel et al. 2017). OmpG may provide a route for D-lactate/D-3-hydroxybutyrate oligo-ester secretion as well as sugar uptake (Utsunomia et al. 2017). OmpG lacks a central constriction and has an exceptionally wide pore diameter of about 13 Å. The equatorial plane of OmpG harbors an annulus of four alternating basic and acidic patches, and manipulation of charge distribution in the arginine and glutamate clusters alters sugar specificity and ion selectivity (Schmitt et al. 2019). |
Bacteria | Pseudomonadota | OmpG of E. coli |
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1.B.21.1.2 | Putative porin |
Bacteria | Fusobacteriota | Putative porin of Fusobacterium mortiferum |
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1.B.21.1.3 | Uncharacterized protein of 355 aas |
Bacteria | Fusobacteriota | UP of Sebaldella termitidis |
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1.B.21.1.4 | OmpG family monomeric porin of 331 aa |
Bacteria | Pseudomonadota | OmpG homolog of Chania multitudinisentens |
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1.B.21.2.1 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of E. coli |
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1.B.21.2.2 | Putative porin of 361 aas |
Bacteria | Pseudomonadota | Putative porin of Providencia burhodogranariea |
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1.B.21.2.3 | OmpG of 299 aas and 1 N-terminal TMS. |
Bacteria | Fusobacteriota | OmpG of Sebaldella termitidis |
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1.B.21.2.4 | Uncharacterized porin homolog of 308 aas with 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of Photobacterium gaetbulicola |
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1.B.21.2.5 | Uncharacterized porin of 333 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of E. coli |
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1.B.21.3.1 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Vibrio sinaloensis |
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1.B.21.3.2 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Vibrio harveyi |
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1.B.21.3.3 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Vibrio parahaemolyticus |
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1.B.22.1.1 | PulD protein secretin. Involved in protein secretion via the Type II MTB system (TC# 3.A.15). PulD allows the efflux of small fluorescent molecules with a permeation cutoff similar to that of general porins and is constitutively open (Disconzi et al. 2014). |
Bacteria | Pseudomonadota | PulD of Klebsiella oxytoca |
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1.B.22.1.2 | XcpQ secretin protein | Bacteria | Pseudomonadota | XcpQ of Pseudomonas aeruginosa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.22.1.3 | The dodecameric secretin, GspD of 650 aas. The 3-d structure is known (PDB 5WQ8) (Korotkov et al. 2013). It reveals a double β-barrel channel with about 60 β-strands in each barrel (Yan et al. 2017). |
Bacteria | Pseudomonadota | GspD of E. coli |
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1.B.22.2.1 | PilQ fimbrial subunit secretin | Bacteria | Pseudomonadota | PilQ of Pseudomonas aeruginosa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.22.2.2 | The Type IV pilus biogenesis/competence secretin precursor, PilQ (may serve as a pore for (1) pilus export, (2) DNA uptake, (3) heme uptake, (4) antimicrobial uptake (Tønjum et al., 1998); Binds DNA (Assalkhou et al., 2007); Structure known to 12 Å resolution (Collins et al., 2004) The pilus biogenesis factor, PilW (ABX73034) facilitates formation and/or stability of secretin (PilQ) multimers. The 3-D structure of PilW is known (Trindade et al., 2008). |
Bacteria | Pseudomonadota | PilQ of Neisseria meningitidis (Q9ZHF3) |
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1.B.22.2.3 | Fimbrial usher, HofQ of 760 aas |
Bacteria | Chlamydiota | HofQ of Chlamydia trachomatis |
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1.B.22.2.4 | The secretin, PilQ (SglA) of 901 aas, required for pilus biogenesis, social motility and development of fruiting bodies (Wall et al. 1999). |
Bacteria | Myxococcota | PilQ of Myxococcus xanthus |
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1.B.22.3.1 | HrpH hypersensitivity response secretin | Bacteria | Pseudomonadota | HrpH of Pseudomonas syringae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.22.3.2 | InvG invasion protein secretin | Bacteria | Pseudomonadota | InvG of Salmonella typhimurium | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.22.3.3 | YscC secretin | Bacteria | Pseudomonadota | YscC of Yersinia enterocolitica | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.22.4.1 | ComE competence protein secretin | Bacteria | Pseudomonadota | ComE of Haemophilus influenzae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.22.4.2 | HofQ, may facilitate double stranded DNA uptake in E. coli (Sun et al., 2009). |
Bacteria | Pseudomonadota | HofQ of E. coli (Q1R5P6) |
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1.B.22.4.3 | HofQ competence protein, the outer membrane DNA translocase (Tarry et al., 2011). The 2.3Å structures of the extramembraneous domains are known (Tarry et al., 2011). |
Bacteria | Pseudomonadota | HofQ of Aggregatibacter actinomycetemcomitans (C6ALC5) |
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1.B.22.4.4 | DNA uptake porin, HofQ, of 428 aas and 1 N-terminal TMS and 36 beta strands, is required for the use of extracellular DNA as a nutrient. |
Bacteria | Pseudomonadota | HofQ of Klebsiella pneumoniae |
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1.B.22.4.5 | Outer membrane porin of 382 aas and 1 or 2 N-terminal TMSs. |
Bacteria | Bacillota | OMP of Megasphaera sp. |
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1.B.22.5.1 | Gene IV protein secretin | Viruses | Loebvirae, Hofneiviricota | Gene IV protein of bacteriophage f1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.22.5.2 | Putative pilus assembly transmembrane protein of 509 aas, PilQ. |
Bacteria | Bdellovibrionota | PilQ of Bdellovibrio bacteriovorus |
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1.B.22.6.1 | NolW secretin | Bacteria | Pseudomonadota | NolW of Rhizobium spp. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.22.7.1 | Bundle-forming pilus-B (BfpB) secretin (catalyzes export of pilins and EPEC proteins; uptake of vancomycin). (BfpB complex formation requires BfpG, 113 aas; gbBAA84839). While the N-terminus is periplasmic, the C-terminus is extracelllular. BfpB may form a beta barrel with 16 transmembrane beta strands with a C-terminal segment passing through the center of each monomer (Lieberman et al. 2015). |
Bacteria | Pseudomonadota | BfpB of enteropathogenic E. coli |
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1.B.23.1.1 | SomA porin | Bacteria | Cyanobacteriota | SomA of Synechococcus PCC 6301 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.23.1.10 | Putative outer membrane porin |
Bacteria | Bacillota | OMP of Megasphaera elsdenii (G0VLV3) |
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1.B.23.1.11 | Arginine/agmatine porin, AaxA (Smith and Graham 2008). |
Bacteria | Chlamydiota | AaxA of Chlamydia (Chlamydiophila) pneumoniae |
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1.B.23.1.12 | OprB homologue of 430 aas |
Bacteria | Aquificota | OprB homologue of Thermovibrio ammonificans |
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1.B.23.1.13 | OprB homologue of 408 aas |
Bacteria | Verrucomicrobiota | OprB homologue of Coraliomargarita akajimensis |
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1.B.23.1.14 | OprB homologue |
Bacteria | Nitrospirota | OprB homologue of Thermodesulfovibrio yellowstonii |
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1.B.23.1.15 | OprB homologue of 435 aas |
Bacteria | Acidobacteriota | OprB homologue of Terriglobus saanensis |
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1.B.23.1.16 | Putative porin, OprB, of 494 aas |
Bacteria | Verrucomicrobiota | OprB of Akkermansia muciniphila |
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1.B.23.1.17 | Putative porin of 488 aas |
Bacteria | Pseudomonadota | Putative porin of Magnetospirillum magneticum |
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1.B.23.1.18 | Putative porin of 470 aas in the outer membrane of an atypical firmicute |
Bacteria | Bacillota | Putative porin of Megasphaera elsdenii |
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1.B.23.1.19 | Putative porin |
Bacteria | Planctomycetota | Porin of Candidatus Kuenenia stuttgartiensis |
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1.B.23.1.2 | Putative HCO3-/Fe+3 porin, slr0042 gene product of 576 aas (Qiu et al. 2018). |
Bacteria | Cyanobacteriota | Slr0042 of Synechocystis PCC6803 |
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1.B.23.1.20 | Putative porin of 500 aas |
Bacteria | Synergistota | Putative porin of Synergistes sp. 3_1_syn1 |
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1.B.23.1.21 | OprB of 415 aas |
Bacteria | Verrucomicrobiota | OprB of Pedosphaera parvula |
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1.B.23.1.22 | Carbohydrate-selective porin OprB of 405 aas |
Bacteria | Verrucomicrobiota | OprB of Akkermansia muciniphila |
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1.B.23.1.23 | Porin (residues 250 - 433) with an N-terminal S-layer domain, SLH, residues 1 - 250 (Kalmokoff et al. 2009). |
Bacteria | Bacillota | Outer membrane porin of Mitsuokella multacida |
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1.B.23.1.24 | Major envelope protein, Mep45, of 432 aas and 1 N-terminal TMS. Mep45 contains two distinct domains: an N-terminal S-layer homologous (SLH) domain that protrudes into the periplasm and binds to peptidoglycan, and the remaining C-terminal transmembrane domain that forms a non-selective pore able to transport molecules of <600 Da (Kojima et al. 2016). The estimated pore radius is 0.58 nm; truncation of the SLH domain does not affect the channel. |
Bacteria | Bacillota | Mep45 of Selenomonas ruminantium |
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1.B.23.1.25 | Porin of 546 aas. Capable of facilitating the uptake of ferric iron (Qiu et al. 2018). |
Bacteria | Cyanobacteriota | Porin of Synechocystis sp. strain PCC 6803 |
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1.B.23.1.3 | Major Omp, OmpM1 |
Bacteria | Bacillota | OmpM1 of Selenomonas sputigena |
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1.B.23.1.4 | Putative porin |
Bacteria | Bacillota | Putative porin of Thermosinus carboxydivorans |
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1.B.23.1.5 | S-layer domain protein |
Bacteria | Bacillota | S-layer domain protein of Selenomonas noxia |
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1.B.23.1.6 | Outer membrane porin homologue |
Bacteria | Bacillota | OMP homologue of Veillonella atypica (E1L471) |
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1.B.23.1.7 | Outer membrane porin homologue |
Bacteria | Bacillota | OMP homologue of Megasphaera micronuciformis (E2ZDM6) |
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1.B.23.1.8 | Outer membrane porin homologue |
Bacteria | Bacillota | OMP of Anaeroglobus geminatus (G9YIN5) |
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1.B.23.1.9 | Putative outer membrane porin |
Bacteria | Cyanobacteriota | OMP of Fischerella sp. JSC-11 (G6FN26) |
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1.B.23.2.1 | Putative porin |
Bacteria | Acidobacteriota | Putative porin of Holophaga foetida |
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1.B.23.2.2 | Putative porin |
Bacteria | Acidobacteriota | Porin of Holophaga foetida |
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1.B.23.2.3 | Putative porin |
Bacteria | Acidobacteriota | Porin of Holophaga foetida |
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1.B.23.3.1 | Putative porin |
Bacteria | Fibrobacterota | Porin of Fibrobacter succinogenes |
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1.B.23.3.2 | Putative porin |
Bacteria | Fibrobacterota | Porin of Fibrobacter succinogenes |
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1.B.23.3.3 | Putative porin |
Bacteria | Fibrobacterota | Porin of Fibrobacter succinogenes |
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1.B.23.3.4 | Putative porin of 371 aas |
Bacteria | Fibrobacterota | Porin of Fibrobacter succinogenes |
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1.B.23.4.1 | Uncharacterized protein of 518 aas |
Bacteria | Chlorobiota | UP of Chloroherpeton thalassium |
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1.B.23.4.2 | Uncharacterized protein of 704 aas with 23 putative β-strains and one N-terminal α-TMS. |
Bacteria | Bacteroidota | UP of Flavobacterium psychrophilum |
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1.B.24.1.1 | M. smegmatis porin, MspA (cation selective due to a high density of negative charges in the constriction zone, but it transports glucose, serine, hydrophilic β-lactams and (slowly) phosphate (Wolschendorf et al., 2007). The MspC paralogue appears to have the same specificity as MspA. Both can also transport fluoroquinolones and chloramphenicol but not the larger erythromycin, kanamycin, and vancomycin (Danilchanka et al., 2008). Also allows uptake of ferric iron (Jones and Niederweis, 2010). The 3-d structure is known (PDB#1UUN). It is a β-barrel with N- and C-termini of their single hairpins on the outside, and their chains run in an anti-clockwise direction around the central pore. Both of these characteristics are opposite in most gram-negative bacterial β-barrels (Remmert et al., 2010). Forms homo-octameric voltage-gated nanopores where each subunit contributes 2 TMSs to the 16 stranded β-barrel (Faller et al. 2004; Rodrigues et al. 2011; Pavlenok et al. 2012) that can be used for nanopore sequencing (Laszlo et al. 2016). MspA is a biosensor for DNA sequencing and many other applications by enabling the production of pores with distinct subunit mutations and pore diameters (Pavlenok et al. 2022). See Samineni et al. 2023 for details of this and other pore-forming proteins. MspA forms pores in the outer mycobacterial membrane (Samineni et al. 2023). |
Bacteria | Actinomycetota | MspA of Mycobacterium smegmatis |
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1.B.24.1.2 |
MspA porin (233aas; one N-terminal alpha-helical TMS). This protein is almost identical to a cholate-transporting porin in R. jostii (RjpA; porin A) that is involved in cholate uptake (Somalinga and Mohn 2013). |
Bacteria | Actinomycetota | MspA porin of Rhodococcus opacus (C1B943) |
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1.B.24.1.3 |
MspA porin homologue (227aas; 1 N-terminal TMS) (shows significant similarity with members of both 1.B.24 and 1.B.58). |
Bacteria | Actinomycetota | MspA porin of Gordonia effusa (H0QY58) |
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1.B.24.1.4 | MspA porin homologue (289aas; 1 N-terminal TMS) |
Bacteria | Actinomycetota | MspA porin of Tsukamurella paurometabola (D5UQW2) |
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1.B.24.1.5 | RjpA outer membrane porin of 233 aas and 3 TMSs. Transports bile acids such as cholate (Somalinga and Mohn 2013). |
Bacteria | Actinomycetota | RjpA of Rhodococcus jostii |
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1.B.24.1.6 | RjpB outer membrane porin of 233 aas and 3 TMSs. Transports bile acids such as cholate (Somalinga and Mohn 2013). |
Bacteria | Actinomycetota | RjpB of Rhodococcus justii |
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1.B.24.1.7 | RjpC outer membrane porin of 283 aas and 1 - 3 TMSs. Transports bile acids such as cholate (Somalinga and Mohn 2013). |
Bacteria | Actinomycetota | RjpC of Rhodococcus justii |
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1.B.24.1.8 | RjpD outer membrane porin of 233 aas and 3 TMSs. Transports bile acids such as cholate (Somalinga and Mohn 2013). |
Bacteria | Actinomycetota | RjpD of Rhodococcus justii |
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1.B.25.1.1 | OprD2; OccD1; porin D transports cationic amino acids, peptides and other compounds: lysine, arginine, histidine, ornithine, basic di- and tri-peptides, and cationic antibiotics such as imipenem (n-formimidoylthienamycin) and other penems and carbapenems (Tamber et al., 2006). The 3-d structure and drugs transported are known (4FOZ; Parkin and Khalid 2014). OprD is the vitronectin receptor. Vitronectin enhances P. aeruginosa adhesion to host epithelial cells and thereby enhances virulence (Paulsson et al. 2015). Loss promotes carbapenem resistance (Shen and Fang 2015; Cavalcanti et al. 2015). Loss results in resistance to meropenem (Fluit et al. 2019). Carbapenem resistance in difficult-to-treat P. aeruginosa strains can be mediated by loss or reduction of the OprD porin (Do Rego and Timsit 2023). |
Bacteria | Pseudomonadota | OprD2 of Pseudomonas aeruginosa (P32722) |
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1.B.25.1.10 | A tricarboxylate transporting porin, OdpH (Occk5) induced by and transports cis-aconitate, isocitrate and citrate; exhibits a large single channel conductance (Tamber et al., 2006; 2007). This porin exhibits a high degree of anion selectivity, and the outer core and O-antigens of LPS sterically occlude the channel entrance to decrease the diffusion constants of approaching ions (Lee et al. 2018). |
Bacteria | Pseudomonadota | OpdH of Pseudomonas aeruginosa (AAG04144) |
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1.B.25.1.11 | OpdB proline-selective porin (Tamber et al., 2006) | Bacteria | Pseudomonadota | OpdB of Pseudomonas aeruginosa (AAG06088) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.12 |
OpdC or OccD2 histidine-selective porin (Tamber et al., 2006). The 3-D structure and substrate spcificities are known (PDB 3SY9; Eren et al. 2012). |
Bacteria | Pseudomonadota | OpdC of Pseudomonas aeruginosa (AAG03552) |
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1.B.25.1.13 | Chitoporin, ChiP or YbfM of 468 aas. Takes up chitosugars such as chitobiose. It also plays a role in carbapenem (imipenem) resistance. The orthologue in Proteus mirabilis is ImpR, and that in Salmonella species is YbfM. It is subject to regulation by the small RNA, MicM (Tsai et al. 2015). Loss of OmpC and OmpF results in poor growth, by expression of chiP restores growth (Knopp and Andersson 2015). |
Bacteria | Pseudomonadota | ChiP of E. coli (P75733) |
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1.B.25.1.14 | OdpF (OccK2) glucuronate-selective porin; may also transport benzoate and vanillate (Eren et al., 2012). 3-d structure is known (3SZD). |
Bacteria | Pseudomonadota | OdpF of Pseudomonas aeruginosa (Q9I6P8) |
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1.B.25.1.15 | Outer membrane porin | Bacteria | Bacteroidota | Ftrac_3105 of Marivirga tractuosa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.16 | Outer membrane porin | Bacteria | Pseudomonadota | Tint_2055 of Thiomonas intermedia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.17 | Outer membrane porin | Bacteria | Campylobacterota | Sdel_0469 of Sulfurospirillum deleyianum | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.18 | Outer membrane porin, OprD family | Bacteria | Aquificota | SULAZ_1441 of Sulfurihydrogenibium azorense | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.19 | Outer membrane porin, OprD family | Bacteria | Pseudomonadota | PROVRUST_07396 of Providencia rustigianii DSM 4541 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.2 | OprE1 (OprE; OccK8) porin (anaerobically induced). May participate in chromate resistance (Rivera et al., 2008). The high-resolution X-ray structure and electrophysiology highlight a very narrow pore. However, transport of natural amino acids and antibiotics, among them ceftazidime, has been demonstrated (Samanta et al. 2018). As in general porins, the internal electric field favors the translocation of polar molecules by gainful energy compensation in the central constriction region. The comparatively narrow pore can undergo a substrate-induced expansion to accommodate relatively large-sized substrates (Samanta et al. 2018). |
Bacteria | Pseudomonadota | OprE1 of Pseudomonas aeruginosa (Q51510) |
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1.B.25.1.20 | Outer membrane porin | Bacteria | Campylobacterota | Sulku_2564 of Sulfuricurvum kujiense | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.21 | Outer membrane porin | Bacteria | Pseudomonadota | Atc_1106 of Acidithiobacillus caldus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.22 | Outer membrane porin | Bacteria | Campylobacterota | Sdel_0019 of Sulfurospirillum deleyianum | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.23 | Outer membrane porin, OprD family | Bacteria | Pseudomonadota | Dsui_2952 of Azospira oryzae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.24 | Outer membrane porin, OprD family | Bacteria | Proteobacteria | CBGD1_2399 of Campylobacterales bacterium GD 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.25 | Uncharacterized protein | Bacteria | Campylobacterota | SMGD1_0130 of Sulfurimonas gotlandica GD1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.26 | Outer membrane porin | Bacteria | Campylobacterota | Sulku_1154 of Sulfuricurvum kujiense | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.27 | Outer membrane porin | Bacteria | Pseudomonadota | Sputcn32_0255 of Shewanella putrefaciens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.28 | Putative outer membrane porin | Bacteria | Campylobacterota | SMGD1_2744 of Sulfurimonas gotlandica GD1 |
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1.B.25.1.29 | Outer membrane porin | Bacteria | Campylobacterota | Sdel_2087 of Sulfurospirillum deleyianum | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.3 | OprE3 (OprQ) porin (Okamoto et al. 1999). |
Bacteria | Pseudomonadota | OprE3 of Pseudomonas aeruginosa (O24779) |
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1.B.25.1.30 | Outer membrane porin | Bacteria | Campylobacterota | Sulku_1034 of Sulfuricurvum kujiense | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.31 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Shewanella sediminis |
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1.B.25.1.32 |
Outer membrane tyrosine-specific porin, OpdT (Tamber et al. 2006). |
Bacteria | Pseudomonadota | OpdT of Pseudomonas aeruginosa |
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1.B.25.1.33 | Putative porin |
Bacteria | Aquificota | Porin of Sulfurihydrogenibium azorense |
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1.B.25.1.34 | The outer membrane porin, OdpQ of 421 aas. opdQ is transcriptionally repressed under low oxygen but increased in the presence of nitrate. The nitrate-induced regulation is dependent on NarL via the NarXL two-component system. In addition, NaCl-induced osmotic stress increases OpdQ production among most of the clinical strains evaluated (Fowler and Hanson 2015). |
Bacteria | Pseudomonadota | OdpQ of Pseudomonas aeruginosa |
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1.B.25.1.35 | Benzoate-specific porin protein of 397 aas and 1 N-terminal TMS, BenF (Choudhary et al. 2017). |
Bacteria | Pseudomonadota | BenF of Pseudomonas putida |
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1.B.25.1.36 | BenP porin (Clark et al. 2002). Probably transports aromatic compounds such as benzoate for degradation. |
Bacteria | Pseudomonadota | BenP of Acinetobacter sp.ADP1 (Acinetobacter baylyi) |
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1.B.25.1.37 | Putative porin of 430 aas and 1 N-terminal TMS, NicP. |
Bacteria | Pseudomonadota | NicP of Pseudomonas putida |
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1.B.25.1.38 | OprD or OccAB1 of 418 aas and 1 N-terminal TMS. The 3-d structure has been determined for 4 similar porins, OccAB1 - 4 (Zahn et al. 2016). Probably allows the uptake of small molecules including sugars, amino acids and some antibiotics. The transport properties have been studied (Benkerrou and Ceccarelli 2018). |
Bacteria | Pseudomonadota | OprD of Acinetobacter baumannii |
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1.B.25.1.39 | Outer membrane porin of 446 aas, OprE. |
Bacteria | Pseudomonadota | OprE of Pseudomonas putida (Arthrobacter siderocapsulatus) |
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1.B.25.1.4 | Bacteria | Pseudomonadota | PhaK of Pseudomonas putida (O84986) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.5 |
GusC (UidC) putative glucuronide porin (Liang et al., 2005). Reported to enhance the activity of the UidB (GusB) glucuronide transporter (TC# 2.A.2.1.5). Glucuronide transport does not occur in strain K12 due to a variant at position 100 of the UidB protein. |
Bacteria | Pseudomonadota | GusC of E. coli (Q47706) |
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1.B.25.1.6 | Vanillate trafficing porin, VanP. 85% identical to OprD of Acinetobacter baumannii which when mutated confers MDR (Yang et al. 2015). |
Bacteria | Pseudomonadota | VanP of Acinetobacter sp. ADP1 (Q6FDI3) |
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1.B.25.1.7 | OpdO pyroglutamate-specific porin (Tamber et al., 2006) | Bacteria | Pseudomonadota | OpdO of Pseudomonas aeruginosa (AAG05501) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.1.8 |
Anion-selective OpdK (OccK1 or OpdK) benzoate/vanillate-selective porin (Tamber et al., 2006; Eren et al., 2012; Liu et al. 2012). The structure of the OpdK porin, specific for vanillate and related small aromatic acids, has been solved by x-ray crystallography (3SYS_A). It is a labile trimer with monomers of an 18 β-stranded barrel and with an inner diameter of 8Å (Biswas et al., 2008). Other substrates transported (but less well) include 4-nitrobenzoate, caproate, octanoate, carbenicillin, cefoxitin, tetracycline antibiotics, and carbapenem antibioitics (imipenem and meropenem) (Eren et al., 2012). Molecular dynamic simulations and mutant analyses have been reported (Wang et al. 2012). |
Bacteria | Pseudomonadota | OpdK of Pseudomonas aeruginosa (AAG08283) |
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1.B.25.1.9 | OpdP glycine-glutamate-selective porin (Tamber et al., 2006) | Bacteria | Pseudomonadota | OpdP of Pseudomonas aeruginosa (AAG07889) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.25.2.1 | Putative porin of 278 aas |
Bacteria | Lentisphaerota | PP of Lentisphaera araneosa |
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1.B.25.2.2 | Uncharacterized outer membrane porin of 388 aas and 1 N-terminal TMS. |
Bacteria | Campylobacterota | OMP of Sulfurospirillum barnesii |
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1.B.25.2.3 | Putative porin of 402 aas. |
Bacteria | Campylobacterota | Porin of Arcobacter porcinus] |
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1.B.25.3.1 | Outer membrane porin, OprD, of 448 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | OprD of Acinetobacter baumannii |
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1.B.26.1.1 | Cyclodextrin (high affinity)/linear malto-oligosaccharide (low affinity) porin, CymA (Orlik et al. 2003). Electroosmosis influences the transport efficiency of cyclodextrins through the CymA pore (Bhamidimarri et al. 2016). |
Bacteria | Pseudomonadota | CymA of Klebsiella oxytoca |
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1.B.26.1.2 |
Putative porin, CymA |
Bacteria | Pseudomonadota | Putative porin of Vibrio cholerae |
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1.B.26.2.1 | Putative porin of 331 aas |
Bacteria | Pseudomonadota | Putative porin of Yersinia pestis |
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1.B.26.2.2 | Putative porin of 392 aas |
Bacteria | Pseudomonadota | Putative porin of Rahnella aquatilis |
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1.B.27.1.1 | large channel porin, HopE (Lienlaf et al. 2010). |
Bacteria | Campylobacterota | HopE of Helicobacter pylori |
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1.B.27.1.10 | SabA adhesion domain-containing protein of 711 aas. The extracellular domain is a conserved coiled-coil stem domain that connects to transmembrane beta-strands 1 and 2 (Coppens et al. 2018). SabA is 96% identical to LabA of the same organism (Paraskevopoulou et al. 2019). It is one of many porins found in Helicobacter pylori (Sedarat and Taylor-Robinson 2024). |
Bacteria | Campylobacterota | SabA of Helicobacter pylori |
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1.B.27.1.11 | HopQ of 632 aas |
Bacteria | Campylobacterota | HopQ of Helicobacter pylori (Campylobacter pylori) |
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1.B.27.1.12 | HopZ of 666 aas |
Bacteria | Campylobacterota | HopZ of Helicobacter pylori (Campylobacter pylori) |
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1.B.27.1.13 | Outer membrane porin, AlpA, of 517 aas with 1 N-terminal TMS. It is also indicated as an adhesin. |
Bacteria | Campylobacterota | AlpA of Heilcobacter pylori |
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1.B.27.1.14 | Outer membrane porin, BabB of 135 aas and 1 N-terminal TMS (Sedarat and Taylor-Robinson 2024). |
None | Pseudomonadati, Campylobacterota | BabB of Helicobacter pylori |
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1.B.27.1.2 |
Putative outer membrane porin, HopK |
Bacteria | Campylobacterota | HopK of Helicobacter pylori |
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1.B.27.1.3 | Putative porin, HorG |
Bacteria | Campylobacterota | HorG of Helicobacter pylori |
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1.B.27.1.4 | Putative porin, HomA |
Bacteria | Campylobacterota | HomA of Helicobacter pylori |
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1.B.27.1.5 | Outer membrane porin/adhesin, BabA (HopZ) (Peck et al. 1999). Exhibits phase variation (Kennemann et al. 2012). |
Bacteria | Campylobacterota | BabA of Helicobacter pylori |
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1.B.27.1.6 | Outer membrane porin/adhesion, SabB or HopO of 623 aas (de Jonge et al. 2004). |
Bacteria | Campylobacterota | HopO of Helicobacter pylori |
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1.B.27.1.7 | Outer membrane porin, HopF of 485 aas |
Bacteria | Campylobacterota | HopF of Helicobacter pylori |
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1.B.27.1.8 | Outer membrane porin, HopV, of 248 aas (Lienlaf et al. 2010). |
Bacteria | Campylobacterota | HopV of Helicobacter pylori |
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1.B.27.1.9 | Putative proin, HopK, of 284 aas |
Bacteria | Campylobacterota | HopK of Helicobacter cetorum |
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1.B.27.2.1 | Putative porin (based on homology) of 222 aas, Hop-2. |
Bacteria | Campylobacterota | hop-2 of Helicobacter hepaticus |
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1.B.27.2.2 | Putative porin (based on homology) of 209 aas, Omp30. |
Bacteria | Campylobacterota | Omp30 of Helicobacter hepaticus |
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1.B.27.2.3 | Putative porin of 284 aas. |
Bacteria | Campylobacterota | Porin of Helicobacter pylori |
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1.B.28.1.1 | High conductance chloroplast outer envelope OEP24 porin (Pohlmeyer et al. 1998). |
Eukaryota | Viridiplantae, Streptophyta | OEP24 of Pisum sativum |
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1.B.28.1.2 | OEP24 homologue |
Eukaryota | Viridiplantae, Streptophyta | OEP24 homologue of Selaginella moellendorffii |
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1.B.28.1.3 | OEP24 homologue |
Eukaryota | Viridiplantae, Chlorophyta | OEP24 homologue of Chlorella variabilis |
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1.B.28.1.4 | Oep24 of 213 aas. High-conductance voltage-dependent solute channel with a slight selectivity for cations, transporting triosephosphates, dicarboxylic acids, ATP, inorganic phosphate (Pi), sugars, and positively or negatively charged amino acids. The central mitochondrial components that mediate the import of yeast β-barrel proteins can deal with precursors of chloroplast β-barrel proteins (Ulrich et al. 2012). Targeting and surface recognition of mitochondrial β-barrel proteins in yeast, humans and plants depends on the hydrophobicity of the last β-hairpin of the β-barrel, but the presence of a hydrophilic amino acid at the C-terminus of the penultimate β-strand is also required for mitochondrial targeting (Klinger et al. 2019). |
Eukaryota | Viridiplantae, Streptophyta | Oep24 of Arabidopsis thaliana (Mouse-ear cress) |
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1.B.28.2.1 | Putative OEP24 homologue of 286 aas |
Eukaryota | Viridiplantae, Chlorophyta | OEP24 homologue of Coccomyxa subellipsoidea |
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1.B.29.1.1 | OEP21 of 177 aas. Voltage-dependent rectifying anion channel that facilitates the translocation between chloroplast and cytoplasm of phosphorylated carbohydrates such as triosephosphate, 3-phosphoglycerate and inorganic phosphate (Pi), depending on the ATP to triosephosphate ratio in the plastidial intermembrane space. In high triosephosphate/ATP conditions (e.g. photosynthesis), export of triosphophate from the chloroplast occurs (outward rectifying channels), but in high ATP/triosephosphate conditions (e.g. dark phase), import of phosphosolutes (inward rectifying channels) occurs (Bölter et al. 1999). The channel is formed by eight beta-strands with a wider pore vestibule of dvest approximately 2.4 nm at the intermembrane site and a narrower filter pore of drestr approximately 1 nm. The Oep21 pore contains two high affinity sites for ATP, one located at a relative transmembrane electrical distance delta = 0.56 and the second close to the vestibule at the intermembrane site. The ATP-dependent current block and reduction in anion selectivity of the Oep21 channel is relieved by the competitive binding of phosphorylated metabolic intermediates like 3-phosphoglycerate and glycerinaldehyde 3-phosphate (Hemmler et al. 2006). |
Eukaryota | Viridiplantae, Streptophyta | OEP21 of Pisum sativum |
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1.B.29.1.2 | OEP21 homologue |
Eukaryota | Viridiplantae, Chlorophyta | OEP21 homologue of Coccomyxa subellipsoidea |
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1.B.29.1.3 | OEP21 homologue |
Eukaryota | Viridiplantae, Chlorophyta | OEP21 homologue of Chlorella variabilis |
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1.B.29.1.4 | Oep21 of 167 aas is a voltage-dependent rectifying anion channel that facilitates the translocation between the chloroplast and cytoplasm of phosphorylated carbohydrates such as triosephosphate, 3-phosphoglycerate and inorganic phosphate (Pi), depending on the ATP to triosephosphate ratio in the plastidial intermembrane space; in high triosephosphate/ATP conditions (e.g. photosynthesis), export of triosphophate from chloroplasts occurs (outward rectifying channels), but in high ATP/triosephosphate conditions (e.g., the dark phase), import of phosphosolutes occurs (inward rectifying channels). |
Eukaryota | Viridiplantae, Streptophyta | Oep21 of Arabidopsis thaliana (Mouse-ear cress) |
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1.B.29.2.1 | OEP21 homologue |
Eukaryota | Viridiplantae, Chlorophyta | OEP21 homologue of Chlamydomonas reinhardtii |
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1.B.29.2.2 | OEP21 homologu of 169 aas |
Eukaryota | Viridiplantae, Chlorophyta | OEP21 homologue of Volvox carteri |
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1.B.3.1.1 | LamB (MalL) maltoporin (maltose–maltoheptose). Also catalyzes the uptake of antibiotics (Lin et al. 2014). LamB preferentially binds maltodextrins from the periplasmic side, and thus, sugar binding and uptake are asymmetric (Mulvihill et al. 2019). Expression of the lamB gene is regulated by EnvZ and OmpR in response to osmolarity and thereby influences antibiotic resistance (Gerken et al. 2024). |
Bacteria | Pseudomonadota | LamB of E. coli |
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1.B.3.1.10 | Uncharacterized protein |
Bacteria | Nitrospirota | Putative porin of Candidatus Nitrospira defluvii |
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1.B.3.1.11 | Putative porin of 385 aas |
Bacteria | Planctomycetota | Porin of Planctomycete KSU-1 |
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1.B.3.1.12 | Putative porin of 447 aas |
Bacteria | Verrucomicrobiota | PP of Pedosphaera parvula |
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1.B.3.1.13 | sucrose porin, ScrY, of 521 aas (Löwe et al. 2018). |
Bacteria | Pseudomonadota | ScrY of Pseudomonas putida |
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1.B.3.1.14 | Maltoporin, LamB; MalL, of 439 aas and 1 -terminal TMS. |
Bacteria | Pseudomonadota | LamB of Aeromonas veronii |
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1.B.3.1.2 | Oligosaccharide porin, ScrY (transports sucrose, raffinose and maltooligo-saccharides) (Kim et al. 2002). The 3-d structure known (PDB ID 1A0S). Sucrose translocation through the pore showed two main energy barriers within the constriction region of ScrY. Three asparate residues are key residues, opposing the passage of sucrose, all located within the L3 loop (Sun et al. 2016). |
Bacteria | Pseudomonadota | ScrY of Salmonella typhimurium |
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1.B.3.1.3 | Porin with specificity for β-glucosides, BglH of 538 aas. High affinity binding was observed with the aromatic beta-D-glucosides arbutin and salicin as well as with gentibiose and cellobiose. Binding of maltooligosaccharides to BglH was much weaker, indicating that the binding site of BglH for carbohydrates is different from that of LamB (maltoporin) (Andersen et al. 1999). |
Bacteria | Pseudomonadota | BglH (YieC) of E. coli |
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1.B.3.1.4 | Maltoporin | Bacteria | Pseudomonadota | LamB of Alteromonas sp. |
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1.B.3.1.5 | Outer membrane porin homologue |
Bacteria | Pseudomonadota | Omp of Glaciecola mesophila (K6YXR7) |
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1.B.3.1.6 | Putative outer membrane porin |
Bacteria | Pseudomonadota | Omp of Rheinheimera nanhaiensis (I1DXN7) |
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1.B.3.1.7 | Putative outer membrane porin |
Bacteria | Aquificota | OMP of Aquifex aeolicus (O67300) |
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1.B.3.1.8 | Putative porin |
Bacteria | Pseudomonadota | Porin of Chromohalobacter salexigens |
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1.B.3.1.9 | Putative porin |
Bacteria | Verrucomicrobiota | Porin of Verrucomicrobiae bacterium |
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1.B.3.2.1 | Putative porin of 411 aas |
Bacteria | Verrucomicrobiota | PP of Opitutus terrae |
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1.B.3.2.2 | Putative porin of 397 aas |
Bacteria | Pseudomonadota | PP of Thioflavicoccus mobilis |
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1.B.3.2.3 | Putative porin of 401 aas |
Bacteria | Pseudomonadota | PP of Marinobacter aquaeolei (Marinobacter hydrocarbonoclasticus) |
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1.B.3.2.4 | Uncharacterized protein of 355 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of Vibrio celticus |
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1.B.3.3.1 | Uncharacterized putative porin of 448 aas |
Bacteria | Bdellovibrionota | UP of Bdellovibrio bacteriovorus |
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1.B.30.1.1 | Outer envelope porin, OEP16. Has an N-terminal 4 β-strand structure that forms the pore, and a C-terminla domain consisting of 3 α-helices (Steinkamp et al. 2000). Cation-selective channel activity for amino acids and amines has been demonstrated following reconstitution (Linke et al. 2000; Ni et al. 2011). It mediates metabolic fluxes during seed development and germination (Pudelski et al. 2012). |
Eukaryota | Viridiplantae, Streptophyta | OEP16 of Pisum sativum |
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1.B.30.1.2 | Outer envelope pore protein 16-2, chloroplastic (Chloroplastic outer envelope pore protein of 16 kDa 2) (AtOEP16-2) (OEP16-2) (Outer plastid envelope protein 16-S) (AtOEP16-S) (Seeds outer plastid envelope protein 16) | Eukaryota | Viridiplantae, Streptophyta | OP162 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.30.2.1 | OEP16-4; Tim17/Tim22/Tim23/Pmp24 family member (TC# 3.A.8.1.3) of 136 aas and possibly 5 TMSs. |
Eukaryota | Viridiplantae, Streptophyta | OEP16-4 of Arabidopsis thaliana |
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1.B.30.3.1 | Hypothetical protein of 190 aas |
Eukaryota | Bacillariophyta | HP of Thalassiosira pseudonana |
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1.B.30.4.1 | Outer envelope pore protein 16-3 (OEP16-3) of 159 aas. Probable protein translocase. |
Eukaryota | Viridiplantae, Streptophyta | OEP16-3 of Solanum lycopersicum |
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1.B.30.5.1 | Uncharacterized protein translocase subunit of 161 aas and 4 TMSs. |
Eukaryota | Rhodophyta | UP of Galdieria sulphuraria |
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1.B.31.1.1 | The major MomP or PorA porin can exist as functional monomers and trimers; both exhibit ion conduction activity as well as the same cationic selectivity and sensitivity to low voltage (Dé et al. 2000; Bolla et al. 2004). It can transport polyarginine peptides (Dhanasekar et al. 2017). Nanobodies against MomP restrict Campylobacter colonization (Vanmarsenille et al. 2017). Healthy cats can carry C. jejuni of limited genetic diversity (Mohan and Habib 2019). |
Bacteria | Campylobacterota | MomP of Campylobacter jejuni |
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1.B.31.1.2 | Putative porin |
Bacteria | Campylobacterota | Putative porin of Wolinella succinogenes |
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1.B.31.1.3 | Putative porin |
Bacteria | Campylobacterota | Putative porin of Helicobacter canadensis |
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1.B.31.1.4 | Putative porin |
Bacteria | Campylobacterota | Putative porin of Arcobacter bulzleri |
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1.B.31.1.5 | Putative porin |
Bacteria | Campylobacterota | Putative porin of Caminibacter mediatlanticus |
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1.B.31.1.6 | Putative porin of 392 aas |
Bacteria | Campylobacterota | Putative porin of Campylobacter rectus |
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1.B.31.1.7 | PorA1 of 425 aas |
Bacteria | Campylobacterota | PorinA1 of Campylobacter lari |
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1.B.32.1.1 | Non-specific FomA porin precursor (Kleivdal et al. 1995). The N-terminal region is periplasmic while the C-terminus is a 14 stranded β-barrel (Puntervoll et al. 2002). The β-barrel may have a tilt angle of 45° relative to the barrel axis (Anbazhagan et al., 2008). FomA is fusogenic (Pszon-Bartosz et al., 2011). Its unique solute transport activity with size exclusion limit has been described (Kattner et al. 2015). FomA is a voltage-dependent porin, predicted to form a 14 stranded beta-barrel. It folds in a range of model membranes of very different phospholipid compositions. A study on FomA folding into lipid bilayers indicated the presence of parallel folding pathways for OMPs with larger transmembrane beta-barrels (Kleinschmidt 2006). |
Bacteria | Fusobacteriota | FomA of Fusobacterium nucleatum (Q47905) |
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1.B.32.1.2 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Providencia rustigianii |
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1.B.32.2.1 | Putative porin |
Bacteria | Fusobacteriota | Putative porin of Ilyobacter polytropus |
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1.B.32.2.2 | FomA homologue of 294 aas |
Bacteria | Fusobacteriota | FomA homologue of Ilyobacter polytropus |
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1.B.33.1.1 | Omp85 outer membrane OMP translocase, YaeT. The high resolution 3-d structure of the N. gonorrhoea orthologue has been solved (Noinaj et al. 2013). |
Bacteria | Pseudomonadota | Omp85 of Neisseria meningitidis |
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1.B.33.1.2 | Protective surface antigen D15 precursor. The high resolution 3-d structure of the H. ducreyi orthologue has been solved (Noinaj et al. 2013). |
Bacteria | Pseudomonadota | D15 of Haemophilus influenzae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.33.1.3 | Outer membrane biogenesis complex (Wu et al., 2005). YaeT (BamA) may serve as an outer membrane ""receptor"" for the CdiA/CdiB 2-partner secretion system that mediates direct cell-cell contact-dependent growth inhibition (Aoki et al., 2008). High-resolution structures of crystal forms of BamA POTRA4-5 from E. coli has been reported (Zhang et al., 2011; Sinnige et al. 2014). Solid-state NMR on BamA, a large multidomain integral membrane protein, revealed dynamic conformational states (Renault et al., 2011). In contrast to the N-terminal periplasmic polypeptide-transport-associated (POTRA) domains, the C-terminal transmembrane β-barrel domain of BamA is mechanically much more stable. Exposed to mechanical stress, this β-barrel stepwise unfolds β-hairpins until unfolding has been completed. The mechanical stabilities of β-barrel and β-hairpins are thereby modulated by the POTRA domains, the membrane composition and the extracellular lid closing the β-barrel. The NMR structure of SmpA (OmlA) is also known (Vanini et al. 2006). The periplasmic region of BamA is firmly attached to the β-barrel and does not experience fast global motion around the angle between POTRA 2 and 3, but the barrel is flexible (Sinnige et al. 2014). It appears that the BAM complex does not catalyze insertion and assembly of all out membrane (α- and β-)porins (Dunstan et al. 2015). YfgL shows significant sequence similarity (e-9) with YxaL/K of Bacillus subtilis. The E. coli periplasmic chaperones, Skp and SurA, and BamA, the central subunit of the BAM complex, have been examined with respect to the folding kinetics of a model OMP (tOmpA) (Schiffrin et al. 2017), showing that prefolded BamA promotes the release of tOmpA from Skp, despite the nM affinity of the Skp for tOmpA. This activity is located in the BamA β-barrel domain, but is greater when full-length BamA is present, indicating that both the beta-barrel and POTRA domains are required for maximal activity. By contrast, SurA is unable to release tOmpA from Skp, providing direct evidence against a sequential chaperone model. BamA has a greater catalytic effect on tOmpA folding in thicker bilayers, suggesting that BAM catalysis involves lowering the kinetic barrier imposed by the hydrophobic thickness of the membrane (Schiffrin et al. 2017). While BamA is the primary translocator, TamB is involved in folding and maturation of autotransporters (Babu et al. 2018). The TAM complex is a "Translocation and Assembly Module" for protein assembly and potential conduit for phospholipid transfer (Goh et al. 2024). |
Bacteria | Pseudomonadota | OM biogenesis complex of E. coli |
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1.B.33.1.4 | The BAM complex required for outer membrane integrity and correct assembly of outer membrane β-barrel proteins, including one or more substrates required for the initiation of stalk biogenesis (Ryan et al., 2010). |
Bacteria | Pseudomonadota | The BamABDE complex of Caulobacter crescentus |
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1.B.33.1.5 | Omp85 homologue of 1,107 aas |
Bacteria | Planctomycetota | Omp85 of Planctomyces limnophilus |
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1.B.33.1.6 | Outer membrane protein assembly factor BamA of 611 aas and 1 N-terminal TMS. |
Bacteria | Bacteroidota | BamA of Tangfeifania diversioriginum |
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1.B.33.2.1 | The chloroplast import-associated channel porin, IAP75 or Toc75 that functions with two receptor GTPases, Toc34 and Toc159 (see 3.A.9, the CEPT family). It contains a polyglycine sequence (residues 91 - 110) that acts as a "rejection signal" at the outer envelope for protein transport into the chloroplast (Endow et al. 2016). |
Eukaryota | Viridiplantae, Streptophyta | IAP75 of chloroplasts in Pisum sativum |
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1.B.33.2.2 | Chloroplast Outer Envelope Protein, 80 KD (OEP80) (One of two; Toc75 (TC #) and OEP80). OEP80 is essential for viability (Patel et al., 2008). This β-barrel protein imported into the chloroplast via components of the general import apparatus (Day et al. 2019). |
Eukaryota | Viridiplantae, Streptophyta | OEP80 of Arabidopsis thaliana (Q9C5J8) |
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1.B.33.2.3 | Omp85 family member |
Bacteria | Bacillota | Omp85 homologue of Selenomonas sputigena |
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1.B.33.2.4 | TamA (YftM) of 577 aas; has a 16 transmembrane β-stranded β-barrel with 3 PORTRA domains. The 2.3 Å crystal structure is known revealing that the barrel is closed by a lid-loop (Gruss et al. 2013). The C-terminal β-strand of the barrel forms an unusual inward kink, which weakens the lateral barrel wall and creates a gate for substrate access to the lipid bilayer. TamA is an Omp85 homologue that may function in autotransporter biogenesis together with TamB (TC# 1.B.22.1.2) and OMP85 (Selkrig et al. 2012). The TAM complex likely evolved from an original combination of BamA and TamB, with a later gene duplication event of BamA, giving rise to an additional Omp85 sequence that evolved to be TamA in Proteobacteria and TamL in Bacteroidetes/Chlorobi (Heinz et al. 2015). Possibly TamB nucleates folding of the passenger domain while TamA/B-BamA interact to catalyze β-domain membrane insertion and pore enlargement to facilitate translocation of partially folded autotransporters (M. Babu et al., unpublished hypothesis). |
Bacteria | Pseudomonadota | TamA of E. coli |
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1.B.33.2.5 | TamA of 604 aas; surface antigen D15; involved in autotransporter protein insertion in the outer membrane together with TamB (TC# 9.B.22.1.5). |
Bacteria | Pseudomonadota | TamA of Sagittula stellata |
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1.B.33.2.6 | Outer envelope protein of 80 KDa and 748 aas with 1 N-terminal TMS. |
Eukaryota | Viridiplantae, Streptophyta | OEP of Klebsormidium nitens |
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1.B.33.2.7 | Uncharacterized protein of 530 aas and 1 N-terminal TMS |
Bacteria | Calditrichota | UP of Calditrichaeota bacterium (hot springs metagenome) |
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1.B.33.2.8 | Omp85 outer membrane protein assembly factor of 707 aas and 1 N-terminal TMS. |
Bacteria | Fusobacteriota | Omp85 of Fusobacterium necrophorum |
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1.B.33.3.1 | The mitochondrial Sorting and Assembly Machinery (SAM) includes SAM50, Tom37 (Mas37; Sam37), Tom13 (Mim1), Mim2, and porin; see 3.A.8 (Paschen et al., 2005). The MIM complex can assemble N- and C-terminal α-helical anchor proteins. SAM and TOM insert β-barrel proteins in the outer mitochondrial membrane (Stojanovski et al., 2007). Mim1 (Tom13) is required for the biogenesis of the beta-barrel protein Tom40 and also for membrane insertion and assembly of signal- and C-terminally-anchored Tom receptors (Becker et al., 2008; 2011). It has cation-selective ion transport activity (Checchetto and Szabo 2018; Krüger et al. 2017). Tom7 regulates Mdm10-mediated assembly of the mitochondrial import channel protein Tom40 (Yamano et al., 2010). Homologous Omp85 proteins are essential for membrane insertion of β-barrel precursors. Precursors are apparently threaded through the Omp85-channel interior and exit laterally. Höhr et al. 2018 mapped the interaction of a precursor in transit with the mitochondrial Omp85-channel Sam50 in the native membrane environment. The precursor is translocated into the channel interior, interacts with an internal loop, and inserts into the lateral gate by β-signal exchange. Transport through the Omp85-channel interior followed by release through the lateral gate into the lipid phase represents a basic mechanism for membrane insertion of β-barrel proteins (Höhr et al. 2018). The TOM and SAM complexes cooperate in the import of beta-barrel proteins, whereas the mitochondrial import (MIM) complex (Mim1/Mim2/porin) inserts precursors of multi-spanning alpha-helical proteins. Single-spanning proteins constitute more than half of the integral outer membrane proteins. Doan et al. 2020 reported that the yeast MIM complex promotes the insertion of proteins with N-terminal (signal-anchored) or C-terminal (tail-anchored) membrane anchors. The MIM complex exists in three dynamic populations. MIM interacts with TOM to accept precursor proteins from the receptor Tom70. Free MIM complexes insert single-spanning proteins that are imported in a Tom70-independent manner. Finally, coupling of MIM and SAM promotes early assembly steps of TOM subunits. Thus, the MIM complex is a major and versatile protein translocase of the mitochondrial outer membrane (Doan et al. 2020). |
Eukaryota | Fungi, Ascomycota | SAM of Saccharomyces cerevisiae: |
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1.B.33.3.10 | SAM50 homologue in hydrogenosomes, Sam50 of 398 aas (Makki et al. 2019). |
Eukaryota | Parabasalia | Sam50 of Trichomonas vaginalis |
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1.B.33.3.11 | Uncharacterized protein of 872 aas with three domains: first, a large SAM50-like domain, then a glycine rich region similar to proteins in TC family 9.B.96 with glycine-rich domains, and then a Yip domain with 4 TMSs in a 1 + 3 TMS arrangement (see TC#9.B.135.1.5). Yip domains may be involved in protein trafficking and folding. |
Eukaryota | Fungi | SAM50 - Yip hybrid protein of Histoplasma capsulatum |
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1.B.33.3.12 | The Sorting and Assembly Machinery (SAM) complex consists of three proteins that assemble as a 1:1:1 complex to fold beta-barrel proteins and insert them into the mitochondrial outer membrane. Diederichs et al. 2020 reported cryoEM structures of the SAM complex from Myceliophthora thermophila, which show that Sam50 forms a 16-stranded transmembrane beta-barrel with a single polypeptide-transport-associated (POTRA) domain extending into the intermembrane space. Sam35 and Sam37 are located on the cytosolic side of the outer membrane, with Sam35 capping Sam50, and Sam37 interacting extensively with Sam35. Sam35 and Sam37 each adopt a GST-like fold, with no functional, structural, or sequence similarity to their bacterial counterparts. Structural analyses showed how the Sam50 beta-barrel opens a lateral gate to accommodate its substrates (Diederichs et al. 2020). |
Eukaryota | Fungi, Ascomycota | SAM complex of Myceliophthora thermophila (Sporotrichum thermophile) |
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1.B.33.3.2 | Sam50 of 475 aas |
Eukaryota | Fungi, Ascomycota | Sam50 of Schizosaccharomyces pombe |
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1.B.33.3.3 | Sam50 of 521 aas |
Eukaryota | Fungi, Ascomycota | Sam50 of Neurospora crassa |
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1.B.33.3.4 | Sam50 (SAMM50, CGI-51, TRG3) of 469 aas. Höhr et al. 2018 mapped the interaction of a precursor in transit with the mitochondrial Omp85-channel, Sam50, in the native membrane environment. The precursor translocates into the channel interior, interacts with an internal loop, and inserts into the lateral gate by β-signal exchange. Transport through the Omp85-channel interior followed by release through the lateral gate into the lipid phase represents a basic mechanism for membrane insertion of β-barrel proteins (Höhr et al. 2018). PNPLA3, TM6SF2 (TC# 8.A.93.2.1) and SAMM50 are associated with the development and severity of pediatric non-alcoholic fatty liver disease (NAFLD) (Lee et al. 2022). |
Eukaryota | Metazoa, Chordata | Sam50 of Homo sapiens |
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1.B.33.3.5 | Sam50 of 443 aas |
Eukaryota | Metazoa, Arthropoda | Sam 50 of Drosophila melanogaster |
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1.B.33.3.6 | Sam50 of 453 aas |
Eukaryota | Rhodophyta | Sam50 of Galdieria sulphuraria |
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1.B.33.3.7 | Sam50-like protein, Gop-3 of 434 aas |
Eukaryota | Metazoa, Nematoda | Gop-3 of Caenorhabditis elegans |
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1.B.33.3.8 | Sam50 of 521 aas |
Eukaryota | Viridiplantae, Chlorophyta | Sam50 of Ostreococcus tauri |
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1.B.33.3.9 | Sam50 of 672 aas |
Eukaryota | Bacillariophyta | Sam50 of Thalassiosira pseudonana (Marine diatom) (Cyclotella nana) |
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1.B.33.4.1 | Omp85 homologue of 527 aas |
Bacteria | Spirochaetota | Omp85 of Leptospira interrogans |
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1.B.33.4.2 | Omp85 homologue of 446 aas |
Bacteria | Nitrospirota | Omp85 of Leptospirillum ferriphilum |
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1.B.33.4.3 | BamA/TamA family outer membrane protein of 862 aas and 2 probable TMSs, one N-terminal and one C-terminal. |
Bacteria | Bacteroidota | BamA of Pontibacter akesuensis |
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1.B.33.4.4 | Uncharacterized surface antigen-like protein of 471 aas |
Bacteria | Bacteroidota | UP of Coprobacter fastidiosus |
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1.B.33.4.5 | Uncharacterized protein of 438 aas and 1 N-terminal TMS |
Bacteria | Elusimicrobiota | UP of Elusimicrobia bacterium |
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1.B.33.4.6 | Uncharacterized protein of 1213 aas and one N-terminal TMS and 3 possible C-terminal TMSs. |
Bacteria | Bacteroidota | UP of Chitinophaga cymbidii |
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1.B.33.4.7 | Uncharacterized protein of 733 aas and two TMSs, one N-terminal and one central. |
Bacteria | Ignavibacteriota | UP of Ignavibacteria bacterium |
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1.B.33.4.8 | BamA/TamA family outer membrane protein of 395 aas. Corresponds to the C-terminal domain of many BamA homologues and may be a fragment. |
Bacteria | Verrucomicrobiota | BamA of Rubritalea marina |
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1.B.33.4.9 | Uncharacterized protein of 895 aas and 1 N-terminal TMS. |
Bacteria | Ignavibacteriota | UP of Ignavibacteriae bacterium (groundwater metagenome) |
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1.B.34.1.1 | Outer membrane porin with a single transmembrane α-helical TMS, PorA (Lichtinger et al. 2001; Costa-Riu et al. 2003; Costa-Riu et al. 2003). |
Bacteria | Actinomycetota | PorA of Corynebacterium glutamicum (Q9X711) |
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1.B.34.1.2 |
PorA homologue |
Bacteria | Actinomycetota | PorA of Corynebacterium efficiens (C8NJV5) |
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1.B.34.1.3 | Putative porin of 41 aas |
Bacteria | Actinomycetota | PP of Corynebacterium casei |
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1.B.34.1.4 | Putative porin |
Bacteria | Actinomycetota | PP of Corynebacterium matruchotii |
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1.B.34.1.5 | Uncharacterized porin of 45 aas. |
Bacteria | Actinomycetota | UP of Corynebacterium mustelae |
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1.B.34.1.6 | Putative porin of 68 aas and possibly 2 TMSs, one N-terminal and one C-terminal. |
Bacteria | Actinomycetota | PP of Corynebacterium pollutisoli |
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1.B.34.1.7 | Uncharacterized porin of 68 aas |
Bacteria | Actinomycetota | UP of Corynebacterium testudinoris |
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1.B.34.1.8 | Uncharacterized porin of 43 aas |
Bacteria | Actinomycetota | UP of Corynebacterium cystitidis |
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1.B.34.1.9 | Uncharacterized porin of 43 aas |
Bacteria | Actinomycetota | UP of Corynebacterium choanis |
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1.B.34.2.1 | Outer membrane porin, PorA (Schiffler et al. 2007). |
Bacteria | Actinomycetota | PorA of Corynebacterium diphtheriae (A5PGX0) |
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1.B.34.2.2 | PorA homologue |
Bacteria | Actinomycetota | PorA of Corynebacterium ulcerans (G0CNV6) |
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1.B.34.2.3 | Uncharacterized porin of 46 aas and 1 TMS |
Bacteria | Actinomycetota | UP of Corynebacterium diphtheriae |
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1.B.34.3.1 | Homooligomeric anion-selective outer envelope porin of 40 aas with a channel diameter of 1.4 nm, PorA (Abdali et al. 2013). Positively charged residues in the channel lumen formed by the oligomeric α-helical wheels account for its anionic selectivity. Based on the sequence of PorA, a large functional transmembrane 40 aa peptide porin, built entirely from short synthetic α-helical peptides, has been construced (Krishnan R et al. 2019). |
Bacteria | Actinomycetota | PorA of Corynebacterium jeikeium |
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1.B.34.3.2 | Uncharacterized porin with 73 aas and one TMS. |
Bacteria | Actinomycetota | UP of Corynebacterium nuruki |
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1.B.34.3.3 | Uncharacterized α-helical porin of 97 aas and 1 TMS. |
Bacteria | Actinomycetota | UP of Corynebacterium resistens |
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1.B.34.3.4 | Uncharacterized porin of 43 aas and 1 α-helical TMS |
Bacteria | Actinomycetota | UP of Corynebacterium jeikeium |
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1.B.34.3.5 | Uncharacterized porin of 41 aas and one α-helical TMS. |
Bacteria | Actinomycetota | Porin of Corynebacterium jeikeium |
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1.B.34.4.1 | Uncharacterized protein of 59 aas and one putative C-terminal TMS. |
Bacteria | Actinomycetota | UP of Corynebacterium sp. BCW_4722 |
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1.B.34.4.2 | Uncharacterized porin of 55 aas and 1 C-terminal TMS |
Bacteria | Actinomycetota | UP of Corynebacterium coyleae |
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1.B.34.4.3 | Uncharacterized porin of 48 aas and 1 C-terminal TMS |
Bacteria | Actinomycetota | UP of Corynebacterium afermentans |
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1.B.35.1.1 | The oligogalacturonate-specific porin, KdgM. The 3-D structure is known at 1.9 Å resolution (Hutter et al. 2014). KdgM folds into a 12-stranded antiparallel beta-barrel with a circular cross-section defining a transmembrane pore with a minimal radius of 3.1 Å. Most loops that face the cell exterior in vivo are disordered but nevertheless mediate contact between densely packed membrane-like layers in the crystal. The channel is lined by two tracks of arginine residues facing each other across the pore, a feature that is conserved within the KdgM family and is likely to facilitate the diffusion of acidic oligosaccharides (Hutter et al. 2014). |
Bacteria | Pseudomonadota | KdgM of Erwinia chrysanthemi (Dickeya dadantii) |
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1.B.35.1.2 | The second oligogalacturonate-specific Gram negative porin, KdgN (60% identical to KdgM; 1.B.35.1.1) (Condemine and Ghazi, 2007). |
Bacteria | Pseudomonadota | KdgN of Dickeya dadantii (Erwinia carotovora) (Q6D4T8) |
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1.B.35.1.3 | Alginate-oligosaccharide-specific porin, KdgM (Wargacki et al., 2012). |
Bacteria | Pseudomonadota | KdgM of Vibrio speldidus (A3UR43) |
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1.B.35.1.4 | Alginate-oligosaccharide-specific porin, KdgN (Wargacki et al., 2012) |
Bacteria | Pseudomonadota | KdgN of Vibrio splendidus (A3UR51) |
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1.B.35.1.5 | KdgM homologue of 227 aas |
Bacteria | Pseudomonadota | KdgM homologue of Enterobacter cloacae |
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1.B.35.1.6 | Putative KdgM porin of 224 aas |
Bacteria | Pseudomonadota | KdgM porin of Serratia marcescens |
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1.B.35.1.7 | OmpK26 porin (YjhA) of 231 aas; associated with carbapenem resistance (García-Sureda et al. 2011). |
Bacteria | Pseudomonadota | OmpK26 of Klebsiella pneumoniae |
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1.B.35.2.1 | The N-acetylneuraminic acid-inducible, anion selective porin, NanC (Condemine et al., 2005). A crystal structure (3.3 Å resolution) is available (2WJQ; Wirth et al., 2009). It forms a 28 Å high 12 stranded β barrel like the autotransporter, NalP. The pore is lined by basic residues (conserved in other KdgM family members) allowing diffusion of acidic oligosaccharides (Wirth et al., 2009). Single channels of NanC at pH 7.0 have: (1) conductance 100 to 800 pS in 100 mM: KCl to 3 M: KCl), (2) anion over cation selectivity, and (3) two forms of voltage-dependent gating (channel closures above 200 mV). Phosphate interferes with channel conductance (Giri et al. 2012). |
Bacteria | Pseudomonadota | NanC (YjhA) of E. coli (P69856) |
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1.B.35.2.2 | OmpL porin. Nearly identical to Salmonella typhimurium YshA which appears to be a 10 β-stranded transmembrane β-barrel which forms a pore with a radius of 0.7nm (Freeman et al., 2011). May be an oligogalacturonate-specific porin (Shevchik and Hugouvieux-Cotte-Pattat, 2003). |
Bacteria | Pseudomonadota | OmpL of E. coli |
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1.B.35.2.3 | Putative porin of 233 aas |
Bacteria | Bacteroidota | Putative porin of Owenweeksia hongkongensis |
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1.B.35.2.4 | Uncharacterized protein of 218 aas. |
Bacteria | candidate division Zixibacteria | UP of Zixibacteria bacterium SM1_73 |
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1.B.35.3.1 | Putative porin of 230 aas |
Bacteria | Pseudomonadota | Putative porin of Vibrio parahaemolyticus |
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1.B.35.3.2 | Putative porin of 236 aas |
Bacteria | Pseudomonadota | Putative porin of Psychromonas sp. |
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1.B.35.4.1 | Putative porin of 263 aas |
Bacteria | Pseudomonadota | Putative porin of Photobacterium profundum |
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1.B.35.4.2 | Putative porin of 282 aas |
Bacteria | Pseudomonadota | Putative porin of Photobacterium profundum |
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1.B.35.4.3 | Putative porin of 267 aas |
Bacteria | Pseudomonadota | Porin of Vibrio orientalis |
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1.B.36.1.1 | The p13 porin (Ostberg et al. 2002). P13 displays a general (non-specific) channel-forming activity of 0.6 nanosiemens in 1 m KCl, has no preference for either cations or anions and shows no voltage-gating up to ±100 mV. The native P13 protein complex has a high molecular mass of about 300 kDa and is composed only of P13 monomers. The channel diameter was estimated to be about 1.4 nm with a 400-Da molecular mass cut-off (Bárcena-Uribarri et al. 2014). |
Bacteria | Spirochaetota | p13 porin of Borrelia burgdorferi |
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1.B.36.1.2 | The BBA01 protein | Bacteria | Spirochaetota | BBA01 porin of Borrelia burgdorferi (O50896) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.36.1.3 | P13 homologue |
Bacteria | Spirochaetota | P13 homologue of Sphaerochaeta globosa |
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1.B.37.1.1 | The OmpL1 porin | Bacteria | Spirochaetota | OmpL1 of Leptospira kirschneri | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.37.1.2 | OmpL1 |
Bacteria | Spirochaetota | OmopL1 of Leptonema illini |
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1.B.37.2.1 | δ-proteobacterial OmpL1 homologue |
Bacteria | Myxococcota | Homologue of OmpL1 in Haliangium ochraceum (D0LRV8) |
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1.B.38.1.1 | Large non-selective MSP porin of 574 aas, with short lived large ion conduction (Mathers et al. 1996). Contains MOSP_N and MOSP_C domains which exists as periplasmic hydrophilic monomers and trimeric porins, respectively. MOSP_C, destined for the OM, follows the canonical BAM pathway, but formation of a stable periplasmic conformer of MOSP_N involves an export-related, folding pathway not present in E. coli (Puthenveetil et al. 2017). |
Bacteria | Spirochaetota | Msp of Treponema denticola |
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1.B.38.1.10 | SusD protein of 570 aas and 1 N-terminal TMS (Joglekar et al. 2018). |
Bacteria | Bacteroidota | SusD of Bacteroides thetaiotaomicron |
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1.B.38.1.2 |
Treponema repeat protein K (TprK), an outer membrane surface exposed variable antigen which plays a role in immune evasion and persistence (Giacani et al. 2012; Reid et al. 2014). |
Bacteria | Spirochaetota | TprK of Treponema pallidum |
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1.B.38.1.3 |
Repeat protein, TprEb |
Bacteria | Spirochaetota |
Repeat protein, TprEb |
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1.B.38.1.4 | Major outer membrane sheath protein, Msp or MOSP, of 543 aas. Msp has a bipartide structure and exists as periplasmic and outer membrane-integrated trimeric conformers (Anand et al. 2013). The N-terminal domain (residues 77 - 286) does not insert into the membrane, but the C-terminal domain (residues 332 - 543) does to form pores (Anand et al. 2013). It resembles the surface exposed variable antigen, TprK (Giacani et al. 2012) which plays roles in immune evasion and persistence. MOSP is one of its principal cell surface virulence determinants. Bioinformatics predicts that MOSP consists of N- and C-terminal domains, MOSPN and MOSPC. Biophysical analysis of constructs refolded in vitro demonstrated that MOSPC, which has porin activity, forms amphiphilic trimers, while MOSPN forms an extended hydrophilic monomer (Puthenveetil et al. 2017). It is also a constituent of the outer membrane lipoprotein-protease complex of the Dentilisin Family (see TC# 9.B.355.1.1). Msp has been characterized by deletion analysis and advanced molecular modeling (Goetting-Minesky et al. 2022). It is a large-diameter, trimeric outer membrane porin-like protein. |
Bacteria | Spirochaetota | Major outer sheath protein, Msp, of Treponema denticola |
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1.B.38.1.5 | Outer membrane bipartite trimeric porin of 598 aas with an N-terminal MOSPN domain (in the periplasm), and a C-terminal MOSPC domain (cell surface localized), TprC/TprD. The MOSPN domain confers envelope integrity by anchoring the C-terminal porin domain to periplasmic structural constituents (Anand et al. 2015). Selection pressures exerted within human populations drive T. pallidum subsp. pallidum TrpC diversity by mutation of loop regions and by recombination(Kumar et al. 2018). |
Bacteria | Spirochaetota | TprC of Treponema pallidum |
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1.B.38.1.6 | Outer membrane trimeric porin, TprI of 598 aas with a structure similar to that of TprC (TC# 1.B.38.1.5) (Anand et al. 2015). |
Bacteria | Spirochaetota | TprI of Treponema pallidum |
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1.B.38.1.7 | SusD of 502 aas and 1 N-terminal TMS. |
Bacteria | Bacteroidota | SusD of Bacteroides fragilis |
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1.B.38.1.8 | Uncharacterized major outer membrane protein of 511 aas and 1 N-terminal TMS. |
Bacteria | Spirochaetota | UP of Treponema vincentii |
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1.B.38.1.9 | Outer membrane pore-forming TprA protein of 607 aas. This protein is 91% identical to the TprA protein of T. pallidum. |
Bacteria | Spirochaetota | TprA of Treponema paraluiscuniculi |
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1.B.38.2.1 | Putative outer membrane protein of 460 aas. Shows some sequence similarity to autotransporters (1.B.40) |
Bacteria | Spirochaetota | OMP of Spirochaeta thermophila |
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1.B.38.2.2 | Putative outer membrane protein of 446 aas. Shows some sequence similiarity to autotransporters (1.B.40) |
Bacteria | Spirochaetota | OMP of Spirochaeta thermophila |
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1.B.38.2.3 | Uncharacterized porin of 389 aas and 1 N-terminal TMS. |
Bacteria | Spirochaetota | UP of Spirochaetae bacterium |
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1.B.38.2.4 | Uncharacterized protein of 469 aas. |
Bacteria | Spirochaetota | UP of Spirochaeta perfilievii |
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1.B.38.3.1 | Putative sheath protein of 520 aas with 14 putative β-TMSs at the N-terminus and a fairly long C-terminal extension. |
Bacteria | Spirochaetota | Putative sheath protein of Treponema brennaborense |
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1.B.38.3.2 | Putative outer membrane protein of 575 aas and 24 putative β-TMSs, MspA |
Bacteria | Spirochaetota | MspA of Treponema maltophilum |
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1.B.38.3.3 | Putative outer membrane protein of 590 aas and 22 putative β-TMSs. |
Bacteria | Spirochaetota | OMP of Treponema lecithinolyticum |
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1.B.38.4.1 | Outer membrane maltooligosaccharide uptake protein, SusE, of 387 aas and 1 N-terminal TMS. It forms a complex with the SusC porin (TC# 1.B.14.6.1), the SusD porin (TC# 1.B.38.1.10), the SusF porin (TC# 1.B.38.4.2) and SusG (α-amylase; TC# 8.A.9.1.3) in the outer membrane (Foley et al. 2018). The complex binds starch and maltooligosaccharides (Cho and Salyers 2001). |
Bacteria | Bacteroidota | OMP of Bacteroides thetaiotaomicron |
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1.B.38.4.2 | Outer membrane protein, SusF, of 485 aas and 1 N-terminal TMS. The protein has an N-terminal DUF5115 domain followed by two C-terminal CBM-SusEF-like domains. SusF mediates starch-binding (or maltooligosaccharde-binding) before transport into the periplasm for further degradation. SusE and SusF do not constitute the major starch-binding proteins in the starch degradative pathway. SusF has lower affinity for starch compared to SusE (Shipman et al. 2000). The 3-d structure of the complex has been determined (Cameron et al. 2012). The SusCDEFG complex in the outer membrane is described in more detail in TC# 1.B.38.4.1 (Foley et al. 2018). |
Bacteria | Bacteroidota | OMP, SusF, of Bacteroides thetaiotaomicron |
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1.B.38.4.3 | SusE/F homologue of 347 aas and 1 N-terminal TMS. |
Bacteria | Bacteroidota | AusE of Pontibacter lucknowensis |
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1.B.38.4.4 | Uncharacterized DUF5115 domain-containing protein of 477 aas and 1 N-terminal TMS. |
Bacteria | Bacteroidota | UP of Chryseobacterium chaponense |
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1.B.38.4.5 | Uncharacterized SusD homologue of 531 aas and 1 N-terminal TMS. |
Bacteria | Bacteroidota | SusD homologue of Phaeodactylibacter xiamenensis |
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1.B.39.1.1 | Outer membrane porin, OmpW. Involved in paraquot efflux (Gil et al. 2007). OmpW also participates in the efflux of EmrE-specific substrates across the OM (Beketskaia et al. 2014). The 3-d structure is available (PDB#2F1C). |
Bacteria | Pseudomonadota | OmpW of Salmonella typhimurium |
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1.B.39.1.2 | OCT plasmid-encoded AlkL outer membrane cation-selective porin, (probably transports alkanes) (van Beilen et al., 1992). Has been used for the uptake of dodecanoic acid methyl ester (DAME) in E. coli for the production of 12-aminododecanoic acid methyl ester (ADAME), a building block for the high-performance polymer Nylon 12 (Ladkau et al. 2016). |
Bacteria | Pseudomonadota | AlkL of Pseudomonas oleovorans (Q00595) |
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1.B.39.1.3 | The anaerobically induced outer membrance porin, OprG. Transports small neutral amino acids (Kucharska et al. 2015). The 3-d structure is available (Touw et al. 2010). Essential for normal biofilm formation (Ritter et al. 2012). It is an eight-stranded β-barrel monomer that is too narrow to accommodate even the smallest transported amino acid, glycine, raising the question of how OprG facilitates amino acid uptake (Sanganna Gari et al. 2018). Pro-92 of OprG is important for amino acid transport, with a P92A substitution inhibiting transport and the NMR structure of this variant revealing that this substitution produces structural changes in the barrel rim and restricts loop motions. OprG assembles into oligomers in the OM whose subunit interfaces could form a transport channel, and conformational changes in the barrel-loop region may be crucial for its activity (Sanganna Gari et al. 2018). |
Bacteria | Pseudomonadota | OprG of Pseudomonas aeruginosa (Q9HWW1) |
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1.B.39.1.4 | The Naphthalene polycyclic aromatic hydrocarbon porin, OmpW (Neher and Lueking, 2009). | Bacteria | Pseudomonadota | OmpW of Pseudomonas fluorescens (Q3K638) |
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1.B.39.1.5 | Porin of 230 aas; encoded within the NifA-RpoN regulon and required for normal symbiosis. (Sullivan et al. 2013). |
Bacteria | Pseudomonadota | Porin of Mesorhizobium loti |
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1.B.39.1.6 | Outer membrane porin, OmpW, of 212 aas. Mediates transport of quaternary cationic ammonium compounds (Beketskaia et al. 2014). It is involved in anaerobic carbon and energy metabolism, mediating the transition from aerobic to anaerobic lifestyles (Xiao et al. 2016). |
Bacteria | Pseudomonadota | OmpW of E. coli |
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1.B.39.1.7 | Outer membrane porin selective for cations, OmpW of 226 aas (Benz et al. 2015). |
Bacteria | Pseudomonadota | OmpW of Caulobacter crescentus |
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1.B.39.1.8 | Outer membrane porin of 214 aas, OmpW, selective for cations (Benz et al. 2015). |
Bacteria | Pseudomonadota | OmpW of Caulobacter crescentus |
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1.B.39.1.9 | OmpW of 216 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | OmpW of Shewanella decolorationis |
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1.B.39.2.1 | Putative outer membrane porin of 224 aas |
Bacteria | Thermodesulfobacteriota | OMP of Geobacter uraniireducens (Geobacter uraniumreducens) |
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1.B.39.2.2 | Uncharacterized protein of 200 aas |
Bacteria | Thermodesulfobacteriota | UP of Geobacter daltonii |
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1.B.4.1.1 | Fusion porin protein of 1115 aas with two domains that are homologous to members of family 1.B.4 at the N- and C-termini of this protein and a central domain homologous to members of family 1.B.13 proteins. These fusion proteins are found in several closely related species of α-proteobacteria such as those in the genuses, Methylosinus and Methylocystis (BL Reddy and MH Saier, unpublished observations). |
Bacteria | Pseudomonadota | Fusion porin protein of Methylosinus trichosporium |
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1.B.4.1.2 | Fusion porin protein of 840 aas with an N-terminal domain that is homologous to members of family 1.B.13, and a C-terminal domain that is homologous to members of family 1.B.4 proteins. It is 60% identical to the last two domains in 1.B.4.2.15 but it lacks the N-terminal domain of that protein. |
Bacteria | Pseudomonadota | Fusion protein of Methylosinus trichosporium |
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1.B.4.2.10 | Hypothetical protein of 259 aas |
Bacteria | Pseudomonadota | HP of Coxiella burnetii |
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1.B.4.2.11 | Putative porin of 200 aas |
Bacteria | Pseudomonadota | PP of Octadecabacter antarcticus |
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1.B.4.2.12 | Putative porin of 233 aas |
Bacteria | Pseudomonadota | PP of Azorhizobium caulinodans |
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1.B.4.2.13 | Porin of 240 aas |
Bacteria | Pseudomonadota | Porin of Brucella canis |
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1.B.4.2.14 | Putative porin of 199 aas |
Bacteria | Pseudomonadota | PP of Octadecabacter antarcticus |
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1.B.4.2.15 | Outer membrane immunogenic protein, Omp31 | Bacteria | Pseudomonadota | Omp31 of Brucella melitensis (Q45322) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.4.2.16 | High affinity Mn2+ (but not Co2+ or Cu2+) porin, MnoP (675 aas) (Hohle et al., 2011). This protein seems to be a fusion protein between an Omp_b-br1 family porin (N-terminus) and an OprB porin (C-terminus). It shows little sequence similiarity with the OprB family proteins of 1.B.19. |
Bacteria | Pseudomonadota | MnoP of Bradyrhizobium japonicum (Q89Y60) |
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1.B.4.2.17 | Opacity protein of 188 aas |
Bacteria | Pseudomonadota | Opacity protein of Sphingomonas witichii |
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1.B.4.2.18 | Outer membrane porin, Omp25c, of 228 aas. The collective Th1 plus Th2 immune responses induced by Omp25c protects against Brucella infections (Paul et al. 2018). |
Bacteria | Pseudomonadota | Omp25c of Brucella abortus
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1.B.4.2.19 | RopB of 211 aas and 1 N-terminal TMS. RopA (TC# 1.B.70.1.2) and RopB, which have β-barrel structures, may be involved in the control of plant-microbial symbiosis. Kosolapova et al. 2019 demonstrated that the full-length RopA and RopB proteins form amyloid fibrils in vitro. These fibrils are β-sheet-rich, bind Thioflavin T (ThT), exhibit green birefringence upon staining with Congo Red (CR), and resist treatment with ionic detergents and proteases. Heterologously expressed RopA and RopB intracellularly aggregate in yeast and assemble into amyloid fibrils at the surface of E. coli. The capsules of the R. leguminosarum cells bind CR, exhibit green birefringence, and contain fibrils of RopA and RopB in vivo (Kosolapova et al. 2019). |
Bacteria | Pseudomonadota | RopB of Rhizobium leguminosarum |
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1.B.4.2.2 | Uncharacterized porin homologue of 242 aas. Shows similarity with 9.B.184.1.1 which also shows similarity with members of 1.B.6; it is likely to be a porin. |
Bacteria | Pseudomonadota | Putative porin of Bradyrhizobium sp. ORS 285 |
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1.B.4.2.20 | Omp25 porin of 213 aas. Omp25, LPS and peptidoglycan are incorporated at the new pole and the division site, the expected growth sites (Vassen et al. 2019). |
Bacteria | Pseudomonadota | Omp25 of Brucella abortus biovar 1 |
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1.B.4.2.3 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Rhizobium sp. AP16 |
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1.B.4.2.4 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Bradyrhizobium japonicum |
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1.B.4.2.5 | Putative porin of 252 aas |
Bacteria | Proteobacteria | Porin of Bradyrhizobium sp. |
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1.B.4.2.6 | Porin of 252 aas |
Bacteria | Pseudomonadota | Porin of Xanthobacter autotrophicus |
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1.B.4.2.7 | Putative porin of 289 aas |
Bacteria | Pseudomonadota | Putative porin of Methylobacterium extorquens |
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1.B.4.2.8 | Porin of 241 aas |
Bacteria | Pseudomonadota | Porin of Nitrobacter winogradskyi |
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1.B.4.2.9 | Probable carbohydrate-selective outer membrane porin, OprB, of 302 aas (Brunen et al. 1991). |
Bacteria | Pseudomonadota | OMP of Acidovorax delafiedii |
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1.B.40.1.1 | YadA consists of 3 domains: an adhesion head, a stalk involved in serum resistance, and an anchor that forms a pore for auto-transport (Grosskinsky et al., 2007). | Bacteria | Pseudomonadota | YadA of Yersinia enterocolitica (P0C2W0) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.40.1.2 | Membrane anchored cell surface haemagglutinin (4726aas) |
Bacteria | Pseudomonadota | Haemagglutinin of Burkholderia xenovorans (Q13U92) |
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1.B.40.1.3 | The YadB adhesin (364 aas) (Forman et al., 2008) |
Bacteria | Pseudomonadota | YadB of Yersinia pestis (Q7CHJ4) |
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1.B.40.1.4 | The YadC adhesin (622 aas) (Forman et al., 2008) |
Bacteria | Pseudomonadota | YadC of Yersinia pestis (Q7CHJ5) |
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1.B.40.1.5 | The cryptic trimeric Haemophilus adhesin, Cha (Sheets et al., 2008). | Bacteria | Pseudomonadota | Cha of Haemophilus sp. (B3FNS7) |
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1.B.40.1.6 | Aegerolysin domain-containing protein of 314 aas |
Bacteria | Actinomycetota | UP of Streptomyces griseus |
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1.B.40.1.7 | Auto transporter adhesin, BpaC, of 1125 aas. BpaC plays a central role in the initiation of the infectious process (Kiessling et al. 2019). |
Bacteria | Pseudomonadota | BpaC of Burkholderia pseudomallei |
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1.B.40.1.8 | Trimeric autotransporter, HadA, of 256 aas. It is an atypical coliled-coil multifunctional adhesin of Haemophilus influenzae biogroup aegyptius, which promotes entry of the bacteria into host cells (Serruto et al. 2009). |
Bacteria | Pseudomonadota | HadA of Haemophilus influenzae |
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1.B.40.2.1 | The NhhA bacteria adhesin (Scarselli et al., 2006). | Bacteria | Pseudomonadota | NhhA of Neisseria meningitidis |
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1.B.40.2.2 | The extracellular matrix/adhesin autotransporter, EmaA, (collagen-binding adhesin of 1965 aas) (Tang et al., 2007). The extended signal peptide of the trimeric autotransporter EmaA modulates secretion (Jiang et al., 2011). |
Bacteria | Pseudomonadota | EmaA of Aggregatibacter (Actinobacillus) actinomycetemcomitans (Q6VBQ2) |
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1.B.40.2.3 | The trimeric AT adhesin, essential for virulence, UpaG (1674aas) (Valle et al., 2008). The high resolution structure has been solved using the "dictionary" approach (Hartmann et al. 2012). |
Bacteria | Pseudomonadota | UpaG of EPEC E. coli (A8A667) |
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1.B.40.2.4 | Adhesin (Hia) The 3-d structure is available (PDB#2GR7). Mediates bacterial adhesion to the respiratory epithelium. The crystal structure of the C-terminal end of Hia, corresponding to the entire Hia translocator domain and part of the passenger domain (residues 992-1098) shows that this domain forms a beta-barrel with 12 transmembrane beta-strands, including four strands from each subunit. The beta-barrel has a central channel of 1.8 nm in diameter that is traversed by three N-terminal alpha-helices, one from each subunit. Mutagenesis studies demonstrated that the transmembrane portion of the three alpha-helices and the loop region between the alpha-helices and the neighboring beta-strands are essential for stability, and that trimerization of the translocator domain is a prerequisite for translocator activity (Meng et al. 2006). Electrostatic repulsion between the positive charges of Arg1077 is important to prevent the formation of misassembled oligomers by the Hia transmembrane domain in vitro (Aoki et al. 2017). |
Bacteria | Pseudomonadota | Hia Adhesin of Haemophilus influenzae (Q8GM76) |
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1.B.40.2.5 | The trimeric AT adhesin, essential for virulence, SadA (1461 aas). The high resolution structure has been solved using the "dictionary" approach (Hartmann et al. 2012). It's insertion into the outer membrane may be dependent on the BAM complex (TC# 1.B.33) as well as a small inner membrane lipoprotein, SadB (Grin et al. 2013). |
Bacteria | Pseudomonadota | SadA of Salmonella enterica |
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1.B.40.2.6 | Adhesin Aha (Acinetobacter trimeric autotransporter) of 1873 aas. Ata contains all of the typical features of trimeric autotransporters, including a long signal peptide followed by an N-terminal, surface-exposed passenger domain and a C-terminal domain encoding 4 β-strands. Ata plays a role in biofilm formation and binds to various extracellular matrix/basal membrane (ECM/BM) components, including collagen types I, III, IV, and V and laminin (Bentancor et al. 2012). |
Bacteria | Pseudomonadota | Aha of Acinetobacter baumannii |
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1.B.40.2.7 | Carbohydrate-binding autotransporter of 879 aas and 1 N-terminal TMS. |
Bacteria | Bacillota | AT of Streptococcus salivarius |
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1.B.40.2.8 | Outer membrane haemaglutinin autotransporter of 2012 aas |
Bacteria | Bacillota | AT2 of Veillonella parvula |
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1.B.40.3.1 | Putataive cell surface membrane anchored adhesin; haemagglutinin |
Bacteria | Chlamydiota | Adhesin of Parachlamydia acanthamoebae (F8KWP8) |
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1.B.40.3.2 | Hypothetical protein |
Bacteria | Mycoplasmatota | HP of Mycoplasma penetrans (Q8EWJ7) |
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1.B.40.4.1 | Autotransporter of 516 aas, BimA. A polarly localized iron binding protein, BimC, determines the polar targeting as well as polar actin tail formation for motility (Lu et al. 2015). |
Eukaryota | Metazoa, Platyhelminthes | BimA of Burkholderia pseudomallei (Pseudomonas pseudomallei) |
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1.B.41.1.1 | Outer mycolate membrane porin, PorB | Bacteria | Actinomycetota | PorB of Corynebacterium glutamicum (CAD79638) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.41.1.2 | Outer mycolate membrane porin, PorC | Bacteria | Actinomycetota | PorC of Corynebacterium glutamicum (BAB98364) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.41.1.3 | PorB homologue |
Bacteria | Actinomycetota | PortB homologue of Corynebacterium aurimucosum (C3PFA5) |
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1.B.41.1.4 | PorB homologue |
Bacteria | Actinomycetota | PorB homologue of Corynebacterium glucuronolyticum (C0VT35) |
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1.B.41.1.5 | PorB of 157 aas |
Bacteria | Actinomycetota | PorB of Corynebacterium efficiens |
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1.B.41.1.6 | PorB homologue of 140 aas |
Bacteria | Actinomycetota | PorB of Corynebacterium lipophiloflavum |
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1.B.42.1.1 | LPS-export porin (organic solvent tolerance protein, OstA) | Bacteria | Pseudomonadota | OstA of Neisseria meningitidis (NP_273336) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.42.1.10 | OstA homologue of 991 aas |
Bacteria | Spirochaetota | OstA homologue of Leptospira interrogans |
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1.B.42.1.11 | OstA of 975 aas |
Bacteria | Spirochaetota | OstA of Brachyspira hyodysenteriae |
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1.B.42.1.12 | OstA of 537 aas |
Bacteria | Bacillota | OstA of Halobacteroides halobius |
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1.B.42.1.13 | Putative LptF-LptG-LptD (OstA) fusion protein of 1040 aas (may be an artifact due to a sequencing error, and may also be a contaminant, accounting for its occurance in a Firmicute. However, it shows an N-terminal domain resembling ABC membrane proteins (3.A.1.152) and a hydrophilic C-terminal domain resembling members of porin family 1.B.42. NCBI BLAST results show that there are several homologues of the same "fused" protein in several species of Halothermothrix, Halanaerobium and Candidatus Frackibacter. |
Bacteria | Bacillota | OstA of Halothermothrix orenii |
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1.B.42.1.14 | LPS assembly protein, LptD, of 691 aas and possibly two TMSs, N- and C-terminal. |
Bacteria | Acidobacteriota | LptD of Thermoanaerobaculales bacterium (marine sediment metagenome) |
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1.B.42.1.15 | Permease [Mesotoga sp. SC_NapDC of 1443 aas and possibly 8 TMSs, 7 at the N-terminus in a 3 + 4 TMS arrangement plus possibly 1 TMS at the C-terminus. It has the ABC-type membrane protein domain at the N-terminus followed by other hydrophilic domains, possibly involved in LPS transport from the inner membrane to the outermembrane including an LptD domain. |
Bacteria | Thermotogota | Permease of Mesotoga sp. SC_NapDC |
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1.B.42.1.16 | LPS-assembly protein, LptD, of 799 aas and 1 N-terminal TMS. |
Bacteria | Bdellovibrionota | LptD of Bacteriovorax sp. (wastewater metagenome) |
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1.B.42.1.2 |
LPS export porin complex, LptBCFG-A-DE, consists of LptD (Omp; OmpA; 784 aas)-LptE (RlpB; 193 aas; O.M. lipoprotein)-LptA (KdsD; YhbN; OstA small; 185 aas periplasmic chaparone protein)-LptB (KdsC; YhbG; 241 aas cytoplasmic ABC-type ATPase)-LptC (YrbK, 199aas;1 N-terminal TMS)- LptFG, part of the ABC transporter. LptDE (1:1 stoichiometry) comprise a two-protein β-barrel-lipoprotein complex in the outer membrane that assembles and exports LPS (Chng et al., 2010). After LPS (or a precursor) is transported across the inner membrane by MsbA (3.A.1.106.1), this seven component system translocates LPS from the outer surface of the inner membrane to the outer surface of the outer membrane using ATP hydrolysis to sequentially energize transfer from one binding site to another in several steps (Freinkman et al. 2012; Okuda et al. 2012; Sherman et al. 2014). LPS interacts with LptC and LptA sequentially before being passed to the LptD outer membrane porin, anchored by the LptE lipoprotein on the inner surface of the outer membrane. LptF and LptG are the transmembrane consituents of the ABC pump, and LptB is the ATPase of an ABC-like system that energizes the transport using several ATP molecules (Okuda et al. 2012; Sherman et al. 2014). LptC interconnects the LptBFG ABC system with the periplasmic LptA protein via its large periplasmic domain (Villa et al. 2013). LptDE form a complex in the outer membrane which inserts LPS into this membrane. The 3-D strcture of the complex shows that the LptE lipoprotein inserts into the 26 stranded barrel of LptD as a plug. The first two strands of LptD contain prolines and are therefore distorted, possibly creating a portal for lateral diffusion of LPS into the outer leaflet of the outer membrane (Qiao et al. 2014). The 3-d structure of the Pseudomonas aeruginosa LptA, LptH, has been solved at 2:75 Å resolution revealing a β-jellyroll fold similar to that in LptD (Bollati et al. 2015). Direct interaction of LptB and LptC has been demonstrated (Martorana et al. 2016). A specific binding site in the LptB ATPase for the coupling helices of the transmembrane LptFG complex is responsible for coupling ATP hydrolysis by LptB with LptFG function to achieve LPS extraction (Simpson et al. 2016). After biosynthesis, bacterial lipopolysaccharides (LPS) are transiently anchored to the outer leaflet of the inner membrane (IM). The ABC transporter LptB2FG extracts LPSs from the IM and transports them to the outer membrane. Luo et al. 2017 reported the crystal structure of nucleotide-free LptB2FG from P. aeruginosa. It shows that LPS transport proteins LptF and LptG each contain a TM domain (TMD), a periplasmic beta-jellyroll-like domain and a coupling helix that interacts with LptB on the cytoplasmic side. The LptF and LptG TMDs form a large outward-facing V-shaped cavity in the IM. Mutational analyses suggested that LPS may enter the central cavity laterally, via the interface of the TMD domains of LptF and LptG, and is expelled into the beta-jellyroll-like domains upon ATP binding and hydrolysis by LptB. These studies suggest a mechanism for LPS extraction by LptB2FG that is distinct from those of classical ABC transporters that transport substrates across the IM (Luo et al. 2017). Transport involves a stable association between the inner (LptBFG) and outer (LptDE) membrane components, supporting a mechanism in which lipopolysaccharide molecules are pushed one after the other across a protein bridge (LptCA) that connects the inner and outer membranes (Sherman et al. 2018). The ABC transporter, LptB2FG, which tightly associates with LptC, extracts lipopolysaccharide out of the inner membrane.Li et al. 2019 characterized the structures of LptB2FG and LptB2FGC in nucleotide-free and vanadate-trapped states, using single-particle cryo-electron microscopy. These structures resolve the bound lipopolysaccharide, reveal transporter-lipopolysaccharide interactions with side-chain details and uncover how the capture and extrusion of lipopolysaccharide are coupled to conformational rearrangements of LptB2FGC. LptC inserts its TMS between the two transmembrane domains of LptB2FG, which represents a previously unknown regulatory mechanism for ABC transporters. These results suggest a role for LptC in achieving efficient lipopolysaccharide transport, by coordinating the action of LptB2FG in the inner membrane and Lpt protein interactions in the periplasm (Li et al. 2019). cryo-EM structures of LptB2FG alone and complexed with LptC are known, revealing conformational changes between these states. Two functional transmembrane arginine-containing loops interact with bound AMP-PNP which induces an inward rotation and shift of the transmembrane helices of LptFG and LptC to tighten the cavity, with the closure of two lateral gates, to eventually expel LPS into the bridge (Tang et al. 2019). The ABC transporter, LptB2FGC extracts LPS from the inner membrane and places it onto a periplasmic protein bridge. Lundstedt et al. 2020 showed that residue E86 of LptB is essential for coupling the function of this ATPase to that of its membrane partners, LptFG, at the step where ATP binding drives the closure of the LptB dimer and the collapse of the LPS-binding cavity in LptFG that moves LPS to the Lpt periplasmic bridge consisting of LptC, A and D (from inside to out) and then to the outer membrane insertase, LptE. Defects caused by changing residue E86 are suppressed by mutations altering either the LPS structure or TMSs in LptG. These suppressors fix defects in the coupling helix of LptF, but not of LptG. These observations support a transport mechanism in which the ATP-driven movements of LptB and those of the substrate-binding cavity in LptFG are bi-directionally coordinated through the rigid-body coupling, with LptF's coupling helix being important in coordinating cavity collapse with LptB dimerization (Lundstedt et al. 2020). The TMS of LptC participates in LPS extraction by the LptB2 FGC transporter (Wilson and Ruiz 2022). A small molecule, IMB-0042, inhibits the interaction of LPS transporter proteins, LptA and LptC. This give rise to filament morphology, impaired OM integrity, and an accumulation of LPS in the periplasm (Dai et al. 2022). Macrocyclic peptide (MCP) antibiotics have potent antibacterial activity and represent a new class of antibiotics (Zampaloni et al. 2024), and LptB2FGC is target. Pahil et al. 2024 showed that novel antibiotics trap a substrate-bound conformation of the LPS transporter that stalls this machine. The inhibitors accomplish this by recognizing a composite binding site made up of both the Lpt transporter and its LPS substrate. The identity of an unusual mechanism of lipid transport inhibition reveals a druggable conformation of the Lpt transporter and provides the foundation for extending this class of antibiotics to other Gram-negative pathogens (Pahil et al. 2024). Residues within the LptC transmembrane helix are critical for E. coli LptB(2) FG ATPase (Cina et al. 2024). Regulation of the LPS entry gate occurs through the dynamic behavior of the LptC transmembrane helix, while its β-jellyroll domain is anchored in the periplasm, and long-range ATP-dependent allosteric gating of the LptF β-jellyroll domain may ensure efficient and unidirectional transport of LPS across the periplasm (Dajka et al. 2024). The lipopolysaccharide transport (Lpt) complex, consisting of seven proteins (A-G), exports LPS across the cellular envelope. LptB2FG forms an ATP-binding cassette transporter that transfers LPS to LptC. Dajka et al. 2024 observed the conformational heterogeneity of LptB2FG and LptB2FGC in micelles and/or proteoliposomes using pulsed dipolar electron spin resonance spectroscopy. Additionally, they monitored LPS binding and release using laser-induced liquid bead ion desorption mass spectrometry. The β-jellyroll domain of LptF stably interacts with the LptG and LptC β-jellyrolls in both the apo and vanadate-trapped states. ATP binding at the cytoplasmic side is allosterically coupled to the selective opening of the periplasmic LptF β-jellyroll domain. In LptB2FG, ATP binding closes the nucleotide binding domains, causing a collapse of the first lateral gate as observed in structures. However, the second lateral gate, which forms the putative entry site for LPS, exhibits a heterogeneous conformation. LptC binding limits the flexibility of this gate to two conformations, likely representing the helix of LptC as either released from or inserted into the transmembrane domains. These results reveal the regulation of the LPS entry gate through the dynamic behavior of the LptC transmembrane helix, while its β-jellyroll domain is anchored in the periplasm. This, combined with long-range ATP-dependent allosteric gating of the LptF β-jellyroll domain, may ensure efficient and unidirectional transport of LPS across the periplasm (Dajka et al. 2024). This transporter may be part of a nanomachine (Bilsing et al. 2023). New LPS is inserted throughout the cell cylinder and at the division site, but not at the cell poles. A similar pattern was observed previously for PG synthesis and OM protein insertion in E. coli, suggesting that LPS transport to the OM is coordinated with these processes (Dubois et al. 2025). |
Bacteria | Pseudomonadota | LptA-G of E. coli: |
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1.B.42.1.3 | OstA homologue (Bhat et al. 2011). |
Bacteria | Myxococcota | OstA homologue of Myxococcus xanthus |
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1.B.42.1.4 | OstA of 842 aas |
Bacteria | Pseudomonadota | OstA of Rhodopseudomonas palustris |
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1.B.42.1.5 | OstA of 753 aas |
Bacteria | Campylobacterota | OstA of Helicobacter pylori |
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1.B.42.1.6 | OstA 0f 680 aas |
Bacteria | Aquificota | OstA of Hydrogenobaculum sp. |
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1.B.42.1.7 | OstA of 880 aas |
Bacteria | Chlorobiota | OstA of Chlorobium luteolum |
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1.B.42.1.8 | OstA of 894 aas |
Bacteria | Bacteroidota | OstA of Nonlabens dokdonensis |
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1.B.42.1.9 | OstA of 833 aas |
Bacteria | Verrucomicrobiota | OstA of Methylacidiphilum infernorum |
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1.B.42.2.1 | OstA homologue of 1069 aa |
Bacteria | Spirochaetota | OstA of Treponema denticola |
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1.B.43.1.1 | Porin P1 |
Bacteria | Pseudomonadota | Porin P1 of Coxiella burnetii (AAM03442) |
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1.B.43.1.2 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Legionella longbeachae |
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1.B.43.1.3 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Polynucleobacter necessarius |
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1.B.44.1.1 | The putative PorT porin (Sato et al., 2005) | Bacteria | Bacteroidota | PorT of Porphyromonas gingivalis (BAA36600) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.44.1.2 | Putative porin |
Bacteria | Bacteroidota | Putative porin of Prevotella buccae |
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1.B.44.1.3 | Putative porin |
Bacteria | Bacteroidota | Putative porin of Cytophaga hutschinsonii |
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1.B.44.1.4 | Putative porin |
Bacteria | Bacteroidota | Putative porin of Chryseobacterium gleum |
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1.B.44.1.5 | PorT homologue of 276 aas |
Bacteria | Bacteroidota | PorT homologue of Sphingobacterium spiritivorum |
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1.B.44.2.1 | Putative porin |
Bacteria | Bacteroidota | Putative porin on Flavobacterium johnsoniae |
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1.B.44.2.10 | Uncharacterized protein of 212 aas |
Bacteria | Bacteroidota | UP of Marivirga tractuosa (Microscilla tractuosa) (Flexibacter tractuosus) |
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1.B.44.2.11 | Uncharacterized protein of 202 aas |
Bacteria | Bacteroidota | UP of Bacteroides salanitronis |
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1.B.44.2.12 | Uncharacterized protein of 228 aas |
Bacteria | Myxococcota | UP of Haliangium ochraceum |
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1.B.44.2.13 | Uncharacterized protein of 301 aas |
Bacteria | Rhodothermota | UP of Salinibacter ruber |
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1.B.44.2.14 | Uncharacterized protein of 193 aas |
Bacteria | Bdellovibrionota | UP of Bdellovibrio bacteriovorus |
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1.B.44.2.15 | Uncharacterized protein of 243 aas |
Bacteria | Bacteroidota | UP of Porphyromonas gingivalis |
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1.B.44.2.16 | Uncharacterized protein of 211 aas. |
Bacteria | Rhodothermota | UP of Rhodothermus marinus (Rhodothermus obamensis) |
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1.B.44.2.17 | Uncharacterized protein of 218 aas |
Bacteria | Pseudomonadota | UP of Aliivibrio salmonicida (Vibrio salmonicida) |
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1.B.44.2.18 | Putative porin of 224 aas |
Bacteria | Bacteroidota | UP of Spirosoma linguale |
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1.B.44.2.2 | Putative porin of 229 aas and 10 putative beta strands. |
Bacteria | Bacteroidota | PP of Riemerella anatipestifer |
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1.B.44.2.3 | Uncharacterized protein of 207 aas |
Bacteria | Bacteroidota | UP of Nonlabens dokdonensis (Donghaeana dokdonensis) |
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1.B.44.2.4 | Uncharacterized protein of 256 aas |
Bacteria | Fibrobacterota | UP of Fibrobacter succinogenes |
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1.B.44.2.5 | Uncharacterized protein of 210 aas |
Bacteria | Bacteroidota | UP of Paludibacter propionicigenes |
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1.B.44.2.6 | Uncharacterized protein of 194 aas |
Bacteria | Bacteroidota | UP of Belliella baltica |
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1.B.44.2.7 | Uncharacterized protein of 194 aas |
Bacteria | Bacteroidota | UP of Leadbetterella byssophila |
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1.B.44.2.8 | Uncharacterized protein of 227 aas |
Bacteria | Bacteroidota | UP of Haliscomenobacter hydrossis |
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1.B.44.2.9 | Uncharacterized protein of 218 aas |
Bacteria | Bacteroidota | UP of Alistipes finegoldii |
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1.B.45.1.1 | Treponema porin, TP0453 of 287 aas. May be involved in ligand transport, altering membrane permeability at acidic pH (4.0 to 5.5) (Luthra et al. 2011). Incubation of the non-lipidated form with lipid vesicles increases their permeability (Hazlett et al. 2005). |
Bacteria | Spirochaetota | TP0453 of Treponema pallidum |
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1.B.45.1.2 | Putative porin |
Bacteria | Spirochaetota | Putative porin of Treponema vincentii |
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1.B.45.1.3 | Porin of 312 aas |
Bacteria | Spirochaetota | Porin of Treponema succinifaciens |
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1.B.45.2.1 | Putative porin |
Bacteria | Spirochaetota | Putative porin of Spirchaeta caldaria |
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1.B.45.2.2 | Putative porin |
Bacteria | Spirochaetota | Putative porin of Treponema brennoborense |
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1.B.45.3.1 | Putative porin |
Bacteria | Spirochaetota | Putative porin of Borrelia afzelii |
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1.B.46.1.1 | The lipoprotein insertase, LolAB, of Gram-negative bacteria. Genetic analysis revealed a robust and hierarchical recruitment of the LolA chaperone protein to the LolCDE lipoprotein transporter (Lehman et al. 2024). |
Bacteria | Pseudomonadota | LolAB of E. coli |
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1.B.46.1.2 | Outer membrane lipoprotein carrier, LolAB |
Bacteria | Pseudomonadota | LolAB of Shewanella baltica |
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1.B.46.1.3 | Outer membrane lipoprotein carrier, LolAB |
Bacteria | Pseudomonadota | LolAB of Ralstonia Solanacearum |
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1.B.46.1.4 | Outer membrane lipoprotein carrier, LolAB |
Bacteria | Pseudomonadota | LolAB of Neisseria meningitidis |
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1.B.46.1.5 | LolB of 213 aas |
Bacteria | Pseudomonadota | LolB of Pseudoxanthomonas spadix |
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1.B.46.1.6 | LolA of 216 aas and 1 TMS |
Bacteria | Bdellovibrionota | LolA of Bdellovibrio bacteriovorus |
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1.B.47.1.1 | Chloroplast outer envelope protein 37, Oep37 |
Eukaryota | Viridiplantae, Streptophyta | Oep37 of Pisum sativum (CAB50915) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.47.1.2 | Chloroplast outer envelope protein 37, Oep37 (Goetze et al. 2006; Ulrich et al. 2012). |
Eukaryota | Viridiplantae, Streptophyta | Oep37 of Arabidopsis thaliana |
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1.B.47.1.3 | Chloroplast outer envelope protein 37, Oep37 |
Eukaryota | Viridiplantae, Streptophyta | Oep37 of Hordeum vulgare (barley) |
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1.B.48.1.1 | The 36 β-stranded outer membrane porin, CsgG with auxiliary subunits, CsgE and CsgF (Goyal et al. 2014). Curli are functional amyloid fibres that constitute the major protein component of the extracellular matrix in pellicle biofilms formed by Bacteroidetes and Proteobacteria (predominantly of the α and γ classes). They provide a fitness advantage in pathogenic strains and induce a strong pro-inflammatory response during bacteraemia. Curli formation requires a dedicated protein secretion machinery comprising the outer membrane lipoprotein CsgG and two soluble accessory proteins, CsgE and CsgF. Curli formation requires a dedicated protein secretion machinery comprising the outer membrane lipoprotein CsgG and two soluble accessory proteins, CsgE and CsgF. Goyal et al. 2014 reported the X-ray structure of Escherichia coli CsgG in a non-lipidated, soluble form as well as in its native membrane-extracted conformation. CsgG forms an oligomeric transport complex composed of nine anticodon-binding-domain-like units that give rise to a 36-stranded β-barrel that traverses the bilayer and is connected to a cage-like vestibule in the periplasm. The transmembrane and periplasmic domains are separated by a 0.9-nm channel constriction composed of three stacked concentric phenylalanine, asparagine and tyrosine rings that may guide the extended polypeptide substrate through the secretion pore. The specificity factor CsgE forms a nonameric adaptor that binds and closes off the periplasmic face of the secretion channel, creating a 24,000 Å pre-constriction chamber. The structural, functional and electrophysiological analyses imply that CsgG is an ungated, non-selective protein secretion channel that is expected to employ a diffusion-based, entropy-driven transport mechanism (Goyal et al. 2014). SuFEx chemistry for cross-linking enables covalent assembly of a 280-kDa 18-subunit pore-forming complex used for DNA sequencing (Schnaider et al. 2024). |
Bacteria | Pseudomonadota | CsgEFG of E. coli |
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1.B.48.1.10 | Uncharacterized protein of 248 aas |
Bacteria | Spirochaetota | UP of Leptospira biflexa |
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1.B.48.1.11 | Putative porin of 333 aas and 1 N-terminal TMS |
Bacteria | Bdellovibrionota | PP of Bdellovibrio exovorus |
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1.B.48.1.2 | Curli assembly/transport compenent, CsgG. (TolB-N Superfamily of CDD) |
Bacteria | Chlorobiota | CsgG of Chlorobium phaeobacteroides |
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1.B.48.1.3 | CsgG homologue |
Bacteria | Cyanobacteriota | CsgG homologue of Synechococcus sp. JA-2-3B'a(2-13) |
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1.B.48.1.4 | CsgG homologue |
Bacteria | Deinococcota | CsgG homologue of Thermus thermophilus |
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1.B.48.1.5 | CsgG homologue of 272 aas |
Bacteria | Pseudomonadota | CsgG homologue of Glaciecola nitratireducens |
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1.B.48.1.6 | CsgG homologue of 347 aas |
Bacteria | Bacillota | CsgG homologue of Halobacteroides halobius |
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1.B.48.1.7 | Putative lipoprotein of 187 aas |
Bacteria | Spirochaetota | Putative lipoprotein of Leptospira interrogans |
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1.B.48.1.8 | Uncharacterized protein of 303 aas |
Bacteria | Thermodesulfobacteriota | UP of Desulfarculus baarsii |
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1.B.48.1.9 | CsgG homologue of 485 aas |
Bacteria | Spirochaetota | CsgG homologue of Leptospira interrogans |
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1.B.48.2.1 | Putative porin of 394 aas |
Bacteria | Thermotogota | Porin of Thermosipho melanesiensis |
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1.B.48.2.2 | Putative curli porin, CgsG of 489 aas |
Bacteria | Spirochaetota | CgsG of Brachyspira pilosicoli |
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1.B.48.2.3 | CsgG homologue of 412 aas |
Bacteria | Thermotogota | CsgG homologue of Marinitoga piezophila |
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1.B.48.2.4 | CsgG homologue of 399 aas |
Bacteria | Aquificota | CsgG homologue of Persephonella marina |
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1.B.48.2.5 | Uncharacterized protein of 275 aas |
Bacteria | Bacteroidota | UP of Bacteroides xylanisolvens |
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1.B.48.2.6 | Uncharacterized protein of 588 aas |
Bacteria | Thermotogota | UP of Thermosipho melanesiensis |
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1.B.48.3.1 | Protein with N-terminal CsgG domain and two central PEGA domains (similar to beta-barrel S-layer domains of 464 aas. |
Bacteria | Spirochaetota | CsgG/PEGA protein of Spirochaeta thermophila |
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1.B.48.3.2 | Protein with N-terminal CsgG domain, central PEGA domain and C-terminal autotransporter domain of 422 aas. The PEGA domain (residues 160 - 220) is found in the OMR Ferripyochelin receptor, FptA (1.B.14.1.8), repeated at least 3 times every ~36 aas. |
Bacteria | Spirochaetota | Uncharacterized protein of Turneriella parva (Leptospira parva) |
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1.B.48.3.3 | Putative adenylate cyclase of 478 aas with N-terminal CsgG domain. |
Bacteria | Myxococcota | Uncharacterized protein of Myxococcus stipitatus |
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1.B.48.3.4 | S-layer-like β-barrel domain protein of 527aas and 2 N- and C-terminal TMSs. |
Bacteria | Spirochaetota | S-layer-like protein of Leptospira interrogans (Q8F8C2) |
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1.B.48.4.1 | CsgG homologue of 397 aas |
Bacteria | Aquificota | CsgG homologue of Thermovibrio ammonificans |
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1.B.48.4.2 | Uncharacterized protein of 430 aas |
Bacteria | Pseudomonadota | UP of Alcanivorax borkumensis |
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1.B.48.5.1 | Uncharacterized protein, YcfM of 196 aas |
Bacteria | Pseudomonadota | YcfM of Vibrio parahaemolyticus |
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1.B.48.6.1 | Uncharacterized protein of 448 aas |
Bacteria | Spirochaetota | UP of Treponema denticola |
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1.B.49.1.1 | The major porin, P44 (transports sugars, oligosaccharide, amino acids, etc.) (Huang et al., 2007) | Bacteria | Pseudomonadota | P44 of Anaplasma phagocytophilum (Q6VYR7) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.49.1.2 | Major antigenic protein 1 |
Bacteria | Pseudomonadota | Major antigen 1 of Ehrlichia ruminantium |
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1.B.49.1.3 | Putative porin of 401 aas |
Bacteria | Pseudomonadota | PP of Anaplasma maginale |
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1.B.49.1.4 | Outer membrane protein, Omp1-3 of 284 aas |
Bacteria | Pseudomonadota | Omp1-3 of Ehrlichia erwingii |
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1.B.49.1.5 | Outer surface protein of 191 aas, Wsp |
Bacteria | Pseudomonadota | Wsp of Wolbachia pipientis |
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1.B.49.1.6 | Outer surface protein Wsp of 210 aas |
Bacteria | Pseudomonadota | Wsp of Wolbachia endosymbiont of Drosophila septentriosaltans |
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1.B.49.1.7 | Outer surface protein of 212 aas, Osp |
Bacteria | Pseudomonadota | Osp of Wolbachia endosymbiont of Araneus ventricosus |
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1.B.49.1.8 | Msp2 porin of 365 aas. Major surface protein encoded by a paralogous gene family; implicated in a variety of pathobiological processes, including antigenic variation, host adaptation, adhesion, porin activity, and structural integrity. (Sarkar et al. 2008). |
Bacteria | Pseudomonadota | Msp2 porin of Anaplasma phagocytophilum (Ehrlichia phagocytophila) |
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1.B.49.1.9 | Major surface protein-4, Msp4, of 320 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | Msp4 of Anaplasma marginale |
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1.B.5.1.1 | Outer membrane phosphate-selective porin OprP (PorP) of 440 aas. Binds and transports a variety of mono, di- and trivalent anions (Benz et al. 1993). An arginine in the pore determines the anion selectivity (Modi et al. 2013). Residues involved in anion affinity and a preference for Pi versus P2 have been identified (Modi et al. 2015). Both monomeric and trimeric OprP are belived to maintain their anion selectivity (Niramitranon et al. 2016). The phosphonic-acid antibiotic fosfomycin is highly permeable through the OprO and OprP channels (Citak et al. 2018). |
Bacteria | Pseudomonadota | OprP of Pseudomonas aeruginosa |
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1.B.5.1.10 | Putative polyphosphate porin, OprO |
Bacteria | Planctomycetota | OprO of Rhodopirellula baltica |
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1.B.5.1.11 | Phosphate-selective porin OmpO/P of 412 aas |
Bacteria | Verrucomicrobiota | OmpO/P of Verrucomicrobiae bacterium |
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1.B.5.1.12 | Anion-selective porin O/P |
Bacteria | Rhodothermota | Porin O/P of Salinibacter ruber |
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1.B.5.1.13 | Anion-selective porin O/P |
Bacteria | Rhodothermota | Porin O/P of Salinibacter ruber |
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1.B.5.1.14 | Porin of 627 aas with an N-terminal domain of about 140 aas that is recognized by CDD as a tumor supressor myostatin domain (Pfam 13868). |
Bacteria | Pseudomonadota | Porin fusion protein of Gluconobacter morbifer |
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1.B.5.1.15 | Phosphate/pyrophosphate-specific porin of 625 aas, OprP/OprO/OprD. |
Bacteria | Pseudomonadota | OprD/O/P of Methylophaga aminisulfidivorans |
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1.B.5.1.2 | Pyrophosphate-selective porin OprO (Hancock et al. 1992). The residue basis for the selectivity of P2 over Pi has been determined and involves two residues (Modi et al. 2015). The phosphonic-acid antibiotic fosfomycin is highly permeable through the OprO and OprP channels (Citak et al. 2018). Fosfidomycin is also transported (Lapierre and Hub 2023). |
Bacteria | Pseudomonadota | OprO of Pseudomonas aeruginosa |
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1.B.5.1.3 | Outer membrane porin, OprP |
Bacteria | Planctomycetota | OprP of Rhodopirellula baltica |
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1.B.5.1.4 | Outer membrane putative phosphate-specific porin, OprP |
Bacteria | Proteobacteria | OprP of Pseudoalteromonas atlantica |
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1.B.5.1.5 | Putative outer membrane porin |
Bacteria | Bacteroidota | OMP of Capnocytophaga ochracea |
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1.B.5.1.6 | Putative outer membrane porin |
Bacteria | Bacteroidota | OMP of Bacteroides helcogenes |
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1.B.5.1.7 | Putative phosphate-specific porin |
Bacteria | Planctomycetota | OMP of Singulisphaera acidiphila |
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1.B.5.1.8 | Putative porin O |
Bacteria | Verrucomicrobiota | Porin O of Coraliomargarita akajimensis |
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1.B.5.1.9 | Porin O |
Bacteria | Pseudomonadota | Porin O of Shewanella violacea |
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1.B.5.2.1 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Sideroxydans lithotrophicus |
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1.B.5.2.2 | Putative porin |
Bacteria | Aquificota | Porin of Thermocrinis albus |
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1.B.50.1.1 | Outer membrane porin, Rv1698 (314aas). Rv1698 accumulates 100-fold more Cu than WT (Wolschendorf et al., 2011). |
Bacteria | Actinomycetota | Rv1698 of Mycobacterium tuberculosis (P64883) |
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1.B.50.1.2 | DUF3186 protein |
Bacteria | Actinomycetota | DUF3186 protein of Actinomyces odontolyticus |
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1.B.50.2.1 | Uncharacterized protein of 296 aas |
Bacteria | Bacillota | UP of Desulfotomaculum acetoxidans |
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1.B.50.2.2 | Exported protein of 291 aas |
Bacteria | Bacillota | Exported protein of Clostridium difficile |
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1.B.50.2.3 | Uncharacterized protein of 289 aas |
Bacteria | Armatimonadota | UP of Chthonomonas calidirosea |
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1.B.51.1.1 | Outer membrane-spanning porin, Oms66 (P66) (Skare et al., 1997). This porin has a β-barrel structure (Kenedy et al. 2013) and pore diameters at the mouth of 1.6nm and at the central constriction of 0.8nm (Bárcena-Uribarri et al. 2013). Oms66 plays a role in resistance to host immune defenses (Curtis et al. 2018). The contribution of P66 porin function to B. burgdorferi pathogenesis has been evaluated (Fierros et al. 2024). |
Bacteria | Spirochaetota | Oms66 of Borrelia burgdorferi (Q44881) |
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1.B.52.1.1 | The outer membrane-spanning porin, Oms28 (Skare et al., 1996) |
Bacteria | Spirochaetota | Oms28 of Borrelia burgdorferi (O50963) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.52.1.2 | Putative porin of 289 aas |
Bacteria | Spirochaetota | Putative porin of Borrelia garinii |
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1.B.53.1.1 | The coat protein A precursor (gp3) (minor coat protein) (424 aas and two TMSs, one N-terminal and one C-terminal) (Identical to gp3 or pIII of enterobacterial phage fd). It is involved in the late stage of filamentous phage translocation mediated by multiple interactions with each individual component of the host TolQRA proton-pore complex (TC# 2.C.1.2.1) (Pellegri et al. 2023).
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Viruses | Loebvirae, Hofneiviricota | gp3 of phage fd (P69169) |
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1.B.53.1.2 | Coat protein A |
Bacteria | Pseudomonadota | Coat protein A of Yersina enterocolitica |
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1.B.53.1.3 | Attachment GIII (G3P) capsid protein precursor of 434 aa |
Viruses | Loebvirae, Hofneiviricota | G3P of E. coli phage IKe |
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1.B.53.1.4 | Phage coat protein A of 442 aas. |
Bacteria | Pseudomonadota | Phage coat protein A of E. coli |
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1.B.54.1.1 | γ-Intimin (Eae protein) (934 aas; Wentzel et al., 2001) | Bacteria | Pseudomonadota | Eae protein of E. coli O157:H7 (P43261) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.54.1.10 | "Inverse" autotransporter (IAT) of 2,358 aas, YeeJ. Functions in adhesion and biofilm formation. It contains a LysM domain that interacts with peptidoglycan and thus assists in localization to the outer membrane. Polynucleotide Phosphorylase PNPase is a repressor of yeeJ transcription (Martinez-Gil et al. 2017). |
Bacteria | Pseudomonadota | YeeJ of E. coli |
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1.B.54.1.2 | Invasin 985aas (Gal-Mor et al., 2008) (crystal structure of the c-terminal passenger domain has been solved; Hamburger et al., 1999) | Bacteria | Pseudomonadota | Invasin of Yersinia pseudotuberculosis (P11922) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.54.1.3 | Putative chlamydial invasin (1305aas) | Bacteria | Chlamydiota | Putative Invasin of Chlamydia suis (Q4FED0) |
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1.B.54.1.4 | Putative α-proteobacterial invasin (291aa) | Bacteria | Pseudomonadota | Putative invasin of Candidatus Pelagibacter ubique (Q4FMH8) |
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1.B.54.1.5 | Putative β-proteobacterial Invasin (1937aas) | Bacteria | Pseudomonadota | Putative Invasin of Bordetella parapertusis (Q7W286) |
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1.B.54.1.6 | Putative Invasin/Adhesin (β-domain begins at ~residue 200) (1459aas) | Bacteria | Campylobacterota | Invasin of Campylobacter lari (Q4HIR3) |
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1.B.54.1.7 | Putative cyanobacterial Intimin (372aas) | Bacteria | Cyanobacteriota | Putative Intimin of Prochlorococcus marinus (Q31A57) |
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1.B.54.1.8 | The ZirS/T (ZirS (276 aas)) is the putative exoprotein passenger domain, but it shows no sequence similarity to passenger domains of other Int/Inv family members. ZirT (660 aas) is the outer membrane β-barrel postulated transporter (Gal-Mor et al., 2008). |
Bacteria | Pseudomonadota | ZirST of Salmonella enterica |
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1.B.54.1.9 | Putative outer membrane porin of 464 aas, YchO. |
Bacteria | Pseudomonadota | YchO of E. coli |
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1.B.54.2.1 | Putative chlorobial Intimin (302aas) | Bacteria | Chlorobiota | Putative intimin of Pelodictyon luteolum (Q3B5D9) |
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1.B.54.3.1 | Hypothetical Protein (436aas) | Bacteria | Cyanobacteriota | Hypothetical protein of Synechococcus sp RCC307 (A5GRI1) |
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1.B.54.3.2 | Hypothetical Protein (428aas) | Bacteria | Cyanobacteriota | Hypothetical protein of Synechococcus sp RCC307 (A5GWU2) |
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1.B.55.1.1 | The β-barrel porin with a superhelical domain containing tetratricopeptide repeats, PgaA or YcdS; exports (deacetylated) poly β-1,6-N-acetyl glucosamine (PGA), a biofilm adhesin that may also play a role in immune evasion (Itoh et al., 2008; Cerca and Jefferson 2008). |
Bacteria | Pseudomonadota | PgaA of E. coli (P69434) |
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1.B.55.1.2 | PgaA homologue |
Bacteria | Pseudomonadota | PgaA homologue of Burkholderia cepacia |
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1.B.55.1.3 |
PgaA homologue |
Bacteria | Pseudomonadota | PgaA homologue of Neisseria wadsworthii |
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1.B.55.2.1 | Putative porin of 604 aas |
Bacteria | Planctomycetota | Porin of Blastopirellula marina |
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1.B.55.2.2 | Uncharacterized protein of 555 aas and 20 predicted beta strands with an N-terminal TMS. |
Bacteria | Nitrospirota | UP of Candidatus Nitroospira defluvii |
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1.B.55.2.3 | TRP-repeat containing protein of 492 aas and 16 predicted beta strands. |
Bacteria | Thermodesulfobacteriota | Trp repeat protein of Geobacter daltonii |
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1.B.55.3.1 | Cellulose synthase operon, protein C of 1157 aas and up to 18 C-terminal (720 - 1157 aas) β-strands with a single N-terminal α-TMS, BcsC or YhjL (Zogaj et al. 2001). Translocation across the outer membrane occurs through the BcsC porin, which extends into the periplasm via 19 tetra-tricopeptide repeats (TPR). Acheson et al. 2019 presented the crystal structure of a truncated BcsC, encompassing the last TPR repeat and the complete outer membrane channel domain, revealing a 16-stranded, β barrel pore architecture. The pore is blocked by an extracellular gating loop, while the extended C terminus inserts deeply into the channel and positions a conserved Trp residue near its extracellular exit. The channel is lined with hydrophilic and aromatic residues suggesting a mechanism for facilitated cellulose diffusion based on aromatic stacking and hydrogen bonding (Acheson et al. 2019). |
Bacteria | Pseudomonadota | BcsC of E. coli |
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1.B.55.3.2 | Uncharacterized protein of 963 aas |
Bacteria | Nitrospirota | UP of Leptospirillum ferriphilum |
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1.B.56.1.1 | Outer membrane porin, Oms38 (slightly anion selective) |
Bacteria | Spirochaetota | Oms38 of Borrelia duttonii (B5RLX6) |
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1.B.56.1.2 | Putative porin of 319 aas |
Bacteria | Spirochaetota | Putative porin of Treponema denticola |
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1.B.56.1.3 | Putative porin of 316 aas |
Bacteria | Spirochaetota | Putative porin of Spirochaeta africana |
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1.B.56.1.4 | Putative porin of 326 aas |
Bacteria | Spirochaetota | Putative porin of Treponema saccharophilum |
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1.B.56.1.5 | Putative porin of 327 aas |
Bacteria | Fibrobacterota | Putative porin of Firbrobacter succinogenes |
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1.B.56.2.1 | Putative porin of 345 aas |
Bacteria | Spirochaetota | Putative porin of Treponema saccharophilum |
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1.B.56.3.1 | Putative toxin of 318 aas |
Bacteria | Myxococcota | Putative toxin of Cystobacter fuscus |
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1.B.56.3.2 | Putative toxin of 325 aas |
Bacteria | Myxococcota | Putative toxin of Myxococcus xanthus |
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1.B.57.1.1 | Legionella Major OMP (LM-OMP) of 297 aas. It is a voltage-dependent, anion-selective ion permeable porin. |
Bacteria | Pseudomonadota | LM-OMP of Legionella pneumophila (Q5ZU34) |
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1.B.57.1.2 | OMP of 404 aas |
Bacteria | Pseudomonadota | OMP of Rhodopseudomonas palustris (Q21BQ4) |
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1.B.57.1.3 | OMP of 392 aas |
Bacteria | Thermodesulfobacteriota | OMP of Pelobacter carbinolicus (Q3A8N9) |
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1.B.57.1.4 | Putative porin of 397 aas |
Bacteria | Planctomycetota | PP of Pirellula staleyi (Pirella staleyi) |
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1.B.57.1.5 | Uncharacterized protein of 557 aas |
Bacteria | Cyanobacteriota | UP of Oscillatoriales cyanobacterium |
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1.B.57.2.1 | OMP of 413 of aas |
OMP of Gemmata obscuriglobus (ZP_02735776) |
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1.B.57.2.2 | OMP of 403 aas |
Bacteria | Planctomycetota | OMP Blastopirellula marina (A3ZSY5) |
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1.B.57.3.1 | OMP of 430 aas |
Bacteria | Pseudomonadota | OMP of Bradyrhizobium sp. BTAi1 (A5EHQ1) |
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1.B.57.3.2 | Putative porin of 302 aas |
Bacteria | Pseudomonadota | Putative porin of Nitrobacter winogradskyi |
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1.B.57.4.1 | Uncharacterized protein of 371 aas |
Bacteria | Elusimicrobiota | UP of Elusimicrobium minutum |
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1.B.57.4.2 | Uncharacterized protein of 323 aas |
Bacteria | Bacteroidota | UP of Alistipes putredinis |
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1.B.57.4.3 | Uncharacterized protein of 327 aas |
Bacteria | Bacteroidota | UP of Odoribacter splanchnicus |
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1.B.57.4.4 | Uncharacterized protein of 326 aas. This protein is homologous to 8 and 9 repeats in TC protein #s 9.B.133.1.1 and 9.B.133.1.2, respectively in TC Blast searches. |
Bacteria | Bacteroidota | UP of Alistipes shahii |
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1.B.57.4.5 | Uncharaterized protein of 382 aas |
Bacteria | Bacteroidota | UP of Pedobacter saltans |
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1.B.57.4.6 | Uncharacterized protein of 388 aas |
Bacteria | Bacteroidota | UP of Prevotella melaninogenica |
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1.B.58.1.1 | The heteromeric porin, NfpA/NfpB (Kläckta et al., 2010). Sugars, amino acids and antibiotics are transported. The cation selective N. farcinica channel exhibits strong interactions with the positively charged antibiotics; amikacin and kanamycin, and the negatively charged ertapenem (Singh et al. 2015). |
Bacteria | Actinomycetota | NfpA/NfpB of Nocardia farcinica |
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1.B.58.1.2 | MspA porin homologue (200aas; 1 N-terminal TMS) |
Bacteria | Actinomycetota | MspA porin of Nocardia brasiliensis (H5RPX4) |
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1.B.58.1.3 | MspA family member (263aas; 1 N-terminal TMS) |
Bacteria | Actinomycetota | MspA porin of Segniliparus rotundus (D6Z9R0) |
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1.B.58.1.4 | MspA porin homologue (212 aas; 1 N-terminal TMS) |
Bacteria | Actinomycetota | MspA porin of Mycobacterium abscessus |
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1.B.58.1.5 | Putative porin |
Bacteria | Actinomycetota | Porin of Rhodococcus erythropolis |
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1.B.58.1.6 | Putative porin of 222 aas. |
Bacteria | Actinomycetota | MspA homologue of Gordonia soli |
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1.B.58.1.7 | Putative porin, MspA of 221 aas. |
Bacteria | Actinomycetota | MspA of Gordonia bronchialis |
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1.B.59.1.1 | Anion-specific porin, PorH (57aas) (Hünten et al., 2005) |
Bacteria | Actinomycetota | PorH of Corynebacterium efficiens (Q8FME6) |
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1.B.59.1.10 | Putative porin of 69 aas and 1 TMS. |
Bacteria | Actinomycetota | Porin of Corynebacterium minutissimum |
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1.B.59.1.11 | Putative porin of 81 aas and 1 TMS |
Bacteria | Actinomycetota | Porin of Corynebacterium phocae |
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1.B.59.1.12 | Uncharacterized porin of 51 aas and 1 TMS |
Bacteria | Actinomycetota | UP of Corynebacterium imitans |
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1.B.59.1.13 | Uncharacterized protein of 81 aas and 1 TMS |
Bacteria | Actinomycetota | UP of Corynebacterium stationis |
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1.B.59.1.14 | Uncharacterized porin of 64 aas and 1 TMS |
Bacteria | Actinomycetota | UP of Corynebacterium renale |
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1.B.59.1.15 | Uncharacterized porin of 69 aas and 1 TMS. |
Bacteria | Actinomycetota | UP of Corynebacterium pyruviciproducens |
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1.B.59.1.16 | Uncharacterized porin of 66 aas and 1 TMS |
Bacteria | Actinomycetota | UP of Corynebacterium pilosum |
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1.B.59.1.17 | Uncharacterized protein of 55 aas |
Bacteria | Actinomycetota | UP of Corynebacterium coyleae |
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1.B.59.1.18 | Uncharacterized protein of 104 aas with 1 or 2 TMSs, one N-terminal and one near the C-terminus. |
Bacteria | Actinomycetota | UP of Corynebacterium diphtheriae |
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1.B.59.1.2 | Outer membrane porin, PorH (57aas). It is O-mycoloylated on Serine-56 (Rath et al. 2013). |
Bacteria | Actinomycetota | PorH of Corynebacterium glutamicum (Q6M2D2) |
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1.B.59.1.3 | Outer membrane cation-specific porin, PorH (Hünten et al., 2005) |
Bacteria | Actinomycetota | PorH of Corynebacterium callunae (D2T1T1) |
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1.B.59.1.4 | Outer membrane porin, PorH (63aas) |
Bacteria | Actinomycetota | PorH of Corynebacterium aurimucosum (C3PJG7) |
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1.B.59.1.5 | Uncharacterized protein of 51 aas |
Bacteria | Actinomycetota | UP of Corynebacterium diphtheriae |
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1.B.59.1.6 | Uncharacterized protein of 44 aas |
Bacteria | Actinomycetota | UP of Corynebacterium argentoratense |
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1.B.59.1.7 | Uncharacterized protein of 102 aas |
Bacteria | Actinomycetota | UP of Corynebacterium halotolerans |
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1.B.59.1.8 | Uncharacterized protein of 63 aas |
Bacteria | Actinomycetota | UP of Corynebacterium ulcerans |
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1.B.59.1.9 | PorH of 58 aas |
Bacteria | Actinomycetota | PorH of Corynebacterium diphtheriae |
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1.B.59.2.1 | Uncharacterized porin of 58 aas and 1 TMS |
Bacteria | Actinomycetota | UP of Corynebacterium falsenii |
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1.B.59.2.2 | Characterized porin of 37 aas and 1 TMS, PorCu. The slightly cation-selective pore is wide and water-filled and has a diameter of about 1.8 nm, clearly indicative of a multisubunit complex (Abdali et al. 2018).. |
Bacteria | Actinomycetota | Porin of Corynebacterium urealyticum |
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1.B.59.3.1 | Uncharacterized porin of 77 aas and 1 TMS |
Bacteria | Actinomycetota | UP of Corynebacterium mycetoides |
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1.B.6.1.1 | Weakly anion-selective OmpA porin. Can exist in two distinct conductance states (Arora et al. 2000). May function in the transport of phenylpropanoids (resveratrol, naringenin and rutin) (Zhou et al. 2014). Three membrane-bound folding intermediates of OmpA were discovered in folding studies with dioleoylphosphatidylcholine bilayers. A highly synchronized mechanism of secondary and tertiary structure formation, applicable to this and other β-barrel membrane proteins has been described (Kleinschmidt 2006). |
Bacteria | Pseudomonadota | OmpA of E. coli (P0A910) |
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1.B.6.1.10 | Outer membrane insertion signal domain protein of 190 aas and one N-terminal TMS. An ortholog in Veillonella parvula is 84% identical, and was considered to be a porin by Poppleton et al. 2017. |
Bacteria | Bacillota | OMISD protein of Veillonella atypica |
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1.B.6.1.11 | OmpA of 210 aas. The 3-d structure has been solved by NMR (Renault et al. 2010), and its dynamics have been examined (Renault et al. 2009). |
Bacteria | Pseudomonadota | OmpA of Klebsiella pneumoniae |
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1.B.6.1.12 | Omp34 outer membrane porin of 346 aas. Also known as the Major antigen Fc binding protein (White et al. 1998). |
Bacteria | Pseudomonadota | Omp34 of Aggregatibacter actinomycetemcomitans (Actinobacillus actinomycetemcomitans) (Haemophilus actinomycetemcomitans) |
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1.B.6.1.13 | Putative porin of 253 aas |
Bacteria | Actinomycetota | Putative porin of Nocardioidaceae bacterium Broad-1 |
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1.B.6.1.14 | Outer membrane protein of 638 aas, OmpF |
Bacteria | Bacteroidota | OmpF of Cecembia lonarensis |
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1.B.6.1.15 | OmpA/F |
Bacteria | Spirochaetota | OmpA/F of Treponema pallidum |
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1.B.6.1.16 | OmpA family porin of 410 aas |
Bacteria | Pseudomonadota | OmpA porin of Phenylobacterium zucineum |
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1.B.6.1.17 | Putative OmpF homologue |
Bacteria | Spirochaetota | Putative OmpF homologue of Leptospira interrogans |
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1.B.6.1.18 | Outer membrane protein of 210 aas and 8 putative TMSs |
Bacteria | Pseudomonadota | OMP of Thiothrix nivea |
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1.B.6.1.19 | Outer membrane protein of 218 aas and 8 putative TMSs |
Bacteria | Bacteroidota | OMP of Mariniradius saccharolyticus |
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1.B.6.1.2 |
OmpF (OprF) porin. The N-terminal domain has pore activity (Saint et al. 2000). The protein can exist in multiple conformations of variable conductivities (Nestorovich et al. 2006). Factors affecting its one-domain open conformer have been studied by Sugawara et al. (2010). OprF is a complement component C3 receptor (Mishra et al. 2015) and is a target of antibacterial drugs (Maccarini et al. 2017). OprF assumes dual conformations and is involved in solute transport, cell envelope integrity, biofilm formation and pathogenesis (Cassin and Tseng 2019). OprF in Pseudomonas aeruginosa is involved in biofilm stimulation by subinhibitory antibiotics (Yaeger et al. 2024). |
Bacteria | Pseudomonadota | OmpF (OprF) of Pseudomonas aeruginosa (P13794) |
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1.B.6.1.20 | OmpA homologue of 189 aas |
Bacteria | Spirochaetota | OmpA homologue of Leptospira biflexa |
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1.B.6.1.21 | OmpA-type porin of 160 aas, YfiB The yfiRNB locus in E. coli CFT073 contains genes for YfiN, a diguanylate cyclase, and its activity regulators, YfiR and YfiB.(Raterman et al. 2013). |
Bacteria | Pseudomonadota | YfiB of E. coli |
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1.B.6.1.22 | Constitutively expressed OmpA of 365 aas (Gao et al. 2015). |
Bacteria | Pseudomonadota | OmpA of Shewanella oneidensis |
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1.B.6.1.23 | OmpA of 354 aas with 1 N-terminal α-TMS, 10 putative β-TM Strands and a periplasmic C-terminal domain, probably a peptidoglycan-binding domain (Khalid et al. 2008). Plays a role in virulence (pneumonia in pigs and ruminants) (Verma et al. 2016; Confer and Ayalew 2013) and has been used for vaccine development (Dabo et al. 2008). |
Bacteria | Pseudomonadota | OmpA of Pasteurella multocida |
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1.B.6.1.24 | Omp38; OmpA of 356 aas and 1 N-terminal TMSs. It is a selective antibiotic transporting porin (Iyer et al. 2018; Jyothisri et al. 1999) and induces apoptosis in human cell lines through caspase-dependent and
AIF-dependent pathways. Purified Omp38 enters host cells and localizes to
the mitochondria, which presumably leads to a release of proapoptotic
molecules such as cytochrome c and AIF (apoptosis-inducing factor)
(Choi et al. 2005). It is a virulence factor (Scribano et al. 2024). |
Bacteria | Pseudomonadota | omp38 of Acinetobacter baumannii |
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1.B.6.1.25 | Putative OmpA porin of 345 aas and one N-terminal TMS. Its gene is adjacent to an autoinducer exporter-like protein (2.A.86.1.11) (Poppleton et al. 2017). |
Bacteria | Bacillota | OmpA-like protein of Veillonella parvula |
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1.B.6.1.26 | OmpA -like protein of 159 aas and 1 N-terminal TMS, PsaB or YfiB. It is involved in stress tolerance and negatively correlates to stress tolerance (Scribano et al. 2024). |
Bacteria | Pseudomonadota | PsaB of Acinetobacter baumannii |
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1.B.6.1.27 | PalA of 157 aas |
None | Pseudomonadati, Campylobacterota | PalA pf Helicobacter pylori |
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1.B.6.1.3 |
OmpATb (ArfA). The central domain (residues 73-220) has been reported to exhibit channel activity (Molle et al., 2006). Its expression is dependent on small single TMS membrane proteins which are encoded in a single operon with it (Veyron-Churlet et al., 2011). The rv0899 gene, encoding OmpATb, is part of an operon (rv0899-rv0901) that is required for fast ammonia secretion, pH neutralization, and growth of M. tuberculosis in acidic environments (Song et al. 2011). Homologues are widespread in bacteria with functions in nitrogen metabolism, adaptation to nutrient poor environments, and/or establishing symbiosis with host organisms (Marassi, 2011). The high resolution 3-d structure is known, revealing two independent domains separated by a proline-rich hinge region.The C-terminal domain (OmpATb(198-326)) revealed a module structurally related to other OmpA-like proteins from Gram-negative bacteria, but the N-terminal domain(73-204), which forms channels in planar lipid bilayers, exhibits a fold, which belongs to the α+β sandwich class fold. It exists in a major monomeric form and a minor oligomeric form yielding rings able to insert into phospholipid membranes (Yang et al. 2011). The OmpA-like domain (residues 196-326) binds M. tuberculosis peptidoglycan. Overexpression in M. bovis or M. smegmatis gives channels with average conductance value of 1,600 +/- 100 pS (Raynaud et al. 2002). |
Bacteria | Actinomycetota | OmpATb of Mycobacterium tuberculosis (P65593) |
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1.B.6.1.4 | HMP-AB outer membrane porin, OmpAb or Omp38 (Gribun et al., 2004). It is the principle porin with an inner diameter of 2 nm which allows transport of cephalothin, cephaloridine, other antibiotics as well as other small molecules across the outer membrane (Sugawara and Nikaido 2012). Structural studies have been reported (Vashist and Rajeswari 2006). It is a secreted emulifier in some strains of Acinetobacter (Walzer et al. 2006). The sequence provided may be slightly incorrect (see the Q6BYW5 sequence of 356 aas). |
Bacteria | Pseudomonadota | HMP-AB of Acinetobacter baumannii (Q8KWW6) |
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1.B.6.1.5 | The OmpA-OmpF porin (OOP) family member, GmpA (involved in acetic acid fermentation; under quorum sensing control) (Iida et al., 2008). (most similar to 1.B.6.1.4) |
Bacteria | Pseudomonadota | GmpA of Gluconacetobacter intermedius (B3A000) |
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1.B.6.1.6 | Outer membrane protein 40 (Omp40) (PG33) | Bacteria | Bacteroidota | PG_0694 of Porphyromonas gingivalis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.6.1.7 | OmpA homologue |
Bacteria | Bacillota | OmpA homologue of Megasphaera elsdenii |
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1.B.6.1.8 | OmpA homologue |
Bacteria | Bacillota | OmpA homologue of Megasphaera sp. UPII 135-E |
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1.B.6.1.9 | OMP_b-br1 family protein |
Bacteria | Bacillota | Outer membrane protein of Megasphaera elsdenii |
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1.B.6.10.1 | Putative OmpW homologue of 219 aas (Giacani et al. 2015). |
Bacteria | Spirochaetota | Putative OmpW homologue of Treponema pallidum |
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1.B.6.10.2 | Putative OmpW homologue of 291 aas (Giacani et al. 2015). |
Bacteria | Spirochaetota | Putative OmpW homologue of Treponema pallidum |
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1.B.6.10.3 | Putative OmpW porin of 211 aas and 8 β-strands |
Bacteria | Spirochaetota | Putative OmpW homologue of Treponema azotonutricium |
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1.B.6.10.4 | Putative OmpW homologue of 206 aas and 8 β-strands. |
Bacteria | Spirochaetota | Putative OmpW homologue of Spirochaeta africana |
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1.B.6.10.5 | Putative OmpW homologue of 211 aas |
Bacteria | Spirochaetota | OmpW homologue of Borrelia hermsii |
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1.B.6.10.6 | Uncharacterized protein of 196 aas. |
Bacteria | Spirochaetota | UP of Sphaerochaeta pleomorpha |
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1.B.6.10.7 | Uncharacterized protein of 205 aas. |
Bacteria | Spirochaetota | UP of Treponema denticola |
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1.B.6.11.1 | Putative porin of 357 aas and 1 N-terminal TMS |
Archaea | Euryarchaeota | Porin of Candidatus Methanoperedenaceae archaeon |
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1.B.6.11.2 | Uncharacterized protein of 407 aas |
Ciliophora | UP of Stentor coeruleus |
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1.B.6.12.1 | A major outer membrane protein of 298 aas and 1 N-terminal TMS, from Methylacidiphilum fumariolicum SolV (Liu et al. 2023). This porin has a β-barrel structure consisting of ten antiparallel β-sheets and with a small amphipathic N-terminal α-helix in the periplasm. Because M. fumariolicum SolV, lives in a geothermal environment with low pH and high temperatures, this protein may act as barrier to resist the extreme conditions found in its natural environment (Liu et al. 2023). |
Bacteria | Verrucomicrobiota | Major OM Porin, WP_009059494, of Methylacidiphilum fumariolicum SolV |
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1.B.6.12.2 | Uncharacterized opacity protein or related surface antigen of 278 aas and 1 N-terminal TMS. This protein is also distantly related to members of TC family 1.B.49. |
Bacteria | Planctomycetota | UP of a Bradyrhizobium sp. S23321 [Gemmataceae bacterium] |
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1.B.6.12.3 | Outer membrane beta-barrel protein of 306 aas and 1 N-terminal TMS. This protein resembles members of TC family 1.B.49. a member of theOMPP1 Superfamily. |
Bacteria | Verrucomicrobiota | OMP of Candidatus Methylacidithermus pantelleriae |
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1.B.6.13.5 | ArfA, a member of the OmpA family. It is of 471 aas with 3 N-terminal TMSs. It affects cell stiffness, cell shape and virulence (Scribano et al. 2024). |
Bacteria | Pseudomonadota | ArfA of Acinetobacter baumannii |
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1.B.6.2.1 | Outer membrane porin precursor, OmpX (8 TM β-strands). The NMR structures in lipid bilayers has been solved (Mahalakshmi et al., 2007; Mahalakshmi and Marassi, 2008; Fernández et al. 2004). Expression of the encoding gene is induced by acid or base compared to pH 7 (Stancik et al. 2002). |
Bacteria | Pseudomonadota | OmpX of E. coli (P0A917) |
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1.B.6.2.10 | Outer membrane porin, OmpX of 171 aas (Dupont et al. 2004). |
Bacteria | Pseudomonadota | OmpX of Enterobacter (Aerobacter) aerogenes |
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1.B.6.2.11 | Outer membrane porin, opacity type, of 189 aas |
Bacteria | Chlorobiota | OMP of Prosthecochloris vibrioformis |
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1.B.6.2.12 | Outer membrane porin, opacity type, of 230 aas |
Bacteria | Chlorobiota | OMP of Chlorobaculum parvum |
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1.B.6.2.13 | Putative invasin of 242 aas |
Bacteria | Pseudomonadota | Putative invasin of E. coli |
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1.B.6.2.14 | Uncharacterized protein of 290 aas |
Bacteria | Pseudomonadota | UP of Nitrobacter hamburgensis |
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1.B.6.2.15 | Putative porin of 199 aas |
Bacteria | Pseudomonadota | Putative porin of Rhodanobacter thiooxydans |
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1.B.6.2.16 | Uncharacterized protein of 196 aas |
Bacteria | Pseudomonadota | UP of Vibrio fischeri |
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1.B.6.2.17 | Putative porin of 195 aas |
Bacteria | Pseudomonadota | Putative porin of Vibrio alginolyticus |
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1.B.6.2.18 | Uncharacterized protein of 186 aas |
Bacteria | Pseudomonadota | UP of Agarivorans albus |
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1.B.6.2.19 | Putative porin of 182 aas |
Bacteria | Pseudomonadota | PP of Grimontia hollisae |
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1.B.6.2.2 | The attachment inversion locus (Ail) (Bartra et al., 2007). Membrane-bound proteins, Ail and OmpF, are involved in the adsorption of T7-related bacteriophage (Zhao et al. 2013). |
Bacteria | Pseudomonadota | Ail of Yersinia pestis (Q0WCZ9) |
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1.B.6.2.20 | Ail/Lom protein of 199 aas |
Bacteria | Pseudomonadota | Ail/Lom protein of E. coli |
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1.B.6.2.3 | Opacity family porin protein | Bacteria | Pseudomonadota | UMN179_00549 of Gallibacterium anatis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.6.2.4 | Opacity family porin protein | Bacteria | Pseudomonadota | UMN179_00948 of Gallibacterium anatis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.6.2.5 | Neisserial surface protein A, NspA of 174 aas and 8 TMSs (Hou et al. 2003). |
Bacteria | Pseudomonadota | NspA of Neisseria meningitidis |
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1.B.6.2.6 | Porin opacity type | Bacteria | Pseudomonadota | AM202_02155 of Actinobacillus minor 202 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.6.2.7 | Outer membrane porin homolog, but annotated as arginine transporter permease subunit, ArtM, in Uniprot. |
Bacteria | Pseudomonadota | GGC_0882 of Haemophilus haemolyticus M21621 |
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1.B.6.2.8 | Opa-like protein A | Bacteria | Pseudomonadota | E9U_09445 of Moraxella catarrhalis BC8 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.6.2.9 | Surface protein A | Bacteria | Pseudomonadota | NspA of Neisseria wadsworthii 9715 |
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1.B.6.3.1 | Putative porin of 197 aas |
Bacteria | Verrucomicrobiota | PP of Opitutaceae bacterium TAV1 |
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1.B.6.3.2 | Putative porin of 277 aas |
Bacteria | Verrucomicrobiota | PP of Coraliomargarita sp. CAG:312 |
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1.B.6.3.3 | Putative porin |
Bacteria | Verrucomicrobiota | PP of Opitutus terrae |
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1.B.6.4.1 | Putative porin of 183 aas |
Bacteria | Pseudomonadota | Putative porin of Vibrio parahaemolyticus |
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1.B.6.4.2 | Porin of 190 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | Porin of Shewanella psychrophila |
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1.B.6.4.3 | Porin of 198 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | Porin of Pseudoalteromonas luteoviolacea |
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1.B.6.4.4 | Porin of 180 aas and 1 N-terminal TMS |
Bacteria | Pseudomonadota | Porin of Vibrio caribbeanicus |
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1.B.6.4.5 | Porin of 186 aas and 1 N-terminal TMS |
Bacteria | Pseudomonadota | Porin of Litorilituus sp. RZ04 |
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1.B.6.5.1 | Outer membrane protein of 205 aas and 8 putative TMSs. |
Bacteria | Fibrobacterota | OMP of Fibrobacter succinogens |
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1.B.6.5.2 | Outer membrane protein of 197 aas and 8 putative TMSs. |
Bacteria | Fibrobacterota | OMP of Fibrobacter succinogenes |
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1.B.6.5.3 | Outer membrane protein of 534 aas and 6 - 22 beta strands. |
Bacteria | Spirochaetota | OMP of Turneriella parva |
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1.B.6.5.4 | Outer membrane protein of 211 aas and 8 beta strands. |
Bacteria | Myxococcota | OMP of Myxococcus xanthus |
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1.B.6.5.5 | Outer membrane protein of 201 aas and 9 putative beta strands. |
Bacteria | Pseudomonadota | OMP of Vibrio tubiashii |
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1.B.6.5.6 | Outer membrane protein, OmpA of 196 aas and 8 putative TMSs |
Bacteria | Pseudomonadota | OmpA of Aliivibrio salmonicida |
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1.B.6.6.1 | Outer membrane protein of 201 aas and 8 putative β-TMSs. |
Bacteria | Bacteroidota | OMP of Cyclobacterium marinum |
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1.B.6.6.10 | Putative porin of 157 aas and 8 beta strands |
Bacteria | Bacteroidota | Putative porin of Paludibacter propionicigenes |
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1.B.6.6.11 | Uncharacterized protein of 208 aas. |
Bacteria | Bacteroidota | UP of Pedobacter saltans |
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1.B.6.6.12 | Putative porin of 192 aas |
Bacteria | Bacteroidota | Putative porin of Capnocytophaga sputigena |
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1.B.6.6.2 | Outer membrane protein of 224 aas and 8 TMSs |
Bacteria | Bacteroidota | OMP of Dyadobacter fermentans |
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1.B.6.6.3 | Outer membrane protein of 204 aas and 8 TMSs |
Bacteria | Bacteroidota | OMP of Solitalea canadensis |
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1.B.6.6.4 | Outer membrane protein of 221 aas and 8 TMSs |
Bacteria | Bacteroidota | OMP of Psychroflexus torquis |
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1.B.6.6.5 | Outer membrane protein of 222 aas |
Bacteria | Bacteroidota | OMP of Echinicola vietnamensis |
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1.B.6.6.6 | Outer membrane protein of 199 aas |
Bacteria | Bacteroidota | OMP of Chitinophaga pinensis |
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1.B.6.6.7 | Porin of 193 aas and 8 beta strands |
Bacteria | Bacteroidota | Porin of Flavobacterium johnsoniae |
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1.B.6.6.8 | Porin of 180 aas and 8 beta strands |
Bacteria | Nitrospirota | Porin of Candidatus Nitrospira defluvii |
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1.B.6.6.9 | Porin of 207 aas and 8 beta strands |
Bacteria | Myxococcota | Porin of Myxococcus xanthus |
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1.B.6.7.1 | Outer membrane protein of 257 aas and 8 beta strands |
Bacteria | Bacteroidota | OMP of Bacteroides fragilis |
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1.B.6.7.2 | Porin of 275 aas and 1 N-terminal TMS |
Bacteria | Bacteroidota | Porin of Bacteroides xylanisolvens |
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1.B.6.7.3 | DUF4421 domain-containing protein of 334 aas and 1 N-terminal TM |
Bacteria | Bacteroidota | Putative porin of Flavobacterium rivuli |
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1.B.6.8.1 | Porin of 224 aas and 8 beta strands, TtoA (Estrada Mallarino et al. 2015). The crystal structure is known (3DZM) (Nesper et al. 2008). The 2.8 Å structure reveals a transmembrane 8 stranded β-barrel, an extracellular cation-binding region and an external 5-β stranded sheet (Brosig et al. 2009). |
Bacteria | Deinococcota | Porin of Thermus thermophilus |
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1.B.6.8.2 | Putative porin of 222 aas. |
Bacteria | Deinococcota | Putative porin of Deinococcus geothermalis |
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1.B.6.8.3 | Putative porin of 227 aas and 1 N-terminal TMS |
Bacteria | Ignavibacteriota | Porin of Ignavibacterium album |
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1.B.6.9.1 | Uncharacterized protein of 186 aas. |
Bacteria | Ignavibacteriota | UP of Ignavibacterium album |
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1.B.6.9.2 | Uncharacterized putative porin protein of 189 aas. |
Bacteria | Bacteroidota | UP of Owenweeksia hongkongensis |
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1.B.6.9.3 | Uncharacterized putative porin of 205 aas |
Bacteria | Bacteroidota | Putative porin of Owenweeksia hongkongensis |
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1.B.6.9.4 | Uncharacterized protein of 167 aas |
Bacteria | Bacteroidota | UP of Elizabethkingia anophelis |
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1.B.60.1.1 | The outer membrane, monomeric, large conductance, cation-selective Omp50 porin of 453 aas (Bolla et al. 2000). |
Bacteria | Campylobacterota | Omp50 of Campylobacter jejuni (Q0P986) |
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1.B.60.1.10 | Uncharacterized protein of 443 aas and 1 N-terminal TMS. |
Bacteria | Bdellovibrionota | UP of Bdellovibrio bacteriovorus |
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1.B.60.1.2 | Putative outer membrane porin, Despr_2770 |
Bacteria | Thermodesulfobacteriota | Omp of Desulfobulbus propionicus (E8RCF8) |
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1.B.60.1.3 | Putative outer membrane porin, Shew185-0459 |
Bacteria | Pseudomonadota | Omp of Shewanella baltica (A6WII8) |
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1.B.60.1.4 | Putative outer membrane porin, Glov_2218 |
Bacteria | Thermodesulfobacteriota | Omp of Geobacter lovleyi (B3E4B3) |
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1.B.60.1.5 | Putative outer membrane porin Rfer_3633 |
Bacteria | Pseudomonadota | Omp of Rhodoferax ferrireducens (Q21SB8) |
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1.B.60.1.6 | Putative outer membrane porin, Flexsi_1177 |
Bacteria | Deferribacterota | Omp of Flexistipes sinusarabici (F8E6J5) |
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1.B.60.1.7 | Putative outer membrane porin |
Bacteria | Myxococcota | Omp of Anaeromyxobacter dehalogenans (Q2IPL5) |
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1.B.60.1.8 | Putative outer membrane porin |
Bacteria | Campylobacterota | Omp of Caminibacter mediatlanticus (A6DB68) |
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1.B.60.1.9 | Putative outer membrane porin |
Bacteria | Myxococcota | Omp of Haliangium ochraceum (D0LXF9) |
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1.B.61.1.1 | OmpJ-related outer membrane channel |
Bacteria | Thermodesulfobacteriota | OmpJ-like porin of Pelobacter carbinolicus |
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1.B.61.1.2 | LamB porin family protein |
Bacteria | Thermodesulfobacteriota | LamB porin family protein of Pelobacter propionicus |
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1.B.61.1.3 | Putative porin |
Bacteria | Thermodesulfobacteriota | Putative porin of Geobacter uraniireducens |
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1.B.61.1.4 | Putative porin |
Bacteria | Thermodesulfobacteriota | Putative porin of Desulfovibrio vulgaris |
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1.B.61.1.5 | Putative porin of 433 aas |
Bacteria | Thermodesulfobacteriota | Putative porin of Syntrophus aciditrophicus |
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1.B.61.1.6 | Putative outer membrane porin of 608 aas and 16 beta-TMSs |
Bacteria | Myxococcota | OMP of Myxococcus xanthus |
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1.B.61.1.7 | Outer membrane homotrimeric porin with a preference for anionic sugars, DVU0799, of 466 aas (Zeng et al. 2017).
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Thermodesulfobacteriota | DVU0799 of Desulfovibrio vulgaris (strain Hildenborough) |
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1.B.62.1.1 | Putative porin |
Bacteria | Chlorobiota | Putative porin of Chlorobium limicola |
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1.B.62.1.2 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Pseudomonas fluorescens |
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1.B.62.1.3 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Pseudomonas fluorescens |
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1.B.62.1.4 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Thiobacillus denitrificans |
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1.B.62.1.5 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Pseudomonas fluorescens |
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1.B.62.1.6 | Putative porin |
Bacteria | Verrucomicrobiota | Putative porin of Opitutaceae bacterium |
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1.B.62.1.7 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Achromobacter xylosoxidans |
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1.B.62.1.8 | Putative porin |
Bacteria | Pseudomonadota | Putative porin of Rhodopseudomonas palustris |
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1.B.62.1.9 | Porin of 408 aas |
Bacteria | Lentisphaerota | Porin of Lentisphaera araneosa |
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1.B.63.1.1 | The CarO porin is slightly cation-selective and can be mutated to give rise to imipenem-resistance (Zhu et al. 2019). It is of 243 aas (Siroy et al. 2005) and plays a role in cabapenum resistance (Fonseca et al. 2013) as well as MDR (Yang et al. 2015). It has been implicated in the uptake of ornithine as well as carbapenem antibiotics. Zahn et al. 2015 reported crystal structures of three isoforms of CarO. The structures show a monomeric eight-stranded barrel lacking an open channel. CarO has a substantial extracellular domain resembling a glove that contains all the divergent residues between the different isoforms. A6XB80 is another isoform with 77% identity to the one listed here in TCDB. Overexpression of carO is associated with carbapenem resistance (AlQumaizi et al. 2022). |
Bacteria | Pseudomonadota | CarO of Acinetobacter baumannii |
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1.B.63.1.2 | CarO homologue of 310 aas |
Bacteria | Cyanobacteriota | CarO homologue of Oscillatoria acuminata |
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1.B.63.1.3 | CarO homologue of 275 aas |
Bacteria | Acidobacteriota | CarO homologue of Acidobacterium capsulatum |
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1.B.63.1.4 | CarO homologue of 223 aas |
Bacteria | Pseudomonadota | CarO homolgoue of Hirschia baltica |
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1.B.63.1.5 | CarO homolgue of 233 aas |
Bacteria | Bacteroidota | CarO homologue of Sprosoma linguale |
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1.B.63.1.6 | CarO homologue of 273 aas. |
Bacteria | Bacteroidota | CarO homologue of Porphyromonas gingivalis |
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1.B.64.1.1 | Omp2a porin of 386 aas. The 3-d structure reveals a 16-stranded β-barrel with an α-helix on the third loop folding inside the barrel and forming the constriction zone of the channel, a typical feature of general porins (Lopes-Rodrigues et al. 2019). The preferential diffusion of cations over anions has been experimentally observed. Transports maltotetraose (Lopes-Rodrigues et al. 2019). |
Bacteria | Pseudomonadota | Omp2a of Brucella melitensis biovar Abortus |
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1.B.64.1.2 | Outer membrane porin of 428 aas, Omp2 |
Bacteria | Pseudomonadota | Omp2 of Rhizobium freirei |
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1.B.64.1.3 | Putative porin of 384 aas. |
Bacteria | Pseudomonadota | Porin of Agrobacterium deltaense |
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1.B.65.1.1 | Outer membrane porin/adhesin/invasin of 272 aas and 10 established beta strands, OpcA. The crystal structure (PDB#2VDF) is known (Prince et al. 2002). |
Bacteria | Pseudomonadota | OpcA of Neisseria meningitidis |
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1.B.65.1.10 | OpcA homologue of 268 aas |
Bacteria | Pseudomonadota | OpcA homologue of Pasteurella bettyae |
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1.B.65.1.2 | OpcA homologue of 264 aas. |
Bacteria | Elusimicrobiota | OpcA homologue of Elusimicrobium minutum |
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1.B.65.1.3 | OpcA homologue of 264 aas |
Bacteria | Thermodesulfobacteriota | OpcA homologue of Thermodesulfobacterium geofontis |
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1.B.65.1.4 | OpcA homologue of 289 aas |
Bacteria | Chlorobiota | OpcA homologue of Pelodictyon (Chlorobium) luteolum |
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1.B.65.1.5 | OpcA homologue of 259 aas |
Bacteria | Pseudomonadota | OpcA homologue of Marinomonas posidonica |
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1.B.65.1.6 | OpcA homologue of 256 aas |
Bacteria | Pseudomonadota | OpcA homologue of Marinomonas posidonica |
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1.B.65.1.7 | OpcA homologue of 126 aas |
Bacteria | Pseudomonadota | OpcA homolgoue of Neisseria lactamica |
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1.B.65.1.8 | OpcA of 271 aas |
Bacteria | Pseudomonadota | OpcA homoplogue of Pseudogulbenkiania ferrooxidans |
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1.B.65.1.9 | OpcA homologue of 273 aas |
Bacteria | Pseudomonadota | OpcA homologue of Neisseria macacae |
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1.B.66.1.1 | Putative outer membrane beta-barrel porin of 447 aas. |
Bacteria | Planctomycetota | Porin of Rhodopirellula baltica |
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1.B.66.1.2 |
Outer membrane protein of 404 aas. TC BLAST give a score of e-5 with 1.B.71.1.6 and 0.003 with 1.B.1.1.15, suggesting that all three familes are members of Porin Superfamily I. This suggestion has been confirmed. The protein transports glucose and is induced by low glucose concentrations in the medium (Wang et al. 2019). |
Bacteria | Bacteroidota | OM Porin of Cytophaga hutchinsonii |
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1.B.66.1.3 |
Putative porin of 371 aas. TC BLAST give a score of 0.002 with 1.B.12.5.2 and hits four repeats. |
Bacteria | Pseudomonadota | Porin of Thiomonas sp. 3As |
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1.B.66.1.4 |
Outer membrane protein of 530 aas. TC BLAST gives a scroe of 0.004 with 1.B.16.1.3. |
Bacteria | Spirochaetota | OMP of Leptospira sp. B5-022 |
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1.B.66.1.5 | Putative porin of 367 aas. |
Bacteria | Myxococcota | Porin of Myxococcus xanthus |
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1.B.66.1.6 | Putative porin |
Bacteria | Planctomycetota | Porin of Candidatus Kuenenia stuttgartiensis |
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1.B.66.1.7 | Putative porin |
Bacteria | Spirochaetota | Putative porin of Leptospira biflexa |
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1.B.66.1.8 | Putative porin of 359 aas |
Bacteria | Verrucomicrobiota | PP of Coraliomargarita akajimensis |
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1.B.66.1.9 | Putative porin of 524 aas (DUF3138 family) |
Bacteria | Pseudomonadota | PP of Burkholderia pseudomallei |
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1.B.66.2.1 | Putative porin of 413 aas |
Bacteria | Lentisphaerota | Putative porin of Lentisphaera araneosa |
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1.B.66.3.1 | Putative porin of 474 aas |
Bacteria | Thermodesulfobacteriota | Porin of Desulfocapsa sulfexigens |
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1.B.66.3.2 | Putative porin of 428 aas |
Bacteria | Pseudomonadota | Porin of Hahella chejuensis |
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1.B.66.3.3 | Putative porin |
Bacteria | Pseudomonadota | PP of Oligotropha carboxidovorans |
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1.B.66.3.4 | Putative porin (DUF2320 family) |
Bacteria | Pseudomonadota | PP of Agrobacterium vitis |
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1.B.66.4.1 | Putative porin of 405 aas; OMP protective antigen OMA87 |
Bacteria | Pseudomonadota | OMP87 of Thioflavicoccus mobilis |
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1.B.66.5.1 | Putative porin of 511 aas; DUF2320 family. |
Bacteria | Pseudomonadota | PP of Thiobacillus denitrificans |
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1.B.67.1.1 | Putative porin |
Bacteria | Ignavibacteriota | Porin of Melloribacter roseus |
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1.B.67.1.2 | Putative outer membrane channel superfamily member |
Bacteria | Pseudomonadota | Putative porin of Rhodanobacter sp. |
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1.B.67.1.3 | Putative porin |
Bacteria | Thermodesulfobacteriota | Putative porin of Thermodesulfobacterium geofontis |
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1.B.67.1.4 | Putative porin |
Bacteria | Ignavibacteriota | Putative porin of Melioribacter roseus |
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1.B.67.1.5 | Putative porin |
Bacteria | Ignavibacteriota | Putative porin of Ignavibacterium album |
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1.B.67.1.6 | Putative porin |
Bacteria | Myxococcota | Putative porin of Anaeromyxobacter dehalogans |
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1.B.67.1.7 | Putative holin |
Bacteria | Aquificota | Putative porin of Sulfurihydrogenibium azorense |
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1.B.68.1.1 | Putative porin, YfaZ of 187 aas (OF07437) |
Bacteria | Pseudomonadota | YfaZ of E. coli |
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1.B.68.1.2 | Putative porin of 179 aas |
Bacteria | Pseudomonadota | Putative porin of Shewanella woodyi |
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1.B.68.1.3 | Putative outer membrane porin of 195 aas |
Bacteria | Campylobacterota | Putative porin of Suflurvicurvum kyjiense |
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1.B.68.1.4 | YfaZ family protein of 192 aas |
Bacteria | Pseudomonadota | Putative porin of Thioalkalimicrobium cyclicum |
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1.B.69.1.1 | PxMP4 or MPM24 of 212 aas and 4 TMSs. |
Eukaryota | Metazoa, Chordata | PxMP4 of Homo sapiens |
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1.B.69.1.2 | PMP24 of 226 aas and 4 TMSs. |
Eukaryota | Euglenozoa | PMP24 of Leishmania mexicana |
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1.B.69.1.3 | PMP24 of 216 aas. |
Eukaryota | Discosea | PMP24 of Acanthamoeba castellanii |
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1.B.69.1.4 | PMP24 of 217 aas. |
Eukaryota | Fungi, Ascomycota | PMP24 of Aspergillus niger |
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1.B.69.1.5 | Uncharacterized protein of 230 aas and 3 TMSs |
Eukaryota | Evosea | UP of Polysphondylium pallidum (Cellular slime mold) |
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1.B.69.1.6 | Uncharacterized protein of 211 TMSs |
Eukaryota | Fungi, Basidiomycota | UP of Laccaria bicolor |
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1.B.69.1.7 | Uncharacterized protein of 202 aas and 4 TMSs |
Eukaryota | Ciliophora | UP of Paramecium tetraurelia |
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1.B.69.1.8 | Uncharacterized protein of 248 aas and 3 TMSs |
Eukaryota | Fungi, Basidiomycota | UP of Ustilago maydis |
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1.B.69.2.1 | Putative internally duplicated porin of 555 aas with each half probably having 4 TMSs. |
Eukaryota | Viridiplantae, Streptophyta | Sorghum bicolor (Sorghum) (Sorghum vulgare) |
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1.B.69.2.2 | Uncharacterized protein of 559 aas |
Eukaryota | Viridiplantae, Streptophyta | UP of Brachypodium distachyon (Purple false brome) (Trachynia distachya) |
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1.B.69.2.3 | Internally duplicated putative porin of 513 aas and 8 - 10 TMSs. |
Eukaryota | Fungi, Ascomycota | UP of Cladophialophora psammophila |
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1.B.69.2.4 | Uncharacterized protein of 513 aas and ~8 TMSs. |
Eukaryota | Euglenozoa | UP of Leishmania donovani |
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1.B.69.2.5 | Uncharacterized protein of 453 aas and 9 TMSs. |
Eukaryota | Metazoa, Chordata | UP of Xenopus laevis (African clawed frog) |
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1.B.7.1.1 | PorCa (B10) porin. The 3-d structure is known (PDB ID 2POR). |
Bacteria | Pseudomonadota | PorCa porin of Rhodobacter capsulatus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.7.1.2 | Paracoccus ion non-selective porin with 16 putative beta-strands, PorG (Saxena et al. 1997). |
Bacteria | Pseudomonadota | Porin of Paracoccus denitrificans |
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1.B.7.1.3 | PorI (OpmA) porin. Forms channels that allow the passive diffusion of small hydrophilic solutes up to an exclusion limit of about 600 Da. The 3-d structure is known (PDB ID 1PRN). |
Bacteria | Pseudomonadota | PorI porin of Rhodobacter (Rhodopseudomonas) blastica |
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1.B.7.1.4 | OmaA major-porin (Burdman et al., 2000). |
Bacteria | Pseudomonadota | OmaA of Azospirillum brasilense (Q9F9L3) |
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1.B.7.1.5 | Porin 41 (Por41) (Kleeberg, V., Neumann, U., Schultz, G.E. and Weckesser, J., unpublished) |
Bacteria | Pseudomonadota | Por41 of Rhodospirillum rubrum (Q9K556) |
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1.B.7.1.6 | Outer membrane porin | Bacteria | Pseudomonadota | SPO3430 of Silicibacter pomeroyi | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.7.1.7 | Putative porin of 332 aas |
Bacteria | Pseudomonadota | Putative porin of Rhodopseudomonas sphaeroides |
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1.B.7.1.8 | Porin of 385 aas (Moumène et al. 2015). |
Bacteria | Pseudomonadota | Porin of Ehrlichia ruminantium |
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1.B.70.1.1 | Putative outer membrane porin |
Bacteria | Pseudomonadota | OMP of Acinetobacter johnsonii (D0SAV4) |
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1.B.70.1.10 | Putative porin of 450 aas |
Bacteria | Chlorobiota | Porin of Pelodictyon luteolum |
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1.B.70.1.11 | Probable porin of 345 aas and 16 beta strands, RopA1. Required for infection by two phage, ΦM12 and N3 (Crook et al. 2013). |
Bacteria | Pseudomonadota | RopA1 of Sinorhizobium meliloti |
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1.B.70.1.12 | Putative porin of 506 aas, BLpp. Induced by glyphosate (N-[phosphonomethyl] glycine) when applied to Bradyrhizobium sp. (Lupinus)-nodulated lupin plants but not when applied to free living cultures (de María et al. 2007). |
Bacteria | Pseudomonadota | BLpp of Bradyrhizobium sp. (Lupinus) |
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1.B.70.1.13 | Outer membrane porin, RopAe of 338 aas. It is induced by copper deficiency and transports copper ions (González-Sánchez et al. 2018). |
Bacteria | Pseudomonadota | RopAe of Rhizobium etli |
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1.B.70.1.14 | Omp43 of 402 aas and 1 N-terminal TMS. This 43-kDa OMP is the major porin protein in Bartonella henselae strains, and its loss leads to changes to the expression of many genes (Kang et al. 2018). |
Bacteria | Pseudomonadota | Omp43 of Bartonella henselae |
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1.B.70.1.15 | Porin Omp2B of 362 aas. Allows facilitated diffusion of solutes through the porin (Vassen et al. 2019). Among surface protein antigens, the Omp2a and Omp2b porins display the highest diversity in Brucella species. The genes coding for these proteins are closely linked in the Brucella genome and oriented in opposite directions. They share between 85 and 100% sequence identity depending on the Brucella species, biovar, or genotype. Only the omp2b gene copy has been shown to be expressed, and genetic variation is extensively generated by gene conversion between the two copies. Size reduction occurred affecting the region encoding the surface L5 loop of the porin, previously shown to be critical in sugar permeability, followed by a nucleotide reduction in the surface L8 loop-encoding region. It resulted in a final omp2b gene size shared between two distinct clades of non-classical Brucella spp. (African bullfrog isolates) and the group of classical Brucella species (Leclercq et al. 2019). |
Bacteria | Pseudomonadota | Omp2B of Brucella abortus |
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1.B.70.1.2 | OmpIIIA or RopA of 340 - 166 aas and 1 N-terminal TMS. RopA and RopB (TC# 1.B.4.2.19), which have β-barrel structures, may be involved in the control of plant-microbial symbiosis. Kosolapova et al. 2019 demonstrated that the full-length RopA and RopB proteins form amyloid fibrils in vitro. These fibrils are β-sheet-rich, bind Thioflavin T (ThT), exhibit green birefringence upon staining with Congo Red (CR), and resist treatment with ionic detergents and proteases. Heterologously expressed RopA and RopB intracellularly aggregate in yeast and assemble into amyloid fibrils at the surface of E. coli. The capsules of the R. leguminosarum cells bind CR, exhibit green birefringence, and contain fibrils of RopA and RopB in vivo (Kosolapova et al. 2019). Based on similarity, they form passive diffusion pores that allow small molecular weight hydrophilic materials to cross the outer membrane. |
Bacteria | Pseudomonadota | OmpIIIA or RopA of Rhizobium leguminosarum |
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1.B.70.1.3 | Porin family protein | Bacteria | Pseudomonadota | HMPREF0731_0100 of Roseomonas cervicalis ATCC 49957 |
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1.B.70.1.4 | Porin | Bacteria | Pseudomonadota | MetexDRAFT_5733 of Methylobacterium extorquens DSM 13060 |
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1.B.70.1.5 | Porin | Bacteria | Pseudomonadota | Bind_1873 of Beijerinckia indica subsp. indica | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.70.1.6 | Putative uncharacterized protein | Bacteria | Pseudomonadota | Smlt2944 of Stenotrophomonas maltophilia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.70.1.7 | Secreted porin family protein | Bacteria | Pseudomonadota | Sfri_0510 of Shewanella frigidimarina | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.70.1.8 | Putative uncharacterized protein | Bacteria | Pseudomonadota | Bpro_0404 of Polaromonas sp. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.70.1.9 | Putative porin of 539 aas |
Bacteria | Planctomycetota | Porin of Rhodopirellula sallentina |
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1.B.71.1.1 | Putative porin of 231 aas |
Bacteria | Verrucomicrobiota | PP of Coraliomargarita akajimensis |
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1.B.71.1.2 | Putative porin of 258 aas |
Bacteria | Pseudomonadota | PP of Shewanella sediminis |
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1.B.71.1.3 | Putative porin of 269 aas |
Bacteria | Pseudomonadota | PP of Pseudoalteromonas haloplanktis |
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1.B.71.1.4 | Putative porin of 221 aas |
Bacteria | Pseudomonadota | PP of Hyphomonas neptunium |
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1.B.71.1.5 | Putative porin of 259 aas |
Bacteria | Verrucomicrobiota | PP of Akkermansia muciniphila |
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1.B.71.1.6 | Putative porin of 244 aas |
Bacteria | Thermodesulfobacteriota | PP of Desulfocapsa sulfexigens |
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1.B.71.1.7 | Putative porin of 227 aas and 1 N-terminal TMS |
Bacteria | Bdellovibrionota | PP of Bdellovibrio bacteriovorus |
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1.B.72.1.1 | Outer membrane porin, PomS of 317 aas (Aistleitner et al. 2013). |
Bacteria | Chlamydiota | PomS of Protochlamydia amoebophila |
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1.B.72.1.2 | Outer membrane porin, PomT of 345 aas (Aistleitner et al. 2013). |
Bacteria | Chlamydiota | PomT of Protochlamydia amoebophila |
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1.B.72.1.3 | Putative porin of 366 aas |
Bacteria | Pseudomonadota | PP of Accumulibacter phosphatis |
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1.B.72.1.4 | Putative porin of 300 aas |
Bacteria | Bacteroidota | PP of Pedobacter saltans |
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1.B.72.1.5 | Uncharacterized protein of 308 aas |
Bacteria | Bacteroidota | UP of Chitinophaga pinensis |
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1.B.72.1.6 | Uncharacterized protein of 325 aas |
Bacteria | Chlamydiota | UP of Protochlamydia amoebophila |
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1.B.72.2.1 | Uncharacterized protein of 343 aas. This sequence is homologous to the C-terminal 300 aas of 1.B.72.2.2, 2.3 and 2.4. |
Bacteria | Nitrospirota | UP of Candidatus Nitrospira defluvii |
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1.B.72.2.2 | Uncharacterized protein of 487 aas. This protein has an N-terminal 200 aas that are proline rich, and a C-terminal region homologous to 1.B.72.2.1, 2.3 and 2.4. Shows a region of 90 aas that is 31% identical to 1.B.72.1.3. |
Bacteria | Pseudomonadota | UP of Rhodovulum sp. PH10 |
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1.B.72.2.3 | Uncharacterized protein of 577 aas. This protein has an N-terminal 250 aas that are homologous to 1.B.4.2.1 and other members of the BRP family, but a C-terminal 300 aas that are homologous to the other members of subfamily 2 of the PomS/T family (1.B.72). |
Bacteria | Pseudomonadota | UP of Hyphomicrobium nitrativorans |
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1.B.72.2.4 | Uncharacterized protein of 1086 aas. Only the C-terminal 300 aas show sequence similiarity with other members of subfamily 1.B.72.2. Residues 235 - 291 show 35% identity (e-5)with YgbF of E. coli (2.C.1.2.1). |
Bacteria | Pseudomonadota | UP of Bradyrhizobium oligotrophicum |
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1.B.72.2.5 | Uncharacterized protein of 315 aas. |
Bacteria | Pseudomonadota | UP of Pelagibacterium halotolerans |
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1.B.73.1.1 | The outer membrane group 1 antigen capsule biogenesis/assembly protein, Wzi of 477 aas. It forms an 18 stranded beta barrel, is a lectin, and plays a role in generating the end product of capsule assembly (Rahn et al. 2003). The 2.6 Å structure reveals long extracellular loops that block the barrel entrance while a helical bundle blocks the other end of the pore (Bushell et al. 2013). Also functions as a passive bidirectional water specific porin (Sachdeva et al. 2016). |
Bacteria | Pseudomonadota | Wzi of E. coli |
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1.B.73.1.2 | Uncharacterized protein of 472 aas and 22 putative β-strands and one α-TMS. |
Bacteria | Thermodesulfobacteriota | UP of Thermodesulfobacterium geofontis |
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1.B.73.1.3 | Uncharacterized protein of 592 aas |
Bacteria | Thermodesulfobacteriota | UP of Syntrophobacter fumaroxidans |
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1.B.73.1.4 | Uncharacterized protein of 512 aas and 16 putative β-strains and one α-TMS. |
Bacteria | Pseudomonadota | UP of Saccharophagus degradans |
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1.B.73.1.5 | Uncharacterized protein of 575 aas with 13 putative β-strains and one N-terminal α-TMS. |
Bacteria | Bacteroidota | UP of Echinicola vietnamensis |
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1.B.73.2.1 | Uncharacterized protein of 498 aas with 20 putative β-strands and one N-terminal α-TMS. |
Bacteria | Bacteroidota | UP of Dyadobacter fermentans |
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1.B.73.2.2 | Uncharacterized protein of 470 aas |
Bacteria | Bacteroidota | UP of Paludibacter propionicigenes |
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1.B.74.1.1 | The outer membrane β-barrel protein, OmpL32 (Eshghi et al. 2012). |
Bacteria | Spirochaetota | OmpL32 of Leptospira interrogans |
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1.B.74.1.2 | Putative porin of 277 aas and 10 - 12 β-strands. |
Bacteria | Spirochaetota | Putative porin of Leptospira biflexa |
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1.B.74.1.3 | Putative porin of 242 aas |
Bacteria | Spirochaetota | Putative porin of Turneriella (Leptospira) parva |
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1.B.74.1.4 | Putative porin of 306 aas |
Bacteria | Spirochaetota | Putative porin of Leptonema illini |
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1.B.75.1.1 | DUF481 outer membrane protein of 241 aas, an N-terminal signal sequence and 10 putative β-TMSs. |
Bacteria | Pseudomonadota |
DUF481 OMP of Salmonella enterica |
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1.B.75.1.2 | DUF481 outer membrane protein of 358 aas, an N-terminal signal sequence and 12 putative β-TMSs. |
Bacteria | Planctomycetota | DUF481 OMP of Rhodopirellula sallentina |
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1.B.75.1.3 | YdiY OMP of 252 aas. Acid induces its synthesis (Stancik et al. 2002). |
Bacteria | Pseudomonadota | YdiY of E. coli K12 |
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1.B.75.1.4 | DUF481 outer membrane protein of 234 aas, an N-terminal signal sequence and 12 putative β-TMSs. |
Bacteria | Campylobacterota | OMP of Arcobacter butzleri |
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1.B.75.1.5 | DUF481 outer membrane protein of 240 aas, an N-terminal signal sequence and 12 putative β-TMSs. |
Bacteria | Aquificota | OMP of Persephenella marina |
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1.B.75.1.6 | DUF481 outer membrane protein of 247 aas, an N-terminal signal sequence and 11 putative β-TMSs. |
Bacteria | Pseudomonadota | OMP of Hirschia baltica |
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1.B.75.1.7 | Putative outer membrane protein of 330 aas and 12 putative beta strands. |
Bacteria | Myxococcota | Putative porin of Myxococcus xanthus |
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1.B.75.2.1 | DUF481 outer membrane protein of 276 aas, an N-terminal signal sequence and 12 putative β-TMSs. |
Bacteria | Bacteroidota | OMP of Saprospira grandis |
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1.B.75.2.2 | DUF481 outer membrane protein of 259 aas, an N-terminal signal sequence and 11 putative β-TMSs. |
Bacteria | Myxococcota | OMP of Myxococcus fulvus |
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1.B.75.3.1 | DUF481 outer membrane protein of 310 aas, an N-terminal signal sequence and 12 putative β-TMSs. |
Bacteria | Cyanobacteriota | OMP of Synecococcus sp. |
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1.B.75.3.2 | Salt-induced DUF481 outer membrane protein of 296 aas with an N-terminal signal sequence and 12 putative β-TMSs. |
Bacteria | Cyanobacteriota | OMP of Prochlorococcus marinus |
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1.B.76.1.1 | Putative outer membrane porin, CopB of 422 aas. It has an N-terminal TMS, followed by a hydrophilic proline/alanine-rich domain and a C-terminal putative 10 β-strand domain. It confers copper resistance (Behlau et al. 2011). |
Bacteria | Pseudomonadota | PP of Xanthomonas citri |
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1.B.76.1.2 | Copper resistance protein, CopB of 251 aas. It has an N-terminal TMS followed by a putative beta barrel domain of 10 - 12 beta strands. This protein is 95% identical to the ortholog in Acinetobacter baumannii which is involved in copper efflux and virulence (Williams et al. 2020). |
Bacteria | Pseudomonadota | CopB of Acinetobacter sp. |
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1.B.76.1.3 | Copper resistance protein, PcoB of 224 aas and 12 putative β-strands |
Bacteria | Pseudomonadota | PcoB of Simiduia agarivorans |
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1.B.76.1.4 | Fusion protein of 799 residues with an N-terminal extracytoplasmic (probably periplasmic) multicopper oxidase (Fet3; TC# 2.A.108) domain (residues 1-550) and a C-terminal putative copper resistance porin domain (residues 610 - 795). It is 50% identical to another fusion protein in Fluoribacter dumoffii of 827 aas (WP_010653677.1). |
Bacteria | Pseudomonadota | Fusion protein of Legionella drancourtii |
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1.B.76.1.5 | Copper resistance protein in the outer membrane, PcoB of 296 aas and 10 putative β-strands. Required for the copper-inducible expression of copper resistance. Encoded on plasmid pRJ1004 (Silver and Ji 1994). |
Bacteria | Pseudomonadota | PcoB of E. coli |
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1.B.76.1.6 | Copper resistance protein B, CopB of 332 aas and 12 putative β-strands. May function with the copper uptake system, CopCD and the periplasmic CopA protein (TC# 9.B.62.6.1) (Wijekoon et al. 2015). |
Bacteria | Pseudomonadota | CopCD of Pseudomonas fluorescens |
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1.B.76.1.8 | Blue multi-copper oxidase of 516 aas, CueO. CueO is involved in copper tolerance under aerobic conditions. It features the four typical copper atoms that act as electron transfer (T1) and dioxygen reduction (T2, T3; trinuclear) sites. In addition, it displays a methionine- and histidine-rich insert that includes a helix that blocks physical access to the T1 site (Cortes et al. 2015). It catalyzes oxidation of Mn2+ (Su et al. 2014). Also referred to as copper efflux oxidase (Kataoka et al. 2013). |
Pseudomonadota | CueO of E. coli |
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1.B.77.1.1 | The chloroplast outer membrane ion channel-forming porin of 207 aas and 9 predcted transmembrane β-strands, Oep23. A member of the DUF1990 Superfamily; found in chloroplast outer membranes from simple algae to higher plants (Goetze et al. 2015). |
Eukaryota | Viridiplantae, Streptophyta | Oep23 of Medicago truncatula (Barrel medic) (Medicago tribuloides) |
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1.B.77.1.10 | Uncharacterized protein with 9 N-terminal TMSs, homologous to members of the YndJ Family (9.B.227) and a C-terminal domain with extensive sequence similarity to members of the Oep23 family. |
Bacteria | Actinomycetota | UP of Cellulomonas fimi |
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1.B.77.1.2 | Bacterial Oep23 homologue of 219 aas. |
Bacteria | Planctomycetota | Oep23 homologue of Rhodopirellula baltica |
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1.B.77.1.3 | Oep23 homologue of 234 aas |
Eukaryota | Discosea | Oep23 homologue of Acanthamoeba castellanii |
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1.B.77.1.4 | Oep23 homologue of 255 aas |
Eukaryota | Viridiplantae, Chlorophyta | Oep23 homologue of Chlorella variabilis (Green alga) |
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1.B.77.1.5 | Oep23 homologue of 197 aas |
Bacteria | Acidobacteriota | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.77.1.6 | Oep23 homologue of 196 aas |
Bacteria | Actinomycetota | Oep23 homologue of Kitasatospora setae (Streptomyces setae) |
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1.B.77.1.7 | Putative glycogen metabolism protein of 197 aas |
Bacteria | Actinomycetota | Oep23 homologue of Leifsonia rubra |
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1.B.77.1.8 | Oep23 homologue of 198 aas |
Bacteria | Deinococcota | Oep23 homologue of Deinococcus radiodurans |
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1.B.77.1.9 | Oep23 of 242 aas |
Eukaryota | Rhodophyta | Oep23 of Chondrus crispus (Carrageen Irish moss) (Polymorpha crispa) |
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1.B.77.2.1 | Oep23 homologue of 279 aas (DUF1990 superfamily). |
Eukaryota | Bacillariophyta | Oep23 homologue of Thalassiosira oceanica (Marine diatom) |
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1.B.77.2.2 | Oep23 homologue of 362 aas |
Eukaryota | Bacillariophyta | Oep23 homologue of Phaeodactylum tricornutum |
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1.B.77.2.3 | Oep23 homologue of 238 aas |
Eukaryota | Haptophyta | Oep23 homologue of Emiliania huxleyi |
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1.B.77.2.4 | Oep23 homologue of 333 aas |
Eukaryota | Oep23 homologue of Nannochloropsis gaditana |
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1.B.78.1.1 | MtrB of 660 aas |
Bacteria | Pseudomonadota | MtrB of Vibrio vulnificus |
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1.B.78.1.2 | Decaheme-associated OMP of 662 aas. Similar to TC# 5.B.5.2.1. |
Bacteria | Pseudomonadota | DUF3374 homologue of Ferrimonas balparica |
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1.B.78.1.3 | DUF3374 homologue of 706 aas. |
Bacteria | Pseudomonadota | DUF3374 protein of Rhodoferax ferrireducens |
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1.B.78.1.5 | Decaheme-associated porin |
Bacteria | Pseudomonadota | Porin of Rhodanobacter fulvus |
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1.B.78.1.6 | Outer Membrane Receptor of 835 aas |
Bacteria | Thermodesulfobacteriota | OMR of Geobacter uraniireducens (Geobacter uraniumreducens) |
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1.B.79.1.1 | SpmT porin (N-terminus)-sphingomyelinase (external; C-terminus) of 490 aas and 8 putative transmembrane β-strands in a β-barrel. Transports glucose and phosphocholine (Speer et al. 2015) |
Bacteria | Actinomycetota | SpmT of Mycobacterium tuberculosis |
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1.B.79.1.2 | Putative endo/exonuclease/phosphatase family protein of 439 aas |
Bacteria | Actinomycetota | Uncharacterized protein of Streptomyces ipomoeae |
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1.B.8.1.1 | Voltage-dependent anion channel-1 (VDAC1; OMP2; Por1) porin. It is a component of the mitochondrial permeability transition pore (mPTP) which includes cyclophilin D, VDAC and the adenine nucleotide translocator (TC subfamily 2.A.29.1) (Austin et al. 2013). Mitochondrial synthesis of cardiolipin (CL) and phosphatidylethanolamine requires the transport of their precursors, phosphatidic acid and phosphatidylserine, respectively, to the mitochondrial inner membrane. The Ups1-Mdm35 and Ups2-Mdm35 complexes transfer phosphatidic acid and phosphatidylserine, respectively, between the mitochondrial outer and inner membranes. A Ups1-independent CL accumulation pathway requires several mitochondrial proteins with unknown functions including Mdm31. Miyata et al. 2018 identified VDAC1 (Por1) as a protein that interacts with both Mdm31 and Mdm35. Depletion of the porins Por1 and Por2 destabilized Ups1 and Ups2, decreased CL levels by ~90%, and caused loss of Ups2-dependent phosphatidylethanolamine synthesis, but did not affect Ups2-independent phosphatidylethanolamine synthesis in mitochondria. Por1 mutations that affected its interactions with Mdm31 and Mdm35, but not respiratory growth, also decreased CL levels. Using HeLa cells, the authors showed that mammalian porins also function in mitochondrial CL metabolism. Thus, yeast porins function in mitochondrial phospholipid metabolism, and porin-mediated regulation of CL metabolism appears to be evolutionarily conserved. VDACs are targeted to mitocondria via a C-terminal hydrophobic β-strand terminated by a hydrophiic residue (Klinger et al. 2019). Pentenediol-type compounds bind to VDAC1 (Unten et al. 2019). VDACs play a major role in the mitochondrial permeability transition, and inhibition of the MPT improves bone fracture repair (Shares et al. 2020). Gallic acid inhibits the celecoxib-induced mitochondrial permeability transition and reduces its toxicity (Salimi et al. 2021). Small molecules targeting VDAC (sorafenib, regorafenib and lenvatinib) have synergetic effects on hepatocarcinoma cell proliferation and survival (Ventura et al. 2023). Phosphorylation has the potential to modulate Por1, causing a marked effect on mitochondrial function. It also impacts cell morphology and growth both in respiratory and in fermenting conditions (Sousa et al. 2024). |
Eukaryota | Fungi, Ascomycota | Mitochondrial outer membrane VDAC of Saccharomyces cerevisiae |
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1.B.8.1.10 | Outer membrane porin, VDAC of 346 aas. This protein may function in the thylacoid membrane of the chloroplast as a non-selective voltage-indiependent porin (see TC# 1.B.8.8.7 and Kojima et al. 2018). |
Eukaryota | Rhodophyta | VDAC of Galdieria sulphuraria |
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1.B.8.1.11 | Porin, VDAC of 309 aas |
Eukaryota | Rhodophyta | VDAC of Galdieria sulphuraria |
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1.B.8.1.12 | Mitochondrial outer membrane voltage-dependent anion-selective channel protein 2, VDAC-2 of 294 aas. Protein:micelle ratios and cysteine residues in the protein influence VDAC2 stability and unfolding rates (Maurya and Mahalakshmi 2014). VDAC-2 performs a different subset of regulatory functions than VDAC1. It has anti-apoptotic features and contributes to gametogenesis.It may also regulate ROS, steroidogenesis and mitochondria-associated endoplasmic reticulum membrane regulatory pathways (Maurya and Mahalakshmi 2015). Plays a role in mitochondrial import of Bak and tBid-induced apoptosis (Naghdi et al. 2015). VDAC2 plasticity and stability in the mitochondrial outer membrane are modulated by physical properties of the bilayer (Srivastava et al. 2018). VDAC1 and VDAC2 are overall, very similar, exhibiting similar dynamic behavior and conformational homogeneity (Eddy et al. 2019). Altered skeletal muscle microtubule-mitochondrial VDAC2 binding is related to bioenergetic impairments after paclitaxel but not vinblastine chemotherapies (Ramos et al. 2019). Intramolecular disulfide bridges are present in VDAC2 from Rattus norvegicus (Pittalà et al. 2024). Voltage-dependent anion channel 2 (VDAC2) plays a crucial role in the host response to viral infection. The receptor for activated C kinase 1 (RACK1) is also a key host factor involved in viral replication. |
Eukaryota | Metazoa, Chordata | VDAC2 of Homo sapiens |
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1.B.8.1.13 | Mitochondrial outer membrane porin, PorA or VDAC (Troll et al. 1992). |
Eukaryota | Evosea | Mitochondrial outer membrane porin of Dictyostelium discoideum (Q01501) |
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1.B.8.1.14 | Voltage-dependent anion-selective channel (VDAC) protein of 282 aas |
Eukaryota | Oomycota | VDAC of Albugo laibachii |
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1.B.8.1.15 | VDAC1 of 276 aas, one of five isoforms. A knock out mutation (Δvdac1) resulted in abnormal ovule formation during female gametogenesis, and both the mitochondrial transmembrane potential and ATP synthesis were reduced (Pan et al. 2014). Targeting and surface recognition of mitochondrial β-barrel proteins in yeast, humans and plants depends on the hydrophobicity of the last β-hairpin of the β-barrel, but the presence of a hydrophilic amino acid at the C-terminus of the penultimate β-strand is also required for mitochondrial targeting (Klinger et al. 2019). Kanwar et al. 2020 presented a comparative overview to provide an integrative picture of the interactions of VDAC with different proteins in both animals and plants. |
Eukaryota | Viridiplantae, Streptophyta | VDAC1 of Arabidopsis thaliana |
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1.B.8.1.16 | Voltage-dependent anion channel, VDAC, of 283 aas |
Eukaryota | Metazoa, Chordata | VDAC of Paralichthys olivaceus (Bastard halibut) (Hippoglossus olivaceus) |
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1.B.8.1.17 | Non-selective channel of the thylakoid membrane of 275 aas and one TMSs, CpTPOR (Kojima et al. 2018). The channels are large enough for permeation of small organic compounds (e.g. carbohydrates and amino acids with Mr < 1500). The pore has an estimated radius of ∼1.3 nm and exhibits a typical single-channel conductance of 1.8 nS in 1 m KCl with infrequent closing transitions. CpTPOR exhibits no obvious selectivity for anions and no voltage-dependent gating. It presumably enables rapid transfer of various metabolites between the lumen and stroma (Kojima et al. 2018). |
Eukaryota | TPOR of Cyanophora paradoxa chloroplasts (muroplasts) |
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1.B.8.1.18 | VDAC2 of 281 aas, 1 N-terminal α-TMS and 19 β-TMSs. Forms channels much like those of VDAC1 (Guardiani et al. 2018). |
Eukaryota | Fungi, Ascomycota | VDAC2 of Saccharomyces cerevisiae |
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1.B.8.1.19 | Outer membrane porin, VDAC3 (HSR2) of 274 aas. This protein may function in the thylacoid membrane of the chloroplast as a non-selective voltage-indiependent porin (see TC# 1.B.8.8.7 and Kojima et al. 2018). |
Eukaryota | Viridiplantae, Streptophyta | HSR2 of Arabidopsis thaliana (Mouse-ear cress) |
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1.B.8.1.2 |
VDAC3 porin. The human orthologue forms small pores in membranes (Checchetto et al. 2014). VDAC3 is a sensor of the oxidative state in the mitochondrial intermembrane space, and cysteyl residue modification appears to play a role (Reina et al. 2016). Post translational modifications of VDAC3 that can impact its protective role against reactive oxygen species (ROS), which is particularly important in the ALS context (Pittalà et al. 2022). |
Eukaryota | Metazoa, Chordata | Mitochondrial outer membrane VDAC3 of Mus musculus |
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1.B.8.1.20 | Miltochondrial outer membrane porin, VDAC, of 283 aas. The channel adopts an open conformation at low or zero membrane potential and a closed conformation at potentials above 30-40 mV. The open state has a weak anion selectivity whereas the closed state is cation-selective. The absence of VDAC is associated with increased reactive oxygen species (ROS) production (Shuvo et al. 2019). |
Eukaryota | Fungi, Ascomycota | VDAC of Neurospora crassa |
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1.B.8.1.3 | VDAC1, VDAC-1 or VDAC porin of 283 aas, which is > 99% identical to human (P21796) and mouse (60932) VDAC1. Mammals possess three VDACs (VDAC1, 2 and 3) encoded by three genes, but they are all similar in sequence (~60-70% identical) (Messina et al., 2011). The 3-d structure of the human VDAC1 is known (PDB ID 2JK4; Bayrhuber et al. 2008). Reviewed by Shoshan-Barmatz et al. 2015. VDAC1 is found both in mitochondria and the plasma membrane (Lawen et al. 2005) where it may cause cytoplasmic ATP loss.. It may be involved in cancer (Shoshan-Barmatz et al. 2017) and Alzheimer's disease (AD) (Shoshan-Barmatz et al. 2018). Along with its low toxicity profile and high antioxidant activity, the gallic acid derivative, AntiOxBEN3, strongly inhibits calcium-dependent mitochondrial permeability transition pore (mPTP) opening (Teixeira et al. 2018). VDAC dimerization plays a role in mitochondrial
metabolic regulation and apoptosis in response to cytosolic
acidification during cellular stress, and E73 is involved (Bergdoll et al. 2018). Inhibiting VDAC1 overproduction and plasma membrane insertion in β-cells preserves insulin secretion in diabetes (Zhang et al. 2018). βII and βIII-tubulin, bound to VDAC, regulate VDAC permeability (Puurand et al. 2019). This VDAC porin interacts
with carrier precursors arriving in the intermembrane space and
recruits TIM22 complexes, thus ensuring efficient transfer of the
precursors to the inner membrane translocase (Ellenrieder et al. 2019). A method has been develped to determine the number of VDAC1 channels (and other integral membrane proteins) in nanodiscs under various assembly conditions (Häusler et al. 2020). Stable low-conducting states of human VDAC1 predominantly take place from disordered events and do not result from the displacement of a voltage sensor or a significant change in the pore. Conductance jumps reveal entropy as a key factor for VDAC gating (Preto et al. 2022). The lysyl residue at position 12 in the pore interior is responsible for most of VDAC's voltage sensitivity (Ngo et al. 2022). Oral administration of VDAC1-derived small peptides increases circulating testosterone levels in male rats (Martinez-Arguelles et al. 2022). Possible alternative conformational states of VDAC have been considered for the closed state (Mannella 2023). HSP90 C-terminal domain inhibition promotes
VDAC1 oligomerization via decreasing K274 mono-ubiquitination in hepatocellular carcinoma (Zhang et al. 2023). Silencing the mitochondrial gatekeeper, VDAC1, is a potential treatment for bladder cancer (Alhozeel et al. 2024). TRO19622 at 5 μM and 50 μM is an inhibitor of VDACs (Garriga et al. 2024). VDAC1 oligomerization inhibitors increase pigmentation in zebrafish and in human skin explants (Lv et al. 2024). VDAC1-based peptides are potential modulators
of VDAC1 interactions with its partners and as a therapeutic for cancer,
NASH, and diabetes (Shteinfer-Kuzmine et al. 2024). VDAC1 is an important negative regulator of melanogenesis (Wang et al. 2022). Knockdown of human VDAC1 promotes ferroptosis in diffuse large B-cell lymphoma (Lin et al. 2025). The human ortholog is almost identical.
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Eukaryota | Metazoa, Chordata | Mitochondrial and plasma membrane VDAC1 of Bos taurus. |
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1.B.8.1.4 | VDAC porin. The open state has a weak anion selectivity whereas the closed state is cation-selective. |
Eukaryota | Viridiplantae, Streptophyta | Mitochondrial outer membrane VDAC of Triticum aestivum | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.8.1.5 | Non green plastid porin | Eukaryota | Viridiplantae, Streptophyta | Plastid porin of Pisum sativum | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.8.1.6 | Voltage-dependent anion-selective porin1 (Porin-1, VDAC or Por-1) (De Pinto et al. 1989; Aiello et al., 2004) (one of three paralogues). Mutations in VDAC leads to neurologic dysfunction and male infertility in Drosophila (Graham et al., 2010). Porin 1 is abundantly expressed in both male and female germ cell tissues; Porin 2 is abundant in testis but in small amounts in ovaries. The immuno-histological stain of ovaries shows that Porin isoform 1 is selectively targeted to follicular cells while Porin isoform 2 is present in mitochondria of the epithelial sheath cells of the ovariole (Guarino et al. 2006; Specchia et al. 2008). |
Eukaryota | Metazoa, Arthropoda | Porin 1 of Drosophila melanogaster |
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1.B.8.1.7 | Voltage-independent, cation-selective porin2 (Porin-2 or Por-2) (converted to anion selective by changing Glu-66 and Glu-163 to lysines; Aiello et al., 2004). One of three paralogues (Craigen and Graham, 2008). Porin 1 is abundantly expressed in both male and female germ cell tissues; Porin 2 is abundant in testis but in small amounts in ovaries. The immuno-histological stain of ovaries shows that Porin 1 is selectively targeted to follicular cells while Porin 2 is present in mitochondria of the epithelial sheath cells of the ovariole (Specchia et al. 2008). |
Eukaryota | Metazoa, Arthropoda | Porin 2 of Drosophila melanogaster |
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1.B.8.1.8 |
Rice VDAC4. Channels formed in planar bilayers exhibit large conductance (4.6 ± 0.3 nS in 1 M KCl), strong voltage dependence and weak anion selectivity. The open state of the channel is permeable to ATP (Godbole et al. 2011). |
Eukaryota | Viridiplantae, Streptophyta | VDAC4 of Oryza sativa |
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1.B.8.1.9 | Mitochondrial outer membrane porin, VDAC, of 292 aas (De Pinto et al. 1989). Voltage-dependent anion channel 2 (VDAC2) is an important channel protein that plays a crucial role in the host response of insects to viral infection. The receptor for activated C kinase 1 (RACK1) is also a key host factor involved in viral replication.Bombyx mori VDAC2 (BmVDAC2) and B. mori RACK1 (BmRACK1) may interact with Bombyx mori nucleopolyhedrovirus (BmNPV) (Zhu et al. 2024). |
Eukaryota | Metazoa, Arthropoda | VDAC of Drosophila melanogaster |
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1.B.8.2.1 | 19 β-stranded barrel translocase across the outer membrane, Tom40 (Pfam Porin 3 Superfamily). |
Eukaryota | Fungi, Ascomycota | Tom40 of Saccharomyces cerevisiae |
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1.B.8.2.10 | Porin protein of 368 aas |
Eukaryota | Ciliophora | Porin protein of Tetrahymena thermophila |
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1.B.8.2.11 | Putative porin of 284 aas |
Eukaryota | Fungi, Microsporidia | Putative porin of Encephalitozoon cuniculi |
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1.B.8.2.12 | Entamoeba histolytica, an anaerobic intestinal parasite causing dysentery and extra-intestinal abscesses in humans, possesses highly reduced and divergent mitochondrion-related organelles (MROs) called mitosomes. This organelle lacks many features associated with canonical aerobic mitochondria and even other MROs such as hydrogenosomes. The Entamoeba mitosome has been found to have a compartmentalized sulfate activation pathway, which has a role in amebic stage conversion. It also features a unique shuttle system that delivers proteins from the cytosol to the mitosome. Only Entamoeba mitosomes possess a novel subclass of β-barrel outer membrane protein called MBOMP30.The mitosome protein import complex consisting of at least two proteins, TOM40, which provides the channel, and TOM60, which seems to be necessary for protein import (Makiuchi et al. 2013; Santos et al. 2016). |
Eukaryota | Evosea | TOM40/TOM60 of Entamoeba histolytica |
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1.B.8.2.13 | TOM40 (377 aas)/TOM22 (105 aas)/TOM7 (66 aas) of the mitochondrial import receptor, 3 subunits (Wunderlich 2022). |
Eukaryota | Apicomplexa | TOM complex of Plasmodium falciparum |
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1.B.8.2.2 | Tom40 of 344 aas |
Eukaryota | Metazoa, Arthropoda | Tom40 of Drosophila melanogaster |
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1.B.8.2.3 | Eukaryotic porin family, Tom40-2 of 310 aas |
Eukaryota | Viridiplantae, Streptophyta | Tom40 of Arabidopsis thaliana |
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1.B.8.2.4 | Tom40 of 361 aas |
Eukaryota | Discosea | Tom40 of Acanthamoeba castellanii |
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1.B.8.2.5 | Mitochondrial import receptor, Tom40 of 361 aas |
Eukaryota | Metazoa, Chordata | Tom40 of Homo sapiens |
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1.B.8.2.6 | Tom40 of 314 aas |
Eukaryota | Evosea | Tom40 of Dictyostelium discoideum |
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1.B.8.2.7 | Tom40 of 264 aas |
Eukaryota | Bacillariophyta | Tom40 of Thalassiosira occanica |
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1.B.8.2.8 | Tom40 of 301 aas |
Eukaryota | Metazoa, Nematoda | Tom40 of Caenorhabditis elegans |
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1.B.8.2.9 | Mitochondrial import receptor, Tom40 of 394 aas |
Eukaryota | Apicomplexa | Tom40 of Plasmodium knowlesi |
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1.B.8.3.1 | Putative mitochondrial porin of 309 aas (Porin3_VDAC superfamily) |
Eukaryota | Ciliophora | MPP family member of Tetrahymena thermophila (Q22Z08) |
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1.B.8.3.2 | Mitochondrial porin of 305aas (Porin3_VDAC superfamily). Exhibits the properties of a voltage-dependent general diffusion porin with cation-selectivity and a pore diameter of 1.3 nm (Ludwig et al. 1989). |
Eukaryota | Ciliophora | MPP family member of Paramecium tetraurelia (Q3SE03) |
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1.B.8.3.3 | Putative mitochondrial porin of 301aas (Porin3_VDAC superfamily) |
Eukaryota | Ciliophora | MPP family member of Oxytricha trifallax (J9JBL0) |
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1.B.8.4.1 | VDAC homologue of 277 aas |
Eukaryota | Euglenozoa | VDAC of Leishmania mexicana |
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1.B.8.5.1 | VDAC homologue |
Eukaryota | Apicomplexa | VDAC of Theileria orientalis |
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1.B.8.5.2 | VDAC (OMPP) homologue of 289 aas and 0 TMSs. |
Eukaryota | Apicomplexa | VDAC of Plasmodium falciprarum |
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1.B.8.6.1 | The Mdm10 protein of 493 aas, a putative eukaryotic porin. It belongs to the eukaryotic porin 3 superfamily together with VDAC and Tom40 (Flinner et al. 2013). This protein is also listed under TC# 1.B.33.3.1 and TC#9.B.58.1.1 as part of two complexes: the mitochondrial Sorting and Assembly Machinery (SAM) and the TULIP complex, respectively. |
Eukaryota | Fungi, Ascomycota | Mdm10 of Saccharomyces cerevisiae |
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1.B.8.6.2 | Mdm10 protein of 646 aas |
Eukaryota | Fungi, Basidiomycota | Mdm10 of Ustilago maydis |
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1.B.8.6.3 | Mdm10 protein of 317 aas |
Eukaryota | Discosea | Mdm10 of Acanthamoeba castellanii |
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1.B.8.6.4 | Uncharacterized protein of 323 aas |
Eukaryota | Evosea | Mdm10 of Dictyostelium discoideum |
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1.B.8.6.5 | Uncharacterized protein of 435 aas |
Eukaryota | Fungi, Ascomycota | UP of Pyrenophora tritici-repentis |
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1.B.8.7.1 | Porin protein of 290 aas |
Eukaryota | Euglenozoa | Porin protein of Euglena gracilis |
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1.B.8.8.1 | Pore-forming β-barrel porin of 308 aas in hydrogenosomes, Tom40-1 (Makki et al. 2019). |
Eukaryota | Parabasalia | Tom40-1 of Trichomonas vaginalis |
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1.B.8.8.2 | Pore-forming β-barrel porin of 290 aas, present in hydrogenosomes, Tom40-2 (Makki et al. 2019). |
Eukaryota | Parabasalia | Tom40-2 of Trichomonas vaginalis |
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1.B.8.8.3 | Pore-forming β-barrel porin of 305 aas in hydrogenosomes, Tom40-3 (Makki et al. 2019). |
Eukaryota | Parabasalia | Tom40-3 of Trichomonas vaginalis |
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1.B.8.8.4 | Pore-forming β-barrel porin of 296 aas in hydrogenosomes, Tom40-4 (Makki et al. 2019). |
Eukaryota | Parabasalia | Tom40-4 of Trichomonas vaginalis |
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1.B.8.8.5 | Pore-forming β-barrel porin of 397 aas in hydrogenosomes, Tom40-5 (Makki et al. 2019). |
Eukaryota | Parabasalia | Tom40-5 of Trichomonas vaginalis |
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1.B.8.8.6 | Pore-forming β-barrel porin of 298 aas in hydrogenosomes, Tom40-6 (Makki et al. 2019). |
Eukaryota | Parabasalia | Tom40-6 of Trichomonas vaginalis |
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1.B.80.1.1 | Putative outer membrane porin, possibly involved in trans outer membrane electon flow, of 444 aas (Liu et al. 2015) |
Bacteria | Myxococcota | OM porin of Anaeromyxobacter dehalogenans |
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1.B.80.1.2 | Putative porin of 526 aas |
Bacteria | Myxococcota | PP of Plesiocystis pacifica |
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1.B.80.1.3 | Putative porin of 475 aas |
Bacteria | Deferribacterota | PP of Denitrovibrio acetiphilus |
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1.B.80.1.4 | Putative porin of 464 aas |
Bacteria | Myxococcota | PP of Stigmatella aurantiaca |
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1.B.80.1.5 | Putative porin of 574 aas |
Bacteria | Myxococcota | PP of Sorangium cellulosum (Polyangium cellulosum |
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1.B.80.2.1 | Putative porin of 515 aas and 24 predicted β-strand |
Bacteria | Pseudomonadota | PP of Thiolapillus brandeum |
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1.B.80.2.2 | Putative porin of 470 aas and 22 predicted β-strands. |
Bacteria | Pseudomonadota | PP of Methylococcus capsulatus |
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1.B.80.2.3 | Putative porin of 418 aas |
Bacteria | Aquificota | PP of Desulfurobacterium thermolithotrophum |
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1.B.80.2.4 | Putative porin of 424 aas |
Bacteria | Aquificota | PP of Thermovibrio ammonificans |
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1.B.80.2.5 | Putative porin of 421 aas |
Bacteria | Ignavibacteriota | PP of Melioribacter roseus |
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1.B.81.1.1 | DUF 2490 domain protein of 228 aas |
Bacteria | Bacteroidota | DUF2490 porin of Nonlabens dokdonensis |
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1.B.81.1.10 | Uncharacterized protein of 238 aas |
Bacteria | Bacteroidota | UP of Chryseobacterium indologenes |
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1.B.81.1.11 | DUF2940 protein of 220 aas |
Bacteria | Bacteroidota | UP of Nonlabens dokdonensis (Donghaeana dokdonensis) |
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1.B.81.1.12 | Uncharacterized protein of 246 aas |
Bacteria | Bacteroidota | UP of Mariniradius saccharolyticu |
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1.B.81.1.13 | Uncharacterized protein of 219 aas |
Bacteria | Bacteroidota | UP of Fluviicola taffensis |
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1.B.81.1.14 | Uncharacterized DUF2490 domain-containing protein of 241 aas |
Bacteria | Pseudomonadota | UP of Methylosarcina fibrata |
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1.B.81.1.15 | Uncharacterized protein of 234 aas |
Bacteria | Pseudomonadota | UP of Sphingomonas sanxanigenens |
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1.B.81.1.16 | Uncharacterized protein of 350 aas, one N-terminal α-TMS and 12 predicted β-TMSs |
Bacteria | Pseudomonadota | UP of Nitrosomonas sp. (strain Is79A3) |
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1.B.81.1.2 | Putative porin of 230 aas |
Bacteria | Bacteroidota | PP of Pedobacter saltans |
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1.B.81.1.3 | Putative porin of 221 aas |
Bacteria | Pseudomonadota | PP of Spingobium indicum |
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1.B.81.1.4 | Putative porin of 228 aas |
Bacteria | Pseudomonadota | PP of Methylobacterium populi |
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1.B.81.1.5 | Uncharacterized protein of 253 aas |
Bacteria | Bacteroidota | UP of Owenweeksia hongkongensis |
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1.B.81.1.6 | Uncharacterized protein of 244 aas |
Bacteria | Bacteroidota | UP of Cellulophaga algicola |
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1.B.81.1.7 | Uncharacterized protein of 254 aas |
Bacteria | Bacteroidota | UP of Runella slithyformis |
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1.B.81.1.8 | Uncharacterized protein of 244 aas |
Bacteria | Bacteroidota | UP of Haliscomenobacter hydrossis |
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1.B.81.1.9 | Uncharacterized protein of 222 aas |
Bacteria | Pseudomonadota | UP of Legionella oakridgensis |
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1.B.81.2.1 | Uncharacterized protein of 223 aas |
Bacteria | Chlorobiota | UP of a Chlorobium species |
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1.B.81.2.2 | Uncharacterized DUF2490 domain-containing protein of 237 aas with one N-terminal α-TMS and 11 predicted β-TMSs. |
Bacteria | UP of Bacterium 336/3 |
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1.B.82.1.1 | TGD4 of 479 aas and 19 - 21 putative beta strands in a β-barrel structure (Wang et al. 2013) that may form a porin to transfer lipids from the ER across the outer chloroplast membrane. TGD5 (TC#8.A.86; 91 aas and 2 TMSs) may function to transfer lipids from the ER to TGD4, and then to the TGD123 ABC complex (TC# 3.A.1.27.1.2) in the inner envelope membrane for import into the chloroplast inner membrane or matrix (Fan et al. 2015). |
Eukaryota | Viridiplantae, Streptophyta | TGD4 of Arabidopsis thaliana (Mouse-ear cress) |
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1.B.82.1.2 | TDG4 homologue |
Eukaryota | Viridiplantae, Chlorophyta | TDG4 of Ostreococcus lucimarinus |
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1.B.82.1.3 | Uncharacterized protein of 701 aas. |
Eukaryota | Viridiplantae, Streptophyta | UP of Vitis vinifera (Grape) |
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1.B.84.1.1 | The Outer Membrane Porin/Phospholipase A1 (OMPLA1) of 355 aas and 12 - 14 transmembrane β-strands in a β-barrel having porin properties. Transports urea, ammonium ions and small molecules with diameters of less than 4 Å. Besides its role as a phospholipase, it lets urea enter and ammonium exit the periplasm, thereby contributing to acid tolerance (Vollan et al. 2017).
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Bacteria | Campylobacterota | OMPLA1 of Helicobacter pylori |
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1.B.84.1.2 | Outer membrane phospholipase A-like protein, PldA, of 273 aas and 13 predicted transmembrane β-strands in a β-barrel with putative porin activity. |
Bacteria | Bacteroidota | PldA of Flavobacterium johnsoniae Å (Cytophaga johnsonae) |
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1.B.84.1.3 | Putative porin/phospholipase A1 of 252 aas and 10 - 11 β-strands in a β-barrel. |
Bacteria | Pseudomonadota | PLase A1 of Vibrio parahaemolyticus |
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1.B.84.1.4 | Uncharacterized protein of 406 aas with an-N-terminal TMS followed by a 190 aa long N-terminal hydrophilic domain and a C-terminal putative 11 strainded β-barrel domain. Putative phospholipase A1. |
Bacteria | Pseudomonadota | UP of Sphingobium baderi |
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1.B.84.1.5 | Phospholipase A1 of 417 aas and 14 predicted β-strands. |
Bacteria | Pseudomonadota | Phospholipase A1 of Acidovorax avenae |
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1.B.84.1.6 | Phospholipase A1 of 407 aas and 10 predicted β-strands. |
Bacteria | Verrucomicrobiota | PLA1 of Opitutus terrae |
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1.B.84.1.7 | Uncharacterized protein of 316 aas |
Bacteria | Elusimicrobiota | UP of Elusimicrobia bacterium GWD2_63_28 (subsurface metagenome) |
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1.B.84.1.8 | Uncharacterized protein of |
Bacteria | Fibrobacterota | UP of Fibrobacter sp. (anaerobic digester metagenome) |
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1.B.85.1.1 | The pellicle exporting porin of 1193 aas and 1 N-terminal α-helical TMS with up to 48 β-strands, PelB. The porin is in the N-terminal domain while the 19 predicted periplasmic TPRs are C-terminal. These repeats bind PelA, a periplasmic hydrolase (see the family description and Marmont et al. 2017). PelA and PelB together form a modification and secretion complex essential for Pel polysaccharide-dependent biofilm formation in P. aeruginosa (Marmont et al. 2017).
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Bacteria | Pseudomonadota | PelB of Pseudomonas aeruginosa |
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1.B.85.1.2 | Extracellular Matrix protein, PelB, of 1332 aas and 2 TMSs, one N-terminal and one C-terminal. |
Bacteria | Pseudomonadota | UP of Ralstonia solanacearum |
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1.B.85.1.3 | Biofilm formation protein, PelB, of ``59 aas and 1 N-terminal TMS and possibly a second near the C-terminus. |
Bacteria | Pseudomonadota | of Alishewanella agri |
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1.B.85.1.4 | Tetratricopeptide repeat-containing protein, TPR_4, of 900 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | TPR_4 of Nitrosospira multiformis |
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1.B.85.1.6 | Uncharacterized protein of 1278 aas and 1 N-terminal TMS plus 1 possible C-terminal TMS. |
Bacteria | Pseudomonadota | UP of Delftia acidovorans |
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1.B.85.1.7 | Uncharacterized protein of 1025 aas and 1 N-terminal TMS and possibly one C-terminal TMS. |
Bacteria | Pseudomonadota | UP of Marinobacter vinifirmus |
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1.B.89.1.1 | The pore-forming protein, GjpA of 558 aas and up to 9 TMSs in a 1 (N-terminal) + 2 + 2 + 2 + 2 TMS arrangement with a fairly long (~ 120 aas) hydrophilic C-terminal domain. The channel has an average single-channel conductance of 800 pS in 1 M KCl, is moderately anion-selective, and does not show a voltage dependence for voltages between +100 and -100 mV. GjpA may import and export negatively charged molecules across the outer cell envelope (Jiménez-Galisteo et al. 2017). |
Bacteria | Actinomycetota | GjpA of Gordonia jacobaea |
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1.B.89.1.10 | Uncharacterized protein of 524 aas and ~ 8 putative TMSs. TC BLAST with this protein brings up TC# 9.B.94.1.5 with a score of 0.0066 ( residues 198 - 318 aligning with residues 224 -351 in the protein with TC# 9.B.94.1.5. |
Bacteria | Actinomycetota | UP of Mycobacterium cookii |
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1.B.89.1.11 | PE family protein of 556 aas and ~ 8 putative TMSs. In TC BLAST, this protein hits9.B.94.1.2 with an e-value of e-6 with filters, aligning residues 45 - 122 with residues 45 - 118 in 9.B.94.1.2. |
Bacteria | Actinomycetota | PE family protein of Mycobacterium ulcerans |
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1.B.89.1.12 | PE family protein of 469 aas and ~ 8 putative TMSs. This protein brings up homologues of 1.B.89, 9.B.96 and 1.B.94 (the PE proteins of the latter systems). |
Bacteria | Actinomycetota | PE family protein of Mycobacterium gordonae |
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1.B.89.1.13 | PE family protein of 1018 aas and ~ 8 putative TMSs. |
Bacteria | Actinomycetota | PE family protein of Mycobacterium canettii |
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1.B.89.1.14 | PE family protein of 914 aas and up to ~12 TMSs. |
Bacteria | Actinomycetota | PE family protein of Mycobacterium tuberculosis |
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1.B.89.1.15 | Uncharacterized protein of 486 aas and ~8 TMSs |
Bacteria | Actinomycetota | UP of Mycolicibacterium flavescens |
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1.B.89.1.16 | Uncharacterized protein of 521 aas and ~ 8 TMSs. |
Bacteria | Actinomycetota | UP of Mycolicibacterium hodleri |
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1.B.89.1.17 | Uncharacterized protein of 370 aas and ~ 8 TMSs |
Bacteria | Actinomycetota | UP of Mycolicibacterium porcinum |
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1.B.89.1.18 | PE family protein of 325 aas and ~8 TMSs |
Bacteria | Actinomycetota | PE protein of Mycobacterium tuberculosis |
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1.B.89.1.19 | Uncharacterized protein of 450 aas and ~8 TMSs. |
Bacteria | Actinomycetota | UP of Mycobacterium grossiae |
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1.B.89.1.2 | Uncharacterized protein with 476 aas and up to 8 predicted TMSs. |
Bacteria | Actinomycetota | UP of Mycolicibacterium smegmatis |
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1.B.89.1.20 | Uncharacterized protein of 399 aas and ~ 10 TMSs. |
Bacteria | Actinomycetota | UP of Mycobacterium botniense |
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1.B.89.1.21 | Putative porin protein encoded bya gene adjacent to one encoding a 6 TMS protein, YvaB, that may function in the export of a peptide toxin. The exporter has TC# 9.A.31.1.2. |
Bacteria | Actinomycetota | YvaB of Streptomyces coelicolor |
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1.B.89.1.22 | The PE12 protein of 308 aas with possibly 3 - 5 α-helical TMSs. PE12 can suppress apoptosis and inhibit the proinflammatory cytokine response. PE12 is related to macrophage phagocytosis (Xu et al. 2024). |
Bacteria | Actinomycetota | PE12 of Mycobacterium tuberculosis |
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1.B.89.1.3 | PE family protein of 503 aas and up to 10 TMSs. The PE family is described under TC# 9.B.96 and is also called the PE-PGRS Family. |
Bacteria | Actinomycetota | PE family protein of Mycobacterium gordonae |
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1.B.89.1.4 | Uncharacterized protein of 482 aas and up to 8 putative TMSs. |
Bacteria | Actinomycetota | UP of Gordonia polyisoprenivorans |
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1.B.89.1.5 | Uncharacterized protein of 472 aas and ~ 6 putative TMSs. |
Bacteria | Actinomycetota | UP of Mycolicibacterium porcinum |
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1.B.89.1.6 | Uncharacterized protein of 462 aas and ~ 8 putative TMSs |
Bacteria | Actinomycetota | UP of Mycobacterium aquaticum |
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1.B.89.1.7 | Uncharacterized protein of 321 aas and ~ 8 TMSs. |
Bacteria | Actinomycetota | UP of Mycobacterium eburneum |
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1.B.89.1.8 | Uncharacterized protein of 506 aas and ~ 8 putative TMSs. |
Actinomycetota | UP of Mycolicibacterium aubagnense |
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1.B.89.1.9 | Uncharacterized protein of 766 aas and more than 8 potential TMSs. |
Bacteria | Actinomycetota | UP of Mycolicibacter senuensis |
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1.B.89.2.1 | Uncharacterized protein of 279 aas and ~6 apparent TMSs asumming an α-helical structure. However, it might have a beta structure as an alternative. |
Bacteria | Actinomycetota | UP of Mycolicibacter heraklionensis |
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1.B.89.2.2 | Uncharacterized protein of 21- aas and 2 TMSs. |
Bacteria | Actinomycetota | UP of Mycolicibacter arupensis |
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1.B.89.2.3 | Uncharacterized protein of 233 aas and 4 or more TMSs |
Bacteria | Actinomycetota | UP of Mycobacterium shimoidei |
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1.B.89.2.4 | PE-PPE domain-containing protein of 508 aas and ~8 TMSs. |
Bacteria | Actinomycetota | PE-PPE domain protein of Mycolicibacter icosiumassiliensis |
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1.B.9.1.1 | Fatty acid outer membrane porin. Gated by high affinity ligand (fatty acid) binding which causes conformational changes in the N-terminus that open up a channel for substrate diffusion (Lepore et al., 2011). May function in the transport of phenylpropanoids (resveratrol, naringenin and rutin) (Zhou et al. 2014). |
Bacteria | Pseudomonadota | FadL of E. coli |
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1.B.9.1.2 | FadL homologue (Bhat et al. 2011). |
Bacteria | Myxococcota | FadL homologue of Myxococcus xanthus |
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1.B.9.1.3 | Putative porin of 441 aas |
Bacteria | Nitrospirota | Porin of Candidatus Nitrospira defluvii |
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1.B.9.1.4 | Outer membrane protein P1 of 459 aas |
Bacteria | Pseudomonadota | OmpP1 of Haemophilus influenzae |
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1.B.9.1.5 | Putative fatty acid-transporting porin of 434 aas, OmpP1, FadL, TodX. It has used to generate an effective vaccine against Bordetella bronchiseptica (Zhang et al. 2019). |
Bacteria | Pseudomonadota | OmpP1 of Bordetella bronchiseptica (Alcaligenes bronchisepticus) |
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1.B.9.1.6 | Long alkane hydrocarbon chain (~C28) transporting outer membrane porin, FadL of 546 aas (Gregson et al. 2018). |
Bacteria | Pseudomonadota | FadL porin of the obligate marine hydrocarbon-degrading bacterium, Thalassolituus oleivorans MIL-1. |
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1.B.9.2.1 | Toluene/m-xylene outer membrane porin, XylN or FadL. May also transport medium-chain-length 3-hydroxyalkanoic acids (Yuan et al. 2008). |
Bacteria | Pseudomonadota | XylN of Pseudomonas putida |
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1.B.9.2.2 | The 14 TMS hydrocarbon porin, TodX. The x-ray structure is known (3BS0-A) (Hearn et al., 2008). | Bacteria | Pseudomonadota | TodX of Pseudomonas putida (3BS0_A) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.9.2.3 | The 14 TMS hydrocarbon porin, TbuX. The crystal structure is known. (3BRY_A) (Hearn et al., 2008). | Bacteria | Pseudomonadota | TbuX of Ralstonia pickettii (3BRY_A)(Q9RBW8) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.B.9.2.4 | Putative aromatic hydrocarbon degradation pathway porin, FadL homologue, with an N-terminal transmembrane α-helix and about 16 putative β-TMSs. |
Bacteria | Spirochaetota | FadL homologue of Treponema succinifaciens |
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1.B.9.3.1 | Salicylate ester (methyl and ethyl salicylates)/hydrocarbon outer membrane porin, SalD (Jones et al. 2000). |
Bacteria | Pseudomonadota | SalD of Acinetobacter sp. strain ADPI |
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1.B.9.3.2 | FadL homologue of 432 aas |
Bacteria | Chlamydiota | FadL of Parachlamydia acanthamoebae |
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1.B.9.3.3 | FadL homologue of 468 aas |
Bacteria | Spirochaetota | FadL homologue of Leptospira interrogans |
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1.B.9.4.1 | Putative hemin receptor of 479 aas and ~20 β-strand |
Bacteria | Bacteroidota | Hemin receptor of Riemerella anatipestifer |
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1.B.9.4.2 | Uncharacterized porin of 542 aas |
Bacteria | Bacteroidota | UP of Prevotella oralis |
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1.B.9.4.3 | Putative porin of 543 aas |
Bacteria | Bacteroidota | Porin of Porphyromonas endodontalis |
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1.B.9.4.4 | Outer membrane protein transport protein (OmpP1/FadL/TodX family) |
Bacteria | Bacteroidota | OmpP1 of Saprospira grandis |
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1.B.9.4.5 | Membrane protein involved in aromatic hydrocarbon degradation of 481 aas |
Bacteria | Calditrichota | OM porin of Caldithrix abyssi |
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1.B.9.4.6 | Uncharacterized protein of 472 aas |
Bacteria | Ignavibacteriota | UP of Ignavibacterium album |
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1.B.9.4.7 | Porin protein involved in aromatic hydrocarbon degradation; putative hemin receptor of 479 aas |
Bacteria | Bacteroidota | Putative porin of Pedobacter heparinus |
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1.B.9.4.8 | Uncharacterized membrane protein, predicted to be involved in aromatic hydrocarbon degradation; of 437 aas. |
Bacteria | Planctomycetota | UP of planctomycete KSU-1 |
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1.B.90.1.1 | Putative Trichomonas Hydrogenosome Porin-1 of 302 aas and 16 predicted β-strands (Rada et al. 2011). |
Eukaryota | Parabasalia | Porin-1 of Trichomonas vaginalis |
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1.B.90.1.2 | Homologue of Porin 1 of 397 aas and 17 predicted transmembrane β-strands. |
Eukaryota | Parabasalia | Porin-1 of Tritrichomonas foetus |
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1.B.91.1.1 | Putative porin-2 of 270 aas and 15 predicted β-strands (Rada et al. 2011). |
Eukaryota | Parabasalia | Porin-2 of Trichomonas vaginalis |
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1.B.91.1.2 | Putative porin-2 of 275 aas and 14 predicted β-strands. |
Eukaryota | Parabasalia | Porin-2 of Tritrichomonas foetus |
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1.B.92.1.1 | NilB; 14 β-TMS outer membrane porin of 466 aas (Bhasin et al., 2012). |
Bacteria | Pseudomonadota | NilB of Xenorhabdus nematophila (Q8RLV4) |
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1.B.92.1.2 | OmpU |
Bacteria | Pseudomonadota | OmpU of Neisseria meningitidis (Q5F674) |
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1.B.92.1.3 | Outer membrane protein, OMP |
Bacteria | Pseudomonadota | OMP of Mannheimia haemolytica (E2PBK0) |
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1.B.92.1.4 | Outer membrane protein, OMP |
Bacteria | Pseudomonadota | OMP of Taylorella equigenitalia (E8UCW3) |
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1.B.92.1.5 | Putative porin of 415 aas |
Bacteria | Pseudomonadota | Putative porin of Bibersteinia trehalosi |
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1.B.92.1.6 | Uncharacterized DUF560 domain-containing protein of442 aas. |
Bacteria | Pseudomonadota | UP of Aestuariibacter salexigens |
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1.B.92.1.7 | Uncharacterized protein of 456 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of Arsenophonus nasoniae |
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1.B.92.1.8 | Uncharacterized DUF560 domain-containing protein of 436 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of Martelella mediterranea |
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1.B.92.2.1 | Uncharacterized DUF560 domain-containing proteinof384 aa |
Bacteria | Pseudomonadota | UP of Amylibacter cionae |
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1.B.93.1.1 | YiaT putative porin of 246 aas and 10 putative TM β-strands (Yang et al., 2011). |
Bacteria | Pseudomonadota | YiaT of E. coli (P37681) |
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1.B.93.1.10 | MipA/OmpV family protein of 276 aas and 1 N-terminal TM |
Bacteria | Pseudomonadota | MipA of Cellvibrio mixtus |
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1.B.93.1.11 | MipA/OmpV family protein of 286 aa |
Bacteria | Fusobacteriota | MipA of Fusobacterium nucleatum |
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1.B.93.1.12 | MipA family protein of 429 aa |
Bacteria | Pseudomonadota | MipA of Ferrimonas kyonanensis |
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1.B.93.1.13 | MipA/OmpV family protein of 275 aa |
Bacteria | Pseudomonadota | MipA of Niveispirillum cyanobacteriorum |
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1.B.93.1.14 | Uncharacterized protein of 295 aas [Candidatus Muproteobacteria bacterium |
Bacteria | Pseudomonadota | UP of Candidatus Muproteobacteria bacterium |
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1.B.93.1.2 | MipA (YeaF) (Vollmer et al., 1999). This outer membrane protein of 248 aas and 10 TM β-strands is involved in antibiotic resistance (Li et al. 2015). It is also an MltA (outer membrane lytic transglycosylase (P0A935))-interacting protein (van Straaten et al. 2005; Vollmer et al. 1999). |
Bacteria | Pseudomonadota | MipA of E. coli (P0A908) |
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1.B.93.1.3 | The putative outer membrane scaffolding protein for murein-synthesizing holoenzyme of 245 aas and 10 putative TM β-strands, MipA. Resembles several porins. |
Bacteria | Pseudomonadota | MipA of Pseudoalteromonas haloplanktis |
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1.B.93.1.4 | N-terminal DUF2141 domain/C-terminal MipA domain protein. The N-terminal domain may be an artifactual fusion of a full length DUF2141 domain with a full length putative C-terminal porin domain, but this seems less likely since the same fusion has been observed in another family member (TC# 1.B.93.2.8). |
Bacteria | Thermodesulfobacteriota | DUF2141 homologue of Desulfurivibrio alkaliphilus (D6Z2E5) |
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1.B.93.1.5 | Outer membrane protein, OmpV |
Bacteria | Pseudomonadota | OmpV of Vibrio parahaemolyticus |
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1.B.93.1.6 | Uncharacterized protein of 282 aas and 10 predicted β-strands. |
Bacteria | Thermodesulfobacteriota | UP of Geobacter lovleyi |
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1.B.93.1.7 | MipA,OmpV family protein of 295 aas and one N-terminal TMS. |
Bacteria | Pseudomonadota | MipA of Thalassotalea euphylliae |
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1.B.93.1.8 | MipA/OmpV family protein of 248 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | MipA of Thiofilum flexile |
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1.B.93.1.9 | MipA/OmpV family protein of 253 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | MipA of unclassified Herbaspirillum |
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1.B.93.2.1 | Uncharacterized DUF2141 protein of 153 aas. This protein is homologous only to the N-terminal domain in 9.B.99.1.4, but no other members of subfamily 9.B.99.1. It is therefore not homologous to other members of subfamily 9.B.99.1. The N-terminal domain of 9.B.99.1.4 may be artifactual. |
Bacteria | Cyanobacteriota | UP of Calothrix sp. PCC 6303 |
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1.B.93.2.2 | Uncharacterized DUF2141 protein of 157 aas. This protein is homologous to the N-terminal domain in 9.B.99.1.4, but not to other members of subfamily 9.B.99.1. The N-terminal domain of 9.B.99.1.4 may be a fusion of a DUF2141 domain with a putative C-terminal porin domain of the MipA type, distant from other proteins listed in subfamily 1.B.93.1. |
Bacteria | Chlorobiota | UP of Chlorobium tepidum |
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1.B.93.2.3 | DUF2141 domain-containing protein of 249 aas and 1 central TMS. |
Bacteria | Pseudomonadota | DUF2141 protein of Brevundimonas sp. |
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1.B.93.2.4 | Uncharacterized DUF2141 protein of 138 aas and one N-terminal TMS. |
Bacteria | Bacteroidota | UP of Psychroflexus sediminis |
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1.B.93.2.5 | Uncharacterized conserved protein, DUF2141 family, 175 aas and 1 C-terminal TMS. |
Bacteria | Pseudomonadota | UP of Cribrihabitans marinus |
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1.B.93.2.6 | DUF2141 domain-containing protein of 161 aas and 1 N-terminal TMS |
Bacteria | Pseudomonadota | DUF2141 domain protein of Henriciella algicola |
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1.B.93.2.7 | Uncharacterized protein (DUF2141 family) of 264 aa |
Bacteria | Pseudomonadota | UP of Rhodothalassium salexigens |
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1.B.93.2.8 | Uncharacterized fatty acid hydroxylase domain protein of 711 aas and 7 TMSs in a 6 + 1 TMS arrangement. This protein has three domains, first an integral membrane fatty acid hydroxylase domain, second, a DUF2141 domain, and third, a MipA domain with an N-terminal TMS. The protein with TC# 1.B.93.1.4 has the latter two domains fused together in the same order as for this protein. |
Eukaryota | Metazoa, Nematoda | UP of Diploscapter pachys |
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1.B.93.2.9 | Uncharacteerized DUF2141 protein of 171 aas and 1 N-terminal TMS |
Bacteria | Pseudomonadota | UP of Sphingopyxis indica |
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1.B.93.3.1 | Uncharacterized protein conserved in bacteria (DUF2141) of 708 aas. |
Bacteria | Bacteroidota | UP of Prevotella denticola |
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1.B.93.3.2 | DUF2141 domain-containing protein of 623 aas. Residues 513 - 583 in this protein align with residues 36 - 105 of TC# 1.B.93.2.2 with 31% identity. The latter protein has a 157 aa DUF2141 domain with an N-terminal TMS. |
Bacteria | Bacteroidota | DUF2141 protein of Odoribacter splanchnicus |
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1.B.93.3.3 | Uncharacterized DUF2141 protein of 609 aas and one N-terminal TMS. |
Bacteria | Bacteroidota | UP of Elizabethkingia meningoseptica (Chryseobacterium meningosepticum) |
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1.B.94.1.1 | Mycobacterial outer membrane porin PPE51 of 380 aas and about 8 TMSs. It is associated with the PE19 protein of 99 aas. The complex probably transports a large range of nutrients and other solutes including propionamide, glucose and glycerol (Wang et al. 2020). |
Bacteria | Actinomycetota | PPE51 of Mycobacterium tuberculosis |
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1.B.94.1.2 | Mg2+-transporting outer membrane porin, PPE31 (399 aas)/PE20 complex (99 aas) (Wang et al. 2020). The PPE31 protein probably has about 8 TMSs |
Bacteria | Actinomycetota | Mg2+ porin, PPE31/PE20, of Mycobacterium tuberculosis |
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1.B.94.1.3 | Heterodimeric outer membrane porin specific for inorganic phosphate, consisting of PPE25 of 365 aas and probably ~ 8 TMSs. The PE19 associated protein is of 99 aas (Wang et al. 2020). |
Bacteria | Actinomycetota | PPE25/PE19 of Mycobacterium tuberculosis |
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1.B.94.1.4 | Heterodimeric outer membrane porin consisting of two proteins, PPE65 of 413 aas and 8 probable TMSs, as well as PE32 of 99 aas. This porin transports inorganic phosphate (Wang et al. 2020). |
Bacteria | Actinomycetota | PPE65/PE32 phosphate porin of Mycobacterium tuberculosis |
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1.B.94.1.5 | Uncharacterized protein of 615 aas and ~ 12 TMSs, with applorimately 7 TMSs at the N-terminus in adomain that is similar to other members of the 1.B.94 family, and another domain of 5 TMSs at the C-terminus that resembles the proteins with TC# 8.A.128.2.4 and 3. |
Bacteria | Actinomycetota | UP of Mycobacterium shinjukuense |
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1.B.94.1.6 | PPE domain-containing protein of 626 aas and ~ 10 TMSs. |
Bacteria | Actinomycetota | PPE protein of Mycobacterium tuberculosis |
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1.B.94.1.7 | PPE20 of 539 aas and maybe as many as 8 TMSs/PE15 of 102 aas and maybe as many as 2 TMSs. The Mycobacterium tuberculosis PE15/PPE20 complex transports calcium across the outer membrane (Boradia et al. 2022). |
Bacteria | Actinomycetota | PPE20/PE15 of Mycobacterium canettii |
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1.B.94.1.8 | Outer membrane porin PPE family protein, MT0318, of 3,186 aas and many (> 8) repeat units (Pajón et al. 2006). |
Bacteria | Actinomycetota | MT0318 of Mycobacterium tuberculosis |
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1.B.94.1.9 | The Proline-Proline-Glutamate (PPE) Family protein, PPE64, of 552 aas. It is a heme-binding protein and forms pores in the outer membrane of Mycobacterium tuberculosis (Sankey et al. 2023). |
Bacteria | Bacillati, Actinomycetota | PPE64 of Mycobacterium tuberculosis |
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1.B.95.1.1 | The outer membrane protein, YaiO of 257 aas with 1 N-terminal α-TMS, and 14 predicted β-strands (Marani et al. 2006). This protein was identified in pathogenic E. coli strains that infect camels and was considered to be a housekeeping gene (Shahein et al. 2021). |
Bacteria | Pseudomonadota | YaiO of E. coli |
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1.B.95.1.2 | YaiO family outer membrane beta-barrel protein of 261 aas and 1 N-terminal TM |
Bacteria | Pseudomonadota | YaiO of Stenotrophomonas sp. CC22-02 |
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1.B.95.1.3 | YaiO family outer membrane beta-barrel protein of 260 aas and 1 N-terminal TM |
Bacteria | Pseudomonadota | YaiO of Pseudoxanthomonas suwonensis |
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1.B.95.2.1 | Uncharacterized outer membrane protein of 258 aas with 1 N-terminal α-TMS, and 14 predicted β-strands. |
Bacteria | Aquificota | UP of Hydrogenobacter thermophilus |
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1.B.95.2.2 | Uncharacterized outer membrane protein of 260 aas with 1 N-terminal α-helix and 13 predicted β-strands. |
Bacteria | Pseudomonadota | UP of Polaromonas naphthalenivorans |
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1.B.95.2.3 | Uncharacterized protein of 418 aas, 1 N-terminal α-TMS and 12 C-terminal β-strands. |
Bacteria | Pseudomonadota | UP of Burkholderia pseudomallei
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1.B.95.3.1 | YaiO family outer membrane beta-barrel protein of 266 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | YaiO of Halomonas subterranea |
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1.B.95.3.2 | YaiO family outer membrane beta-barrel protein of 258 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | YaiO of Polaromonas sp. |
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1.B.95.3.3 | YaiO family outer membrane beta-barrel protein of 375 aas and 1 N-terminal TMS. This protein is similar in sequence to the protein with TC# 1.B.55.4.1, suggesting that this protein is a porin. |
Bacteria | Pseudomonadota | YaiO of Lysobacter soli |
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1.B.95.3.4 | YaiO family outer membrane beta-barrel protein of 375 aas and 1 N-terminal TMS. This protein is similar in sequence to several proteins in family with TC# 1.B.55, and therefore is likely to be a porin. |
Bacteria | Pseudomonadota | YaiO of Pseudomonas xinjiangensis |
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1.B.95.3.5 | YaiO family outer membrane beta-barrel protein of 267 aas and 1 N-terminal TM |
Bacteria | Pseudomonadota | YaiO of Solimonas fluminis |
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1.B.95.3.6 | YaiO family outer membrane beta-barrel protein of 267 aas and 1 N-terminal TM |
Bacteria | Pseudomonadota | YaiO of Methylophilaceae bacterium |
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1.B.95.4.1 | Uncharacterized protein of 242 aas and 1 N-terminal TMS |
Bacteria | Chlamydiota | UP of Waddlia chondrophila |
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1.B.95.4.2 | Uncharacterized protein of 233 aas and 1 N-terminal TM |
Bacteria | Chlamydiota | UP of Candidatus Rubidus massiliensis |
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1.B.95.4.3 | Outer membrane beta-barrel protein of 226 aas and 1 N-terminal TM |
Bacteria | Chlamydiota | OMP of Parachlamydia sp. C2 |
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1.B.95.4.4 | Uncharacterized protein of 245 aas and 1 or 2 N-terminal TMSs |
Bacteria | Pseudomonadota | UP of Acinetobacter haemolyticus |
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1.B.96.1.1 | OEP40 porin of 358 aas and 10 transmembrane β-strands. The reconstituted recombinant OEP40 protein forms a high conductance β-barrel ion channel with subconductant states in planar lipid bilayers. It is slightly cation-selective PK+/PCl- ≈ 4:1 and rectifying (i⃗/i⃖ ≅ 2) with a slope conductance of Ḡmax ≅ 690 picosiemens. It has a restriction zone diameter of ≅ 1.4 nm and is permeable to glucose, glucose 1-phosphate and glucose 6-phosphate, but not for maltose. Moreover, channel properties are regulated by trehalose 6-phosphate, which cannot permeate. Thus, OEP40 is a "glucose-gate" in the outer envelope membrane of chloroplasts, facilitating selective metabolite exchange between chloroplasts and the surrounding cytoplasm of the cell (Harsman et al. 2016).These porins and many others in eukaryotes have been reviewed and analyzed by Roumia et al. 2020. |
Eukaryota | Viridiplantae, Streptophyta | OEP40 of Arabidopsis thaliana (Mouse-ear cress) |
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1.B.96.1.2 | Uncharacterized OEP40 homologue of 304 aas and 10 putative β-strands |
Eukaryota | Viridiplantae, Streptophyta | OEP40 homolog of Nyssa sinensis |
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1.B.96.1.3 | Uncharacterized protein of 506 aas |
Eukaryota | Viridiplantae, Streptophyta | UP of Marchantia paleacea |
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1.B.96.1.4 | Uncharacterized putative beta-barrel protein of 528 aas and 1 N-terminal TMS |
Eukaryota | Viridiplantae, Streptophyta | UP of Physcomitrium patens |
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1.B.96.1.5 | Uncharacterized protein of 426 aas and possibly one N-terminal TMS |
Eukaryota | Viridiplantae, Streptophyta | UP of Klebsormidium nitens |
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1.B.96.1.6 | Uncharacterized protein of 487 aas, possibly with an N-terminal TMS, annotated in the NCBI database as cyclic nucleotide-gated ion channel 2. However, the first 350 aas are homologous to OEP40 family members while the C-terminal residues (residues 400 - 480) are homologous to the cyclic nucleotide-gated ion channel, TMSs 2 - 31/2, of TC# 1.A.1.5.6. |
Eukaryota | Viridiplantae, Streptophyta | UP of Zea mays |
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1.C.1.1.1 | Colicin Ia. Residues lining the channel have been identified (Kienker et al. 2008). The 3D structure is known (PDB acc # 1CII; Gupta et al. 2023). |
Bacteria | Pseudomonadota | Colicin Ia of E. coli |
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1.C.1.1.2 | Colicin Ib | Bacteria | Pseudomonadota | Colicin Ib of E. coli | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.1.1.3 | Alveicin A (Wertz and Riley, 2004) | Bacteria | Pseudomonadota | Alveicin A in Hafnia alvei | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.1.1.4 | Alveicin B (Wertz and Riley, 2004) | Bacteria | Pseudomonadota | Alveicin B in Hafnia alvei | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.1.1.5 | Pore-forming Colicin F(Y) or Colicin FY (Bosák et al. 2012) |
Bacteria | Pseudomonadota | Colicin FY of Yersinia frederiksinii |
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1.C.1.1.6 | Pore-forming pyocin S5 of 498 aas, PyoS5. Active against several P. aeruginosa clinical isolates where it causes membrane damage and leakage (Ling et al. 2010). Uses the ferripyochelin (FptA) receptor (Elfarash et al. 2014). A PyoS5 immunity protein prevents cell damage (Rasouliha et al. 2013). |
Bacteria | Pseudomonadota | PyoS5 of Pseudomonas aeruginosa |
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1.C.1.2.1 | Colicin K. Similar to Colicin 5 (Pilsl and Braun 1995). |
Bacteria | Pseudomonadota | Colicin K of E. coli |
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1.C.1.2.2 | Colicin E1 of 522 aas and 1 C-terminal TMS. Ho et al. (2011) suggested a membrane topological model with a circular arrangement of helices 1-7 in a clockwise direction from the extracellular side and membrane interfacial association of helices 1, 6, 7, and 10 around the central transmembrane hairpin formed by helices 8 and 9. The 3D structure is known (PDB # 2I88; Gupta et al. 2023). ColE1 induces lipid flipping, consistent with the toroidal (proteolipidic) pore model of channel formation (Sobko et al. 2010). The mechanism of channel integration involving the transition of the soluble to membrane-bound form has been presented (Lugo et al. 2016). Colicin E1 uses BtuB as receptor and possibly, the outer membrane TolC protein as the translocator (Cramer et al. 2018). Colicin E1 adopts a closed-channel state at positive transmembrane potentials, correlating with a large tilt angle of alpha-helical TMSs. When the transmembrane potential becomes negative, it inserts into the lipid bilayer with a low tilt angle for the TMSs. Insertion, driven by the negative potential, generates the channel with the open and closed states interconverting reversibly (Su et al. 2019). |
Bacteria | Pseudomonadota | Colicin E1 of E. coli |
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1.C.1.2.3 | Colicin 10. Uses the Tsx receptor for uptake (Pilsl and Braun 1995). |
Bacteria | Pseudomonadota | Colicin 10 of E. coli |
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1.C.1.2.4 | Cell envelope integrity protein TolA of 459 aa |
Bacteria | Pseudomonadota | TolA of Acinetobacter baumannii |
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1.C.1.3.1 | Colicin A. The role of the hydrophobic helical hairpin of the pore-forming domain has been elucidated (Bermejo et al. 2013). Acidic conditions promote membrane insertion (Pulagam and Steinhoff 2013). The 3D structure has been determined (PDB # 1COL |
Bacteria | Pseudomonadota | Colicin A of Citrobacter freundii |
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1.C.1.3.2 | Colicin B. Its structural stability and interactions have been studied (Ortega et al. 2001). It is 80% identical to colicin D, and colicin D has a well defined structure (PDB # 1V74; Gupta et al. 2023). |
Bacteria | Pseudomonadota | Colicin B of E. coli |
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1.C.1.3.3 | Colicin N (OmpF is the receptor and translocator (Baboolal et al., 2008)). The 3D structure has been determined (PDB# 1A87; Gupta et al. 2023). The 3D structure has been determined (PDB # 1RH7; Gupta et al. 2023). |
Bacteria | Pseudomonadota | Colicin N of E. coli |
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1.C.1.3.4 | Colicin S4 (The crystal structure is known (3FEW_X; Arnold et al., 2009)). |
Bacteria | Pseudomonadota | Colicin S4 of E. coli (Q9XB47) |
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1.C.1.3.5 | Colicin R of 629 aas and 2 C-terminal TMSs (Rendueles et al. 2014). Colicin U (Cua of 619 aas; O24681) is 94% identical to Colicin R, and Colicin Y (ColY of 629 aas; Q9KJ98) is 90% identical to Colicin R (Smajs et al. 2006). |
Bacteria | Pseudomonadota | Colicin R of E. coli |
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1.C.1.3.6 | Colicin-like pore-forming domain protein, PmnH, of 462 aas and 2 C-terminal TMSs. This protein has a dual-toxin architecture, having both an N-terminal colicin M-like domain, potentially interfering with peptidoglycan synthesis, and a colicin N-type domain, a pore-forming module distinct from the colicin Ia-type domain in Pseudomonas aeruginosa pyocin S5 (Ghequire et al. 2017). Enhanced killing activity of PmnH under iron-limited growth conditions is due to parasitism of the ferrichrome-type transporter for entry into target cells, a strategy shown here to be used as well by monodomain colicin M-like bacteriocins from pseudomonads (Ghequire et al. 2017). |
Bacteria | Pseudomonadota | PmnH of Pseudomonas synxantha |
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1.C.1.3.7 | Lipid II-degrading bacteriocin PaeM of 289 aas. The 3-d structure is known PDB# (4G75 and 4G76) (Barreteau et al. 2012). |
Bacteria | Pseudomonadota | ColM or PaeM of Pseudomonas aeruginosa |
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1.C.1.3.8 | Colicin M of 278 aas. It's 3D structure is known (PDB # 3DA3; Gupta et al. 2023). |
Bacteria | Proteobacterium | Colicin M of E. coli |
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1.C.1.4.1 | Colicin E2 or E9 (Mosbahi et al., 2002). Colicin E2 is still in contact with its receptor and import machinery when its nuclease domain enters the cytoplasm (Duche, 2007). Colicin E3 is almost identical to Colicin E3 (RNAase). The crystal structure of Colicin E3 with bound BtuB and with the N-terminal translocation (T) domain of E3 and E9 (DNAase) inserted into the OM OmpF porin has been solved (Cramer et al. 2018) revealing: (I) Details of the initial interaction of the colicin central receptor (R)- and N-terminal T-domain with OM receptors/translocators. (II) Features of the translocon include: (a) high-affinity (K d ≈ 10-9 M) binding of the E3 receptor-binding R-domain E3 to BtuB; (b) insertion of disordered colicin N-terminal domain into the OmpF trimer; (c) binding of the N-terminus, documented for colicin E9, to the TolB protein on the periplasmic side of OmpF. Reinsertion of the colicin N-terminus into the second of the three pores in OmpF implies a colicin anchor site on the periplasmic side of OmpF. (III) Studies on the insertion of nuclease colicins into the cytoplasmic compartment imply that translocation proceeds via the C-terminal catalytic domain, proposed here to insert through the unoccupied third pore of the OmpF trimer, consistent with in vitro occlusion of OmpF channels by the isolated E3 C-terminal domain (Cramer et al. 2018). |
Bacteria | Pseudomonadota | Colicin E9 of E. coli (P09883) |
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1.C.1.4.2 | Pyocin-S2, Pys2 of 689 aas. Causes breakdown of chromosomal DNA as well as complete inhibition of lipid synthesis in sensitive cells. Prevents biofilm formation in vitro and in vivo (Smith et al. 2012). Binds the FpvA receptor (Elfarash et al. 2012). It forms pores though which the toxin enters the cytoplasm (Parret and De Mot 2000). |
Bacteria | Pseudomonadota | Pvs2 of Pseudomonas aeruginosa |
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1.C.10.1.1 | The alpha-PFT, Haemolysin E, HlyE or ClyA of 536 aas. A peptide derived from the putative transmembrane domain in the tail region of hemolysin E (aas 88-120) assembles in phospholipid membrane and exhibits lytic activity to human red blood cells (Yadav et al., 2009). Residues important for insertion and activity have been identified (Ludwig et al., 2010). An unusual assembly pathway has been proposed (see family description; Fahie et al. 2013). The pore can be blocked by PAMAM dendrimers (Mandal et al. 2016). The C-terminus directs pore formation and function (Sathyanarayana et al. 2016). Similar in structure to Cry6Aa (TC# 1.C.41.2.1) although sequence similarity could not be discerned (Dementiev et al. 2016 and unpublished results). The C-terminal domain is not directly involved in the pore structure, but is not a passive player in pore formation as it plays important roles in mediating the transition through intermediary steps leading to successful pore formation in a membrane (Sathyanarayana et al. 2016). Transmembrane oligomeric intermediates or "arcs" probably form stable proteolipidic complexes consisting of protein arcs with toroidal lipids lining the free edges (Desikan et al. 2017). High-resolution cryo-EM structures revealed that ClyA pore complexes can exist as oligomers of a tridecamer and a tetradecamer, at estimated resolutions of 3.2 Å and 4.3 Å, respectively. The 2.8 A cryo-EM structure of a dodecamer dramatically improves the existing structural model. Structural analysis indicates that protomers from distinct oligomers resemble each other, and neighboring protomers adopt a conserved interaction mode. A stabilized intermediate state of ClyA during the transition process from soluble monomers to pore complexes was identified. Even without the formation of mature pore complexes, ClyA can permeabilize membranes and allow leakage of particles less than ~400 Daltons. In addition, ClyA forms pore complexes in the presence of cholesterol within artificial liposomes (Peng et al. 2019). The mechanism of pore formation has been reviewed (Sathyanarayana et al. 2020). Maurya et al. 2022 described how to monitor the nanopore assembly of bacterial pore-forming toxin Cytolysin A (ClyA) on crowded lipid membranes with single-molecule photobleaching analysis. This and other pore forming toxins have been reviewed (Gupta et al. 2023). |
Bacteria | Pseudomonadota | HlyE or ClyA of E. coli |
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1.C.10.1.2 | Eukaryotic ClyA homologue of 322 aas. |
Eukaryota | Oomycota | ClyA homologue of Saprolegnia diclina |
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1.C.10.2.1 | ClyA homologue of 316 aas |
Eukaryota | Oomycota | ClyA homologue of Saprolegnia diclina |
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1.C.10.2.2 | Uncharacterized protein of 363 aas and 1 or 2 TMSs, N- and C-terminal. |
Eukaryota | Oomycota | UP of Thraustotheca clavata |
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1.C.10.2.3 | Uncharacterized protein of 320 aas and 1 or 2 TMSs, possibly N- and C-terminal. |
Eukaryota | Oomycota | UP of Saprolegnia diclina |
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1.C.10.3.1 | Insect ClyA homology of 433 aas |
Eukaryota | Metazoa, Arthropoda | ClyA homologue of Nasonia vitripennis (Parasitic wasp) |
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1.C.10.3.2 | Insect ClyA homologue of 354 aas |
Eukaryota | Metazoa, Arthropoda | ClyA homologue of Drosophila ananassae (Fruit fly) |
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1.C.100.1.1 | Thermostable direct hemolysin or Kanagawa haemolysin, TDH, Tdh2, trh of 189 aas. It exhibits monovalent cation selectivity in the order: Cs+ > Li+ > K+ > Rb+ > Na+, confirming that TDH is the important leak-inducing agent (Huntley and Hall 1994). The crystal structure is known (3A57_A); Ohnishi et al., 2011). Assembly of a multivalent aptamer efficiently inhibits the thermostable direct hemolysin toxicity induced by Vibrio parahaemolyticus (Chen et al. 2024). |
Bacteria | Pseudomonadati, Pseudomonadota | TDH of Vibrio parahaemolyticus (B3IW71) |
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1.C.100.1.2 | TDH-related hemolysin, TRH (67% similarity to TDH (Ohnishi et al., 2011)) |
Bacteria | Pseudomonadota | TRH of Vibrio parahaemolyticus (Q5DMU5) |
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1.C.100.1.3 | Thermostable direct hemolysin-family toxin,TDH. partial, 151 aa |
Bacteria | Pseudomonadati, Pseudomonadota | TDH of Vibrio cholerae |
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1.C.101.1.1 | The HIV-1 TAT peptide derives from the 101aa Tat protein (facilitates transport of drugs and macromolecules across membranes) (Herce and Garcia, 2007). TAT peptides can traverse cell membranes and generate pores in artificial membranes (Ciobanasu et al., 2010). Anionic lipids accelerate peptide permeation. Cholesterol hinders transmembrane pore formation and thus modulates solute permeability (Hu and Patel 2016). |
Viruses | Pararnavirae, Artverviricota | TAT peptide of HIV (11aas; 1JM4_A) |
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1.C.101.1.2 | Tat protein, of 112 aas and possibly 1 TMS. |
Viruses | Pararnavirae, Artverviricota | Tat protein of Simian immunodeficiency virus (SIV) |
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1.C.101.1.3 | Tat protein of 103 aas and possibly 1 TMS. |
Viruses | Pararnavirae, Artverviricota | Tat protein of bovine immunodeficiency virus |
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1.C.101.1.4 | Tat1 protein of 97 aas and possibly one TMS. |
Viruses | Pararnavirae, Artverviricota | Tat protein of Jembrana disease virus |
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1.C.101.1.5 | Tat protein of 74 aas and possibly one TMS. |
Viruses | Pararnavirae, Artverviricota | Tat protein of Rabbit endogenous lentivirus type K |
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1.C.102.1.1 | Cerein bacteriocin 7B of 73 aas and 2 TMSs (Anjana and Tiwari 2022). |
Bacteria | Bacillota | Cerein of Bacillus cereus (Q2MDB2) |
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1.C.102.1.2 | Bacteriocin class II with double-glycine leader peptide of 76 aas and 2 TM |
Bacteria | Bacillota | Bacteriocin of Streptococcus mutans |
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1.C.102.1.3 | Abp118 bacteriocin beta peptide (plasmid) of 68 aas and 1 TMS. |
None | Bacillati, Bacillota | Abp118 of Ligilactobacillus salivarius |
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1.C.103.1.1 | The anion-selective, small, pore-forming, multistate, persister-promoting toxin, TisB (Gurnev et al., 2012; Steinbrecher et al., 2012). It forms a transmembrane amphipathic α-helix with all charged and hydrophilic residues on one side of the helix. TisB is activated in response to DNA damage or by ciprofloxacin exposure, often involving the SOS response and promotes persister formation in a manner similar to HokB (TC# 1.E.53.1.3; Harms et al. 2016). TisB protects Escherichia coli cells suffering massive DNA damage from environmental toxic compounds (Su et al. 2022). Toxin/antitoxin (TA) modules are involved in persister formation in E.coli. The SOS response leads to overexpression of TisB and persister formation. TisB is a membrane-acting peptide that apparently sends cells into dormancy by decreasing the proton motive force and ATP levels (Lewis 2010). Protein aggregation is a consequence of the dormancy-inducing membrane toxin TisB in E. coli (Leinberger et al. 2024). TisB is the single molecular determinant underlying multiple downstream effects of ofloxacin in E. coli (Cayron et al. 2024). |
Bacteria | Pseudomonadota | TisB of E. coli (A5A627) |
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1.C.103.1.2 | Small toxic peptide, TisB |
Bacteria | Pseudomonadota | TisB of Klebsiella oxytoca (H3MU69) |
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1.C.104.1.1 | The heterokaryon incompatibility prion/amyloid protein, HET-s (Seuring et al., 2012). |
Eukaryota | Fungi | HET-s of Podospora anserina (Q03689) |
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1.C.104.1.2 |
Ankyrin repeat domain-containing protein 52, ARDP52 (Seuring et al., 2012). |
Eukaryota | Fungi, Ascomycota | ARDP52 of Colletotrichum gloeosporioides (L2GCS0) |
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1.C.104.1.3 | Uncharacterized protein of 277 aas |
Eukaryota | Fungi, Ascomycota | UP of Baudoinia panamericana |
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1.C.104.1.4 | Heterokaryon incompatibility protein S of 298 aa |
Eukaryota | Fungi, Ascomycota | Protein S of Penicillium subrubescens |
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1.C.104.1.5 | Uncharacterized protein of 729 aas. |
Eukaryota | Fungi | UP of Pezoloma ericae |
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1.C.104.1.6 | Uncharacterized protein of 289 aas |
Eukaryota | Fungi, Ascomycota | UP of Tolypocladium paradoxum |
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1.C.104.1.7 | Uncharacterized protein of 1134 aas with 1 or 2 N-terminal TMSs plus 1 or more central TMSs. The domain homologous to other members of TC# 1.C.104 is N-terminal. |
Eukaryota | Fungi, Ascomycota | UP of Scedosporium apiospermum |
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1.C.104.2.1 | Uncharacterized protein of 538 aas |
Eukaryota | Fungi, Ascomycota | UP of Oidiodendron maius |
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1.C.104.2.2 | Uncharacterized protein of 559 aas |
Eukaryota | Fungi, Ascomycota | UP of Fusarium oxysporum |
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1.C.104.2.3 | Small s-like protein of 206 aas |
Eukaryota | Fungi, Ascomycota | Small s protein of Colletotrichum fructicola |
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1.C.104.2.4 | Uncharacterized protein of 1067 aas and 1 or 2 N-terminal TMSs. The domain corresponding to TC# 1.C.104 is N-terminal, and a C-terminal domain is a protein kinase domain. |
Eukaryota | Fungi, Ascomycota | UP of Byssochlamys spectabilis |
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1.C.104.2.5 | Uncharacterized protein of 436 aas |
Eukaryota | Fungi, Ascomycota | UP of Glarea lozoyensis |
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1.C.104.3.1 | Uncharacterized protein of 414 aas |
Eukaryota | Fungi, Ascomycota | UP of Venturia inaequalis |
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1.C.104.3.2 | Uncharacterized protein of 462 aas and 1 N-terminal TMS. |
Eukaryota | Fungi, Ascomycota | UP of Pseudocercospora fijiensis |
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1.C.105.1.1 | The vegetative insecticidal protein, Vip3Aa (Vip3A, Vip3-Bt4, Vip3V) of 789 aas (Sauka et al. 2012). Kunthic et al. 2017 showed it forms pores in a pH range from 5.0 to 8.0 using trypsin-activated Vip3Aa. The toxin formed ion channels with a diameter of 1.4 nm at pH 8.0, and pore size gradually decreased with reduced pH (Kunthic et al. 2017). |
Bacteria | Bacillota | Vip3Aa of Bacillus thuringiensis (F6GPK9) |
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1.C.105.1.2 | The vegetative insecticidal protein Vip3Ca2 (803 aas) (Sauka et al. 2012). |
Bacteria | Bacillota | Vip3Ca2 of Bacillus thuringiensis (G9DCX5) |
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1.C.105.1.3 | Uncharacterized protein of 1179 aas. |
Bacteria | Pseudomonadota | UP of Cellvibrionaceae bacterium AOL6 |
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1.C.105.2.1 | The 235 kDa rhoptry protein (1081 aas) (Proellocks et al. 2010) |
Eukaryota | Apicomplexa | Rhoptry protein of Plasmodium yoelii (Q7RFQ7) |
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1.C.105.2.10 | Reticulocyte binding protein of 2968 aas, a homologue of PSAC throughout half of its length. |
Eukaryota | Apicomplexa | Reticulocyte binding protein of Plasmodium falciparum |
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1.C.105.2.11 | Uncharacterized protein of 1212 aas |
Bacteria | Mycoplasmatota | UP of Mycoplasma anatis |
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1.C.105.2.12 | Uncharacterized protein of 875 aas |
Bacteria | Bacteroidota | UP of of Cellulophaga algicola |
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1.C.105.2.13 | Uncharacterized protein of 710 aa |
Eukaryota | Fungi, Ascomycota | UP of Naumovozyma dairenensis (Saccharomyces dairenensis) |
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1.C.105.2.14 | Uncharacterized protein of 1810 aas |
Eukaryota | Apicomplexa | UP of Plasmodium gallinaceum |
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1.C.105.2.15 | Uncharacterized protein of 1295 aas, similar to AMEV15. |
Viruses | Poxviridae | UP of Choristoneura rosaceana entomopoxvirus L |
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1.C.105.2.16 | Putative Ca2+ channel toxin protein of 620 aas. |
Eukaryota | Apicomplexa | Channel of Plasmodium falciparum |
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1.C.105.2.17 | Protein import across the second inner membane (apicoplast membrane) (Wunderlich 2022). |
Eukaryota | Apicomplexa | channel protein of Plasmodium falciparum |
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1.C.105.2.2 | Viral A-type inclusion protein (2011 aas). This protein includes a large hydrophilic domain that is homologous to regions in the dystrophins (TC# 8.A.66) the nucleoporin, 1.I.1.1.1, Q02455, the TypeIV protein secretion system, 3.A.7.12.1, O25262, and the KX family protein, 2.A.112.3.2, G0ZX98. |
Eukaryota | Parabasalia | Inclusion protein of Trichomonas vaginalis (A2ETW9) |
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1.C.105.2.3 | Uncharacterized protein of 973 aas. This protein is also homologous to the nucleoprin, 1.I.1.1.1; Q02455 and the TypeIV protein secretion system, 3.A.7.12.1; O25262. |
Eukaryota | Ciliophora | UP of Paramecium tetraurelia |
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1.C.105.2.4 | Uncharacterized protein of 642 aas. It has an N-terminal 90 residue domain that resembles a domain (residues 442 - 526) in TrpY1 (TC# 1.A.4.4.1) of 642 aas. |
Eukaryota | Ciliophora | UP of Tetrahymena thermophila |
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1.C.105.2.5 | Uncharacterized protein of 1418 aas |
Eukaryota | Ciliophora | UP of Paramecium tetraurelia |
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1.C.105.2.6 | Fibronectin binding autolysin/adhesin of 1395 aas, AtlC. |
Bacteria | Bacillota | AtlC of Staphylococcus caprae |
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1.C.105.2.7 | Surface protein with adhesive and autolytic activity of 1463 aas, Aas (Hell et al. 1998). |
Bacteria | Bacillota | Aas of Staphylococcus sparophyticus |
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1.C.105.2.8 | Uncharacterized protein of 529 aas. |
Bacteria | Bacillota | UP of Ruminococcus torques |
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1.C.105.2.9 | MCU homologue (872 aas; 2 TMSs) |
Bacteria | Bacillota | MCU homologue of Halanaerobium praevalens (E3DLQ2) |
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1.C.106.1.1 | The vegetative insecticidal protein, Vip2 (448 aas) |
Bacteria | Bacillota | Vip2 of Bacillus thuringiensis (G8FSA8) |
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1.C.106.1.2 | The vegetative insecticidal protein, Vip2Ac (462 aas) |
Bacteria | Bacillota | Vip2Ac of Bacillus thuringiensis (Q844J9) |
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1.C.106.1.3 |
The vegetative insecticida protein, Vip2A (96 aas) |
Bacteria | Bacillota | Vip2A of Bacillus thuringiensis (B2LWZ0) |
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1.C.106.4.1 | ADP-ribosyltransferase toxin AexT (ExoS, YopE) of 453 aas (Cisz et al. 2008). |
Bacteria | Pseudomonadota | AexT of Pseudomonas aeruginosa |
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1.C.106.4.2 | Exoenzyme T, ExoT of 453 aas. 74% identical to ExoS (TC# 1.C.106.4.1). ExoS and ExoT properties have been reviewed (Barbieri and Sun 2004). ExoT causes apoptosis in the target cell (Wood et al. 2015). |
Bacteria | Pseudomonadota | ExoT of Pseudomonas aeruginosa |
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1.C.107.1.1 | Insecticidal toxin complex (TC) component, TcaA (1095 aas) (may mediate toxin-C internalization)(Landsberg et al., 2011). The TcdA1 prepore assembles as a pentamer forming an α-helical, vuvuzela-shaped channel less than 1.5 nanometres in diameter surrounded by a large outer shell (Gatsogiannis et al. 2013). Membrane insertion is triggered not only at low pH as expected, but also at high pH, explaining Tc action directly through the midgut of insects. Comparisons with structures of the TcdA1 pore inserted into a membrane and in complex with TcdB2 and TccC3 reveal large conformational changes during membrane insertion, suggesting a novel syringe-like mechanism of protein translocation (Gatsogiannis et al. 2013). P. luminescens is a nematode symbiont and an insect pathogen. The toxin, TcC, of the tripartite toxin complex, is an ADP ribosyl transferase causing actin clustering, defects in phagocytosis and cell dealth. |
Bacteria | Pseudomonadota | TcaA of Photorhabdus luminescens (Q66PW7) |
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1.C.107.1.2 | Insecticidal toxin complex (TC) component, XptA1 or TccA (1156 aas) (may mediate toxin-C internalization) (Landsberg et al., 2011). |
Bacteria | Pseudomonadota | XptA1 of Xenorhabdus nematophila (D3VHH3) |
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1.C.107.1.3 | Insecticidal toxin complex (TC) component, Yen-Tc (may mediate toxin-C internalization) (Landsberg et al., 2011). |
Bacteria | Pseudomonadota | Yen-Tc of Yersinia enterocolitica (Q693A5) |
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1.C.107.1.4 | The trimeric Tc toxin complex consisting of three subunits, TcdA, TcdB and TccC (TcA, B and C, respectively) of 2525, 1476 and 1043 aas, respectively. Several 3-d structures and their modes of action and secretion have been described (see the family description) (Gatsogiannis et al. 2013; Yang and Waterfield 2013; Moriya et al. 2017). Clostridioides difficile toxins TcdA and TcdB are inhibited by the amiodarone derivative dronedarone (Matylitsky et al. 2024). |
Bacteria | Pseudomonadota | Tc toxin complex of Photorhabdus luminescens |
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1.C.107.1.5 | Pore-forming component, SepA of the tripartite toxin, SepA (Q9F9Z3; 2376 aas)/SepB (Q9F9Z2; 1428 aas)/SepC (Q9F9Z0; 973 aas), that causes amber disease in the grass grub, Costelytra zealandica (Hurst et al. 2000). |
Bacteria | Pseudomonadota | SepA of Serratia entomophila |
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1.C.108.1.1 | Antimicrobial dermcidin, DCD. Based on 3-d structural data, dermcidin forms an architecture of high-conductance transmembrane channels, composed of zinc-connected trimers of antiparallel helix pairs. Molecular dynamics simulations elucidated the unusual membrane permeation pathway for ions and showed adjustment of the pore to various membranes (Song et al. 2013). DCD assembles in solution into a hexameric pre-channel complex before targeting the membrane and integration, the complex follows a deviation of the barrel stave model (Zeth and Sancho-Vaello 2017). The tilt angle and the conductance is determined by the membrane thickness and the cholesterol composition (Song et al. 2019). A soluble 48 residue fragment has been structurally characterized (PDB: 2KSG_A). Membrane interactions and pore formation have been investigated for α-helical AMPs leading to the formulation of three basic mechanistic models: the barrel stave, toroidal, and carpet models. Human cathelicidin (LL-37) and dermcidin (DCD) are α-helical, and their structures have been solved at atomic resolution. DCD assembles in solution into a hexameric pre-channel complex before actual membrane targeting and integration steps occur, and the complex follows a deviation of the barrel stave model (Zeth and Sancho-Vaello 2017). |
Eukaryota | Metazoa, Chordata | Dermcidin of Homo sapiens |
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1.C.108.2.1 | Lacritin of 137 aas and 1 N-terminal TMS. The crystal structure is available for the C-terminal 48 aas (2KSG A). |
Eukaryota | Metazoa, Chordata | Lacritin of Pongo abelii |
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1.C.108.2.2 | Extracellular glycoprotein lacritin-like isoform X2 of 111 aas and 1 N-terminal TMS. |
Eukaryota | Metazoa, Chordata | Lacritin-like peptide of Equus przewalskii |
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1.C.108.2.3 | Extracellular glycoprotein lacritin isoform X1of 119 aas and 1 N-terminal TM |
Eukaryota | Metazoa, Chordata | Lacritin-like protein of Acinonyx jubatus |
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1.C.108.2.4 | Extracellular glycoprotein lacritin of 109 aas and 1 N-terminal TMS. |
Eukaryota | Metazoa, Chordata | lacritin of Myotis lucifugus |
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1.C.108.3.1 | Hypothetical protein |
Eukaryota | Metazoa, Chordata | HP of Homo sapiens |
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1.C.109.1.1 | Hemolysin A, TlyA of 240 aas |
Bacteria | Spirochaetota | TlyA of Brachyspira (Serpulina) hyodysenteriae |
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1.C.109.1.2 | S-Hemolysin of 271 aas (Rajesh et al. 2013). |
Bacteria | Actinomycetota | S-Hemolysin of Streptomyces coelicolor |
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1.C.109.1.3 | Putative hemolysin of 253 aas, TlyA. In one study hemolysin activity was not detected, but adhsion to Caco cells was demonstrated (Sałamaszyńska-Guz and Klimuszko 2008). |
Bacteria | Campylobacterota | TlyA of Campylobacter jejuni |
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1.C.109.1.4 | Hemolysin and RNA methyltransferase of 268 aas, TlyA (Rahman et al. 2010; Monshupanee 2013). The assignment of this protein as an hemolysin has be questioned (Arenas et al. 2011). |
Bacteria | Actinomycetota | TlyA of Mycobacterium tuberculosis |
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1.C.109.1.5 | Haemolysin III, TlyA family member of 279 aas (Ramarao and Sanchis 2013). |
Bacteria | Bacillota | Haemolysin of Bacillus cereus |
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1.C.109.1.6 | The 'non-conventional' hemolysin, TlyA, a pore-forming hemolysin with potent cytotoxic activity, is of 235 aas (Javadi and Katzenmeier 2016). It causes agglutination, fusion and permeability of synthetic liposome vesicles. Agglutination activity could also be observed with erythrocytes before the induction of its pore-forming hemolytic activity. TlyA also induces disruption of liposome membranes (Lata and Chattopadhyay 2014). |
Bacteria | Campylobacterota | TlyA of Helicobacter pylori |
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1.C.11.1.1 | Leukotoxin, HlaA or LktA of 955 aas and 2 TMSs. Cytolysin LktA is one of the major pathogenicity factors of Mannheimia haemolytica (formerly Pasteurella haemolytica) that is the cause of pasteurellosis, also known as shipping fever pneumonia, causing substantial loss of sheep and cattle during transport. LktA belongs to the family of RTX-toxins (Repeats in ToXins) that are produced as pathogenicity factors by a variety of Gram-negative bacteria. Sublytic concentrations of LktA cause inflammatory responses of ovine leukocytes while higher concentrations result in formation of transmembrane channels in target cells that may cause cell lysis and apoptosis. Channel formation by LktA occurs in artificial lipid bilayer membranes made of different lipids. LktA channels had a single-channel conductance of about 60 pS in 0.1 M KCl, which is about one tenth of the conductance of most RTX-toxins with the exception of the adenylate cyclase toxin of Bordetella pertussis (Benz et al. 2019). The LktA channels are highly cation-selective, and the channel diameter is around 1.5 nm. |
Bacteria | Pseudomonadota | HlaA of Mannheimia (Pasteurella) haemolytica |
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1.C.11.1.2 | RTX-toxin IIA; haemolysin IIA; cytolysin IIA, ClyIIA | Bacteria | Pseudomonadota | ClyIIA of Actinobacillus pleuropneumoniae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.11.1.3 | Haemolysin A, HlyA (α-haemolysin) (Wiles and Mulvey 2013). The channel-forming domain may contain β-strands, possibly in addition to alpha-helical structures (Benz et al. 2014). Although homologous, HlyA and CyaA (1.C.11.1.4) exhibit different modes of permeabilization (Fiser and Konopásek 2009). HlyA triggered an increase in mitochondrial Ca2+ levels and manipulated mitochondrial dynamics by causing fragmentation of the mitochondrial network. Alterations in mitochondrial dynamics resulted in severe impairment of mitochondrial functions by loss of membrane potential, increase in reactive oxygen species production, and ATP depletion. HlyA also caused disruption of plasma membrane integrity (Lu et al. 2018). Cholesterol catalyzes unfolding in membrane inserted motifs of the pore forming cytolysin A (Kulshrestha et al. 2023). |
Bacteria | Pseudomonadota | HlyA of E. coli |
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1.C.11.1.4 | Bifunctional adenylate cyclase-haemolysin toxin precursor, CyaA. Although homologous, HlyA (1.C.11.1.3) and CyaA exhibit different modes of permeabilization (Fiser and Konopásek 2009). A pore model comprising three alpha2-loop-alpha3 hairpins suggested that Gly530XXGly533XXXGly537 in TMS2 could function in toxin oligomerization (Juntapremjit et al. 2015). Structural integrity of TMSs 1, 2, 3 and 5, but not 4, is important for haemolytic activity, particularly for transmembrane helices 2 and 3 that might form the pore (Powthongchin and Angsuthanasombat 2009). CyaA forms small cation-selective membrane pores that permeabilize cells for potassium efflux, contributing to cytotoxicity of CyaA and eventually provoking colloid-osmotic cell lysis (Wald et al. 2016). The toxin penetrates myeloid phagocytes expressing the complement receptor 3 and delivers into the cytosol its N-terminal adenylate cyclase enzyme domain (~400 residues). In parallel, the ~1300 residue-long RTX hemolysin moiety of CyaA permeabilizes target cell membranes for efflux of cytosolic potassium ions (Svedova et al. 2016). Positively-charged side-chains substituted at positions Gln574 and Glu581 in the pore-lining alpha3 enhance hemolytic activity and ion-channel opening, mimicing the highly-active RTX (repeat-in-toxin) cytolysins (Kurehong et al. 2017). Residues 529 to 549 participate in membrane penetration and pore-forming activity (Roderova et al. 2019). Two distinct conformers of CyaA appear to accomplish its two parallel activities within target cell membranes. The translocating conformer would deliver the N-terminal adenylyl cyclase domain into the cytosol of cells, while the pore precursor conformer would assemble into oligomeric cation-selective pores and permeabilize cellular membrane. Both toxin activities involve a membrane-interacting 'AC-to-Hly-linking segment' (residues 400 to 500). Two clusters of negatively charged residues within this linking segment (Glu419 to Glu432 and Asp445 to Glu448) regulate the balance between the AC domain translocating and pore-forming capacities of CyaA as a function of the calcium concentration (Sukova et al. 2020). Four cholesterol-recognition motifs in the pore-forming and translocation domains of CyaA are essential for invasion of eukaryotic cells and lysis of erythrocytes (Amuategi et al. 2022). Susceptibility of human airway tissue models derived from different anatomical sites to Bordetella pertussis and its virulence factor, the adenylate cyclase toxin have been identified (Sivarajan et al. 2021). |
Bacteria | Pseudomonadota | CyaA of Bordetella pertussis |
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1.C.11.1.5 | Cytolytic RTX-toxin, GtxA (causes salpingitis and peritonitis in birds (Kristensen et al., 2009) |
Bacteria | Pseudomonadota | GtxA of Gallibacterium anatis |
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1.C.11.1.6 | Enterohemolysin EhxA of 998 aas |
Bacteria | Pseudomonadota | EhxA of E. coli |
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1.C.11.1.7 | Leukotoxin A, LtxA pore-forming toxin of 1055 aas, exhibiting β-hemolytic activity. Plays a role in immune evasion by lysing human lymphocytes and monocytes. It binds to the LFA-1 integrin on the surface of the host cell and to cholesterol-containing membranes, resulting in large LtxA-LFA-1 clusters in lipid rafts (Balashova et al. 2006; Brown et al. 2013). Blocking P2X receptors protects monocytes from LtxA (Fagerberg et al. 2016). |
Bacteria | Pseudomonadota | LtxA of Aggregatibacter (Actinobacillus) actinomycetemcomitans (Haemophilus actinomycetemcomitans) |
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1.C.11.1.8 | Leukotoxin, RtxA or IktA, of 956 aas and 3 or 4 TMSs in a 1 + 1 + 2 TMS arrangement. An interaction between the toxin and cholesterol occurs via two cholesterol recognition/interaction amino acid consensus motifs located in the C-terminal portion of the pore-forming domain of the toxin, and the cytotoxic activity of RtxA depends on post-translational acylation of the K558 and/or K689 residues as well as on the toxin binding to cholesterol in the membrane (Osickova et al. 2018). |
Bacteria | Pseudomonadota | RtxA if Kingella kingae |
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1.C.11.1.9 | FrpC of 1492 aas and 1 or 2 TMSs, one N-terminal and one at about residue 270. |
Bacteria | Pseudomonadota | FrpC of Vibrio anguillarum |
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1.C.110.1.1 | The PNC-37 (32 aas) pore-forming peptide derived from the Mdm-2 binding domain of the p53 tumor-supressor protein which is selectively cytotoxic to cancer cells. The 3-d structure is known from NMR analyses (Sookraj et al. 2010). PNC-37 binds to HDM-2 in a 1:1 stoichiometry to induce pore-formation, and the pores are lined by PNC-37 bound to HDM-2 at the membrane surface with the PNC-37 leader sequence lining the pores (Sarafraz-Yazdi et al. 2022). The interaction of the C-terminal domain of Vaccinia-Related Kinase 2A (VRK2A) with the B-cell lymphoma-extra Large (Bcl-xL) plays an anti-apoptotic role in cancer (Puja et al. 2023). P53 is a multifunctional protein implicated in the regulation of diverse cellular processes via transcription-dependent and transcription-independent mechanisms (Wang et al. 2024). Mitochondria maintain cellular function, and mitochondrial defects or impairment are primary causes of dopaminergic neuron degeneration in PD. Mitochondrial dysfunction-associated dopaminergic neuron degeneration is tightly regulated by p53 in PD pathogenesis. Neurodegenerative stress triggers p53 activation, which induces mitochondrial changes, including transmembrane permeability, reactive oxygen species production, Ca2+ overload, electron transport chain defects and other dynamic alterations, and these changes contribute to neurodegeneration and are linked closely with PD occurrence and development. P53 inhibition has been shown to attenuate mitochondrial dysfunction and protect dopaminergic neurons from degeneration under conditions of neurodegenerative stress (Wang et al. 2024). |
Eukaryota | Metazoa, Chordata | p53 of Homo sapiens |
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1.C.110.1.2 | The p53 protein of 363 aas |
Eukaryota | Metazoa, Chordata | p53 protein of Xenopus laevis |
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1.C.110.1.3 | The p53 protein of 371 aas. |
Eukaryota | Metazoa, Chordata | p53 of Sarcophilus harrisii |
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1.C.111.1.1 | Regenerating islet-derived protein 3-γ precursor, RegIIIγ (174aas) |
Eukaryota | Metazoa, Chordata | RegIIIγ of Mus musculus (O09049) |
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1.C.111.1.10 | C-type lectin 5 of 153 aas |
Eukaryota | Metazoa, Mollusca | Lectin of Azumapecten farreri |
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1.C.111.1.11 | Lectin-like transmembrane protein of 273 aas and 1 N-terminal TMS |
Eukaryota | Metazoa, Chordata | Lectin-like transmembrane protein of Mus musculus |
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1.C.111.1.12 | Dendritic cell natural killer lectin group receptor 1, DNGR-1, of 238 aas and 1 N-terminal TMS. It is also called C-type lectin domain family 9 member A (Cle9a). It functions as an endocytic receptor on a small subset of myeloid cells specialized for the uptake and processing of material from dead cells (Sancho et al. 2009). It recognizes filamentous form of actin in association with particular actin-binding domains of cytoskeletal proteins, including spectrin, exposed when cell membranes are damaged. It mediates the cross-presentation of dead-cell associated antigens in a Syk-dependent manner (Sancho et al. 2009; ). DNGR-1 is a receptor expressed by certain dendritic cell (DC) subsets and by DC precursors in the mouse. It possesses a C-type lectin-like domain (CTLD) followed by a poorly characterized neck region coupled to a transmembrane region and short intracellular tail. The CTLD of DNGR-1 binds F-actin exposed by dead cell corpses and causes the receptor to signal and potentiate cross-presentation of dead cell-associated antigens by DCs.The neck region of DNGR-1 is an integral receptor component that senses receptor progression through the endocytic pathway and has evolved to maximize extraction of antigens from cell corpses (Hanč et al. 2016). |
Eukaryota | Metazoa, Chordata | DNGR-1 of Mus musculus (Mouse) |
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1.C.111.1.13 | NKG2-D type II protein of 216 aas and 1 central TMS. Functions as an activating and costimulatory receptor involved in immunosurveillance upon binding to various cellular stress-inducible ligands displayed at the surface of autologous tumor cells and virus-infected cells. Provides both stimulatory and costimulatory innate immune responses on activated killer (NK) cells, leading to cytotoxic activity (Zafirova et al. 2011). It stimulates perforin-mediated elimination of ligand-expressing tumor cells; signaling involves calcium influx, culminating in the expression of TNF-alpha (Zuo et al. 2017). |
Eukaryota | Metazoa, Chordata | NKG2-D of Homo sapiens |
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1.C.111.1.14 | NK cell receptor F, NKG2-F or NLRC4, of 158 aas and 1 central TMS. It may play a role as a receptor for the recognition of MHC class I HLA-E molecules by NK cells (Plougastel and Trowsdale 1997). It can associate with DAP12 (Kim et al. 2004).
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Eukaryota | Metazoa, Chordata | NKG2-F of Homo sapiens |
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1.C.111.1.15 | C-type lectin domain family 4 member M, CLEC4M or CD209L, of 399 aas and 1 N-terminal TMS. It is a probable pathogen-recognition receptor involved in peripheral immune surveillance in the liver, and may mediate the endocytosis of pathogens which are subsequently degraded in lysosomal compartments. It is a receptor for ICAM3, probably by binding to mannose-like carbohydrates (Bashirova et al. 2001). |
Eukaryota | Metazoa, Chordata | CD209L of Homo sapiens |
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1.C.111.1.16 | C-type lectin domain family 12 protein A, CLEC12A CLL7, DCAL2, MICL, of 265 aas and 1 TMS near its N-terminus. It is a cell surface receptor that modulates signaling cascades and mediates tyrosine phosphorylation of target MAP kinases in granulocytes and monocytes (Marshall et al. 2004). It alters dendrieic cell maturation and cytokine production (Chen et al. 2006). It is also a myeloid inhibitory receptor that negatively regulates inflammation in autoimmune and autoinflammatory arthritis (Vitry et al. 2021). Similarly to other C-type lectin receptors, CLEC12A harbours a stalk domain between its ligand binding and transmembrane domains. The stalk cysteines in CLEC12A differentially modulate this inhibitory receptor's expression, oligomerisation and signaling, suggestive of the regulation of CLEC12A in a redox-dependent manner during inflammation (Vitry et al. 2021). Clec12a inhibits MSU-induced immune activation through lipid raft expulsion (Xu et al. 2023). The transmembrane domain of Clec12a disrupts monosodium uric acid (MSU)-induced lipid raft recruitment and thus attenuates downstream signals. Single amino acid mutagenesis study showed the critical role of phenylalanine in the transmembrane region for the interactions between C-type lectin receptors and lipid rafts, which is critical for the regulation of MSU-mediated lipid sorting and phagocyte activation. This indicates the molecular mechanisms of solid particle-induced immune activation (Xu et al. 2023).
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Eukaryota | Metazoa, Chordata | CLEC12A of Homo sapiens |
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1.C.111.1.17 | Lithostathine-1-alpha, REG1A of 166 aas and 1 N-terminal TMS, possibly with one additional TMS centrally located. It might act as an inhibitor of spontaneous calcium carbonate precipitation, and may be associated with neuronal sprouting in brain, and with brain and pancreas regeneration. REG1A, Claudin 7 and Ki67 expressions correlate with tumor recurrence and prognostic factors in superficial urothelial urinary bladder carcinomas (Yamuç et al. 2022).
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Eukaryota | Metazoa, Chordata | REG1A of Homo sapiens |
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1.C.111.1.18 | CD69 of 199 aas and 1 TMS at residues 40 - 60. It is involved in lymphocyte proliferation and functions as a signal transmitting receptor in lymphocytes, natural killer (NK) cells, and platelets. A review provides a perspective on the molecular pathways, ligands and cellular functions known to be regulated by CD69 (Jiménez-Fernández et al. 2023). |
Viruses | Metazoa, Chordata | CD69 of Homo sapiens |
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1.C.111.1.2 | Regenerating islet-derived protein 3α, RegIIIα or Reg3A. Also called Proliferation-induced Protein 34, PAP or HIP of 157 aas. It is a C-type intestinal lectin and forms hexameric pores in Gram-positive bacterial membranes. The 3-d x-ray structure is known (Mukherjee et al. 2014). Lipopolysaccharides inhibit pore formation, and hence, Gram-negative bacteria are usually not susceptible to its killing action (Mukherjee et al. 2014). |
Eukaryota | Metazoa, Chordata | RegIIIα of Homo sapiens |
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1.C.111.1.3 | C-type lectin of 160 aas |
Eukaryota | Metazoa, Chordata | Lectin of Morelia spilota (Carpet python) |
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1.C.111.1.4 | SnEchinoidin of 192 aas |
Eukaryota | Metazoa, Echinodermata | SnEchinoidin of Mesocentrotus nudus |
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1.C.111.1.5 | Type II antifreeze protein of 192 aas |
Eukaryota | Metazoa, Chordata | Antifreeze protein of Lates calcarifer |
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1.C.111.1.6 | C-type lectin 1 of 155 aas |
Eukaryota | Metazoa, Chordata | C-type lectin of Perca flavescens |
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1.C.111.1.7 | Lactose-binding lectin I-2 of 181 aas |
Eukaryota | Metazoa, Chordata | Lectin I-2 of Ictalurus furcatus |
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1.C.111.1.8 | C-type lectin precursor of 177 aas |
Eukaryota | Metazoa, Chordata | C-type lectin of Lachesis muta |
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1.C.111.1.9 | C-type lecting domain family #4 member D of 205 aas |
Eukaryota | Metazoa, Chordata | Lectin of Chelonia mydas |
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1.C.112.1.1 | Cubozoan toxin, CaTX-A of 463 aas. This toxin has potent hemolytic activity, is lethal to crayfish. causes cutaneous inflammation in humans, and may act as a pore-forming toxin, disrupting normal transmembrane ion concentration gradients in susceptible cells (Nagai et al. 2000; Brinkman and Burnell 2009). |
Eukaryota | Metazoa | CaTX-A of Carybdea alata |
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1.C.112.1.2 | Toxin A of 454 aas; causes cardiiovascular and cytotoxic effects (Brinkman et al. 2014). |
Eukaryota | Metazoa, Cnidaria | Toxin A of Chironex fleckeri |
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1.C.112.1.3 | Toxin TX1 of 486 aas and 2 - 4 N-terminal α-helical TMSs, possibly with up to 15 C-terminal transmembrane β-strands (Law 2018). |
Eukaryota | Metazoa, Cnidaria | Toxin TX1 of Aurelia aurita |
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1.C.112.1.4 | C. fleckeri toxin-1 (CfTX-1) of 456 aas, one of the two most abundant proteins found in the nematocysts of the box jellyfish Chironex fleckeri. One or more of the 5 possible α-helical TMSs may be involved in pore-formation. May be similar to pore-forming insecticidal delta-endotoxins Cry1Aa, Cry3Bb and Cry3A (Brinkman and Burnell 2007). The transmembrane region(s) in CfTX-1 have been predicted on the basis of the behavior of peptides corresponding in sequence to two regions (Andreosso et al. 2018). |
Eukaryota | Metazoa, Cnidaria | CfTX-1 of Chironex fleckeri (Box jellyfish) |
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1.C.112.1.5 | Toxin B precursor, TX-B, of 461 aas and 2 - 4 N-terminal TMSs and up to 15 C-termnal β-strands (Tibballs et al. 2011) . |
Eukaryota | Metazoa, Cnidaria | TXB of Chironex fleckeri (Box jellyfish) |
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1.C.112.1.6 | Toxin CaTx-A of 446 aas. |
Eukaryota | Metazoa | CaTx-A of Exaiptasia pallida
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1.C.112.1.7 | Uncharacterized toxin of 420 aas. |
Eukaryota | Metazoa, Mollusca | UP of Crassostrea gigas (Pacific oyster) (Crassostrea angulata) |
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1.C.112.1.8 | Uncharacterized protein of 292 aas and 2 - 4 TMSs. |
Eukaryota | Metazoa, Cnidaria | UP of Stylophora pistillata |
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1.C.112.1.9 | CrTx-A cytotoxin of 450 aas with 4 probable TMSs, one at the N-terminus, two at about residue110, and a fourth at about residue 230. It has potent hemolytic activity and is lethal to mice and crayfish (Nagai et al. 2000). It causes cutaneous inflammation in humans and may act as a pore-forming toxin, disrupting normal transmembrane ion concentration gradients in susceptible cells. |
None | Metazoa, Cnidaria | CrTx-A of Carybdea rastonii (Box jellyfish) |
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1.C.113.1.1 | The Hly III protein | Bacteria | Bacillota | Hly III of Bacillus cereus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.113.1.10 | YqfA protein of unknown function. It may play a role in furfural resistance (Miller et al. 2009). |
Bacteria | Pseudomonadota | YqfA of E. coli |
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1.C.113.1.11 | ADIPOR2 of 387 aas and 7 TMSs. It may funtion in promoting cholesterol efflux together with ADIPOR1 and adiponectin (Hafiane et al. 2019). |
Eukaryota | Metazoa, Chordata | Adiponectin receptor 2, ADIPOR2, of Homo sapiens |
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1.C.113.1.12 | Progestin (P4) receptor beta of 354 aas and 8 TMSs. It couples to G proteins (Petersen et al. 2013). It seems to act through a Gi mediated pathway and may be involved in oocyte maturation (Petersen et al. 2013). Also binds dehydroepiandrosterone (DHEA), pregnanolone, pregnenolone and allopregnanolone (Pang et al. 2013). |
Eukaryota | Metazoa, Chordata | Progesterone receptor of Homo sapiens |
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1.C.113.1.2 | Hemolysin III-like protein of 229 aas |
Bacteria | Spirochaetota | Hemolysin III-like protein of Borrelia miyamotoi |
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1.C.113.1.3 | Hemolysin D channel protein of the hemolysin III family |
Bacteria | Pseudomonadota | Hemolysin D of Pseudomonas stutzeri |
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1.C.113.1.4 | Hemolysin III of 205 aas |
Bacteria | Deinococcota | Hemolysin of Thermus thermophilus |
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1.C.113.1.5 | Hemolysin III-like protein of 407 aas |
Eukaryota | Rhodophyta | Hemolysin of Galdieria sulphuraria (Red alga) |
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1.C.113.1.6 | Putative hemolysin III of 262 aas |
Bacteria | Actinomycetota | Hemolysin of Corynebacterium diphtheriae |
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1.C.113.1.7 | Hemolysin of 282 aas, HlyIII; forms pores of ~3.2 nm for solutes and ions (Wunderlich 2022). |
Eukaryota | Apicomplexa | Hemolysin of Plasmodium falciparum |
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1.C.113.1.8 | Adiponectin receptor protein of 340 aas |
Eukaryota | Euglenozoa | Adiponectin receptor of Trypanosoma cruzi |
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1.C.113.1.9 | The adiponectin receptor 1 or ADIPOQ, an essential hormone secreted by adipocytes that regulates glucose and lipid metabolism (Tanabe et al. 2015; Yamauchi et al. 2003. Required for normal glucose and fat homeostasis and for maintaining a normal body weight. ADIPOQ-binding activates a signaling cascade that leads to increased AMPK activity, and ultimately to increased fatty acid oxidation, increased glucose uptake and decreased gluconeogenesis. Has high affinity for globular adiponectin and low affinity for full-length adiponectin. The 3-d structure revealed ceramidase activity for both ADIPOR1 and ADIPOR2; however, the two structures are substantially different (Vasiliauskaité-Brooks et al. 2017). It may function with adiponectin to stimulate cholesterol efflux via ABCA1 (Hafiane et al. 2019). The Tyr-Pro dipeptide may function as an AdipoR1 agonist (Lee et al. 2021).
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Eukaryota | Metazoa, Chordata | ADIPOR1 of Homo sapiens |
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1.C.113.2.1 | The monocyte to macrophage differentiation protein (MMDP) | Eukaryota | Metazoa, Chordata | MMDP of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.113.2.2 | Monocyte to macrophage differentiation factor 2 of 363 aas and 7 TMSs |
Eukaryota | Metazoa, Arthropoda | Hemolysin homologue of Culex quinquefasciatus (Southern house mosquito) (Culex pungens) |
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1.C.113.2.3 | Progestin and adipoQ receptor family member 10, PAQR10, of 270 aas and 7 TMSs. Also called Monocyte to macrophage differentiation factor 2, MMD2. PAQR10 is structurally related to some bacterial hemolysins, pore-forming virulence factors that target mitochondria and regulate apoptosis (Góñez et al. 2008). |
Eukaryota | Metazoa, Chordata | PAQR10 of Homo sapiens |
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1.C.114.1.1 | Moricin of 66 aas and 1 TMS is processed to the active 42 aas peptide. The 3-d solution structure has been solved (1KV4). |
Eukaryota | Metazoa, Arthropoda | Moricin of Bombyx mori |
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1.C.114.1.2 | Moricin of 67 aas; known to increase permeability of and disrupt cytoplasmic membranes (Hara and Yamakawa 1995). |
Eukaryota | Metazoa, Arthropoda | Moricin of Manduca sexta |
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1.C.114.1.3 | Moricin-like peptide C2 of 63 aas. |
Eukaryota | Metazoa, Arthropoda | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.114.1.4 | Moricin B3 of 65 aas |
Eukaryota | Metazoa, Arthropoda | Moricin B3 of Bombyx mandarina |
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1.C.114.1.5 | Moricin of 67 aas |
Eukaryota | Metazoa, Arthropoda | Moricin of Spodoptera litura (Asian cotton leafworm) |
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1.C.115.1.1 | Diptericin of 106 aas, Dpt or Dipt. Disrupts bacterial membranes (Winans et al. 1999). In the Pfam attacin superfamily. |
Eukaryota | Metazoa, Arthropoda | Diptericin of Drosophila melanogaster (Fruit fly) |
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1.C.115.1.2 | Diptericin-like peptide, Dpt, of 140 aas and 1 TMS. |
Eukaryota | Metazoa, Arthropoda | Dpt homologue of Dendroctonus ponderosae (Mountain pine beetle) |
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1.C.115.1.3 | Antimicrobial peptide of 181 aas |
Eukaryota | Metazoa, Arthropoda | Peptide of Sitophilus zeamais (Maize weevil) |
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1.C.115.1.4 | Attacin-2 of 166 aas |
Eukaryota | Metazoa, Arthropoda | Attacin2 of Microdera dzhungarica |
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1.C.115.1.5 | Diptericin homologue of 93 aas, LmDpt |
Eukaryota | Metazoa, Arthropoda | Diptericin of Locusta migratoria manilensis (Oriental migratory locust) |
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1.C.115.1.6 | Attacin-A of 224 aas, AttA |
Eukaryota | Metazoa, Arthropoda | AttA of Drosophila melanogaster (Fruit fly) |
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1.C.116.1.1 | Bacteriocidal peptide, Abaecin, of 53 aas (Casteels et al. 1990). |
Eukaryota | Metazoa, Arthropoda | Abaecin of Apis mellifera (Honeybee) |
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1.C.116.1.2 | Abaecin-like protein of 117 aas |
Eukaryota | Metazoa, Arthropoda | Abaecin-like protein of Pteromalus puparum |
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1.C.116.1.3 | Nabaecin-1 of 117 aas |
Eukaryota | Metazoa, Arthropoda | Nabaecin-1 of Nasonia vitripennis (parasitic wosp) |
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1.C.116.1.4 | Nabaecin-3 of 98 aas. |
Eukaryota | Metazoa, Arthropoda | Nabaecin-3 of Nasonia vitripennis |
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1.C.117.1.1 | O-glycosidylated antimicrobial peptide, lebocin-1 (Leb1) of 179 aas and 1 N-terminal TMS (Hara and Yamakawa 1995). |
Eukaryota | Metazoa, Arthropoda | Lebocin of Bombyx mori |
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1.C.117.1.2 | Lebocin precursor of 143 aas |
Eukaryota | Metazoa, Arthropoda | Lebocin of Trichoplusia ni (Cabbage looper) |
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1.C.117.1.3 | Lebocin of 145 aas |
Eukaryota | Metazoa, Arthropoda | Lebocin of Chrysodeixis includens (Soybean looper) (Pseudoplusia includens) |
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1.C.118.1.1 | Polybia-Mastoparan-1 peptide, Polybia-MP1 of 14 aas. Polybia-MP1 (MP1) is a bioactive host-defense peptide with known anticancer properties. Its activity is dependent on phosphatidylserine (PS) and phosphatidyl ethanolamine (PE) in the outer leaflet of cancer cell membranes (Leite et al. 2015). zit is a hemotactic peptide for polymorphonucleated leukocytes (PMNL), but causing no hemolysis to rat erythrocytes and no mast cell degranulation activity at physiological concentrations. It is also a potent antimicrobial peptide against Gram-positive bacteria B. subtilis CCT 2576 (MIC=4 µg/ml), and S. aureus ATCC 6538 (MIC=15 µg/ml) as well as Gram-negative bacteria E. coli ATCC 25922 (MIC=8 µg/ml) and P. aeruginosa ATCC 15422 (MIC=8 µg/ml) (Souza et al. 2005). |
Eukaryota | Metazoa, Arthropoda | Polybia-MP1 of Polybia paulista (Neotropical social wasp) (Swarm-founding polistine wasp) |
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1.C.118.1.2 | Mastoparan (MP) of 14 aas. Potent antimicrobial peptide against both Gram-positive and Gram-negative bacteria. This hemolytic peptide shows potent histamine releasing activities on rat peritoneal mast cells. |
Eukaryota | Metazoa, Arthropoda | MP of Protonectarina sylveirae (Brazilian wasp) |
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1.C.119.1.1 | Aegerolysin Aa-Pri1 of 145 aas |
Eukaryota | Fungi | Aegerolysin of Agrocybe aegerita (Black poplar mushroom) (Agaricus aegerita) |
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1.C.119.1.2 | Ostreolysin A6, OlyA6 of 138 aas |
Eukaryota | Fungi, Basidiomycota | Ostreolysin of Pleurotus ostreatus (Oyster mushroom) (White-rot fungus) |
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1.C.119.1.3 | Terrelysin of 141 aas, a virulence factor with hemolytic activity agains sheep erythrocytes (Nayak et al. 2011). |
Fungi, Ascomycota | Terrelysin of Aspergillus terreus |
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1.C.119.1.4 | Aegerolysin of 150 aas |
Bacteria | Cyanobacteriota | Aegerolysin of Microcystis aeruginosa |
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1.C.119.1.5 | Aegerolysin of 140 aas |
Eukaryota | Fungi, Ascomycota | Aegerolysin of Metarhizium robertsii (Metarhizium anisopliae) |
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1.C.119.1.6 | Aegerolysin of 137 aas |
Bacteria | Pseudomonadota | Aegerolysin of Vibrio mimicus |
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1.C.12.1.1 | Perfringolysin O, PFO. In the formation of the pore forming toxin, the elongated toxin monomer binds stably to the membrane in an "end-on" orientation, with its long axis approximately perpendicular to the plane of the membrane bilayer (Ramachandran et al. 2005). This orientation is largely retained, even after monomers associate to form an oligomeric prepore complex. The domain 3 (D3) polypeptide segments that ultimately form transmembrane beta-hairpins remain far above the membrane surface in both the membrane-bound monomer and prepore oligomer. Upon pore formation, these segments enter the bilayer, whereas D1 moves to a position that is substantially closer to the membrane. Therefore, the extended D2 beta-structure that connects D1 to membrane-bound D4 appears to bend or otherwise reconfigure during the prepore-to-pore transition of the perfringolysin O oligomer (Ramachandran et al. 2005). The prepore to pore transition has been visualized by electron microscopy (Dang et al. 2005). Phosphatidylcholine in the outer leaflet increases the cholesterol concentration required to induce PFO binding while phosphatidylethanolamine and phosphatidylserine in the inner leaflet of asymmetric vesicles stabilized the formation of a deeply inserted conformation that does not form pores, even though it contains transmembrane segments (Lin and London 2014). This conformation may represent an important intermediate stage in PFO pore formation. Cholesterol recognition, oligomerization, and the conformational changes involved in pore formation have been reviewed (Johnson and Heuck 2014), and the involvement of the D1 domain in structural transitions leading to pore formation has been studied (Kacprzyk-Stokowiec et al. 2014). Interaction of PFO with cholesterol is sufficient to initiate an irreversible sequence of coupled conformational changes that extend throughout the toxin molecule and induce pore formation (Heuck et al. 2007). Once this transmembrane beta-barrel protein is inserted, PFO assembles into pore-forming oligomers containing 30-50 PFO monomers. These form a pore of up to 300 Å, far exceeding the size of most other proteinaceous pores. Decreasing the length of the β-strands causes the pore to shrink (Lin et al. 2015). Site-directed mutagenesis data combined with binding studies performed with different sterols, and molecular modeling are beginning to shed light on the interaction with cholesterol (Savinov and Heuck 2017). Fine-tuning of the stability of beta-strands by Y181 in perfringolysin O directs the prepore to pore transition (Kulma et al. 2019)c. Cholesterol-specific binding motifs in perfringolysin Ohave been identified (Šakanović et al. 2024). |
Bacteria | Bacillota | Perfringolysin O of Clostridium perfringens (P0C2E9) |
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1.C.12.1.10 | CDC family protein of 588 aas |
Bacteria | Spirochaetota | CDC protein of Treponema medium |
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1.C.12.1.11 | CDC homologue of 511 aas |
Bacteria | Deinococcota | CDC protein of Deinococcus deserti |
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1.C.12.1.12 | Uncharacterized protein of 656 aas |
Bacteria | Actinomycetota | UP of Streptomyces mobaraensis |
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1.C.12.1.13 | Intermedilysin of 532 aas and 1 N-terminal TMS, ILY or Ply. It binds to membranes containing the human protein CD59 but forms pores only if the membrane contains sufficient cholesterol (Heuck et al. 2007). CD59 is required for the specific coordination of intermedilysin (ILY) monomers and for triggering collapse of an oligomeric prepore. Movement of Domain 2 with respect to Domain 3 of ILY is essential for forming a late prepore intermediate that releases CD59, while the role of cholesterol may be limited to insertion of the TMSs (Boyd et al. 2016). The pore-forming regions are initially folded up on the surfaces of the soluble precursors. To create the transmembrane pores, these regions must extend and refold into membrane-inserted beta-barrels (Tilley and Saibil 2006). The intermedilysin cytolytic activity depends on heparan sulfates and the membrane composition (Drabavicius and Daelemans 2021). |
Bacteria | Bacillota | Intermedilysin of Streptococcus intermedius |
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1.C.12.1.14 | Thiol-activated cytolysin of 500 aas and 1 N-terminal TMS. It is a sulfhydryl-activated toxin that causes cytolysis by forming pores in cholesterol containing host membranes. After binding to target membranes, the protein undergoes a major conformation change, leading to its insertion in the host membrane and formation of an oligomeric pore complex. Biomimetic nanosponges neutralize this cytolysin, protect the retina, preserve vision, and may provide an adjunct detoxification therapy for bacterial infections (LaGrow et al. 2017). |
Bacteria | Bacillota | Cytotoxin of Enterococcus faecalis |
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1.C.12.1.15 | Cholesterol-dependent cytolysin or thiol-activated cytolysin of 532 aas (Pleckaityte 2019). |
Bacteria | Bacillota | CDC or TAC of Gemella bergeri |
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1.C.12.1.16 | Vaginolysin (VLY) of 516 aas and 1 N-terminal TMS. It plays a role in bacterial vaginosis (BV), a vaginal anaerobic dysbiosis that affects women of reproductive age worldwide. BV is microbiologically characterized by the depletion of vaginal lactobacilli and the overgrowth of anaerobic bacterial species. Gardnerella spp. have a pivotal role among BV-associated bacteria in the initiation and development of BV (Pleckaityte 2019). Inerolysin (INY) (TC# 1.C.12.1.17)-induced damage of artificial membranes is directly dependent on the cholesterol concentration in the bilayer, whereas VLY-induced damage occurs only with high levels of membrane cholesterol (>40 mol%) (Ragaliauskas et al. 2019). VLY primarily forms membrane-embedded complete rings in the synthetic bilayer, whereas INY forms arciform structures with smaller pore sizes. VLY activity is high at elevated pH, which is characteristic of BV, whereas INY activity is high at more acidic pH, which is characteristic of a healthy vagina (Pleckaityte 2019). |
Bacteria | Actinomycetota | Vaginolysin of Gardnerella vaginalis |
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1.C.12.1.17 | Inerolysin (INY) or cholesterol-dependent cytolysin of 519 aas and one N-terminal TMS. Lactobacillus iners is a prevalent constituent of healthy vaginal microbiota, but it produces this cytotoxin (Pleckaityte 2019). INY-induced damage of artificial membranes is directly dependent on the cholesterol concentration in the bilayer, whereas VLY (TC# 1.C.12.1.16)-induced damage occurs only with high levels of membrane cholesterol (>40 mol%) (Ragaliauskas et al. 2019). VLY primarily forms membrane-embedded complete rings in the synthetic bilayer, whereas INY forms arciform structures with smaller pore sizes. VLY activity is high at elevated pH, which is characteristic of BV, whereas INY activity is high at more acidic pH, which is specific for a healthy vagina (Pleckaityte 2019). |
Bacteria | Bacillota | INY of Lactobacillus iners |
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1.C.12.1.2 | Pore-forming Alveolysin of 501 aas and one N-terminal TMS. |
Bacteria | Bacillota | Alveolysin of Bacillus alvei (P23564) |
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1.C.12.1.3 | Cereolysin O (hemolysin I) (Ramarao and Sanchis 2013). |
Bacteria | Bacillota | Hemolysin I of Bacillus cereus (Q93LA9) |
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1.C.12.1.4 | Streptolysin O, SLO or SpyM3, (transports NAD-glycohydrolase into the host cell) (Meehl and Caparon, 2004). Injections into cells modulates cell metabolism which induces streptolysin synthesis and S. pyogenes growth (Baruch et al. 2014). This sulfhydryl-activated toxin causes cytolysis by forming pores in cholesterol containing host membranes. After binding to target membranes, the protein undergoes a major conformation change, leading to its insertion. The domino-like prepore-to-pore transition of Streptolysin O has been visualized (Ariyama 2022).
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Bacteria | Bacillota | Streptolysin O of Streptococcus pyogenes (P0C0I3) |
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1.C.12.1.5 | Pneumolysin (PLS or PLY) or Intermedilysin (ILY), the shortest members of the CDC family (Gonzalez et al., 2008). It exhibits a broad range of conductances (El-Rachkidy et al., 2008) and localizes to the cell wall of S. pneumoniae (Price and Camilli, 2009). Binding of ILY to human CD59 initiates a series of conformational changes within the toxin that result in the conversion of the soluble monomer into an oligomeric membrane-embedded pore complex. The assembly intermediates increase the sensitivity of the host cell to lysis by its complement membrane attack complex, apparently by blocking the hCD59-binding site for complement proteins C8α and C9 (LaChapelle et al., 2009). The herbal bioflavonoid, Apigenin, inhibits oligomerization of PLY and protects against pneumonia (Song et al. 2016). Pneumolysin alters lysosomal integrity in epithelial cells, but not in macrophages, inducing lysosomal membrane permeabilization and release of lysosomal content (Malet et al. 2016). A four-step mechanism of membrane attachment and pore formation has been proosed (van Pee et al. 2016). Pneumolysin is both necessary and sufficient to promote inflammation, increasing shedding and causing transmission to others (Zafar et al. 2017). The release of pneumococcal autolysin, which promotes cell lysis and the release of pneumolysin, is inhibited by treatment with azithromycin and erythromycin, but recombinant autolysin restores the release of pneumolysin (Domon et al. 2018). Pneumolyin exhibits direct cardiotoxic and immunosuppressive activities, as well as indirect pro-inflammatory/pro-thrombotic activities (Anderson et al. 2018). The transmembrane beta-hairpins of the PLY pore are stable only for oligomers, forming a curtain-like membrane-spanning beta-sheet, and its hydrophilic inner face draws water into the protein-lipid interface, forcing lipids to recede (Vögele et al. 2019). Formation of pre-pore complexes of pneumolysin is accompanied by a decrease in short-range order of lipid molecules throughout vesicle bilayers (Faraj et al. 2020). Although pneumolysin-induced inflammation drives person-to-person transmission from the nasopharynx, the primary reservoir for pneumococcus, it also contributes to high mortality rates, creating a bottleneck that hampers widespread bacterial dissemination, thus acting as a double-edged sword (Badgujar et al. 2020). Serotype 1 ST306, a widespread pneumococcal clone, harbours a non-hemolytic variant of pneumolysin (Ply-NH). Crystal structural analyses of Ply-NH led to the identification of Y150H and T172I as key substitutions responsible for loss of its pore-forming activity. A novel inter-molecular cation-pi interaction governs formation of the transmembrane beta-hairpins (TMH) in the pore state of Ply, which can be applied to other CDCs. H150 in Ply-NH disrupts this interaction, while I172 provides structural rigidity to domain-3 through hydrophobic interactions, inhibiting TMH formation. Loss of pore-forming activity enables improved cellular invasion and autophagy evasion, promoting an atypical intracellular lifestyle for pneumococcus, a finding that was corroborated in in vivo infection models. Attenuation of inflammatory responses and tissue damage promoted tolerance of Ply-NH-expressing pneumococcus in the lower respiratory tract. Adoption of this altered lifestyle may be necessary for ST306 due to its limited nasopharyngeal carriage with Ply-NH, aided partly by loss of its pore forming ability, facilitating a benign association of SPN in an alternative, intracellular host niche (Badgujar et al. 2020). Apigenin protects mice from pneumococcal pneumonia by inhibiting the cytolytic activity of pneumolysin (Song et al. 2016). PLY can disrupt plasma membrane integrity, deregulating cellular homeostasis. At lytic concentrations, PLY causes cell death, but at sub-lytic concentrations, PLY triggers host cell survival pathways that cooperate to reseal the damaged plasma membrane and restore cell homeostasis (Pereira et al. 2022). While PLY is generally considered a pivotal factor promoting S. pneumoniae colonization and survival, it is also a powerful trigger of the innate and adaptive host immune response against bacterial infection. The dichotomy of PLY as both a key bacterial virulence factor and a trigger for host immune modulation allows the toxin to display both "Yin" and "Yang" properties during infection, promoting disease by membrane perforation and activating inflammatory pathways, while also mitigating damage by triggering host cell repair and initiating anti-inflammatory responses. Due to its cytolytic activity and diverse immunomodulatory properties, PLY is integral to every stage of S. pneumoniae pathogenesis and may tip the balance towards either the pathogen or the host depending on the context of infection (Pereira et al. 2022). Pneumolysin drives pathogenicity through host extracellular vesicles released during infection (Parveen et al. 2024). |
Bacteria | Bacillota | Pneumolysin of Streptococcus pneumoniae (P0C2J9) |
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1.C.12.1.6 | Ivanolysin | Bacteria | Bacillota | Ivanolysin of Listeria ivanovii (P31831) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.12.1.7 | Listeriolysin O, Listeriolysin-O, LLO, Hly, HlyA, Lis of 507 aas and 1 N-terminal TMS (Viala et al., 2008). CFTR transiently increases phagosomal chloride concentrations after infection, potentiating pore formation and vacuole lysis. Thus, Listeria exploits mechanisms of cellular ion homeostasis to escape the phagosome (Radtke et al., 2011). LLO is an example of a large beta-barrel pore that exhibits plasticity, controlled by environmental cues like pH (Podobnik et al. 2015). Pore formation is a multistep process involving the sequential formation of arcs, slits, small rings and larger rings before formation of transmembrane pores (Mulvihill et al. 2015). LLO promotes nanoscale membrane reorganization (Sarangi et al. 2016). It alters lysosomal integrity in epithelial cells, but not in macrophages, inducing lysosomal membrane permeabilization and release of lysosomal content (Malet et al. 2016). LLO pore activity is active at acidic pH (<6), but not at neutral pH because pore-formation is controlled by rapid, irreversible denaturation of its structure at neutral pH at temperatures >30 degrees C. Denaturation is triggered at neutral pH by the premature unfolding of the domain 3 transmembrane beta-hairpins, structures that normally form the transmembrane beta-barrel. A triad of acidic residues within domain 3 functions as the pH sensor (Schuerch et al. 2005). Kisovec et al. 2017 have made a mutant variant with hemolytic activity that is pH-dependent. LLO does not form pores of regular shape or size, but rather forms membrane inserted arcs that propagate and damage lipid membranes as lineactants (Jiao et al. 2021). At low PFT concentrations, a regime of increased lipid diffusivity is attributed to lipid ejection events because of a preponderance of ring-like pore states (Ilangumaran Ponmalar et al. 2021). At higher protein concentrations in which membrane-inserted arc-like pores dominate, lipid ejection is less efficient and the ensuing crowding results in a lowering of lipid diffusion. |
Bacteria | Bacillota | Listeriolysin O of Listeria monocytogenes (P13128) |
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1.C.12.1.8 | Suilysin (SLY, a hemolysin) of 497 aas is a pore-forming cholesterol-dependent cytolysin of S. suis and a true virulence factor (Tenenbaum et al. 2016). It plays a role during the development of S. suis meningitis in pigs and humans, and is a potential vaccine candidate. Amentoflavone, a natural biflavonoid compound isolated from Chinese herbs is a potent antagonist of suilysin (SLY)-mediated hemolysis without interfering with its expression. Amentoflavone effectively inhibited SLY oligomerization, which is critical for its pore-forming activity. Treatment with amentoflavone reduced S. suis-induced cytotoxicity in macrophages, and S. suis-infected mice that received amentoflavone exhibited lower mortality and bacterial burden (Shen et al. 2018). |
Bacteria | Bacillota | Hemolysin of Streptococcus suis (O85102) |
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1.C.12.1.9 | The cholesterol-dependent pore-forming cytoslysin, Pyolysin of 534 aas with one N-terminal TMS. The pathology of Trueperella pyogenes and this pyolysin have been described and reviewed (Rzewuska et al. 2019). Liu et al. 2022 located and mutated two different highly conserved structural sites in the primary sequence of the protein that are critical for PLO structure and function. |
Bacteria | Actinomycetota | Pyolysin of Arcanobacterium pyogenes (Trueperella pyogenes) (O31241) |
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1.C.12.2.1 | Flavomodulin | Bacteria | Bacteroidota | Flavomodulin of Flavobacterium psychrophilum (A6GVU3) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.12.2.2 | Uncharacterized protein of 373 aas |
Bacteria | Bacteroidota | UP of Prevotella micans |
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1.C.12.2.3 | Tetanolysin O of 369 aas. A three dimensional model of the toxin is availalbe (Skariyachan et al. 2012). |
Bacteria | Bacteroidota | Tetanolysin O of Capnocytophaga canimorsus |
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1.C.12.2.4 | CDC homologue of 489 aas |
Bacteria | Bacteroidota | CDC homologue of Chryseobacterium indologenes |
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1.C.12.3.1 | Hypothetical Protein, HP | Bacteria | Cyanobacteriota | HP of Nostoc sp. PCC7120 (Q8YX86) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.12.3.2 | Cytolysin, a secreted calcineurin-like phosphatase of 361 aas |
Bacteria | Pseudomonadota | Cytolysin of Mesorhizobium loti |
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1.C.12.3.3 | Cytolysin, a secreted calcineurin-like phosphatase of 458 aas |
Bacteria | Pseudomonadota | Cytolysin of Candidatus Liberibacter americanus |
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1.C.120.1.1 | Pore-forming toxin, DinQ of 42 aas and 1 TMS (Brielle et al. 2016). |
Bacteria | Pseudomonadota | DinQ of E. coli |
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1.C.120.1.2 | DinQ homologue of 37 aas with 1 TMS. |
Bacteria | Pseudomonadota | DinQ homologue of Pantoea stewartii |
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1.C.120.1.3 | DinQ homologue of 62 aas and 1 TMS |
Bacteria | Pseudomonadota | DinQ homologue of Photorhabdus heterorhabditis |
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1.C.120.1.4 | Uncharacterized peptide of 29 aas and 1 TMS. |
Bacteria | Pseudomonadota | UP of Xenorhabdus bovienii |
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1.C.121.1.1 | β-Conglycinin α-chain of 639 aas. A pore-forming 20 aa peptide that forms pores in bacterial membranes, 7a16 (FQTLFKNQYGHVRVLQRFNK), was derived from this protein (Xiang et al. 2016). |
Eukaryota | Viridiplantae, Streptophyta | β-Conglycinin α-chain of Glycine max (Soybean) (Glycine hispida) |
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1.C.121.1.2 | Glycinin A3 subunit of 516 aas. A pore-forming 20 aa peptide that forms pores in bacterial membranes, G5466 (VFKTHHNAVSSYIKDVFRVI), was derived from this protein (Xiang et al. 2016). |
Eukaryota | Viridiplantae, Streptophyta | Glycinin A3 subunit of Glycine max (Soybean) (Glycine hispida) |
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1.C.122.1.1 | δ-hemolysin of 26 aas and possibly 1 TMS. Lyses red blood cells and other animal cells preferentially to bacteria. Forms dimers on the surfaces of bilayers at low concentrations but pores at higher concentrations (King et al. 2016). |
Bacteria | Bacillota | δ-hemolysin of Staphylococcus aureus |
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1.C.122.1.2 | Delta-lysin of 25 aas |
Bacteria | Bacillota | δ-hemolysin of Staphylococcus intermedius |
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1.C.123.1.1 | Pore-forming Gasdermin D (Gasdermin-A3, GSDMD, DFNA5L, GSDMDC1, FKSG10) of 484 aas (Ding et al. 2016). GSDMD is activated by inflammasome-activated caspases-1/-4/-5/-11 as well as a caspase-8-mediated pathway during Yersinia infection. These caspases cleave GSDMD to release its functional N-terminal fragment (GSDMD-NT) from its auto-inhibitory C-terminal fragment (GSDMD-CT). GSDMD-NTs bind to acid lipids in mammalian cell membranes and bacterial membranes, oligomerize, and insert into the membranes to form large transmembrane pores. Consequently, cellular contents including inflammatory cytokines are released (e.g., IL-1β), and cells can undergo pyroptosis, a highly inflammatory form of cell death (Xia et al. 2019; Muendlein et al. 2020). As organelles of the innate immune system, inflammasomes activate caspase-1 and other inflammatory caspases that cleave gasdermin D. Caspase-1 also cleaves inactive precursors of the interleukin (IL)-1 family to generate mature cytokines such as IL-1beta and IL-18. Cleaved GSDMD forms transmembrane pores to enable the release of IL-1 and to drive cell lysis through pyroptosis. Cryo-EM structures of the pore and the prepore reveal the different conformations of the two states, as well as membrane-binding elements including a hydrophobic anchor and three positively charged patches. The pore conduit is predominantly negatively charged, but IL-1 precursors have an acidic domain that is proteolytically removed by caspase-1. When permeabilized, unlysed liposomes release positively charged and neutral cargoes faster than negatively charged cargoes of similar sizes, and the pores favor the passage of IL-1beta and IL-18 over that of their precursors (Xia et al. 2021). Gasdermin-A3 oligomers assemble on the membrane surface where they remain attached and mobile. Once inserted into the membrane it grows variable oligomeric stoichiometries and shapes, each able to open transmembrane pores. Molecular dynamics simulations resolved how the membrane-inserted amphiphilic beta-hairpins and the structurally adapting hydrophilic head domains stabilize variable oligomeric conformations and open the pore. Without a vertical collapse, gasdermin pore formation propagates along a set of multiple parallel but connected reaction pathways to ensure a robust cellular response (Mari et al. 2022). Gasdermin D (GSDMD) is the common effector for cytokine secretion and pyroptosis downstream of inflammasome activation by forming large transmembrane pores upon cleavage by inflammatory caspases. Du et al. 2023 reported that GSDMD cleavage is not sufficient for its pore formation; GSDMD must be lipidated by S-palmitoylation at Cys191 upon inflammasome activation, and only palmitoylated GSDMD N-terminal domain (GSDMD-NT) is capable of membrane translocation and pore formation. Thus, GSDMD palmitoylation is induced by ROS and required for pore formation (Du et al. 2023). Brain endothelial GSDMD activation mediates inflammatory BBB breakdown (Wei et al. 2024). |
Eukaryota | Metazoa, Chordata | Gasdermin D or A3 of Homo sapiens |
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1.C.123.1.10 | Pajvakin (Gasdermin homologue) of 247 aas with 8 or 9 short peaks of hydrophobicity. |
Eukaryota | Metazoa, Cnidaria | Pejvakin (Gasdermin homolog) of Exaiptasia diaphana |
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1.C.123.1.11 | Uncharacterized protein of 472 aas |
Eukaryota | Metazoa, Cnidaria | UP of Nematostella vectensis (starlet sea anemone) |
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1.C.123.1.2 | Gasdermin A of 445 aas. Gasdermins A and B may be involved in asthma (Zihlif et al. 2016). Induction in the epidermis leads to skin inflammation (Lin et al. 2015). Roles of multiple charged residues in membrane insertion of gasdermin-A3 have been identified (Korn and Pluhackova 2022). |
Eukaryota | Metazoa, Chordata | Gasdermin A of Homo sapiens |
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1.C.123.1.3 | Gasdermin B of 411 aas. Promotes invasioin and metastasis in breast cancer (Hergueta-Redondo et al. 2014). |
Eukaryota | Metazoa, Chordata | Gaseremin B of Homo sapiens |
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1.C.123.1.4 | Gasdermin C of 508 aas. The N-terminal moiety promotes pyroptosis. It may be acting by homooligomerizing within the membrane and forming pores (Ding et al. 2016). Pyroptosis and its role in central nervous system diseases have been reviewed (Hu et al. 2021).
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Eukaryota | Metazoa, Chordata | Gasdermin C of Homo sapiens |
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1.C.123.1.5 | Non-syndromic hearing impairment protein 5, DFNA5, (Gasdermin E precursor; GSDME, ICERE1) of 496 aas. After cleavage by CASP3, it moves to the plasma membrane, homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis (Wang et al. 2017, Zhang et al. 2020). It plays a role in hearing loss and the TP53-regulated cellular response to DNA damage, probably by cooperating with TP53 (Masuda et al. 2006; Kim et al. 2008; Op de Beeck et al. 2011). The N-terminal moiety promotes pyroptosis (inflamatory cell death) and exhibits bactericidal activity (Ding et al. 2016). |
Eukaryota | Metazoa, Chordata | DFNA5 of Homo sapiens |
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1.C.123.1.6 | DNFB59 protein of 361 aas. |
Eukaryota | Metazoa, Chordata | DNFB59 protein of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.C.123.1.7 | Pejvakin (DFNB59; PJVK) of 357 aas. It is a constituent of the afferent auditory pathway, causing DFNB59 auditory neuropathy (Delmaghani et al. 2006), autosomal recessive nosyndromic hearing impairment (Collin et al. 2007). It is also called the diaphanous homologue 3 (DIAPH3). |
Eukaryota | Metazoa, Chordata | Pejvakin of Homo sapiens |
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1.C.123.1.8 | Gasdermin family protein of 252 aas and 1 or 2 central TMSs. The 3-D structure is known (7N52_A-D). Bacterial gasdermins are activated by caspase-like proteases, oligomerize into large membrane pores, and defend against pathogenic bacteriophage (Johnson et al. 2022). They mediate an ancient mechanism of prokaryotic cell death (Johnson et al. 2022). |
Bacteria | Pseudomonadota | Gasdermin protein of Salmonella enterica subsp. enterica serovar Typhi (Salmonella typhi) |
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1.C.123.1.9 | Gasdermin Eb of 472 aas and 1 or 2 TMSs. |
Eukaryota | Metazoa, Chordata | Gasdermin Eb of Danio rerio (zebrafish) |
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1.C.123.2.1 | Uncharacterized protein of 285 aas with one TMS between residues 70 and 90. |
Eukaryota | Fungi, Ascomycota | UP of Fusarium solani-melongenae |
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1.C.123.2.2 | Uncharacterized protein of 336 aas and 1 TMS between residues 70 and 90. |
Eukaryota | Fungi, Ascomycota | UP of Lasiodiplodia theobromae |
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1.C.123.2.3 | Uncharacterized protein of 267 aas and probably 0 TMSs. |
Eukaryota | Fungi, Ascomycota | UP of Trichoderma atroviride |
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1.C.123.2.4 | Uncharacterized protein of 261 aas and possibly 4 TMSs, one N-terminal, one at residue 70, one at residue 130, and one at residue 170. |
Eukaryota | Fungi, Ascomycota | UP of Acephala macrosclerotiorum |
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1.C.123.3.1 | Uncharacterized protein of 323 aas and 4 regions of hydrophobicity that might be TMSs. |
Eukaryota | Viridiplantae, Streptophyta | UP of Ceratodon purpureus |
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1.C.123.3.2 | Uncharacterized protein of 319 aas and 1 N-terminal TMS. |
Eukaryota | Viridiplantae, Streptophyta | UP of Sphagnum fallax |
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1.C.123.3.3 | Uncharacterized protein of 314 aas and an N-terminal TMS plus several possible TMSs. |
Eukaryota | Viridiplantae, Streptophyta | UP of Ceratodon purpureus |
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1.C.124.1.1 | Pandinin2 of 24 aas and 1 TMS. Forms pores and disrupts membranes of bacteria and fungi (Rodríguez et al. 2014). |
Eukaryota | Metazoa, Arthropoda | Pandinin-2 of Pandinus imperator |
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1.C.124.1.2 | Heterin-1 of 43 aas and 1 TMS. Heterin-1 possesses potent activities against both Gram-positive and Gram-negative bacteria. Among the tested bacterial species, Heterin-1 is the most active against Bacillus megaterium and Micrococcus luteus with MICs of 4.0 μM for both (Wu et al. 2014). |
Eukaryota | Metazoa, Arthropoda | Heterin-1 of Heterometrus spinifer (Asia giant forest scorpion) (Malaysian black scorpion) |
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1.C.124.1.3 | Venom toxin of 73 aas and 1 TMS. |
Eukaryota | Metazoa, Arthropoda | Venom toxin of Hemiscorpius lepturus (scorpion) |
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1.C.124.1.4 | Scorpion toxin, OcyC3, of 75 aas and 1 TMS. Also called antimicrobial peptide NDBP 4.1. |
Eukaryota | Metazoa, Arthropoda | OcyC3 of Opisthacanthus cayaporum (South American scorpion) |
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1.C.124.1.5 | Ponericin-W5 of 24 aas and 1 TMS. Has a broad spectrum of activities against both
Gram-positive and Gram-negative bacteria as well as Saccharomyces cerevisiae. It also has
insecticidal and hemolytic activities (Orivel et al. 2001). |
Eukaryota | Metazoa | Ponericin-W5 of Pachycondyla goeldii (Ponerine ant) |
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1.C.124.1.6 | Antimicrobial peptide, AMP, of 76 aas and 1 N-terminal TMS. It is similar to a characterized AMP that forms toroidal pores, reported by Bertelsen et al. 2023. |
Eukaryota | Metazoa, Arthropoda | AMP of Pandinus cavimanus (Tanzanian red clawed scorpion) |
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1.C.124.2.1 | Pandinin 1, Pin1, of 44 aas and 0 TMSs. Pin1 is located at the membrane-water interface, approximately parallel to the bilayer surface. Solid-state NMR results correlated well with the observed biological activity of pin1 in red blood cells and bacteria (Nomura et al. 2005). Pin-1 and Pin-2 are not demonstrably homologous. However, Pin1 shows 30% identity with a central part of 1.C.17.2.2. |
Eukaryota | Metazoa, Arthropoda | Pin-1 of Pandinus imperator |
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1.C.125.1.1 | Two component stonustoxin with alpha and beta subunits, of 703 aas (α-toxin) and 700 aas (β-toxin). See family descriiption for description and references. The two subunits are 47% identical. |
Eukaryota | Metazoa, Chordata | Stonustoxin of Synanceia horrida (Estuarine stonefish) (Scorpaena horrida) |
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1.C.125.1.2 | Cytotoxin with two subunits, α (703 aas) and β (698 aas) (Borges et al. 2018). |
Eukaryota | Metazoa, Chordata | Cytotoxin of Scorpaenopsis oxycephala |
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1.C.125.1.3 | Cytotoxin with three subunits, α (586 aas), β (585 aas) and γ (583 aas). |
Eukaryota | Metazoa, Chordata | Cytotoxin of Dendrochirus xebra |
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1.C.125.1.4 | Patoxin with two subunits, α of 699 aas and β of 698 aas (Borges et al. 2018). |
Eukaryota | Metazoa, Chordata | Patoxin of Pterois antennata |
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1.C.126.1.1 | Hemolysin C, HlyC or TlyC, of 268 aas. Pore formation was demonstrated by the inhibition of hemolysis with molecules of 2.0 to 2.3 nm in diameter and the release of 86rubidium from erythrocytes without hemoglobin release after exposure to native hemolysin (Hyatt and Joens 1997). |
Bacteria | Spirochaetota | HlyC of Brachyspira (Treponema, Serpulina) hyodysenteriae (Q54318) |
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1.C.126.1.2 | Co2+-resistance protein, CorC, of 292 aas and 0 TMSs (Sponder et al. 2010). The E. coli orthologue (P6AE78) is 97% identical to the S. enterica protein. |
Bacteria | Pseudomonadota | CorC of Salmonella typhimurium (P0A2L3) |
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1.C.126.1.3 | DUF21-CBS-HlyC domain-containing protein of286 aas and 0 TMSs. |
Bacteria | Pseudomonadota | HlyC-like protein of Francisella tularensis |
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1.C.126.1.4 | Hemolysin of 159 aas |
Bacteria | Spirochaetota | Hemolysin of Treponema pallidum |
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1.C.127.1.1 | Human Apolipooprotein A1, APOL1, a tripanolytic factor of 398 aas and 4 possible α-helical TMSs in a 1 + 2 + 1 TMS arrangement. Pore-formation has been demonstrated in planar bilayer membranes. APOL1 inserts into such bilayers at acidic pH to form pH-gated non-selective cation channels that open upon pH neutralization. This corresponds to the pH changes encountered during endocytic-recycling, suggesting that APOL1 forms a cytotoxic cation channel in the parasite plasma membrane. Pore-formation is blocked by the serum resistance-associated VSG protein, SRA. See family discussion for a published description of this protein (Thomson and Finkelstein 2015). APOL1 risk variants induce opening of the mitochondrial permeability transition pore (Carney 2019). Cation channel conductance and pH gating of the innate immunity factor APOL1 is governed by pore lining residues in the C-terminal domain (Schaub et al. 2020). Two residues in the C-terminal domain (CTD), tyrosine-351 and glutamate-355 influence pH gating properties, and a single residue, aspartate-348, determines both cation selectivity and pH gating. Thus, the predicted transmembrane region closest to the APOL1 C-terminus is the pore-lining segment of this channel-forming protein (Schaub et al. 2020). |
Eukaryota | Metazoa, Chordata | APOL1 of Homo sapiens |
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1.C.127.1.2 | Uncharacterized protein of 566 aas and 4 TMSs in a 1 + 2 + 1 TMS arrangement. |
Eukaryota | Metazoa, Chordata | UP of Takifugu rubripes (Torafugu) |
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1.C.127.1.3 | Apolipoprotein L domain-containing protein 1 isoform X1 of 319 aas and 2 TM |
Eukaryota | Metazoa, Chordata | Apolipoprotein of Chrysemys picta bellii |
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1.C.127.1.4 | Uncharacterized protein of 1010 aas and 4 TMSs in a 1 (N-terminal) + 2 + 1 TMS arrangement. |
Eukaryota | Metazoa, Arthropoda | UP of Tigriopus californicus (Marine copepod) |
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1.C.127.1.5 | Uncharacterized protein of 313 aas and 3 TMSs in a 2 + 1 TMS arrangement. |
Eukaryota | Metazoa, Chordata | UP of Pygocentrus nattereri (red-bellied piranha) |
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1.C.127.1.6 | Uncharacterized protein of 1075 aas and possibly 6 TMSs in a 1 (N-terminal) + 1 + 2 + 2 TMS arrangement. |
Eukaryota | Metazoa, Mollusca | UP of Crassostrea virginica (eastern oyster) |
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1.C.127.1.7 | Serine/threonine-protein kinase domain (N-terminus) and Lipoprotein domain (C-terminus) protein, Nek5, of 543 aas and 4 TMSs in a 2 + 2 TMS arrangement. |
Eukaryota | Metazoa, Chordata | Kinase of Danio rerio |
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1.C.127.1.8 | Uncharacterized protein of 289 aas and 4 TMSs in a 2 + 2 TMS arrangement. |
Eukaryota | Metazoa, Cnidaria | UP of Acropora millepora (cnidaria) |
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1.C.127.2.1 | Uncharacterized protein of 536 aas and 2 TMSs. This bacterial protein shows sequence similarity to animal members of the family in the region showing the 2 TMSs. |
Bacteria | Campylobacterota | UP of Helicobacter suis |
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1.C.127.2.2 | Prolipoprotein of 553 aas and 0 TM |
Viruses | Heunggongvirae, Uroviricota | Lipoprotein of Helicobacter phage PtB89G |
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1.C.127.2.3 | Uncharacterized protein of 700 aas and 1 - 3 TMSs, two of which may be adjacent to each other. This protein is annotated as a divalent metal ion transporter, but this is probably an error. |
Bacteria | Campylobacterota | UP of Helicobacter canis |
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1.C.129.1.1 | Lysis Protein E |
Viruses | Sangervirae, Phixviricota | Lysis protein E of phage ΦX174 (P03639) |
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1.C.129.1.2 | gpE protein of 105 aas and 1 TMS. |
Viruses | Sangervirae, Phixviricota | gpE of Enterobacteria phage WA2 |
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1.C.129.1.3 | Gene E lysis protein of 96 aas and 1 TMS. |
Viruses | Sangervirae, Phixviricota | E protein of Escherichia phage G4 |
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1.C.13.1.1 | Channel-forming leucocidin cytotoxin, CTX | Bacteria | Pseudomonadota | CTX of phage φCTX of Pseudomonas aeruginosa |
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1.C.13.1.2 | Uncharacterized protein of 285 aas |
Bacteria | Pseudomonadota | UP of Pectobactyerium wasabiae |
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1.C.13.1.3 | Cytotoxic Leucocidin of 290 aas |
Bacteria | Bacteroidota | Cytotoxic leucocidin of Fibrella aestuarina |
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1.C.13.1.4 | Uncharacterized protein with similarity to clostridial epsilon toxin ETX and Bacillus mosquitocidal toxin MTX2. |
Bacteria | Pseudomonadota | UP of Virbio caribbenthicus |
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1.C.13.1.5 | Arthropod secreted salivary gland protein of 278 aas |
Eukaryota | Metazoa, Arthropoda | Secreted protein of Ixodes scapularis |
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1.C.13.1.6 | Secreted salivary gland protein of 291 aas. |
Eukaryota | Ciliophora | Secreted protein of Oxytricha trifallax |
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1.C.13.1.7 | CABIT-domain-contaiining pore-forming toxin protein of 271 aas, Lin-24. |
None | Metazoa, Nematoda | Lin-24 of Caenorhabditis elegans |
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1.C.130.1.2 | Toxin GHoT of 57 aas and 2 TMSs. GhoT is the toxic component of a type V toxin-antitoxin (TA) system. It causes membrane damage when induced by MqsR, slowing cell growth and increasing the formation of dormant persister cells. It is involved with GhoS, its antitoxin, in reducing cell growth during antibacterial stress (Cheng et al. 2014). Overexpression causes cell lysis, forming ghost cells; both effects are neutralized by expression of GhoS. Overexpression in the presence of ampicillin increases persister cell formation (persister cells exhibit antibiotic tolerance without genetic change) (Wang et al. 2012). Overexpression causes about 90-fold reduction in cellular ATP levels and dissipates the membrane potential (Cheng et al. 2014). |
Bacteria | Pseudomonadota | GhoT of E. coli |
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1.C.130.1.3 | GhoT/OrtT family toxin of 61 aas and 2 TMSs. |
Bacteria | Pseudomonadota | Toxin of Hafnia paralvei |
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1.C.132.1.1 | The TseL toxin of 641 aas and 1 or 2 central TMSs. See family description for properties. |
Bacteria | Pseudomonadota | TseL of Vibrio cholerae |
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1.C.132.1.2 | Uncharacterized protein, probably a lipase, of 775 aas and from 0 to 4 possible TMSs. |
Eukaryota | Viridiplantae, Streptophyta | UP of Spirodela intermedia |
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1.C.132.1.3 | Uncharacterized protein, probable lipase, of 340 aas and 3 probable TMSs, one in the middle and two near the C-terminus of the protein. |
Eukaryota | Viridiplantae, Streptophyta | UP of Momordica charantia (bitter melon) |
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1.C.132.1.4 | Uncharacterized protein of 275 aas and possibly 2 TMSs. |
Eukaryota | Ciliophora | UP of Paramecium sonneborni |
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1.C.132.1.5 | Lipase domain protein, putative of 1867 aas and ~ 12 TMSs. |
Eukaryota | Euglenozoa | Lipase of Leishmania panamensis |
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1.C.132.1.6 | Triacylglycerol lipase OBL1-like of 482 aas and ~ 7 TMSs in a 2 + 2 + 3 TMS arrangement. |
Eukaryota | Viridiplantae, Streptophyta | Lipase of Hibiscus syriacus |
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1.C.132.1.7 | Lipase family protein of 371 aas and one N-terminal TMS, with a second possible central TMS. |
Bacteria | Planctomycetota | Lipase of Crateriforma spongiae |
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1.C.133.1.1 | The small polypeptide toxin of 30 aas and 1 TMS. It is a type I toxin and forms pores in the membrane (Nonin-Lecomte et al. 2021). |
Bacteria | Campylobacterota | AapA1 of Helicobacter pylori |
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1.C.133.1.2 | Putative pore-forming toxin, PFT, of 30 aas and 1 C-terminal TMS. |
Bacteria | Campylobacterota | PFT of Helicobacter pylori |
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1.C.133.1.3 | Uncharacterized protein of 30 aas and 1 TMS |
Bacteria | Campylobacterota | UP of Helicobacter pylori |
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1.C.133.1.4 | Uncharacterized protein of 66 aas and 1 TMS |
Bacteria | Bacillota | UP of Helicobacter pylori |
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1.C.133.2.1 | Uncharacterized protein of 45 aas and 1 N-terminal TMS. |
Bacteria | Campylobacterota | UP of Helicobacter pylori |
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1.C.133.2.2 | Uncharacterized protein of 39 aas and 1 TMS. |
Bacteria | Campylobacterota | UP of Helicobacter pylori |
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1.C.133.2.3 | Uncharacterized protein of 42 aas and 1 N-terminal TMS. This protein shows appreciable seqence similarity to the protein with TC# 1.C.133.1.1 and therefore links these two subfamilies. |
Bacteria | Campylobacterota | UP of Helicobacter pylori |
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1.C.133.2.4 | Uncharacterized protein of 48 aas and 1 N-terminal TMS. |
Bacteria | Campylobacterota | UP of Helicobacter pylori |
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1.C.134.1.1 | Pore-forming toxic peptide of 19 aas and 1 TMS |
Bacteria | Pseudomonadota | IbsC of E. coli |
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1.C.134.1.2 | Type I toxin-antitoxin system, Ibs family toxin of 19 aas and 1 very hydrophobic TMS. |
Bacteria | Pseudomonadota | Toxin of E. coli |
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1.C.134.1.3 | Type I toxin-antitoxin system, toxin of 32 aas and 1 C-terminal TMS. |
Bacteria | Pseudomonadota | Toxin of E. coli |
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1.C.135.1.1 | ShoB pore-forming toxin, also called RyfB or YphI, of 26 aas with 1 TMS. More is known about how their expression is regulated than their biological function. Although all are found in E. coli and closely related bacteria, there is great variation among species as to which loci they possess. Fozo 2012 discussed how these sRNA antitoxins prevent toxin production and how the distribution of these loci across species may be providing insights into their true function. Overexpression causes cessation of growth and rapid membrane depolarization. Overexpression induces the stress-response and the induction of a number of membrane protein-encoding genes (Fozo et al. 2008). |
Bacteria | Pseudomonadota | ShoB of E. coli |
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1.C.135.1.2 | Small toxic protein shoB osf 32 aas and 1 TMS. |
Bacteria | Pseudomonadota | ShoB of Salmonella enterica subsp. enterica |
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1.C.136.1.1 | Plantaricin ASM1 of 64 aas |
Bacteria | Bacillota | Plantaricin ASM1 of Lactiplantibacillus plantarum (also named Lactobacillus arabinosus, Lactobacterium plantarum, Streptobacterium plantarum, etc.)
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1.C.136.1.2 | Glycocin F family RiPP peptide of 69 aa |
Bacteria | Bacillota | Glycocin F of Staphylococcus lugdunensis |
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1.C.137.1.1 | Gasdermin bGSDM of 259 aas and 1 possible TMS at residue 85. It is the precursor of a pore-forming protein involved in defense against bacteriophages. Expression of gasdermin bGSDM and the neighboring protease gene (Ga0098714_109514) is toxic in E.coli on solid medium (Johnson et al. 2022). Cleavage of this precursor by its dedicated protease releases the active moiety (gasdermin bGSDM, N-terminus), which inserts into membranes, forming pores and triggering cell death. |
Bacteria | Pseudomonadota | Gasdermin bGSDM of Bradyrhizobium tropiciagri |
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1.C.137.1.10 | Uncharacterized protein of 350 aas and 1 putative TMS. |
Bacteria | Actinomycetota | UP of Streptomyces sp. DSM 40750 |
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1.C.137.1.15 | Uncharacterized protein of 258 aas and possibly 3 TMSs, two near the N-terminus (residues 10 - 50). This protein shows sequence similarity with members of TC subclasses 1, 2, 4, and 5 in family 1.C.137. |
Bacteria | Bacteroidota | UP of Pinibacter aurantiacus |
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1.C.137.1.16 | Uncharacterized protein of 288 aas and possibly two TMSs, one N-terminal and one at about residue 120. |
Bacteria | Acidobacteriota | UP of Acidobacteriota bacterium (soil metagenome) |
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1.C.137.1.2 | Uncharacterized protein of 267 aas and 1 possible TMS near the C-terminus of the protein. |
Bacteria | Pseudomonadota | UP of Ruegeria atlantica |
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1.C.137.1.3 | Uncharacterized protein of 272 aas and 1 or 2 moderately hydrophobic TMSs near the C-terminus of the protein. |
Bacteria | Pseudomonadota | UP of Thiococcus pfennigii |
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1.C.137.1.4 | Uncharacterized protein of 271 aas and possible 3 TMSs, one at about residue 90, and two between residues 190 and 225. |
Bacteria | Pseudomonadota | UP of Lysobacter enzymogenes |
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1.C.137.1.5 | Uncharacterized protein of 267 aas and at least 1 possible TMS between residues 80 and 100, and possibly several less hydrophobic peaks towards the C-terminus of the protein. |
Bacteria | Bacteroidota | UP of Spirosoma sp. KCTC 72228 |
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1.C.137.1.6 | Uncharacterized protein of 272 aas with no strongly hydrophobic peaks that could be TMSs. |
Bacteria | Pseudomonadota | UP of Azospirillum picis |
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1.C.137.1.7 | Uncharacterized protein of 267 aas with possibly two TMSs between residues 80 and 120. |
Bacteria | Thermodesulfobacteriota | UP of Geobacter sp. |
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1.C.137.1.8 | Gasdermin of 268 aas and possibly one TMS at residue 225. The 3-D structure has been determined (PDB# 7N52_A; Johnson et al. 2022). |
Bacteria | Bacteroidota | Gasdermin of Runella zeae |
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1.C.137.1.9 | Uncharacterized protein of 266 aas and possibly 1 or 2 TMSs. |
Bacteria | Bacteroidota | UP of Cytophagia bacterium (microbial mat metagenome) |
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1.C.137.2.1 | Uncharacterized protein of 263 aas and 1 TMS at the N-terminus of the protein. |
Bacteria | Pseudomonadota | UP of Vibrio campbellii |
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1.C.137.2.2 | Uncharacterized protein of 252 aas and 1 N-terminal TMS. |
Bacteria | Deferribacterota | UP of Calditerrivibrio nitroreducens |
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1.C.137.2.3 | Uncharacterized protein of 296 aas and 1 N-terminal TMS + two possible TMSs of lesser hydrophobicity. |
Bacteria | Planctomycetota | UP of Planctomycetota bacterium |
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1.C.137.2.4 | Uncharacterized protein of 264 aas and possibly 3 TMSs, one N-terminal and two between residues 100 and 145. |
Bacteria | Bacteroidota | UP of Cyclobacteriaceae bacterium (bioreactor metagenome) |
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1.C.137.3.1 | Uncharacterized protein of 249 aas and possibly 1 C-terminal TMS. |
Bacteria | Bacteroidota | UP of Bacteroidetes bacterium |
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1.C.137.3.2 | Uncharacterized protein of 276 aas and an unknown number of TMSs. |
Bacteria | Planctomycetota | UP of Pirellulaceae bacterium (hot springs metagenome) |
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1.C.137.3.3 | Uncharacterized protein of 276 aas and possibly three moderately hydrophobic TMSs at residues 90, 160 and 230. |
Bacteria | Bacteroidota | UP of Bacteroidetes bacterium (phycosphere metagenome) |
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1.C.137.4.1 | Uncharacterized protein of 282 aas and possibly 1 C-terminal TMS. |
Bacteria | Bacteroidota | UP of Sphingobacteriales bacterium |
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1.C.137.4.2 | Uncharacterized protein of 264 aas and possibly 2 TMSs between residues 10 and 50. This protein shows sequence similarity between subfamilies 1 and 3 in family 1.C.137. |
Bacteria | Bacteroidota | UP of Chitinophagales bacterium |
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1.C.137.5.1 | Uncharacterized protein of 263 aas and 1 or 2 TMSs. |
Bacteria | Myxococcota | UP of Nannocystis sp. SCPEA4 |
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1.C.137.5.3 | Uncharacterized protein of 216 aas and possibly 1 N-terminal TMS. |
Bacteria | Vulcanimicrobiota | UP of Candidatus Eremiobacteraeota bacterium |
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1.C.137.5.4 | Uncharacterized protein of 272 aas and possibly 1 TMS at about residue 70. |
Bacteria | Pseudomonadota | UP of Pseudomonadota bacterium (soil metagenome) |
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1.C.137.6.1 | Uncharacterized protein of 259 aas and possibly 3 TMSs, one N-terminal and two between residues 100 - 140. |
Bacteria | Actinomycetota | UP of Kribbella monticola |
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1.C.137.6.2 | Uncharacterized protein of 323 aas with possibly 3 TMSs, one N-terminal, one at residue 80 snf one at residue 160. |
Bacteria | Bacillota | UP of Acetobacterium sp. |
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1.C.137.6.3 | Uncharacterized protein of 250 aas and possibly 3 TMSs in the N-terminal half of the protein. |
Bacteria | Actinomycetota | UP of Streptomyces sp. |
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1.C.138.1.1 | M-zodatoxin-Lt8a, Ctx1.1, of 129 aas. See family description for prperties of this pore-forming toxin. |
Eukaryota | Metazoa, Arthropoda | Ctx1.1 (Ctx11) of Lachesana tarabaevi (Spider) |
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1.C.138.1.2 | Cytoinsectotoxin-4, Ctx4, of 124 aas (Kuzmenkov et al. 2016). |
Eukaryota | Metazoa, Arthropoda | Ctx4 of Lachesana tarabaevi |
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1.C.138.1.3 | Antibacterial toxin, LAT1, of 88 aas active against Gram-positie bacteria. |
Eukaryota | Metazoa, Arthropoda | LAT1 of Lachesana tarabaevi (Spider) |
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1.C.138.2.1 | M-zodatoxin-Lt4b, Lat4B, of 179 aas. It is bacteriocidal (Kozlov et al. 2006). |
Eukaryota | Metazoa, Arthropoda | Lat4B of Lachesana tarabaevi (Spider) |
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1.C.139.1.1 | The Candida albicans virulence factor, candidalysin (CA) of 271 aas with 1 N-terminal TMS followed by 4 putative equidistant TMSs. It polymerizes in solution to form membrane pores and damage epithelial cells (Russell et al. 2022) (see famiy description for details). |
Eukaryota | Fungi, Ascomycota | CA of Candida albicans |
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1.C.139.1.2 | Uncharacterized protein of 282 aas with up to 6 TMSs in a 1 (N-terminal) + 5 equispanced putative TMSs. |
Eukaryota | Fungi, Ascomycota | UP of Candida tropicalis |
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1.C.139.1.4 | Putative cell elongation protein of 268 aas with 1 N-terminal TMS + 4 possible TMSs between residies 50 and 180. |
Eukaryota | Fungi, Ascomycota | CEP of Candida dubliniensis |
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1.C.14.1.1 | Cytohemolysin precursor, HlyA (Vibrio cholerae cytolysin, VCC) is a beta-barrel pore-forming toxin (beta-PFT). A cryo-electron microscopic study revealed low resolution structures for different functional forms (Dutta et al., 2009). Crystal structures of the soluble and transmembrane heptamer reveal common features among disparate pore-forming toxins (De and Olson, 2011). The toxin forms transmembrane heptameric β-barrel channels with two lectin activities on the β-prism and the β-trefoil (Rai et al. 2013). A ring of tryptophan residues forms the narrowest constriction in the transmembrane channel reminiscent of the phenylalanine clamp identified in anthrax protective antigen (Krantz et al., 2005). A single point mutation prevents membrane integration and pore formation (Paul and Chattopadhyay 2012). The deletion of the pre-stem segment does not affect membrane binding and pre-pore oligomer formation, but it critically abrogates the functional pore-forming activity of VCC (Paul and Chattopadhyay 2013). The membrane-bound monomer can not form pores (Rai and Chattopadhyay 2014). VCC can be delivered to host cells via extracellular bacterial vesicles (Elluri et al. 2014). Loops within the membrane-proximal region of VCC play critical roles in determining the functional interactions of the toxin with the membrane lipids that allow pore formation (Rai and Chattopadhyay 2015). VCC may interfer with signalling in the target cell as well as form pores (Khilwani and Chattopadhyay 2015). A functional map of the VCC membrane-binding surface has been published (De et al. 2015). Residues involved in oligomerization have been identified (Rai and Chattopadhyay 2016). The multiple membrane interaction mechanisms of VCC have been reviewed (Kathuria and Chattopadhyay 2018). A model of the transmembrane pore has been presented that accounts for some of its properties (Pantano and Montecucco 2006). An overview of the understanding regarding the membrane interaction mechanisms of VCC and their functional implications for the pore-forming activity of the toxin have been reviewed (Kathuria and Chattopadhyay 2018). The specific cholesterol-binding ability of VCC does not appear to dictate its association with the cholesterol-rich micro-domains on human erythrocytes but may be essential for formation of the membrane integraed pore structure (Gupta et al. 2022). Rather, targeting of VCC toward the membrane micro-domains of human erythrocytes possibly acts to facilitate the cholesterol-dependent pore-formation mechanism of the toxin (Cyr 2018). Tyrosine in the hinge region of the pore-forming motif regulates oligomeric beta-barrel pore formation (Mondal et al. 2020). Single-particle cryo-EM was used to characterize the structure of the VCC oligomer in large unilamellar vesicles. The rim domain amino acid residues of VCC interacting with lipid membrane were visualized. Cryo-EM views of lipid bilayer-embedded VCC suggested interesting conformational variabilities, especially in the transmembrane channel, which could have a potential impact on the pore architecture and assist in understanding the pore formation mechanism (Sengupta et al. 2021). The Glu289 residue in the pore-forming motif of VCC is important for efficient beta-barrel pore formation (Mondal et al. 2022). |
Bacteria | Pseudomonadota | HlyA (VCC) precursor of Vibrio cholerae |
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1.C.14.1.2 | Cytohemolysin 1 precursor, Hly1 | Bacteria | Pseudomonadota | Hly1 of Aeromonas hydrophila | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.14.1.3 | Vibrio vulnificus hemolysin (VVH-A). Consists of three domains: Hemolysin N (residues 1 - 200), Leukocidin (residues 220 - 480) and Ricin (690 - 600). |
Bacteria | Pseudomonadota | VVH-A of Vibrio vulnificus (P19247) |
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1.C.14.1.4 | β-barrel pore-forming Cytotoxin of 663 aas from the leukocidin family. |
Bacteria | Pseudomonadota | Toxin of Algicola sagamiensis |
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1.C.14.1.5 | β-barrel pore-forming Toxin of 612 aas, it contains a Ricin-type beta-trefoil lectin domain. |
Bacteria | Pseudomonadota | Toxin of Thalassomonas viridans |
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1.C.14.1.6 | β-barrel pore-forming toxin of 597 aas with a ricin-type beta-trefoil lectin domain. |
Bacteria | Pseudomonadota | Toxin of Pseudomonas mediterranea |
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1.C.14.1.7 | Phobalysin (Cytolysin; Hemolysin; HlyA, PhlyP ("photobacterial lysin encoded on a plasmid") of 603 aas. 48% identical to The Vibrio cholerae hemolysin (1.C.14.1.1). Forms small β-barrel pores in eukaryotic membranes causing efflux of K+ and ATP but not proteins and entry of Ca2+ and dyes (Rivas et al. 2015; von Hoven et al. 2017). |
Bacteria | Pseudomonadota | Phobalysin of Photobacterium damselae (Listonella damsela) |
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1.C.140.1.1 | BMP32r of 41 aas and 1 N-terminal TMS. Recombinant bacteriocin BMP32 (BMP32r) prepared by the Escherichia coli expression system had a broad-spectrum antibacterial activity even against some MDR bacteria and its minimal inhibitory concentration ranged from 9.2 to 36.8 mg/L. BMP32r showed good stable performance in heat, pH and storage. Scanning electron microscopy and transmission electron microscopy revealed that BMP32r killed indicator strains through cell wall destruction, pore formation, and the membrane permeability increases. The wound healing of an animal MDR S. aureus infected model was promoted by BMP32r, and the safety was verified by the cytotoxicity assay that the viability of HFF cells remained 87.3%, even when the concentration of BMP32r was as high as 147.2 mg/L. No abnormalities or damages to major organs was found in vivo assessments after treatment with BMP32r. Thus, BMP32r may be developed as a safe antimicrobial agent to treat MDR bacterial infections (Qiao et al. 2020). |
None | Metazoa, Nematoda | BMP32r of Brugia malayi |
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1.C.15.1.1 | Putative porin TT95 (WSP) | Eukaryota | Metazoa, Nematoda | TT95 (WSP) of Trichuris trichiura | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.15.1.2 | Caltrin II, a Ca2+ transport inhibitor of 76 aas and 1 N-terminal TMS. |
Eukaryota | Metazoa, Chordata | Caltrin II of Cavia porcellus (guinea pig) |
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1.C.15.1.3 | Uncharacterized protein of 105 aas and 1 N-terminal TMS. |
Eukaryota | Metazoa, Chordata | UP of Diceros bicornis minor |
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1.C.15.1.4 | Anti-leukoproteinase-like protein of 132 aas and 1 N-terminal TMS. |
Eukaryota | Metazoa, Chordata | Antileukoproteinase-like protein of Trachemys scripta elegans |
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1.C.15.1.5 | WAP four-disulfide core domain protein 5-like isoform X1of 118 aas and 1 N-terminal TMS. |
Eukaryota | Metazoa, Chordata | Protein 5-like of Geotrypetes seraphini |
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1.C.15.1.6 | Sodium/potassium ATPase inhibitor SPAI-2-like protein of 76 aas with 1 N-terminal TMS. |
Eukaryota | Metazoa, Chordata | SPAI-2-like protein of Parus major |
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1.C.16.1.1 | Magainin precursor of 333 aas and 1 TMS. 3-d structural determinations and simulations show the oligomeric states, transmembrane helices and tilt angles in the various states of the mature Maganin (Pino-Angeles et al. 2016). Forms stable heterooligomers with PglA (TC# 1.C.16.1.5) at lower concentrations of the two peptides than allows each one alone to form pores in which PglA, rather than magainin 2 forms the pore (Strandberg et al. 2016). Mixtures of peptides such as magainin 2 and PGLa, which are stored and secreted naturally as a cocktail, exhibit considerably enhanced antimicrobial activities when investigated together in antimicrobial assays and also in pore forming experiments applied to biophysical model systems. Investigations have revealed that these peptides do not form stable complexes but act by specific lipid-mediated interactions and are influenced by the nanoscale properties of phospholipid bilayers (Juhl et al. 2021). |
Eukaryota | Metazoa, Chordata | Magainin precursor of Xenopus laevis |
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1.C.16.1.2 | Preprocaerulein | Eukaryota | Metazoa, Chordata | Preprocaerulein type I of Xenopus laevis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.16.1.3 | Xenopsin precursor | Eukaryota | Metazoa, Chordata | Xenopsin precursor of Xenopus laevis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.16.1.4 | Prolevitide precursor | Eukaryota | Metazoa, Chordata | Prolevitide precursor of Xenopus laevis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.16.1.5 | PylA/PglA (peptide glycine-leucine-amide) precursor of 64 aas and 1 TMS. 3-d structures and simulations have revealed the overall structure, helix orientations, and tilt angles in the homo- and hetero-multimeric pores (Pino-Angeles et al. 2016). The pore forms stable heterooligomers with magainin 2 (TC# 1.C.16.1.1) in which PglA, rather than magainin 2, forms the pore (Strandberg et al. 2016). This occurs at lower concentrations of the two peptides than is required for each peptide to form homomeric pores. Ulmschneider 2017 suggested that cationic antimicrobial peptides (AMPs) such as PGLa translocate across hydrophobic lipid bilayers without formation of peptide-lined channels, explaining why they induce membrane leakage and antimicrobial activity. PGLa spontaneously translocates across the membrane individually on a timescale of tens of microseconds, without forming pores. Instead, short-lived water bridges, with two or three peptides connecting at their termini, may allow both ion translocation and lipid flip-flop via a brushlike mechanism usually involving the C terminus of one peptide (Ulmschneider 2017). Another study suggested that PGLa translocates across the bilayer before membrane permeation (Parvez et al. 2018). |
Eukaryota | Metazoa, Chordata | PylA/PglA precursor of Xenopus laevis |
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1.C.16.1.6 | Toxic magainin peptide, Magainin-R-2 of 23 aas. Magainins are membrane lytic agents. From the parent protein (1.C.16.1.1), many antimicrobial peptides that inhibit the growth of numerous species of bacteria and fungi and induce osmotic lysis of protozoa can be derived (Tanphaichitr et al. 2016). |
Eukaryota | Metazoa, Chordata | Magainin-R-2 of Xenopus laevis (African clawed frog) |
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1.C.16.2.1 | Hypothetical Protein (99aas) | Eukaryota | Apicomplexa | Hypothetical protein of Toxoplasma gondii (B6K9W1) |
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1.C.16.2.2 | Uncharacterized protein of 99 aas and 1 TMS. |
Eukaryota | Apicomplexa | UP of Hammondia hammondi |
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1.C.16.2.3 | Uncharacterized protein of 93 aas and 1 TMS. |
Eukaryota | Apicomplexa | UP of Neospora caninum |
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1.C.17.1.1 | Cecropin A, B and C precursor. Cecropin A and B form pores, but cecropin P1 doesn't. Insertion and activity are dependent on the lipids present. Can be cation- or anion-selective, or non-selective. The negative pole of the dipole is probably inserted into the membrane first (Efimova et al. 2014). |
Eukaryota | Metazoa, Arthropoda | Cecropin A, B and C precursor of Hyalophora cecropia |
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1.C.17.1.2 | Hyphancin III E precursor | Eukaryota | Metazoa, Arthropoda | Hyphancin III E precursor of Hyphantria cunea | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.17.1.3 | Moricin precursor | Eukaryota | Metazoa, Arthropoda | Moricin precursor of Bombyx mori | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.17.1.4 | Bactericidin B-5P precursor | Eukaryota | Metazoa, Arthropoda | Bactericidin B-5P precursor of Manduca sexta | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.17.1.5 | Sarcotoxin IA precursor | Eukaryota | Metazoa, Arthropoda | Sarcotoxin IA precursor of Sarcophaga peregrina | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.17.2.1 | Styelin D precursor (81 aas) (Taylor et al., 2000) | Eukaryota | Metazoa, Chordata | Styelin D of Styela clava (O18495) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.17.2.2 | The Bradykinin-potentiating peptide homologue (BPPH) with antimicrobial activity (80aas) | Eukaryota | Metazoa, Arthropoda | BPPH of Hadrurus gertschi (P0C8L3) |
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1.C.17.3.1 | Clavanin D precursor (80 aas) (Lee et al., 1997; Zhao et al., 1997) | Eukaryota | Metazoa, Chordata | Clavanin D of Styela clava (P80713) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.18.1.1 | Melittin major precursor (anion selective). Its bacteriocidal activity against Listeria and its cytotoxicity to animal cells have been studied (Wu et al. 2016). In zwitterionic membranes, melittin forms transmembrane toroidal homomeric pores supported by four to eight peptides. Its ability to diffuse freely in a 1,2-dimyristoyl-SN-glycero-3-phosphocholine membrane leads to dynamic pores of vaious diameters with varying molecularity containing from 4 to peptides/channel (Pino-Angeles and Lazaridis 2018). |
Eukaryota | Metazoa, Arthropoda | Melittin major precursor of Apis mellifera |
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1.C.18.1.2 | Melittin (Dwarf honey bee) |
Eukaryota | Metazoa, Arthropoda | Melittin of Apis florea (P01504) |
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1.C.18.1.3 | Ihmlt fusion protein [synthetic peptide] of 66 aas and 2 TMSs. |
Ihmlt synthetic protein |
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1.C.18.1.4 | Melittin-like peptide of 67 aas and 2 TMSs. |
Metazoa, Arthropoda | Melittin-like peptide of Polistes sp. HQL-2001 |
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1.C.19.1.1 | Defensin 1, 2 and 3 precursor, also called human neutrophil peptide. |
Eukaryota | Metazoa, Chordata | Defensin 1-3 precursor of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.19.1.2 | Corticostatin III precursor | Eukaryota | Metazoa, Chordata | Corticostatin III precursor of Oryctolagus cuniculus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.19.1.3 | Neutrophil cationic peptide-1 precursor (permeable to Cl-, Na+ and K+) | Eukaryota | Metazoa, Chordata | Neutrophil defensin GP-CS1 of Cavia porcellus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.19.1.4 | Cryptdin-10 precursor (Cl- permeable) | Eukaryota | Metazoa, Chordata | Cryptdin-10 precursor of Mus musculus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.19.1.5 | Defensin-related cryptdin-4 precursor, Crp4 (structure: 2GW9_A) (Cummings and Vanderlick, 2007). | Eukaryota | Metazoa, Chordata | Crp4 of Mus musculus (P28311) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.19.1.6 | Theta defensin 1a precursor, RTD1a (Tran et al., 2008) |
Eukaryota | Metazoa, Chordata | RTD1 of Macaca mulatta (P82270) |
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1.C.19.1.7 | Non-transporting paneth cell-specific defensin, alpha6 percursor (Chu et al. 2012). The structure is known (PDB# 3QTE). |
Eukaryota | Metazoa, Chordata | Alpha 6 defensin of Homo sapiens |
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1.C.2.1.1 | ICP Cry1Aa. Cry1A (Receptors in Lepidoptera are cadherin-like proteins (Fabrick et al., 2009) but can also be ABC-type efflux pumps (Chen et al. 2018). The pore-forming mechanism has been studied by Groulx et al. (2010). This toxin causes necrosis in Drosophila species (Obata et al. 2015). |
Bacteria | Bacillota | Cry1Aa of Bacillus thuringiensis (P0A367) |
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1.C.2.1.10 | Uncharacterized protein of 617 aas and possibly 3 TMSs, one N-terminal, and two more later on. |
Eukaryota | Fungi, Basidiomycota | UP of Moniliophthora roreri |
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1.C.2.1.11 | RICIN domain-containing protein, putative toxin, of 576 aas and possibly up to 3 central TMSs. |
Bacteria | Pseudomonadota | Putative toxin protein of Pseudolysobacter antarcticus |
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1.C.2.1.14 | Uncharacterized protein of 700 aas and possibly 2 or 3 TMSs near the N-terminus. |
Bacteria | Actinomycetota | UP of Streptomyces hainanensis |
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1.C.2.1.15 | Uncharacterized protein of 639 aas and 2 or 3 possible TMSs. |
Bacteria | Pseudomonadota | UP of Dokdonella sp. (bioanode metagenome) |
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1.C.2.1.2 | Pesticide crystal protein Cry4Ba (δ-endotoxin) (1136aas). Cadherin AgCad1 is the receptor for Cry4Ba (Hua et al., 2008). Asn183 in TMS5 is essential for oligomerizatioin of the protein in the midgut membrane of the insect, and therefore for pore formation and toxicity (Likitvivatanavong et al. 2006). The complete structure of a functional form of the Bacillus thuringiensis Cry4Ba delta-endotoxinhas been solved with nsight into the toxin-induced transmembrane pore architecture (Thamwiriyasati et al. 2022). The 2.0 Å crystal structure revealed a wedge-shaped arrangement of three domains: a well-defined N-terminal domain of eight alpha-helices responsible for pore formation, a three-beta-sheet prism displaying two functional motifs and a C-terminal beta-sandwich domain. Two conserved side-chains-Asn(166) and Tyr(170) in the α4-α5 loop were found to interact directly with phospholipid head groups, leading to pore opening and stability (Thamwiriyasati et al. 2022). |
Bacteria | Bacillota | Cry4Ba of Bacillus thuringiensis (P05519) |
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1.C.2.1.3 |
Pesticidal pre-pore-forming crystal protein, Cry1Ab; insecticidal endotoxin (1155 aas). (90% identical to Cry1Aa; (1.C.2.1.1) Kills Manduca sexta. There are several receptors (Arenas et al., 2010). Also called bt2, Cry1-2, Cry1A(b) and CryIC1. Mutations affecting pre-pore oligomerization and toxin pore formation have been described (Jiménez-Juárez et al. 2007). |
Bacteria | Bacillota | Cry1Ab of Bacillus thuringiensis (P0A370) |
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1.C.2.1.4 | Cry1Ac (85% identical to Cry1Aa (TC#1.C.2.1.1). May use MRP-4-like ABC transporter as a receptor in Bombyx mori (Atsumi et al., 2012). An miR-310 mediated response to Cry1Ac protoxin in Plutella xylostella (L.) has been documented (Yang et al. 2022). The insecticidal crystalline (Cry) and vegetative insecticidal (Vip) proteins derived from Bacillus thuringiensis (Bt) are used globally to manage insect pests, including the cotton bollworm, Helicoverpa armigera, one of the world's most damaging agricultural pests. Cry proteins bind to the ATP-binding cassette transporter C2 (ABCC2) receptor on the membrane surface of larval midgut cells, resulting in Cry toxin pores, and ultimately leading to cell swelling and/or lysis. Insect aquaporin (AQP) proteins within the membranes of larval midgut cells allow the rapid influx of water into enterocytes following the osmotic imbalance triggered by the formation of Cry toxin pores (Cai et al. 2024). |
Bacteria | Bacillota | Cry1Ac of Bacillus thuringiensis (D3XF72) |
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1.C.2.1.5 | Pesticidal crystal protein of 1144 aas, Cry8. |
Bacteria | Bacillota | Cry8 of Bacillus thurengiensis |
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1.C.2.1.6 | The Cry8Ea1 toxin of 1164 aas. The 2.2-Å crystal structure has been reported (Guo et al. 2009). Cry8Ea1 is specifically toxic to the underground larvae of Holotrichia parallela (Jia et al. 2014). |
Bacteria | Bacillota | Cry8Ea1 of Bacillus thuringiensis |
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1.C.2.1.7 | Pesticidal crystal protein (ICP) Cry3Aa (Andreev et al., 2009). |
Bacteria | Bacillota | Cry3Aa of Bacillus thuringiensis (P0A380) |
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1.C.2.1.8 | Parasporin 1, PS1 or Cry41Aa of 825 aas (Akiba and Okumura 2016). Also called Cancer cell-killing Cry protein, parasporin-3. |
Bacteria | Bacillota | PS1 of Bacillus thuringiensis |
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1.C.2.1.9 | Uncharacterized protein of 502 aas and 3 TMSs, one at the N-terminus, and two further on. |
Eukaryota | Fungi, Ascomycota | UP of Fusarium xylarioides |
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1.C.2.2.1 | Insecticidal crystal protein, Cry11Aa of 643 aas. Cry and Cyt toxins are both oligomeric pore-formers that act synergistically with each other via direct protein-protein interactions (López-Diaz et al. 2013). Target tissue cellular responses to the toxin have been determined (Canton et al. 2015). |
Bacteria | Bacillota | Cry11Aa of Bacillus thuringiensis |
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1.C.2.2.2 | Insect pore-forming toxin Cry2Ab (CryB2, CryIIA(b)) of 633 aas. Exposure of helices α4 and α5 is important for the mode of action of Cry2Ab (Xu et al. 2018). It's receptor in the insect membrane is ABCC1 (TC# 3.A.1.208.45) (Chen et al. 2018). |
Bacteria | Bacillota | CryAb of Bacillus thuringiensis |
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1.C.2.2.3 | Bacillus thuringiensis subsp. medellin produces the Cry11Bb protein of 94 kDa (750 aas), which is toxic for mosquito larvae due to permeabilization of the plasma membrane of midgut epithelial cells (Lemeshko et al. 2005). A membrane channel-forming peptide, BTM-P1, has been derived from this protein (Lemeshko et al. 2005). |
Bacteria | Bacillota | Cry11Bb of Bacillus thuringiensis |
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1.C.2.3.1 | Pesticidal crystal protein (ICP) Cry13Aa |
Bacteria | Bacillota | Cry13Aa of Bacillus thuringiensis (Q45755) |
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1.C.2.3.2 | Delta-endotoxin, Cry5B, of 1245 aas is lethal to nematodes. Active Cry5B can be expressed intracellularly in and released extracellularly from Lactococcus lactis via a holin, showing potential for future use as an anthelminthic that could be delivered orally in a food-grade microbe. (Durmaz et al. 2015). |
Bacteria | Bacillota | Cry5B of Bacillus thuringiensis |
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1.C.2.3.3 | Pesticidal crystal protein, Cry5Ac, of 1220 aas. It promotes colloidosmotic lysis by binding to the midgut epithelial cells of hymenopteran species. This and other hymenopteran toxins are the sources of red bull ant venoms that cause pain in mammals (Robinson et al. 2018). |
Bacteria | Bacillota | Cry5Ac of Bacillus thuringiensis |
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1.C.20.1.1 | Class I lantibiotic bacteriocin Nisin precursor (Nisin A; Nisin Z; Nisin F) (has a mersacidin-like Lipid II domain, and forms Lipid II-dependent pores) (Brötz et al., 1998). Its activity is enhanced by the SlpB surface layer protein (Q09FL7) of Lactobacillus crispatus (Sun et al. 2017). Bacteriocin SK2-659 was effective against pathogenic bacteria such as Helicobacter pylori. The bacteriocin produced by L. lactis SK2-659, identified as nisin Z, disrupts bacterial membranes via pore formation, leading to cell lysis. Metabolomic profiling further highlighted its ability to increase carbohydrate and amino acid metabolism, supporting cell growth and survival in acidic environments. Also, amino acid metabolism (elevated tryptophan, tyrosine, histidine) supports acid tolerance and immune modulation (Kingkaew et al. 2025). Nisin monomers dimerize by forming β-sheets in a POPE:POPG lipid bilayer and oligomerize further to form stable transmembrane channels. These nisin dimers use Lipid II as a dimer interface to incur enhanced stability (Kingkaew et al. 2025).An engineered nisin analogue with a hydrophobic moiety attached at position 17 selectively inhibits Enterococcus faecium strains (Guo et al. 2024). |
Bacteria | Bacillota | Nisin precursor of Lactococcus lactis |
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1.C.20.1.2 | Class I lantibiotic bacteriocin Gallidermin precursor (has a mersacidin-like Lipid II domain, and forms Lipid II-dependent pores) (Sahl and Bierbaum, 1998). The genetic organization, biosynthesis, modification, excretion, extracellular activation of the modified pre-peptide by proteolytic processing, self-protection of the producer, gene regulation, structure, and mode of action have been reviewed (Götz et al. 2014). The Gallidermin-lipid II complex probably forms water pores in the membrane (Pokhrel et al. 2019). It complexes Lipid II more tightly than it forms transmembrane channels (Pokhrel et al. 2021). |
Bacteria | Bacillota | Gallidermin precursor of Staphylococcus gallinarum |
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1.C.20.1.4 | Class I lantibiotic bacteriocin Mutacin BNY266 | Bacteria | Bacillota | Mutacin of Streptococcus mutans | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.20.1.5 | Class I lantibiotic bacteriocin, Subtilin precursor | Bacteria | Bacillota | Subtilin of Bacillus subtilis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.20.1.6 | Class I lantibiotic bacteriocin, Epidermin precursor (has a mersacidin-like Lipid II domain, and forms Lipid II-dependent pores) (Sahl & Bierbaum, 2008). The genetic organization, biosynthesis, modification, excretion, extracellular activation of the modified pre-peptide by proteolytic processing, self-protection of the producer, gene regulation, structure, and mode of actionhave been reviewed (Götz et al. 2014). |
Bacteria | Bacillota | Epidermin of Staphylococcus epidermidis |
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1.C.20.1.8 | Mutacin 1140 (MU1140) precursor (homologous to several lantibiotics (Smith et al., 2008)). MU1140-lipid II complexes form water permeating membrane pores (Pokhrel et al. 2019). A single chain of MU1140 complexed with lipid II allows transport across the membrane via a single-file water transport mechanism. The ordering of the water molecules in the single-file chain region as well as the diffusion behavior is similar to those observed in other biological water channels. Multiple complexes of MU1140-lipid II in the membrane showed enhanced permeability for the water molecules, as well as a noticeable membrane distortion and lipid relocation, suggesting that a higher concentration of MU1140 assembly in the membrane can cause significant disruption of the bacterial membrane (Pokhrel et al. 2019). It complexes Lipid II more tightly than it forms transmembrane channels (Pokhrel et al. 2021). |
Bacteria | Bacillota | Mutacin 1140 of Streptococcus mutans (O68586) |
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1.C.20.2.3 | Epilancin 10025 of 55 aas and 0 TMSs. |
Bacteria | Bacillati, Bacillota | Epilancin 10025 of Staphylococcus epidermidia |
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1.C.21.1.1 | Class I lantibiotic bacteriocin Lacticin 481 | Bacteria | Bacillota | Lacticin 481 of Lactococcus lactis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.21.1.10 | Mutacin II (Mutacin-2) of 53 aas. It dissipates the pmf and the H+ gradient and interfers with energy metabolism (Chikindas et al. 1995). |
Bacteria | Bacillota | Mutacin-2 of Streptococcus mutans |
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1.C.21.1.2 | Class I lantibiotic bacteriocin Variacin precursor | Bacteria | Actinomycetota | Variacin of Micrococcus varians | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.21.1.3 | Class I lantibiotic bacteriocin Streptococcin A-M29 precursor | Bacteria | Bacillota | Streptococcin A of Streptococcus pyogenes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.21.1.4 | Class I lantibiotic bacteriocin Salivaricin A precursor | Bacteria | Bacillota | Salivaricin A precursor of Streptococcus salivarius | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.21.1.5 | Nukacin ISK-1 of 57 aas (Okuda et al., 2008). It is active on Gram-positive bacteria, including Lactobacillus sakei, Leuconostoc mesenteroides and Pediococcus
pentosaceus. The bactericidal activity is based on
depolarization of energized bacterial cytoplasmic membranes, initiated
by the formation of aqueous transmembrane pores (Aso et al. 2004). It is processed and secreted by NukT (TC# 3.A.1.111.7) (Zheng et al. 2017). |
Bacteria | Bacillota | Nukacin ISK-1 of Staphylococcus warneri (Q9KWM4) |
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1.C.21.1.6 | Cyclic bacteriocin, Group II, Butyrivibriocin ARIO (BviA; 80 aas) |
Bacteria | Bacillota | BviA of Butyrivibrio fibrisolvens (Q99Q15) |
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1.C.21.1.7 | Salivaricin 9 (SivA; 56 aas; 1 or 2 TMSs) (Wescombe et al., 2011) |
Bacteria | Bacillota | SivA of Strepococcus salivarius (Q09I51) |
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1.C.21.1.8 | Lantibiotic nukacin (Nukacin KQ-1) (Nukacin KQU-131) | Bacteria | Bacillota | nukA of Staphylococcus hominis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.21.1.9 | Macedocin, McdA1, a pore-forming lantibiotic of 53 aas |
Bacteria | Bacillota | Macedocin of Streptococcus macedonicus |
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1.C.21.2.1 | Putative lantibiotic bacteriocin precursor of 71 aas (van Heel et al. 2013). |
Bacteria | Bacillota | Bacteriocin of Streptococcus pneumoniae |
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1.C.21.2.2 | Lichenicidin prepeptide, LanA of 68 aas |
Bacteria | Bacillota | Lichenicidin of Bacillus licheniformis |
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1.C.21.2.3 | Lantibiotic, mersacidin, of 69 aas |
Bacteria | Bacillota | Mersacidin of Bacillus halodurans |
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1.C.21.2.4 | Two component Lacticin 3147 (Ltnα of 59 aas and Ltnβ of 65 aas (Draper et al. 2015). Lacticin 3147 and other lantibiotics target Lipid II to inhibit cell wall synthesis, and then form pores in the membrane (Biswas and Biswas 2014). They target a large number of bacteria, and several mechanisms of pore-formation have been proposed (Draper et al. 2015). |
Bacteria | Bacillota | Lactincin 3147 of Streptococcus mutans |
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1.C.21.2.5 | Uncharacterized protein of 55 aas |
Bacteria | Bacillota | UP of Clostridium saccharobutylicum |
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1.C.21.2.6 | Lantibiotic, mersacadin, MrsA, of 58 aa |
Bacteria | Bacillota | MrsA of Bacillus subtilis |
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1.C.21.2.7 | Uncharacterized protein of 72 aas and 1 TMS. Shows sequence similarity with members of both lantibiotic families, 1.C.21 and 1.C.60. |
Bacteria | Bacillota | UP of Lentibacillus amyloliquefaciens |
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1.C.21.2.8 | Vagococcin T bacteriocin (a two-Peptide Lantibiotic) of 75 aas and 1 C-terminal TMS. It kills many Gram-positive firmicutes. |
None | Bacillati, Bacillota | Vagococcin T of Vagococcus fluvialis |
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1.C.21.3.1 | Bactofencin A family cationic bacteriocin of 53 aas and 0 TMSs (Anjana and Tiwari 2022). |
None | Bacillati, Bacillota | Bacteriocin of Ligilactobacillus salivarius |
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1.C.21.3.2 | Bactofencin A family cationic bacteriocin of 51 aas. |
None | Bacillati, Bacillota | Bactofencin A of Lactobacillus sp. AN1001 |
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1.C.22.1.1 | Class I lantibiotic bacteriocin Lactococcin A | Bacteria | Bacillota | Lactococcin A precursor of Lactococcus lactis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.22.1.10 | Lactococcin Z precursor of 70 aas and 1 TMS. It is a Lactococcus-specific bacteriocin produced by Lactococcus lactis QU 7 that shares 55.6% identity with lactococcin A. Its receptor is the mannose IIC/IID proteins (Daba et al. 2018). |
Bacteria | Bacillota | Lactococcin Z of Lactococcus lactis |
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1.C.22.1.11 | Ubericin K pore-forming bactericin of 81 aas and possibly 1 N-terminal TMS. It uses the mannose Enzyme II of the PTS as a receptor (Oftedal et al. 2021). |
None | Bacillati, Bacillota | Ubericin K of Streptococcus uberis |
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1.C.22.1.2 | Thiol-activated peptide Lactococcin B | Bacteria | Bacillota | Lactococcin B of Lactococcus lactis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.22.1.3 | Carnobactericin A (Piscicolin 61) precursor | Bacteria | Bacillota | Carnobactericin A of Carnobacterium piscicola | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.22.1.4 | Enterocin B precursor | Bacteria | Bacillota | Enterocin B of Enterococcus faecalis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.22.1.5 | Curvaticin FS47 |
Bacteria | Bacillota | Curvaticin FS47 of Lactobacillus curvatus |
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1.C.22.1.6 | Plantaricin A precursor |
Bacteria | Bacillota | Plantaricin A of Lactobacillus plantarum |
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1.C.22.1.7 | Bouicin 255 (Paiva et al., 2011) |
Bacteria | Bacillota | Bouicin 255 of Streptococcus equinus (bovis) (Q6VMM8) |
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1.C.22.1.8 | Amylovorin L471 (Lactobin A) (Callewaert et al. 1999). |
Bacteria | Bacillota | Amylovorin L471 of Lactobacillus amylvorus |
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1.C.22.1.9 | Bacteriocin protein of 51 aas and 1 TMS |
Bacteria | Bacillota | Bacteriocin of Carnobacterium maltaromaticum (Carnobacterium piscicola) |
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1.C.23.1.1 | Class I lantibiotic bacteriocin Lactocin S | Bacteria | Bacillota | Lactocin S of Lactobacillus sake L45 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.23.1.2 | Uncharacterized protein of 122 aas |
Bacteria | Bacillota | UP of Leuconostoc |
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1.C.23.1.3 | Uncharacterized protein of 140 aas |
Bacteria | Bacillota | UP of Weissella cibaria |
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1.C.23.1.4 | Uncharacterized protein of 198 aas |
Bacteria | Pseudomonadota | UP of Hyphomonas sp. |
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1.C.24.1.1 | Class IIa bacteriocin Pediocin PA-1 precursor of 62 aas. Class II bacteriocins are unmodified membrane-active peptides that act over a narrow spectrum of target bacteria. They bind a specific receptor protein on the membrane to form a pore, leading to membrane permeabilization and cell death. The specific receptor acts as a docking molecule, not as a structural piece of the pore, if the bacteriocin is anchored to the membrane (Ríos Colombo et al. 2019). Pediocin-like (or class IIa) bacteriocins (PLBs) exhibit antibacterial activity against several Gram-positive bacterial strains by forming pores in the cytoplasmic membrane of target cells with a specific receptor, the mannose phosphotransferase system (man-PTS) (Zhu et al. 2022). The N-terminal β-sheet region of pediocin PA-1 attaches to the extracellular surface of the man-PTS core domain, whereas the C-terminal half penetrates the membrane and cracks the man-PTS like a wedge. |
Bacteria | Bacillota | Pediocin PA-1 precursor of Pediococcus acidilactici |
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1.C.24.1.10 | Class IIc sec-secreted bacteriocin Enterocin P precursor, EntP | Bacteria | Bacillota | EntP of Enterococcus faecium | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.24.1.11 | Class IIa bacteriocin, Ubericin A (Heng et al., 2007) | Bacteria | Bacillota | Ubericin A of Streptococcus uberis (A9Q0M7) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.24.1.12 | Bacteriocin 41 precursor, BacA (pore-forming ability not demonstrated; Tomita et al., 2008) | Bacteria | Bacillota | BacA of Enterococcus faecalis (B1NRV2) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.24.1.13 | Divergicin M35 (43aas) (Naghmouchi et al., 2008) (The C-terminal residues most resemble BacA (TC#1.C.24.1.12)). | Bacteria | Bacillota | Divergicin M35 of Carnobacterium divergens (P84962) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.24.1.14 | Listeria-active class IIa peptide, Lactococcin MMFII (may form pores in lipid bilayers, but also in combination with proteins of the mannose phosphotransferase system (PTS)) (Ferchichi et al., 2001). | Bacteria | Bacillota | Loctococcin MMFII of Lactococcus lactis (P83002) |
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1.C.24.1.15 | Enterocin CRL35 of 58 aas, MunA. Class II bacteriocins are unmodified membrane-active peptides that act over a narrow spectrum of target bacteria. They bind a specific receptor protein on the membrane to form a pore, leading to membrane permeabilization and cell death. The specific receptor acts as a docking molecule, not as a structural part of the pore, but the bacteriocin must be anchored to the membrane (Ríos Colombo et al. 2019). The ABC efflux porter is MunB (TC# 3.A.1.112.11). The enterocin CR35 immunity protein is MunC (98 aas; possibly 2 TMSs; Q6TGQ5). |
Bacteria | Bacillota | Enterocin ARL35 of Enterococcus mundtii |
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1.C.24.1.16 | Uncharacterized protein of 70 aas and 2 TMSs. |
Bacteria | Chlamydiota | UP of Chlamydia trachomatis |
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1.C.24.1.2 | Class IIa bacteriocin Sakacin P precursor | Bacteria | Bacillota | Sakacin P of Lactobacillus sake | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.24.1.3 | Class IIa bacteriocin Pisciolin 126 precursor | Bacteria | Bacillota | Pisciolin 126 precursor of Carnobacterium piscicola | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.24.1.4 | Class IIa bacteriocin Enterocin A | Bacteria | Bacillota | Enterocin A of Enterococcus faecium | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.24.1.5 | Class IIa bacteriocin Mesentericin Y105 precursor | Bacteria | Bacillota | Mesentericin Y105 precursor of Leuconostoc mesenteroides | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.24.1.6 | Class IIa bacteriocin Leucocin A precursor | Bacteria | Bacillota | Leucocin A precursor of Leuconostoc gelidum | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.24.1.7 | Class IIa bacteriocin Carno(bacterio)cin B2 precursor | Bacteria | Bacillota | Carnocin B2 of Carnobacterium piscicola | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.24.1.8 | Class IIa bacteriocin Sakacin A precursor (Identical to Curvacin A of Lactobacillus curvatus; P0A311) (Haugen et al. 2008). | Bacteria | Bacillota | Sakacin A precursor of Lactobacillus sakei ( P0A310) |
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1.C.24.1.9 | Class IIa bacteriocin Bavaricin MN precursor | Bacteria | Bacillota | Bavaricin MN of Lactobacillus sakei | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.25.1.1 | Class IIb two peptide bacteriocin Lactococcin G (Oppegard et al., 2007) | Bacteria | Bacillota | Lactococcin G of Lactococcus lactis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.26.1.1 | Class IIb two peptide bacteriocin Lactacin F (LafA)-Lactacin X (LafX) | Bacteria | Bacillota | LafA of Lactobacillus johnsonii | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.26.1.2 | Bacteriocin class II with double-glycine leader peptide family protein of 84 aas and 1 or 2 C-terminal TMSs. |
Bacteria | Bacillota | Bacteriocin of Streptococcus pneumoniae |
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1.C.26.1.3 | Blp family class II bacteriocin of 72 aas and 1 C-terminal TMS. |
Bacteria | Bacillota | Blp protein of Bacillus thuringiensis |
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1.C.27.1.1 | Class IIc Sec-secreted bacteriocin Divergicin A precursor (DvnA) | Bacteria | Bacillota | DvnA of Carnobacterium (Cactobacillus) divergens |
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1.C.27.1.2 | Hypothetical protein KPK_A0149 | Bacteria | Pseudomonadota | KPK_A0149 of Klebsiella pneumoniae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.27.1.3 | Hypothetical protein Smed_3677 | Bacteria | Pseudomonadota | Smed_3677 of Sinorhizobium medicae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.27.1.4 | Bacteriocin of 128 aas and 2 N-terminal TMSs. |
None | Pseudomonadati, Pseudomonadota | Bacteriocin of Acidovorax sp. CF316 |
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1.C.27.2.1 | Aquaticin, a bacteriocin-like protein of 86 aas with 1 C-terminal TMS. It is trypsin-resistant and remarkably heat-sensitive, being damaged at 45 degrees C to 55 degrees C. It resembles contracted tails of bacteriophage T4 (Smarda 1987). |
None | Bacillati, Actinomycetota | Aquaticin of Budvicia aquatica |
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1.C.27.2.2 | Bacteriocin of 78 aas with 1 C-terminal TMS. |
None | Heunggongvirae, Uroviricota | Bacteriiocin of Vibrio phage douglas 12A4 |
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1.C.27.2.3 | Putative bacteriocin of 93 aas and 1 C-terminal TMS. |
None | Fungi, Mucoromycota | Putative bacteriocin of Dentiscutata erythropus |
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1.C.28.1.1 | Cyclic bacteriocin, enterocin AS-48, Group I (105 aas; 2 TMSs) (van Belkum et al., 2011) (x-ray structure known (1O82_A)) |
Bacteria | Bacillota | AS-48 of Enterococcus faecalis (Q47765) |
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1.C.28.2.1 | Cyclic bacteriocin, Group I, Circularin A, CirA (72 aas; 2 TMSs) (van Belkum et al., 2011) |
Bacteria | Bacillota | CirA of Clostridium beijerinckii (Q8GB47) |
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1.C.28.3.1 | Putative bacteriocin (69 aas; 1 TMS) |
Bacteria | Bacillota | Putative bacteriocin of Bacillus cereus (B5V1D7)
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1.C.28.3.2 | Uncharacterized bacteriocin |
Bacteria | Bacillota | Bacteriocin of Bacillus sp. INLA3E |
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1.C.28.4.1 | Putative bacteriocin (82 aas; 2 TMSs) |
Bacteria | Bacillota | Putative bacteriocin of Oenococcus oeni (D3L749) |
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1.C.28.5.1 | Putative bacteriocin (73 aas, 1TMS) |
Bacteria | Firmicutes | Putative bacteriocin of Coprobacillus sp. 29_1 (E7G765) |
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1.C.29.1.1 | Cation-selective class IIb two peptide bacteriocin, plantaricin EF (Oppegard et al., 2007). Causes loss of the pmf, K+ release and initiation of apoptosis in Candida species (Sharma and Srivastava 2014). The 3-d structure is known (Fimland et al. 2008). |
Bacteria | Bacillota | PlnE and PlnF of Lactobacillus plantarum |
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1.C.29.1.2 | Plantaricin E, PlnE of 54 aas and 1 TMS. |
Bacillota | PlnE of Lactobacillus plantarum 16 |
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1.C.29.1.3 | Uncharacterized bacteriocin of 46 aas and 1 TMS |
Bacillota | Bacteriocin of Enterococcus pallens |
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1.C.3.1.1 | α-Hemolysin (alpha haemolysin; Hly; Hla; α-toxin). Fragments (13-293 aas) form heptamers like the native full length protein, but a fragment with aas 72-293 formed heptamers, octamers and nonamers. All formed Cl- permeable β-barrel channels (Vécsey-Semjén et al., 2010). The 3-d structure is available (PDB#7AHL). Both symmetry and size of cyclodextrin inhibitors and the toxin pore are important for effective inhibition (Yannakopoulou et al., 2011). Oxoxylin A inhibits hemolysis by hindering self assembly of the hepatmeric pore in which two β-strands are contributed by each subunit (Song et al. 1996; Dong et al. 2013). Applications of pore-forming α-haemolysin include small- and macromolecule-sensing, targeted cancer therapy, and drug delivery (Gurnev and Nestorovich 2014). Sugawara et al. 2015 studied pore formation. Structural comparisons among monomer, prepore and pore revealed a series of motions in which the N-terminal amino latch released upon oligomerization destroys its own key hydrogen bond betweem Asp45 and Try118. This action initiates the protrusion of the prestem. A Y118F mutant and the N-terminal truncated mutant markedly decreased the hemolytic activity, indicating the importance of the key hydrogen bond and the N-terminal amino latch for pore formation. A dynamic molecular mechanism of pore formation was proposed (Sugawara et al. 2015). Release of ATP from cells may occur directly through transmembrane pores formed by α-toxin (Baaske et al. 2016). The amino latch of staphylococcal alpha-hemolysin functions in pore formation via an co-operative interaction between the N terminus and position 217 (Jayasinghe et al. 2006). PLEKHA7 and other junctional proteins are host factors mediating death by S. aureus alpha-toxin. ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C-terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. ADAM10 is locked at junctions through binding of its cytoplasmic C terminus to afadin. Junctionally clustered ADAM10 supports the efficient formation of stable toxin pores. Disruption of the PLEKHA7-PDZD11 complex inhibits ADAM10 and toxin junctional clustering. This promotes toxin pore removal from the cell surface through an actin- and macropinocytosis-dependent process, resulting in cell recovery from initial injury and survival. Thus, a dock-and-lock molecular mechanism targets ADAM10 to junctions, providing a paradigm for how junctions may regulate transmembrane receptors through their clustering (Shah et al. 2018). Airway epithelial cells are sensitivity to S. aureus α-Toxin, but the toxin heptamers are removed by extracellular vesicle formation and lysosomal degradation (Möller et al. 2021). The effect of electroosmotic solvent flow on the binding of a neutral molecule [beta-cyclodextrin (betaCD)] to sites within alpha-hemolysin pore was investigated. Mutant α-hemolysin pores were used to which betaCD can bind from either entrance and through which the direction of water flow can be controlled by choosing the charge selectivity of the pore and the polarity of the applied potential. The Kd values for betaCD for individual mutant pores varied by >100-fold with the applied potential over a range of -120 to +120 mV (Gu et al. 2003). Alpha-hemolysin can be incorporated into bicelles (Dziubak and Sęk 2023). It exhibits long-term memory with respect to ion channel kinetics (Silva et al. 2023). |
Bacteria | Bacillota | α-hemolysin of Staphylococcus aureus |
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1.C.3.2.1 | Hemolysin II |
Bacteria | Bacillota | Hemolysin II of Bacillus cereus |
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1.C.3.2.2 | β-toxin |
Bacteria | Bacillota | β-toxin of Clostridium perfringens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.3.2.3 | Cytotoxin of 336 aas and 1 N-terminal TMS. |
Bacteria | Bacillota | Cytotoxin CytK of Bacillus cereus |
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1.C.3.2.4 | Necrotic enteritis toxin B precursor, NetB (Keyburn et al., 2008) |
Bacteria | Bacillota | NetB of Clostridium perfringens (A8ULG6) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.3.2.5 | CctA (Clostridium chauvoei toxin A; 317 aas) is the main cytotoxic and haemolytic substance secreted by C. chauvoei. Vaccination of guinea pigs with CctA in the form of a fusion protein with the E. coli heat labile toxin B subunit (rCctA::LTB) as a peptide adjuvant protected the animals against challenge with spores of virulent C. chauvoei., (Frey et al. 2012). |
Bacteria | Bacillota | Cytotoxin of Clostridium chauvoei |
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1.C.3.2.6 | Necrotizing enteritis toxin, NetF, of 305 aas. NetF-producing type A Clostridium perfringens is an important cause of canine and foal necrotizing enteritis. NetF, related to the β-sheet pore-forming Leukocidin/Hemolysin superfamily, is considered a major virulence factor for this disease. The NetF receptor is probably a sialic acid-containing glycoprotein (Mehdizadeh Gohari et al. 2018). |
Bacteria | Bacillota | NetF of Clostridium perfringens |
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1.C.3.2.7 | Pore-forming EpX4 toxin of 312 aas |
None | Bacillati, Bacillota | EpX4 toxin of Enterococcus |
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1.C.3.3.1 | Leucocidin/Hemolysin family member, LHF | Bacteria | Pseudomonadota | LHF member of Vibrio species Ex25, (EDN58324) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.3.3.2 | Leucocidin/Hemolysin toxin family member. 90% identical to a Leukocidin of Vibrio proteolyticus of 305 aas that plays an important role in virulence (Ray et al. 2016). |
Bacteria | Pseudomonadota | V12G01_16082 of Vibrio alginolyticus (Q1V718) |
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1.C.3.4.1 | Leucocidin chain F. 3-D structures of the prepore revealed that this is substantially different from the pore structure. The structures revealed a disordered bottom half of the beta-barrel corresponding to the transmembrane region, and a rigid upper extramembrane half (Yamashita et al. 2014). LukF can form an octameric pore with 4 subunits of LukF and 4 subunits of LukS (TC# 1.C.3.4.3) (Jayasinghe and Bayley 2005). Panton-Valentine leukocidin (PVL, encoded by lukSF-PV genes) is a bi-component and pore-forming toxin carried by different staphylococcal bacteriophages (Zhao et al. 2016). The gamma-hemolysin protein is used by the pathogen to escape the immune system of the host, by assembling into octameric transmembrane pores on the surface of the target immune cell, leading to its death by leakage or apoptosis. The interactions between the individual monomers that lead to the formation of a dimer on the cell membrane, which represents the unit for further oligomerization, has not been defined. Paternoster et al. 2023 determined the stabilizing contacts that guide formation of a functional dimer. |
Bacteria | Bacillota | Leucocidin chain F (LukF) of Staphylococcus aureus (Q53747) |
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1.C.3.4.2 | Two component β-barrel γ-haemolysin, HlgA·HlgB. Tomita et al. (2011) reported that Hlg2 and LukF form a complex, and that Hlg pores form clusters that release hemoglobin from erythrocytes. The crystal structure of this octameric pore (PDB# 3B07; 2QK7) reveals the beta-barrel pore formation mechanism by the two components (Yamashita et al., 2011). Dominant-negative mutant toxins may provide novel therapeutics to combat S. aureus infection (Reyes-Robles et al. 2016). S. aureus beta-barrel pore-forming cytotoxins, including the identification of the toxin receptors on host cells, and their roles in pathogenesis have been reviewed (Reyes-Robles and Torres 2016). |
Bacteria | Bacillota | HlgA·HlgB of Staphylococcus aureus |
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1.C.3.4.3 | Two component β-barrel γ-haemolysin, HlgC·HlgB. HglC is identical to Leucocidin chain S (LukS) (P31716), and HlgB is identical to the HlgB protein listed under TC# 1.C.3.4.2 (Roblin et al. 2008). The pore-forming regions are initially folded up on the surfaces of the soluble precursors. To create the transmembrane pores, these regions must extend and refold into membrane-inserted beta-barrels (Tilley and Saibil 2006). |
Bacteria | Bacillota | HlgC·HlgB of Staphylococcus aureus |
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1.C.3.4.4 | Equid-adapted leukocidin PQ, LukPQ, of 311 (LukP) and 326 aas (LukQ), respectively (Koop et al. 2017). |
Bacteria | Firmicutes | LukPQ of Staphylococcus aureus |
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1.C.3.4.5 | Beta-channel-forming cytolysin, the synergohymenotropic toxin, of 310 aas. Bacterial infections from Staphylococcus pseudintermedius are the most common cause of skin infections (pyoderma) affecting dogs. Two component pore-forming leukocidins are a family of potent toxins secreted by staphylococci and consist of S (slow) and F (fast) components. They impair the innate immune system, the first line of defense against these pathogens. Seven different leukocidins have been characterized in Staphylococcus aureus, some of which are host and cell specific. Abouelkhair et al. 2018 identified two proteins, named "LukS-I" and "LukF-I", encoded on a degenerate prophage contained in the genome of S. pseudintermedius isolates. The killing effect of recombinant S. pseudintermedius LukS-I together with LukF-I on canine polymorphonuclear leukocytes depended on both constituents of the two-component pore-forming leukocidin. |
Bacteria | Bacillota | LukS-I/LukF-I of Staphylococcus pseudintermedius |
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1.C.3.4.6 | Beta-channel forming cytolysin, LukNF (HlyII, hlgB, lukD, lukDv) of 327 aas. Geraniol had the highest ligand efficiency and was the most potent phyto-constituent interacting with the HlyII cytotoxin (Mohapatra et al. 2021). |
Bacteria | Bacillota | LukNF of Staphylococcus aureus |
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1.C.3.4.7 | Leukotoxin domain protein B (plasmid) of 329 aas and 1 N-terminal TMS. |
Bacteria | Bacillota | Leukotoxin of Clostridium perfringens |
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1.C.3.5.1 | Prostaglandin-H2 D-isomerase, PTGDS (PDS) of 190 aas and 1 N-terminal TMS. It regulates the calcium channel forming VIC family member with TC# 1.A.1.11.9 (Gomez et al. 2023). It catalyzes the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation (Zhou et al. 2010). It is also involved in a variety of CNS functions, such as sedation, NREM sleep and PGE2-induced allodynia, and may have an anti-apoptotic role in oligodendrocytes. Binds small non-substrate lipophilic molecules, including biliverdin, bilirubin, retinal, retinoic acid and thyroid hormone, and may act as a scavenger for harmful hydrophobic molecules and as a secretory retinoid and thyroid hormone transporter. |
Eukaryota | Metazoa, Chordata | PTGDS of Homo sapiens |
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1.C.30.1.1 | Anion-selective class IIb two peptide bacteriocin, plantaricin J, K (Oppegard et al., 2007). Causes loss of the pmf, K+ loss and initiation of apoptosis in Candida (Sharma and Srivastava 2014). |
Bacteria | Bacillota | PlnJ, K of Lactobacillus plantarum |
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1.C.30.1.2 | Plantaricins Sb, Sa precursors |
Bacteria | Bacillota | Plantaricin Sb, Sa of Lactobacillus plantarum |
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1.C.30.1.3 | Thermophilin 1, 2, precursors ThmA, B (may participate in autolysin maturation and cell surface biogenesis (Ahn and Burne, 2006)). | Bacteria | Bacillota | ThmA, B of Streptococcus thermophilus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.30.1.4 | Uncharacterized plantaricin of 60 aas and 1 TMS near the C-terminus. |
Bacillota | UP of Leuconostoc citreum |
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1.C.30.1.5 | Uncharacterized bacteriocin of 53 aas and possibly 1 C-terminal TMS. |
Bacillota | Bacteriocin of Streptococcus suis R61 |
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1.C.30.1.6 | Two component bacteriocin, plantaricin NC8, PLNC8 αβ. The precursor of alpha is 47 aas and the last 29 aas comprise the active pore-forming bacteriocin subunit (0 TMSs); the precursor of beta is 55 aas and the last 34 aas comprise the active pore-forming bacteriocin subunit (1 TMS). It exerts dual action through inhibition of Porphyromonas gingivalis infection and promotion of cell proliferation (Bengtsson et al. 2017).
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Bacteria | Bacillota | PLNC8 of Lactobacillus plantarum |
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1.C.31.1.1 | Colicin (Microcin) V precursor (CeaV or MccV) of 103 aas and one N-terminal TMS. MccV shows activity against pathogenic coliforms, especially E. coli O1K1H7 involved in avian colibacillosis (Boubezari et al. 2018). |
Bacteria | Pseudomonadota | CeaV of E. coli |
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1.C.31.1.2 | Channel-forming Colicin L precursor (Microcin L; MclC) of 105 aas and one TMS (Sablé et al. 2003) . |
Bacteria | Pseudomonadota | Colicin L of E. coli (Q841V4) |
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1.C.31.1.3 | Microsin M (McmA; 92 aas) | Bacteria | Pseudomonadota | McmA of E. coli (Q83TS1) |
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1.C.31.2.1 | Uncharacterized protein of 58 aas and 1 TMS. |
Bacteria | Bacillota | UP of Clostridium botulinum |
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1.C.32.1.1 | Mastoparan (INWKKMAATALKMI). Amiino acid substitutions gave rise to mastoparans that displayed a broad-spectrum antimicrobial activity against bacteria and fungi (MIC in the range 3-25μM), without being hemolytic or cytotoxic (Irazazabal et al. 2016). |
Eukaryota | Metazoa, Arthropoda | Mastoparan of Parapolybia indica |
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1.C.32.1.2 | Mastoparan X (INWKGIAAMAKKLL) | Eukaryota | Metazoa, Arthropoda | Mastoparan X of Vespa xanthoptera | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.32.1.3 | Mast cell degranulation peptide, Mastoparan (INLKAIAALVKKVL) | Eukaryota | Metazoa, Arthropoda | Mastoparan of Vespa orientalis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.32.1.4 | Mastoparan M (INLKAIAALAKKLL) | Eukaryota | Metazoa, Arthropoda | Mastoparan M of Vespa mandarinia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.32.1.5 | Mastoparan C (LNLKALLAVAKKIL) |
Eukaryota | Metazoa, Arthropoda | Mastoparan C of Vespa crabro |
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1.C.32.1.6 | Mastoparan (INLKALAALAKKIL) | Eukaryota | Metazoa, Arthropoda | Mastoparan of Vespula lewisii | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.32.1.7 | Mastoparan B (LKLKSIVSWAKKVL) | Eukaryota | Metazoa, Arthropoda | Mastoparan B of Vespa basalis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.32.2.1 | Polistes Mastoparan (VDWKKIGQHILSVL) |
Eukaryota | Metazoa | Polistes Mastoparan of Polistes jadwigae |
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1.C.32.2.2 | Eumenitin (LNLKGIFKKVASLLT) (K+ > Cl- selectivity) (Arcisio-Miranda et al., 2008). |
Eukaryota | Metazoa, Arthropoda | Eumenitin of Eumenes rubronotatus (P0C931) |
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1.C.32.3.1 | Cabrolin (FLPLILRKIVTAL) | Eukaryota | Metazoa, Arthropoda | Cabrolin of Vespa crabro | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.33.1.1 | PreProtegrin-2 (prophenin-2; PF-2; PR-2). Exerts antimicrobial activity more effectively against Gram-negative bacteria than Gram-positive bacteria. The high resolution NMR structure has been solved (Usachev et al. 2015). Its antimicrobial activities have been defined (Yasin et al. 1996, Miyasaki et al. 1997, Miyasaki et al. 1998, Cho et al. 1998). The cooperativity exhibited by the activities of this and other antimicrobial peptides has been explained as a non-linear concentration dependence characterized by a threshold and a rapid rise to saturation as the concentration exceeds the threshold (Huang 2006). |
Eukaryota | Metazoa, Chordata | preProtegrin 2 of Sus scrofa |
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1.C.33.1.10 | The LL-37 (LL37) peptide (cathelicidin) selectively permeabilizes the membranes of apoptotic human leukocytes, leaving viable cells unaffected (Björstad et al., 2009). It forms transmembrane pores (Lee et al., 2011). It is derived by proteolysis from the cathelin (FALL-39) precursor in granulocytes (Gudmundsson et al. 1996; Li et al. 2016). LL-37 interacts with lipids and shows the formation of oligomers generating fibril-like supramolecular structures on membranes before it assembles into transmembrane pores expressing a modification of the toroidal pore model (Zeth and Sancho-Vaello 2017). Stable transmembrane pore formation occurs at 2.0-10.0 mμM (Lozeau et al. 2018). LL-37 interacts with lipids and forms oligomers generating fibril-like supramolecular structures on membranes before assembling into transmembrane pores with a deviation of the toroidal pore model (Zeth and Sancho-Vaello 2017). Peptides, indolicidin, aurein 1.2, magainin II, cecropin A and LL-37 all cause a general acceleration of essential lipid transport processes without altering the overall structure of the lipid membranes or creating organized pore-like structures (Nielsen et al. 2020). Rapid scrambling of the lipid composition associated with enhanced lipid transport may trigger lethal signaling processes and enhance ion transport. Cardiolipin prevents membrane-pore formation by magainin and the human cathelicidin LL-37 in phosphatidyl glycerol membranes, and this constitutes a plausible mechanism used by bacteria such as Staphylococcus aureus to act against stress perturbations and, thereby, gain resistance to antimicrobial agents (Rocha-Roa et al. 2021). |
Eukaryota | Metazoa, Chordata | LL-37 peptide precursor of Homo sapiens (P49913) |
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1.C.33.1.11 | Antimicrobial and antitumor cathelicidin 6 or BMAP27 of 158 aas and 1 or 2 TMSs. The structure and dynamics have been examined (Sahoo and Fujiwara 2016). |
Eukaryota | Metazoa, Chordata | Cathelicidin 6 of Bos taurus (Bovine) |
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1.C.33.1.12 | Cathelicidin antimicrobial peptide CATH4 precursor of 172 aas and 3 or 4 TMSs, 1 or 2 near the N-terminus and 2 near the C-terminus. CATH4-type peptides alter the diffusion modes of individual lipids during the membrane-specific action of As-CATH4 peptides (Wu et al. 2023). |
Eukaryota | Metazoa, Chordata | CATH4 of Alligator sinensis |
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1.C.33.1.2 |
PreIndolicidin (pre-Cathelicidin-4) may function by a carrier mechanism to selectively transport anions (Rokitskaya et al., 2011). The pig (ovine) homologue (SMAP29) is the source from which ovispirin, novispirin and novicidin, which may form torroidal pores, are derived (Sawai et al. 2002). Peptides, indolicidin, aurein 1.2, magainin II, cecropin A and LL-37 all cause a general acceleration of essential lipid transport processes without altering the overall structure of the lipid membranes or creating organized pore-like structures (Nielsen et al. 2020). Rapid scrambling of the lipid composition associated with enhanced lipid transport may trigger lethal signaling processes and enhance ion transport. |
Eukaryota | Metazoa, Chordata | PreIndolicidin of Bos taurus |
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1.C.33.1.3 | preBactinecin | Eukaryota | Metazoa, Chordata | preBactinecin of Ovis aries | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.33.1.4 | preCathelin | Eukaryota | Metazoa, Chordata | Cathelin of Sus scrofa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.33.1.5 | preMyeloid cathelicidin 1 | Eukaryota | Metazoa, Chordata | preMyeloid cathelicidin 1 of Equus caballus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.33.1.6 | Lipopolysaccharide (LPS) binding protein precursor | Eukaryota | Metazoa, Chordata | LPS binding protein precursor of Oryctolagus cuniculus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.33.1.7 | Myeloid secondary granule protein | Eukaryota | Metazoa, Chordata | Myeloid secondary granule protein of Mus musculus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.33.1.8 | Cathelicidin-B1; reported to be processed, and the mature C-terminal active peptide is localized to the basolateral surface of M cells where it protects against bacterial infection (Goitsuka et al., 2007). | Eukaryota | Metazoa, Chordata | Cathelicidin-B1 of Gallus gallus (Q5F378) |
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1.C.33.1.9 | Pro-protegrin-1 (PG-1) (149aas;1 N-terminal TMS) produced by porcine leukocytes. It forms an anion-selective β-sheet toroidal channel of 8 β-hairpins in a consecutive NCCN packing organization, yielding both parallel and antiparallel β-sheets (Jang et al., 2008; Capone et al., 2010). The 3-d structure is known. 97% identical to protegrin-2 (1.C.33.1.1). A model of the protein in Gram-negative bacterial membranes has been proposed (Bolintineanu et al. 2012). Protegrin peptides form octameric pores, and about 100 pores are sufficient to kill E. coli (Bolintineanu et al. 2010). The membrane-bound structure, lipid interactions, and dynamics of the arginine-rich beta-hairpin antimicrobial peptide PG-1 as studied by solid-state NMR are described by Tang and Hong 2009. Protegrin stabilizes partial lipid-forming pores (Prieto et al. 2014). A model of the protegrin-1 pore has been presented, suggesting that permeability of water through a single PG-1 pore is sufficient to cause fast cell death by osmotic lysis (Langham et al. 2008). Possibly, toroidal pore formation is driven by guanidinium-phosphate complexation, where the cationic Arg residues drag the anionic phosphate groups along as they insert into the hydrophobic part of the membrane (Tang et al. 2007). Protegrin-1 is an 18-residue beta-hairpin antimicrobial peptide (AMP) that forms transmembrane beta-barrels in biological membranes. All-atom molecular dynamics simulations of various protegrin-1 oligomers on the membrane surface and in transmembrane topologies indicated that protegrin dimers are stable, whereas trimers and tetramers break down (Lipkin et al. 2017). Tetrameric arcs remained stably inserted in lipid membranes, but the pore water was displaced by lipid molecules. Unsheared protegrin beta-barrels opened into beta-sheets that surrounded stable aqueous pores, whereas tilted barrels with sheared hydrogen bonding patterns were stable in most topologies. A third type of pore consisted of multiple small oligomers surrounding a small, partially lipidic pore. Tachyplesin (TC# 1.C.34.1.1) showed less of a tendency to oligomerize than protegrin: the octameric bundle resulted in small pores surrounded by six peptides as monomers and dimers, with some peptides returning to the membrane surface. Theus, multiple configurations of protegrin oligomers may produce aqueous pores (Lipkin et al. 2017). PG-1 can insert into membranes provided that the external electric potential is large enough to first induce a water column or a pore within the lipid bilayer membrane. The highly charged PG-1 is capable, by itself, of inducing molecular electroporation (Lai and Kaznessis 2018). |
Eukaryota | Metazoa, Chordata | Protegrin-1 of Sus scrofa (P32194) |
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1.C.34.1.1 | Tachyplesin I precursor. It's 3-d pore structure has been examined (Lipkin et al. 2017). Its structure/function and toxicity activities have been reviewed (Edwards et al. 2017). |
Eukaryota | Metazoa, Arthropoda | Tachyplesin I of Tachypleus tridentatus |
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1.C.34.2.1 | Polyphemusin I | Eukaryota | Metazoa, Arthropoda | Polyphemusin I of Limulus polyphemus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.34.3.1 | Spider peptide, Gomesin, of 84 aas and 1 N-terminal TMS. Gomesin is active against several Gram-positive bacteria such as Bacillus spp, Staphylococcus spp and E.faecalis, several Gram-negative bacteria such as E. coli, K. pneumoniae, and Salmonella spp, filamentous fungi such as N. crassa, T. viridae and yeasts such as C. albicans. It is active against the parasite L.amazonensis as well. Tanner et al. 2018 concluded that it is hemolytic, permeabilizing cell membranes, probably a pore former, but Zhang et al. 2019 concluded that it induces membrane protrusion, folding and laceration without forming pores. |
Eukaryota | Metazoa, Arthropoda | Gomesin of Acanthoscurria gomesiana (Tarantula spider) (Phormictopus pheopygus) |
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1.C.35.1.1 | Amoebapore A | Eukaryota | Evosea | Amoebapore A of Entamoeba histolytica | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.35.1.2 | Amoebapore B | Eukaryota | Evosea | Amoebapore B of Entamoeba histolytica | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.35.1.3 | Amoebapore C | Eukaryota | Evosea | Amoebapore C of Entamoeba histolytica | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.35.1.4 | Nonpathogenic pore-forming peptide precursor, APNP | Eukaryota | Evosea | APNP of Entamoeba histolytica | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.35.1.5 | Pore-forming protein-like protein of 79 aas, saposin B type, SapB |
Eukaryota | Metazoa, Nematoda | SapB of Steinernema carpocapsae (Entomopathogenic nematode) |
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1.C.35.2.1 | Cerebroside sulfate activator protein, CSAP or prosaposin (PSAP, GLBA, SAP1) of 524 aas. Saposin A, B, C and D are derived from prosaposin by proteolysis. Saposin-A and C stimulate the hydrolysis of glucosylceramide by beta-glucosylceramidase and galactosylceramide by beta-galactosylceramidase. Saposin-C apparently acts by combining with the enzyme and acidic lipids to form an activated complex, rather than by solubilizing the substrate. Saposin-B stimulates the hydrolysis of galacto-cerebroside sulfate by arylsulfatase A, GM1 gangliosides by β-galactosidase and globotriaosylceramide by α-galactosidase A. Saposin-B forms a solubilizing complex with the substrates of the sphingolipid hydrolases. Saposin-D is a specific sphingomyelin phosphodiesterase activator. Prosaposin behaves as a myelinotrophic and neurotrophic factor; these effects are mediated by its G-protein-coupled receptors, GPR37 and GPR37L1, undergoing ligand-mediated internalization followed by ERK phosphorylation signaling (Hiraiwa et al. 1999). |
Eukaryota | Metazoa, Chordata | CSAP of Homo sapiens |
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1.C.35.2.2 | Saposin-like protein (Saplip C; SalA) of 157 aas. Important for lipid interactions and lysosomal degradation of several sphingolipids (Vaccaro et al. 1999). |
Eukaryota | Evosea | Saplip C of Dictyostelium discoideum (Slime mold) |
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1.C.35.2.3 | Saposin of 254 aas and 1 N-terminal TMS (Hao et al. 2010). |
Eukaryota | Metazoa, Nematoda | Saposin of Steinernema carpocapsae (Entomopathogenic nematode) |
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1.C.35.3.1 | Antimicrobial natural killer cell lysin, NK-lysin of 129 aas. NK-lysin is involved in the inducible cytotoxicity of T and NK cells (Andersson et al. 1996). Recombinant NK-lysin inhibits hepatocellular carcinoma metastasis by downregulating FKBP3 and inhibiting oxidative phosphorylation and glycolysis (Fan et al. 2023). |
Eukaryota | Metazoa, Chordata | NK lysin of Sus scrofa |
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1.C.35.3.2 | Granulosin of 145 aas and 1 TMS. Functions probably by pore-formation by natural killer (NK) and T lympocyces to combat intracellular parasites, both bacterial and eukaryotic (Dotiwala et al. 2016). |
Eukaryota | Metazoa, Chordata | Granulosin of Homo sapiens |
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1.C.35.3.3 | Antimicrobial peptide NK-lysin-like protein of 147 aas and 1 N-terminal TMS. It has two sequential domains, Saposin A (SapA) and SapB. |
Eukaryota | Metazoa, Chordata | NK-lysin-like protein of Grus japonensis (Red-crowned crane) |
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1.C.35.3.4 | Antimicrobial peptide NK-lysin isoform X1 of 240 aas and 1 N-terminal TMS. |
Eukaryota | Metazoa, Chordata | NK-lysin of Taeniopygia guttata (zebra finch) |
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1.C.35.3.5 | Uncharacterized protein of 268 aas and 2 TMSs, one N-terminal and one at about residue 140. |
Eukaryota | Metazoa, Chordata | UP of Albula glossodonta |
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1.C.35.4.1 | Countin of 258 aas with 1 N-terminal TMS. |
Eukaryota | Evosea | Countin of Dictyostelium discoideum |
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1.C.35.4.2 | Countin3 of 237 aas and 1 or 2 TMSs, one at the N-terminus and the second at about residue 80. |
Eukaryota | Evosea | Countin3 of Cavenderia fasciculata |
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1.C.35.4.3 | Uncharacterized protein of 413 aas and 4 clear peaks of hydrophobicity between residues 50 and 200. |
Eukaryota | Metazoa, Rotifera | UP of Rotaria sp. Silwood1 |
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1.C.35.4.4 | Uncharacterized protein of 120 aas and possibly one TMS near the N-terminus. |
Eukaryota | Metazoa, Bryozoa | UP of Bugula neritina |
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1.C.35.4.5 | Uncharacterized protein of 176 aas and possibly 2 TMSs at about residies 80 and 120. |
Eukaryota | Heterolobosea | UP of Naegleria fowleri |
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1.C.35.4.6 | Uncharacterized protein of 237 aas and one N-terminal TMS. |
Eukaryota | Metazoa, Mollusca | UP of Lottia gigantea (owl limpet) |
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1.C.36.1.1 | IIITCP protein complex EspB/EspD (SctBE). The topology of and EspD interaction sites in EspB have been defined (Luo and Donnenberg, 2011). EspD inserts into the membrane with its two helical hairpins traversing the membrane with the N- and C-termini on the extraluminal surface, forming 2.5 diameter pores (Chatterjee et al. 2015). EspD (SctE) plays a dominant role in pore formation as it assembles into an oligomeric state, regardless of pH, membrane contact, or the presence of EspB (SctB). Subsequently, EspB subunits integrate into EspD homo-oligomers to create EspB-EspD hetero-oligomers that adopt a transmembrane orientation to create a functional pore complex (Gershberg et al. 2024). |
Bacteria | Pseudomonadota | EspB/EspD of E. coli |
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1.C.36.2.1 | IIITCP protein complex, YopB/YopD (Olsson et al., 2004). TMS2 is essential for function, while TMS1 is partially defective for translocation, pore formation, and signaling (Ryndak et al. 2005). The system forms a multimeric integral membrane complex (Montagner et al., 2011). Mutants have been isoated which show defects in effector translocation and pore formation, and many of these are in a C-terminal domain (Solomon et al. 2015). |
Bacteria | Pseudomonadota | YopB/YopD of Yersinia pseudotuberculosis |
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1.C.36.2.2 | IIITCP protein complex, PopB/PopD. Purified PopB and PopD form pores in model membranes (Romano et al., 2011). PopB in isolation forms a biimodal distribution of two complexes with 6 and 12 subunits while PopD forms a hexameric complex. However when present together, they form a hexadecameric transmembrane complex (Romano et al. 2016). PopB assists with the proper insertion of PopD into cell membranes and is required for the formation of a functional translocon and host infection (Tang et al. 2018). |
Bacteria | Pseudomonadota | PopB/PopD of Pseudomonas aeruginosa |
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1.C.36.2.3 | Translocator complex AopB/AopD of 347 and 299 aas, respectively. AopB has been crystalized and the structure determined for this protein in complex with the AcrH chaperone protein (Nguyen et al. 2015). The structure revealed unique interactions between the various interfaces of AopB and AcrH, with the N-terminal "molecular anchor" of AopB crossing into the "N-terminal arm" of AcrH. AopB adopts a novel fold, and its transmembrane regions form two pairs of helical hairpins. |
Bacteria | Pseudomonadota | AopBD of Aeromonas hydrophila |
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1.C.36.3.1 | IIITCP protein complex, IpaB/IpaC/IpaD. Physical contact with host cells initiates secretion and leads to assembly of a pore, IpaB/IpaC, in the host cell membrane. The active needle tip complex of S. flexneri is composed of a tip protein, IpaD, and the two pore-forming proteins, IpaB and IpaC. The atomic structures of IpaD and a protease-stable coiled-coil fragment in the N-terminal regions of IpaB from S. flexneri and the homologous SipB from Salmonella enterica have been determined (Barta et al. 2012). Structural comparisons revealed similarity to the coiled-coil regions of pore-forming proteins such as colicin Ia (TC# 1.C.1.1.1). Interaction between IpaB and IpaD at the needle tip is key to host cell sensing, orchestration of IpaC secretion and its subsequent assembly at needle tips (Veenendaal et al. 2007). The N-terminus of IpaC is extracellular and the C-terminus is intracellular, and its topology has been studied (Russo et al. 2019). Residures lining the pore channel of the plasma membrane-embedded Shigella flexneri type 3 secretion translocase, IpaB, have been identified (Chen et al. 2021). |
Bacteria | Pseudomonadota | IpaB/IpaD of Shigella dysenteriae |
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1.C.36.3.2 | IIITCP protein complex, SipB/SipD of pathogenicity island 1 (SPI1) | Bacteria | Pseudomonadota | SipB/SipD of Salmonella typhimurium SipB (AAL21765) SipD (AAL21763) |
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1.C.36.3.3 | IIITCP complex, BipB/BipD (BipB, 620aas; BipD, 310aas) |
Bacteria | Pseudomonadota | BipB/BipD of Burkholderia pseudomallei |
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1.C.36.3.4 | IIITCP complex, BipB/BipD (Cell invasion protein complex). |
Bacteria | Pseudomonadota | BipB/D of Protens mirablis |
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1.C.36.3.5 |
IIITCP complex protein, CopB of 852aas; 4TMSs |
Bacteria | Chlamydiota | CopB of Parachlamydia acathamoebae (F8KWQ0) |
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1.C.36.3.6 | Putative channel-forming system of a bacterial type III secretion system (see family description). The two proteins included in this system are encoded by genes that are in a gene cluster that includes a type III secretion system and a chaparone protein of 166 aas, SicA (AKM45441). |
Bacteria | Pseudomonadota | Pore-forming two component system of Burkholderia contaminans |
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1.C.36.3.7 | Type III secretion system translocon, consisting of two subunits, SctB (320 aas and 1 or 2 TMSs) and SctE (575 aas and 2 or 3 TMSs). The TMSs of SctB and SctE dictate membrane destination (bacterial versus host membrane). The TMSs are involved in the ability of the protein to translocate into and across the host cell membrane (Jenia et al. 2021). |
Bacteria | Pseudomonadota | SctB-SctE of E. coli |
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1.C.36.4.1 | IIITCP protein complex, BopB/BopD (Nogawa et al., 2004) | Bacteria | Pseudomonadota | BopB/BopD of Bordetella bronchiseptica BopB (NP_888166) BopD (NP_888165) |
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1.C.36.5.1 | IIICP protein complex SseB/SseC/SseD; SseB: translocon sheath protein; SseC and SseD: translocon pore subunits of the Salmonella pathogenicity island 2 (SPI2) |
Bacteria | Pseudomonadota | SseB/SseC/SseD of Salmonella typhimurium SseB (CAA12185) SseC (CAA12187) SseD (CAA12188) |
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1.C.37.1.1 | Class IIc bacteriocin, Lactococcin 972 of 91 aas and 1 TM |
Bacteria | Bacillota | Lactococcin 972 of Lactococcus lactis |
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1.C.37.1.10 | Lactococcin 972 family bacteriocin of 220 aas and 1 TM |
Bacteria | Actinomycetota | Bacteriocin of Thermoactinospora rubra |
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1.C.37.1.11 | Lactococcin 972 family bacteriocin of 179 aas and 2 TMSs. |
Bacteria | Actinomycetota | Bacteriocin of Mycetocola lacteus |
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1.C.37.1.12 | Uncharacterized protein of 133 aas and 1 TMS |
Bacteria | Bacillota | UP of Melghirimyces algeriensis |
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1.C.37.1.13 | Bacteriocin of 98 aas and 1 TMS |
Bacteria | Chlamydiota | Bacteriocin of Chlamydia trachomatis |
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1.C.37.1.2 | Lactococcin 972 family bacteriocin of 127 aa |
Bacteria | Bacillota | Lactococcin of Mogibacterium diversum |
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1.C.37.1.3 | Uncharacterized protein of 131 aas and 1 N-terminal TMS |
Bacteria | Bacillota | UP of Dorea formicigenerans |
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1.C.37.1.4 | Lactococcin 972 family bacteriocin of 131 aas and 1 TM |
Bacteria | Bacillota | Bacteriocin of Listeria monocytogenes |
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1.C.37.1.5 | Lactococcin 972 family bacteriocin of 99 aas and 1 TM |
Bacteria | Bacillota | Bacteriocin of Clostridium cuniculi |
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1.C.37.1.6 | Lactococcin 972 family bacteriocin of 129 aas and 1 TM |
Bacteria | Actinomycetota | Bacteriocin of Agreia sp. |
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1.C.37.1.7 | Uncharacterized protein of 148 aas and 1 TMS |
Bacteria | Bacillota | UP of Anaerostipes hadrus |
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1.C.37.1.8 | Bacteriocin of 129 aas and 1 TMS |
Bacteria | Pseudomonadota | Bacteriocin of Erwinia sp. |
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1.C.37.1.9 | Uncharacterized protein of 98 aas and 1 TMS |
Bacteria | Actinomycetota | UP of Cellulosimicrobium sp. BI34T |
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1.C.38.1.1 | Equinatoxin II (EqtII) binds sphingomyelin specifically and localizes to the Golgi apparatus (Bakrac et al., 2010). Disrupting the key hydrophobic interaction between V60 and F163 (FraC numbering scheme) in the oligomerization interface of FraC, equinatoxin II (EqtII) and sticholysin II (StII) impairs the pore formation activity (Mesa-Galloso et al. 2016). Reviewed by Gupta et al. 2023. |
Eukaryota | Metazoa, Cnidaria | Equinatoxin of Actinia tenebrosa (P61915) |
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1.C.38.1.10 | Cytolysin RTX-A of 175 aas. Forms cations-selective hydrophilic pores of around 1 nm and causes cardiac stimulation and hemolysis. Pore formation is a multi-step process that involves specific recognition of membrane sphingomyelin (but neither cholesterol nor phosphatidylcholine) and requires oligomerization of the toxin subunits (Frazão et al. 2012). |
Eukaryota | Metazoa, Cnidaria | Cytolysin RTX-A of Heteactis crispa (Radianthus macrodactylus) (Leathery sea anemone) |
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1.C.38.1.11 | Cytolysin Src-1 of 216 aas (Frazão et al. 2012). |
Eukaryota | Metazoa | Cytolysin Src-1 of Sagartia rosea (sea anemone) |
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1.C.38.1.12 | Fragaceatoxin C (FraC), an alpha-barrel pore-forming protein, a cytolytic actinoporin, of 152 aas (Morante et al. 2015; Rojko et al. 2015). Pore formation goes through a dimer intermediate and then generates the active octamer. Disrupting the key hydrophobic interaction between V60 and F163 (FraC numbering scheme) in the oligomerization interface of FraC, equinatoxin II (EqtII) and sticholysin II (StII) impairs the pore formation activity (Mesa-Galloso et al. 2016). |
Eukaryota | Metazoa, Chordata | FraC of Callorhynchus milii |
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1.C.38.1.13 | Conoporin 1 of 242 aas |
Eukaryota | Metazoa, Mollusca | Conotoxin 1 of Conus geographus (Geography cone) (Nubecula geographus) |
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1.C.38.1.14 | Pore-forming toxin, Nigrelysin of 214 aas. The toxin lacks Cys and readily permeabilizes erythrocytes, as well as L1210 cells. CD spectroscopy revealed that its secondary structure is dominated by beta structure (58.5%) with 5.5% α-helix, and 35% random structure. Binding experiments to lipidic monolayers and to liposomes, as well as permeabilization studies in vesicles, revealed that the affinity of this toxin for sphingomyelin-containing membranes is quite similar to sticholysin II (StII) (Alvarado-Mesén et al. 2019). |
Eukaryota | Metazoa, Cnidaria | Nigrelysin of Anthopleura nigrescens |
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1.C.38.1.15 | Pore-forming cytolysin, Src-1-like, isoform X1 of 225 aas (Borges et al. 2018). |
Eukaryota | Metazoa, Chordata | Cytolysin of Notothenia coriiceps |
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1.C.38.1.16 | Bryoporin of 178 aas, possibly with an N-terminal TMS. It has hemolytic activity in vitro and probably binds a phosphocholine derivative with the unique amido or hydroxyl groups found in sphingomyelin. It is involved in drought tolerance and is inhibited by sphingomyelin (Hoang et al. 2009). Pore-forming moss protein bryoporin is structurally and mechanistically related to actinoporins from evolutionarily distant cnidarians (Šolinc et al. 2022). |
Eukaryota | Viridiplantae, Streptophyta | Bryoporin of Physcomitrium pates (spreading leaved earth moss) (Physcomitrella patens) |
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1.C.38.1.17 | Sticholysin II, EstII; She4, of 175 aas. Its 3-D structure has been solved (1GWY).Unveiling Sticholysin II and plasmid DNA interactions which have implications for developing non-viral vectors (Escalona-Rodriguez et al. 2024). |
Eukaryota | Metazoa, Cnidaria | She4 of Stichodactyla helianthus |
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1.C.38.1.18 | Hydra Actinoporin-like toxin 1 of 187 aas. The 3-D structure is known (PDB acc# 7EKZ). |
Eukaryota | Metazoa, Cnidaria | Toxin of Hydra vulgaris (Hydra attenuata) |
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1.C.38.1.2 | Sticholysin I (cytolysin ST1; STNI STII; StiII; FraC) (Alvarez et al., 2009). Pore formation goes through a dimer intermediate and then generates the active octamer. Disrupting the key hydrophobic interaction between V60 and F163 (FraC numbering scheme) in the oligomerization interface of FraC, equinatoxin II (EqtII) and sticholysin II (StII) impairs the pore formation activity (Mesa-Galloso et al. 2016). Sticholysin II-mediated cytotoxicity may involve the activation of regulated intracellular responses that anticipates cell death (Soto et al. 2018). Sticholysins represent a prototype of proteins acting through the formation of protein-lipid toroidal pores. Peptides spanning the N-terminus of sticholysins mimic the permeabilizing activity of the full-length toxins (Mesa-Galloso et al. 2019). Phospholipids integrate into the ring of the toroidal pores, promoting their stabilization. Self-association and folding in the membrane determine the mode of action of peptides from the lytic segment of sticholysins (Ros et al. 2019). STNI and STNII are 94% identical. They form cations-selective hydrophilic pores of around 1 nm and causes cardiac stimulation and cytolysis. Lanio et al. 2001 showed that pore formation is a multi-step process that involves specific recognition of membrane sphingomyelin (but neither cholesterol nor phosphatidylcholine) using an aromatic rich region and an adjacent phosphocholine (POC) binding site, firm binding to the membrane (mainly driven by hydrophobic interactions) accompanied by the transfer of the N-terminal region to the lipid-water interface and finally pore formation after oligomerization of monomers. Cytolytic effects include red blood cell hemolysis, platelet aggregation and lysis, cytotoxic and cytostatic effects on fibroblasts. Lethality in mammals has been ascribed to severe vasospasm of coronary vessels, cardiac arrhythmia, and inotropic effects (Lanio et al. 2001). |
Eukaryota | Metazoa, Cnidaria | Sticholysin I of Stichodactyla helianthus |
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1.C.38.1.3 | Tenebrosin-A (fragment) | Eukaryota | Metazoa, Cnidaria | Tenebrosin-A of Actinia tenebrosa (P30833) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.38.1.4 | Actinoporin Or-A, cation-selective pore forming tetrameric toxin | Eukaryota | Metazoa, Cnidaria | Actinoporin Or-A of Oulactis orientalis (sea anenome) (Q5I4B8) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.38.1.5 | Echotoxin-2 precursor, Echt-2 hemolysin (276 aas). Pore-forming protein; forms cation-selective hydrophilic pores of around 1 nm and causes cardiac stimulation and hemolysis. Pore formation is a multi-step process that involves recognition of membrane sphingomyelin using aromatic rich regions and adjacent phosphocholine binding sites for firm binding to the membrane accompanied by the transfer of the N-terminal region to the lipid-water interface and finally pore formation after oligomerization of several monomers (Kawashima et al., 2003; Shiomi et al., 2002). |
Eukaryota | Metazoa, Mollusca | Echt-2 hemolysin of Monplex echo (a marine gastropod) |
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1.C.38.1.6 | Cytolytic pore-forming tetrameric toxin (forms cation-selective pores (d = 1 nm) (Mebs et al., 1992). | Eukaryota | Metazoa, Cnidaria | Cytolysin of Heteractis magnifica (P39088) |
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1.C.38.1.7 | The plant actinoporin homologue (293aas). Function unknown. | Eukaryota | Viridiplantae | Actinoporin homologue of Physcomitrella patens (A9S8W4) |
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1.C.38.1.8 | Fragaceatoxin C (FraC) of the strawberry anemone (Structure solved to 1.8 Å resolution (PPDB acc # 4TSL); It is a crown-shaped nonamer with an external diameter of about 11.0 nm and an internal diameter of approximately 5.0 nm.) Almost identical to Equinatoxin II/Tenebrosin C (1.C.38.1.1) (Mechaly et al., 2011). Fragaceatoxin C (FraC) is an α-barrel pore-forming toxin (PFT). The crystal structures of FraC at four different stages of the lytic mechanism have been determined at 3.1Å resolution, namely the water-soluble state, the monomeric lipid-bound form, an assembly intermediate and the fully assembled transmembrane pore (Tanaka et al. 2015). The structure of the transmembrane pore exhibits a unique architecture composed of both protein and lipids, with some of the lipids lining the pore wall, acting as assembly cofactors. The pore exhibits lateral fenestrations that expose the hydrophobic core of the membrane to the aqueous environment. The incorporation of lipids from the target membrane within the structure of the pore provides a membrane-specific trigger for the activation of this haemolytic toxin. It has been reconstituted in planar lipid bilayers and engineered for DNA analysis. It shows a funnel-shaped geometry that allows tight wrapping around single-stranded DNA (ssDNA), resolving between homopolymeric C, T, and A polynucleotide stretches (Wloka et al. 2016). Despite the 1.2 nm internal constriction in the FraC pore, double-stranded DNA (dsDNA) can translocate through the nanopore at high applied potentials, presumably through deformation of the alpha-helical transmembrane region (Huang et al. 2017). Therefore, FraC nanopores might be useful for DNA sequencing and dsDNA analysis. Pore formation goes through a dimer intermediate and then generates the active octamer. Disrupting the key hydrophobic interaction between V60 and F163 (FraC numbering scheme) in the oligomerization interface of FraC, equinatoxin II (EqtII) and sticholysin II (StII) impairs the pore formation activity (Mesa-Galloso et al. 2016). It was reviewed by Gupta et al. 2023. FraE is almot identical to this protein. |
Eukaryota | Metazoa, Cnidaria | FraC of Actine fragacea (B9W5G6) |
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1.C.38.1.9 | Equinatoxin 5 of 214 aas (Frazão et al. 2012). Bryoporin-7 (P61914; 214 aas) is 83% identical. |
Eukaryota | Metazoa, Cnidaria | Equinatoxin-5 of Actinia equina |
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1.C.39.1.1 | Uncharacterized MACPF homologue of 1153 aas |
Eukaryota | Evosea | UP of Dictyostelium fasciculatum (Slime mold) |
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1.C.39.1.2 | Uncharacterized protein of 1277 aas |
Eukaryota | Evosea | UP of Polysphondylium pallidum (Cellular slime mold) |
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1.C.39.1.3 | Uncharacterized protein of 1216 aas |
Eukaryota | Evosea | UP of Acytostelium subglobosum |
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1.C.39.1.4 | Uncharacterized protein of 1151 aas |
Eukaryota | Evosea | UP of Polysphondylium pallidum |
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1.C.39.10.1 | Sea anemone toxin, AvTX-60A, of 498aas (Oshiro et al., 2004). |
Eukaryota | Metazoa, Cnidaria | AvTX-60A of Actineria villosa (Q76DT2) |
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1.C.39.10.2 | MACPF-containing actinoporin of 488 aas, PsTX60B (Frazão et al. 2012). |
Eukaryota | Metazoa, Cnidaria | PsTX60B of Phyllodiscus semoni (Night anemone) |
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1.C.39.10.3 | Uncharacterized protein of 449 aas |
Eukaryota | Viridiplantae, Streptophyta | UP of Selaginella moellendorffii (Spikemoss) |
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1.C.39.10.4 | Uncharacterized protein of 474 aas |
Eukaryota | Metazoa, Cnidaria | UP of Nematostella vectensis (Starlet sea anemone) |
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1.C.39.11.1 | MACPF protein (610aas) |
Eukaryota | Viridiplantae, Streptophyta | MACPF protein of Medicago truncatula (Q1SKW8) |
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1.C.39.11.2 | MACPF protein (615aas) |
Eukaryota | Viridiplantae, Streptophyta | MACPF protein of Populus trichocarpa (B9GNC9) |
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1.C.39.11.3 | The constitutively activated cell death 1 protein (CAD1) of 561 aas (Morita-Yamamuro et al. 2005; Tsutsui et al. 2006). |
Eukaryota | Viridiplantae, Streptophyta | CAD1 of Arabidopsis thaliana |
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1.C.39.11.4 | The Necrotic Spotted Lesions 1 (NSL1) protein of 612 aas (Noutoshi et al. 2006). |
Eukaryota | Viridiplantae, Streptophyta | NSL1 of Arabidopsis thaliana |
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1.C.39.12.1 | MACPF protein (809aas) |
Bacteria | Chlamydiota | MACPF protein of Chlamydia muridarum (Q9PKN4) |
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1.C.39.12.2 | MACPF homologue (411aas) |
Bacteria | Chlamydiota | MACPF homologue of Chlamydophila pneumoniae (Q9Z908) |
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1.C.39.12.3 | MACPF protein, CT153 of 810 aas. Mediates interactions with host cell membranes and organelles, and plays a role in intracellular development (Taylor and Nelson 2014). |
Bacteria | Chlamydiota | CT153 protein of Chlamydia trachomatis |
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1.C.39.12.4 | MACPF domain protein of 834 aas |
Bacteria | Chlamydiota | MACPF protein of Chlamydia psittaci |
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1.C.39.13.1 | Hypothetical protein (470aas) |
Bacteria | Bacteroidota | HP of Bacteroides thetaiotaomicron (Q8A335) |
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1.C.39.13.2 | MACPF-domain containing protein, BSAP-1, of 372 aas and 1 N-terminal TMS, secreted in extracellular vesicles. It contains a membrane attack complex/perforin (MACPF) domain that kills bacteria by pore formation, and mutations affecting key residues of this domain abrogated its activity (Chatzidaki-Livanis et al. 2014). Extracellular Vesicles can be relevant to Endocrinology in mammals (Das Gupta et al. 2021). |
Bacteria | Bacteroidota | BSAP1 of Bacteroides fragilis (Q64VU4) |
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1.C.39.13.3 | Hypothetical Protein (486 aas) |
Bacteria | Bacteroidota | HP of Bacteroides fragilis (Q64W10) |
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1.C.39.13.4 | MACPF protein. The structure is known (Xu et al., 2010). |
Bacteria | Bacteroidota | MACPF protein of Bacteroides thetaiotaomicron (Q8A267) |
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1.C.39.13.5 | Uncharacterized protein |
Bacteria | Bacteroidota | UP of Paraprevotella xylaniphila |
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1.C.39.13.6 | MAC/Perforin domain protein BSAP-4 of 506 aas and 1 N-terminal TMS. |
Bacteria | Bacteroidota | BSAP-4 of Bacteroides fragilis |
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1.C.39.13.7 | MACPF domain-containing protein, BASP2, of 508 aas (Roelofs et al. 2016). |
Bacteria | Bacteroidota | BASP2 of Bacteroides uniformis |
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1.C.39.13.8 | MACPF domain-containing protein, BSAP3, of 485 aas and one N-terminal TMS (McEneany et al. 2018). |
Bacteria | Bacteroidota | BSAP3 of Bacteroides dorei |
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1.C.39.14.1 | Macrophage-expressed gene 1 protein, Mpeg1, or perforin-2, PFN2, of 716 aas and one C-terminal TMS. Pore formation has been demonstrated in target bacteria (McCormack et al. 2013). PFN2 undergoes a pre-pore to pore transition upon acidification (Jiao et al. 2021). Rawat and Jakubzick 2023 showed that channeling of antigens to CD8+ T cells is facilitated by perforin-2. It translcates the antigens to the cytosol in cross-presenting dendritic cells. A hexadecameric perforin-2 pore forms in phagosome membranes to fåcilitat transport of antigens to the cytosol (Rawat and Jakubzick 2023). Cytosolic antigens use classical MHC-I pathway molecules for cross presentation (ubiquitination, proteasome degradation, and TAP transport into the endoplasmic reticulum). |
Eukaryota | Metazoa, Chordata | Mpeg1 of Homo sapiens |
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1.C.39.14.2 | MACPF domain protein, Mpeg of 742 aas. This protein is found in late endosomes. Its MACPF domain exhibits anti-bacterial activity against Gram - and Gram + bacteria. It's synthesis is stimulated following infection with Vibrio alginolyticus (He et al. 2011). |
Eukaryota | Metazoa, Mollusca | Mpeg of Crassostrea gigas (Pacific oyster) (Crassostrea angulata) |
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1.C.39.14.3 | Mpeg1 of 728 aas. Contains a cytolytic MACPF domain. Expressed in up to 8x increase in hematocytes and epipodia samples after exposure to heat killed Vibrio anguilarum (Kemp and Coyne 2011). |
Eukaryota | Metazoa, Mollusca | Mpeg1 of Haliotis midae (perlemoen abalone) |
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1.C.39.14.4 | Mpeg1 of 718 aas (Benard et al. 2014). |
Eukaryota | Metazoa, Chordata | Mpeg1 of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.C.39.14.5 | Macrophage-expressed protein 1, Mpeg1, of 784 aas and 2 TMSs, N- and C-terminal. Mpeg1/Perforin-2 (PRF2)) is a family of pore-forming proteins (PFPs) which can form pores and destroy the cell membrane of invading pathogens (Liu et al. 2022). Ct-Mpeg1 is an important immune molecule of C. tritonis that is involved in the bacterial infection resistance of Vibrio species (Liu et al. 2022). |
Eukaryota | Metazoa, Mollusca | Mpeg1 of Charonia tritonis (giant triton snail) |
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1.C.39.15.1 | Torso-like protein, Tsl of 353 aas and containing a MACPF domain. Possible ligand that binds to the torso receptor. Implicated in a receptor tyrosine kinase signaling pathway that specifies differentialtion and terminal cell fate (Martin et al. 1994; Savant-Bhonsale and Montell 1993; Johnson et al. 2013; Mineo et al. 2015). |
Eukaryota | Metazoa, Arthropoda | Tsl of Drosophila melanogaster (Fruit fly) |
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1.C.39.15.2 | Uncharacterized Torso-like protein of 271 aas |
Eukaryota | Metazoa, Arthropoda | Torso-like protein of Daphnia pulex (Water flea) |
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1.C.39.16.1 | Uncharacterized protein of 784 aas |
Eukaryota | Fungi, Ascomycota | UP of Penicillium marneffei |
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1.C.39.16.2 | Uncharacterized protein of 795 aas |
Eukaryota | Fungi, Ascomycota | UP of Cladophialophora psammophila |
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1.C.39.17.1 | The BMP/retinoic acid-inducible neural-specific protein 1, BRINP1 (DBC1, DBCCR1, FAM5A), protein of 761 aas. Inhibits cell proliferation by negative regulation of the G1/S transition and mediates cell death which is not of the classical apoptotic type while regulating expression of components of the plasminogen pathway (Wright et al. 2004; Nishiyama et al. 2001; Louhelainen et al. 2006). |
Eukaryota | Metazoa, Chordata | BRINP-1 of Homo sapiens |
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1.C.39.17.2 | BRINP-2 (BRINP2, FAM5B) of 783 aas. Inhibits neuronal cell proliferation by negative regulation of the cell cycle transition. |
Eukaryota | Metazoa, Chordata | BRINP-2 of Homo sapiens |
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1.C.39.2.1 | Perforin 1 precursor; targets viruses, bacteria and cancer cells (McCormack et al. 2013). It is produced by cytotoxic T lymphocytes and natural killer cells and has been expressed, purified and studied in insect cells (Naneh et al. 2015). |
Eukaryota | Metazoa, Chordata | Perforin of Rattus norvegicus |
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1.C.39.2.2 | Uncharacterized protein of 429 aas |
Eukaryota | Metazoa, Chordata | UP of Astyanax mexicanus (Blind cave fish) (Astyanax fasciatus mexicanus) |
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1.C.39.2.3 | Performin 1-like protein of 545 aas, Prf1 |
Eukaryota | Metazoa, Chordata | Prf1 of Xenopus tropicalis (Western clawed frog) (Silurana tropicalis) |
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1.C.39.2.4 | Uncharacterized protein of 481 aas |
Eukaryota | Metazoa, Chordata | UP of Latimeria chalumnae (West Indian ocean coelacanth) |
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1.C.39.2.5 | Performin 1, Pfn1, of 587 aa |
Eukaryota | Metazoa, Chordata | Pfn1 of Carassius auratus langsdorfii (Japanese silver crucian carp) |
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1.C.39.2.6 | MACPF domain-containing protein (342aas) |
Eukaryota | Ciliophora | MACPF proteins of Tetrahymena thermophila (Q23MJ4) |
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1.C.39.2.7 | Duplicated MACPF protein (681aas) The first half resembles 1.C.39.6.2 more than the second half. |
Eukaryota | Ciliophora | MACPF protein of Tetrahymena thermophila (Q23I78) |
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1.C.39.2.8 | Perforin 1, PRF1 of 555 aas. Plays a key role in secretory granule-dependent cell death and in defense against virus-infected and neoplastic cells. Plays an important role in killing other cells that are recognized as non-self by the immune system, e.g. in transplant rejection or some forms of autoimmune disease. Can insert into the membrane of target cells in its calcium-bound form, oligomerize and form large pores (Law et al. 2010). Promotes cytolysis and apoptosis of target cells by facilitating the uptake of cytotoxic granzymes. Perforin gene mutations contribute to hereditary cancer predisposition (Chaudhry et al. 2016). After perforin is secreted by CD8+ cytotoxic T-lymphocytes (CTLs) and disrupts the membranes of extracellular vesicles (EVs), adenosine is released from the EVs and acts as an immunosuppressive metabolite by binding to the adenosine receptor on the CTL membrane. This mechanism provides a novel survival strategy using cancer cell-derived EVs (Tadokoro et al. 2020). |
Eukaryota | Metazoa, Chordata | Perforin of Homo sapiens |
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1.C.39.2.9 | Two component cytolysin, perivitellin-2, one subunit (P0C8G6) is a 67 KDa subunit, and the other (P0DQP0) is a 31 kDa (286 aas) subunit. The egg defensive protein, perivitellin-2, is thus a pore-forming two-subunit glycoprotein that affects both the nervous and digestive systems of mammals (Heras et al. 2008). It is a source of both structural and energetic molecules during embryonic development. The tachylectin subunit (31 kDa) binds target membranes while the MACPF subunit (67 kDa) disrupts lipid bilayers forming large pores altering the plasma membrance conductance (Dreon et al. 2013). The perivitellin-2 (PV2) from snails is an unusual neuro and enterotoxin comprising a pore-forming domain of the Membrane Attack Complex and Perforin Family (MACPF) linked to a lectin. Both domains have membrane binding capabilities. The apple snail Pomacea maculata PV2's (PmPV2's) interaction with lipid membranes was studied (Vázquez et al. 2025). PmPV2 toxicity decreased when cholesterol (Chol) was diminished from enterocyte cell membranes. Chol enhanced PmPV2 association with phosphatidylcholine membranes but did not induce pore formation. In contrast, using rat brain lipid models, rich in glycolipids, PmPV2 exhibited high affinity and induced vesicle permeabilization. Negative stain electron microscopy and atomic force microscopy confirmed the formation of pore-like structures in brain lipid vesicles. Thus, Chol is a necessary lipid component, but PmPV2-glycolipid interactions are potential activators critical to triggering PmPV2's pore-forming activity (Vázquez et al. 2025). |
Eukaryota | Metazoa, Mollusca | 2-protein Cytotoxin of Pomacea canaliculata (Golden apple snail) |
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1.C.39.3.1 | Pore-forming, membrane attack, complement component 8, α-polypeptide precursor; C8α-MACPF (structure solved to 2.5 Å resolution; Hadders et al., 2007; Rosado et al., 2007). β-Hairpins in C8α and C9 play a direct role in MAC membrane penetration and pore formation (Weiland et al. 2014). The first TMS of complement component-9 inhibits its own self assembly (Spicer et al. 2018). |
Eukaryota | Metazoa, Chordata | C8α-MACPF of Homo sapiens (2QQH_A) (P07357) |
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1.C.39.3.2 | Complement component 7 |
Eukaryota | Metazoa, Chordata | Complement component 7 of Xenopus laevis (Q6INM0) |
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1.C.39.3.3 | Complement component C6 of 934 aas and 1 TMS; targets phagocytic and some non phagocytic cells (McCormack et al. 2013). Expressed constitutively in phagocytes and inducibly in parenchymal tissue-forming cells. It is a transmembrane protein of cytosolic vesicles, derived from multiple organelles that translocate to and fuse with bacterium-containing vesicles. Subsequently, perforin-2 polymerizes and forms large clusters of 100 Å pores in the bacterial surface with perforin-2 cleavage products present in the bacteria. Perforin-2 is also required for the bactericidal activity of reactive oxygen and nitrogen species as well as hydrolytic enzymes (McCormack et al. 2015). Perforin-2 exists in membrane-bound (P2a) and secretory (P2b) isoforms, both present in human macrophages. P2a promotes fusion of vesicles with lysosomes, and may therefore play important roles in immune defense (Xiong et al. 2017). Loss of MPEG1 causes increased susceptibility to microbial infection. MPEG1 expression is upregulated in response to proinflammatory signals such as tumor necrosis factor alpha (TNFα) and lipopolysaccharides (LPS). Furthermore, germline mutations in MPEG1 have been identified in connection with recurrent pulmonary mycobacterial infections. Structural studies on MPEG1 revealed that it can form oligomeric pre-pores and pores. The unusual domain arrangement within the MPEG1 architecture suggests a novel mechanism of pore formation that may have evolved to guard against unwanted lysis of host cells (Bayly-Jones et al. 2020). |
Eukaryota | Metazoa, Chordata | Complement component C of Homo sapiens |
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1.C.39.3.4 | MACPF protein, terminal complement component, TCC-like of 585 aas. |
Eukaryota | Metazoa, Chordata | TCC-like protein of Halocynthia roretzi (Sea squirt) (Cynthia roretzi) |
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1.C.39.3.5 | Complement protein C9; targets bacteria (McCormack et al. 2013). β-Hairpins in C8α and C9 play a direct role in MAC membrane penetration and pore formation (Weiland et al. 2014). |
Eukaryota | Metazoa, Chordata | C9 of Equus caballus |
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1.C.39.3.6 | Complement protein C9. β-Hairpins in C8α and C9 play a direct role in MAC membrane penetration and pore formation (Weiland et al. 2014). |
Eukaryota | Metazoa, Chordata | C9 of Fugu rubripes |
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1.C.39.4.1 | Chain A, MACPF perforin-like protein, Plu-MACPF (structure solved to 2.0 Å resolution; Rosado et al., 2007). |
Bacteria | Pseudomonadota | Plu-MACPF of Photorhabdus luminescens (2QP2_A) (Q7N6X0) |
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1.C.39.4.2 | MACPF protein (453 aas) |
Bacteria | Cyanobacteriota | MACPF protein of Trichodesmium erythraeum (Q117U3) |
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1.C.39.4.3 | Hypothetical Protein (588 aas) |
Bacteria | Pseudomonadota | HP of Marinomonas sp. MED121 (A3YG19) |
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1.C.39.4.4 | Putative perforin of 409 aas |
Archaea | Euryarchaeota | Putative perforin of Halorubrum kocurii |
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1.C.39.4.5 | Uncharacterized protein of 684 aas |
Eukaryota | Viridiplantae, Streptophyta | UP of Selaginella moellendorffii |
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1.C.39.4.6 | Uncharacterized protein of 1085 aas. This protein is a fusion protein with an N-terminal MACPF domain (see TC subfamily # 1.C.39..4) and a C-terminal internalin-A domain (see TC# 8.A.43.1.12). |
Bacteria | Mycoplasmatota | UP of Acholeplasma palmae |
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1.C.39.4.7 | Gram-negative insecticidal protein, GNIP1Aa of 536 aas and 0 TMSs/ Its structure has been determined to 2.5 Å resolution (PDB# 6FBM) (Zaitseva et al. 2019). It consists of two structurally distinct domains, a MACPF domain and a previously uncharacterized type of domain. GNIP1Aa is unique in being a prokaryotic MACPF member to have both its structure and function identified. It is specifically toxic to Diabrotica virgifera virgifera larvae upon feeding. The MACPF domain is probably important for oligomerization and transmembrane pore formation, while the accompanying domain may define the specificity of the target of toxicity. In GNIP1Aa the accompanying C-terminal domain has a unique fold composed of three pseudosymmetric subdomains with shared sequence similarity, a feature not obvious from the initial sequence examination. This domain is in a family named beta-tripod. Important regions in the beta-tripod domain, which may be involved in target recognition, have been identified (Zaitseva et al. 2019).
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Bacteria | Pseudomonadota | GNIP1 of Chromobacterium piscinae |
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1.C.39.4.8 | Uncharacterized phosphodiesterase of 771 aas and 0 TMSs. Only a segment of this protein is homologous to other members of family 1.C.39, and this segment is also distantly related to members of family 1.C.43. |
Bacteria | Cyanobacteriota | UP of Scytonema sp. NIES-4073 |
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1.C.39.4.9 | Phosphodiesterase/alkaline phosphatase D, PhoD, of 837 aas and 0 TMSs. Except for the protein with TC# 1.C.39.4.8, only a segment of this protein is homologous to other members of the MACPF family, Iit is also related to members of family 1.C.43. |
Bacteria | Cyanobacteriota | PhoD of Calothrix brevissima |
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1.C.39.5.1 | MACPF homologue |
Eukaryota | Metazoa, Chordata | MACPF homologue of Branchiostoma floridae (C3YI39) |
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1.C.39.5.2 | MACPF homologue |
Eukaryota | Metazoa, Cnidaria | MACPF homologue of Nematostella vectensis (A7RF41) |
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1.C.39.5.3 | MACPF homologue |
Eukaryota | Metazoa, Chordata | MACPF homologue of Branchiostoma floridae (C3Z435) |
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1.C.39.5.4 | Protein of 1305 aas with an N-terminal MACPF domain and C-terminal extracellular cystine-rich furin-like (Fu-sup), fucolectin (tocylectin; discoidin; FTP; a fucose-binding lectin) and cystine-rich scavenger receptor (SRCR; extracellular protein-protein interaction) domains (in this order, N- to C-terminus). |
Eukaryota | Metazoa, Chordata | MACPF protein of Branchiostoma floridae (Florida lancelet) (Amphioxus) |
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1.C.39.5.5 | Cholesterol-dependent cytolysin of 632 aas |
Bacteria | Pseudomonadota | UP of Pseudomonas thivervalensis |
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1.C.39.6.1 | Sporozoite protein with MAC/Perforin domain (Homologous to Erylysin B) of 810 aas. Interacts and breaches host cell membranes (Tavares et al. 2014). CDC/MACPF proteins contain a characteristic four-stranded beta-sheet that is flanked by two alpha-helical bundles, which unfold to form two transmembrane beta-hairpins. Apicomplexan parasites express CDC/MACPFs termed perforin-like proteins (PLPs). Wade and Tweten 2015 present insights into the assembly and regulation of the Apicomplexan CDC (ApiMACPF) molecular pore-forming mechanisms, necessary for osmotically driven rupture of the parasitophorous vacuole and host cell membrane, and cell traversal by these parasites. |
Eukaryota | Apicomplexa | MACPF protein of Plasmodium knowlesi (B3L016) |
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1.C.39.6.2 | Perforin-like protein, PLP1, of 1150 aas (Tavares et al. 2014). |
Eukaryota | Apicomplexa | PLP1 of Toxoplasma gondii |
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1.C.39.6.3 | MACPF protein |
Eukaryota | Apicomplexa | MACPF protein of Theileria parva (Q4MYP3) |
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1.C.39.6.4 | MACPF domain-containing protein (420aas) |
Eukaryota | Apicomplexa | MACPF protein of Babesia bovis (A7AT97) |
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1.C.39.6.5 | Perforin-like protein 4 of 654 aas and 1 N-terminal TMS. |
Eukaryota | Apicomplexa | Perforin homolog of Plasmodium falciparum |
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1.C.39.6.6 | Perforin-like protein 5 of 676 aas and 1 N-terminal TMS. |
Eukaryota | Apicomplexa | Perforin 5 of Plasmodium falciparum |
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1.C.39.6.7 | Perforin-like protein 1 of 842 aas and possibly 2 TMSs, one N-terminal and the second at residue 250. There are at least 3 perforin homologs in P. falciparum, Perforin 1, 2 and 3. |
Eukaryota | Apicomplexa | Perforin 1 of Plasmodium falciparum |
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1.C.39.7.1 | MAC/Perforin domain protein |
Eukaryota | Ciliophora | MACPF domain protein of Tetrahymena thermophila (Q23QV5) |
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1.C.39.7.2 | Uncharacterized protein of 1040 aas |
Eukaryota | UP of Capsaspora owczarzaki |
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1.C.39.7.3 | The MAC/Perforin domain containing protein of 861 aas |
Eukaryota | Ciliophora | MACPF protein of Oxytricha trifallax |
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1.C.39.7.4 | Apextrin of 853 aas |
Eukaryota | Metazoa, Cnidaria | Apextrin of Acropora millepora (Staghorn coral) |
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1.C.39.7.5 | Putative uncharacterized phospholipase D endonuclease of 487 aas |
Bacteria | Myxococcota | UP of Myxococcus fulvus |
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1.C.39.8.1 | MACPF-Hemopexin protein. The MACPF domain forms pores in the membrane while the hemopexin domain fuctions as a heme scavenging domain, protecting the cell against heme toxicity (Mehta and Reddy 2015). |
Bacteria | Myxococcota | Hemopexin of Plesiocystis pacifica (A6G7F3) |
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1.C.39.8.2 | The MACPF protein homologue with hemopexin-like C-terminal repeats |
Bacteria | Pseudomonadota | MACPF protein of Beggiotoa sp. PS (A7BVI9) |
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1.C.39.8.3 | Photopexin a/b-like protein of 347 aas. |
Bacteria | Pseudomonadota | Photopexin of Photorhabdus temperat |
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1.C.39.9.1 | MACPF homologue |
Eukaryota | Fungi, Basidiomycota | MACPF homologue of Postia placenta (B8PKX3) |
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1.C.39.9.2 | Uncharacterized MACPF protein of 446 aas. The MACPF domain includes residues 120 - 320. |
Eukaryota | Fungi, Ascomycota | UP of Emericella nidulans (Aspergillus nidulans) |
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1.C.39.9.3 | Uncharacterized MACPF protein of 483 aas |
Eukaryota | Fungi, Ascomycota | UP of Fusarium oxysporum f. sp. vasinfectum |
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1.C.39.9.4 | Uncharacterized MACPF protein of 420 aas |
Eukaryota | Fungi, Ascomycota | UP of Trichophyton verrucosum |
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1.C.39.9.5 | Uncharacterized protein of 461 aas |
Eukaryota | Fungi, Basidiomycota | UP of Ceriporiopsis subvermispora (White-rot fungus) |
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1.C.4.1.1 | Aerolysin (β-hemolysin; cytolytic enterotoxin) precursor (Parker et al., 1994). Upon transition from the prepore to pore, the aerolysin heptamer shows a unique concerted swirling movement, accompanied by a vertical collapse of the complex, ultimately leading to the insertion of a transmembrane beta-barrel (Degiacomi et al. 2013). Multiple conformational states lead to rotation of the core lysin to unleash the membrane spanning regions (Whisstock and Dunstone 2013). Monomer activation, dependent on proteolysis, is the rate-limiting step for pore formation (Bischofberger et al. 2016). Cryo-electron microscopy structures of three conformational intermediates and the final aerolysin pore provide insight into the conformational changes that allow pore formation. The structures reveal a protein fold consisting of two concentric beta-barrels, tightly kept together by hydrophobic interactions. This fold suggests a basis for the prion-like ultrastability of aerolysin pore and its stoichiometry (Iacovache et al. 2016). Amentoflavone acts against Aeromonas hydrophila infection by blocking the activity of aerolysin (Dong et al. 2025). |
Bacteria | Pseudomonadota | Aerolysin precursor of Aeromonas hydrophila |
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1.C.4.1.2 | Aerolysin family beta-barrel pore-forming toxin of 443 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | Toxin of Vibrio coralliilyticus |
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1.C.4.2.1 | α-Toxin forms large ion permeable (slightly anion-selective) pores with no lipid specificity. It induces rapid cell necrosis in many cell types (Knapp et al., 2009). The structure of the membrane-spanning domain has been solved (Melton et al. 2004). |
Bacteria | Bacillota | α-toxin of Clostridium septicum (BAC54147) |
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1.C.4.2.2 | A β-pore-forming cytolysin, Biomphalysin of 572 aas. It is involved in Biomphalaria glabrata immune defense against Schistosoma mansoni (Galinier et al. 2013). Its binding properties have been studied (Wu et al. 2017). |
Eukaryota | Metazoa, Mollusca | Biomphalysin of Biomphalaria glabrata (Bloodfluke planorb) (Freshwater snail) |
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1.C.4.3.1 | Enterolobin | Eukaryota | Viridiplantae, Streptophyta | Enterolobin of Enterolobium contortisiliquum (A57982) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.4.4.1 | Hydralysin (Sher et al., 2005; Zhang et al., 2003). Hydrolysins comprise a family of pore-forming proteins that are secreted into the gastrovascular cavity during feeding, probably helping in disintegration of the prey (Sher and Zlotkin 2009). Induces an immediate fast muscle contraction followed by flaccid paralysis when injected into blowfly larvae. The paralytic effect is lower in mice and fish. Has strong cytolytic activity against insect Sf9 cells and human HeLa cells. Binds to erythrocyte membranes and has weak hemolytic activity by mediating oligomerization and pore formation (Zhang et al. 2003; Sher et al. 2008). |
Eukaryota | Metazoa, Cnidaria | Hydralysin of Hydra viridis (Q86LR2) |
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1.C.4.4.2 | Spherulin 2A |
Eukaryota | Evosea | Spherulin 2A of Physarum polycephalum (P09352) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.4.4.3 | Hemolytic lectin LSLc exhibits hemolytic and hemagglutinating activities. The structure at 2.6 Å resolution has been determined (Mancheño et al., 2005). The protein is hexameric. The monomer (35kDa) consists of two distinct modules: an N-terminal lectin module (a β-trefoil scaffold) and a pore-forming module (composed of domains 2 and 4) which resemble the β-pore-forming domains of aerolysin and ε-toxin (Mancheño et al., 2005). |
Eukaryota | Fungi, Basidiomycota | LSLc of Laetiporus sulphureus (BAC78490) |
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1.C.4.4.4 | Parasporin-2 β-toxin (crystal structures are known) (Akiba et al., 2009; Akiba and Okumura 2016). |
Bacteria | Bacillota | Paraspora-2 of Bacillus thuringiensis (Q7WZI1) |
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1.C.4.4.5 | Mosquitocidal toxin, Mpp46Ab, natural product of Bacillus thuringensis (Uniprot Q6AW28) also called parasporin-2Ab andCry46Ab, and synthetic construct of 304 aas; 84% identical to 1.C.4.4.4. Cry46Ab (Mpp46Ab) from Bacillus thuringiensis TK-E6 is a mosquitocidal toxin with an aerolysin-type architecture (Hayakawa et al. 2020). Cry46Ab mutants were constructed by targeting the putative transmembrane beta-hairpin region, showing that charged residues within the beta-hairpin control the flux of ions through channel pores and that channel-pore cation selectivity is correlated with insecticidal activity (Hayakawa et al. 2020). Two mutants, K155E and K155I, exhibited toxicity significantly higher than that of the wild-type toxin, and the cation selectivity was also increased (Miyazaki et al. 2023). The charge of residue 155 may not directly affect the cation selectivity of Mpp46Ab channel pores. Replacement of K(155) with glutamic acid or isoleucine may induce a similar conformational change in the region associated with the ion selectivity of the Mpp46Ab channel pores. Mutagenesis targeting the transmembrane beta-hairpin seems to be an effective strategy for enhancing the ion permeability of the channel pores and the resulting mosquito- larvicidal activity of Mpp46Ab (Miyazaki et al. 2023). |
Cry4Ab Toxin, synthetic construct |
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1.C.4.5.1 | The pore forming toxin-like protein, Hfr-2 | Eukaryota | Viridiplantae, Streptophyta | Hfr-2 of Triticum aestivum (bread wheat) (AAW48295) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.4.5.2 | Fhb1 protein (PFT gene product) of 478 aas with two agglutinin domains followed by a DON (ETX/MTX2) domain that has the toxin activity (Rawat et al. 2016). Counteracts Fusarium head blight (FHB), caused by Fusarium graminearum, a devastating disease of wheat and barley. The fungicidal mechanism of glabridin, an isoflavane, a type of isoflavonoid, against Fusarium graminearum, showed that it acts on ergosterol synthesis-related proteins to destroy the integrity of the cell membrane, resulting in abnormal transmembrane transport and an increased membrane potential (Yang et al. 2021). |
Eukaryota | Viridiplantae, Streptophyta | Fhb1 of Triticum aestivum |
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1.C.4.5.3 | Amaranthin agglutinin of 304 aas and 0 TMSs. The x-ray structure at 2.2 Å resolution of the homodimeric protein is available (1JLX) (Transue et al. 1997) Sequences containing amaranthin domains are widely distributed in plants (Dang et al. 2017). |
Eukaryota | Viridiplantae, Streptophyta | Amaranthin agglutinin of Amaranthus caudatus (Love-lies-bleeding) (Inca-wheat) |
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1.C.4.6.1 | Natterin-3 precursor (venom gland protein) of 364 aas and 1 N-terminal TMS possibly plus 1 - 3 semi-hydrophobic TMSs. See family description for details about the Natterin family (Lima et al. 2021). |
Eukaryota | Metazoa, Chordata | Natterin-3 precursor of Thalassophryne nattereri (AAU11824) |
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1.C.4.6.2 | Natterin-like precursor of 315 aas from zebra fish, Dln1 or Aep1. Aep1 is an innate immune molecule that prevents zebrafish from bacterial infections. Thus, Aep1 may be a pro-inflammatory protein that triggers the antimicrobial immune responses (Chen et al. 2018). |
Eukaryota | Metazoa, Chordata | Natterin-like protein of Danio rerio |
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1.C.4.7.1 | The Bin binary toxin, BinAB. BinA is a toxic P42 protein (protein of 42 KDa) of 362 aas. The 3-d structure of BinB (448 aas; 1.75 Å resolution) is available; it has two domains, an N-terminal sugar-binding lectin-like domain, and a C-terminal aerolysin-like β-barrel pore-forming domain. Although it shows low sequence identity with other members of the family, it is a member of the Aerolysin Family (Srisucharitpanit et al. 2014). Protoxin subunits only form monomers, but in vitro activated toxin forms heterodimers. Maximal toxicity to mosquito larvae is achieved when the two subunits, BinA and BinB, are in a 1:1 molar ratio (Surya et al. 2016). An aromatic residue cluster in the C-terminal domain of BinB is critical for toxin insertion in membranes (Chooduang et al. 2018). |
Bacteria | Bacillota | BinAB of Lysinibacillus (Bacillus) sphaericus |
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1.C.4.7.2 | Cry35 of 385 aas. Shares a common strucure with ε-toxin, ETX (Moar et al. 2016). |
Bacteria | Bacillota | Cry35 of Bacillus thuringiensis |
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1.C.4.7.3 | Toxin of 380 aas and 1 N-terminal TMS. |
Bacteria | Bacillota | Toxin of Bacillus thuringiensis serovar aizawai str. Hu4-2 |
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1.C.4.8.1 | Cellular endolysosome-modulating aerolysin-like pore-forming protein, ALP1, of 156 aas (Wang et al. 2020). The protein shows sequence similarity in its N-terminal half with family 1.C.73 members and in its C-terminal half with family 1.C.4 members. βγ-CAT is a complex of an ALP (BmALP1) and a trefoil factor (BmTFF3) in the firebelly toad (Bombina maxima). It is a secreted endogenous pore-forming protein that modulates the biochemical properties of endolysosomes by inducing pore formation. BmALP3, a paralog of BmALP1 that lacks membrane pore-forming capacity, like BmALP1, has a conserved cysteine in its C-terminal regions. BmALP3 is readily oxidized to a disulfide bond-linked homodimer, and this homodimer can oxidize BmALP1 via disulfide bond exchange, resulting in the dissociation of βγ-CAT subunits and elimination of its biological activity. BmALP3 senses environmental oxygen tension in vivo, leading to modulation of βγ-CAT activity. This C-terminal cysteine site is well conserved in numerous vertebrate ALPs, suggesting that it is a regulatory ALP (BmALP3) that modulates the activity on the active ALP (BmALP1) in a redox-dependent manner (Wang et al. 2020). An aerolysin-like pore-forming protein complex targets viral envelope to inactivate herpes simplex virus type 1 (Liu et al. 2021). |
Eukaryota | Metazoa, Chordata | ALP of Bombina maxima (firebelly toad) |
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1.C.4.8.2 | Epidermal differentiation-specific protein, EDP, of 335 aas. |
Eukaryota | Metazoa, Chordata | EDP of Cynops pyrrhogaster (Japanese firebelly newt) |
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1.C.4.8.3 | Epidermal differentiation-specific protein-like, EDP-L, of 341 aas. |
Metazoa, Chordata | EDP-L of Erpetoichthys calabaricus (reedfish) |
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1.C.4.8.4 | Epidermal differentiation-specific protein, EDP, of 406 aas. |
Eukaryota | Metazoa, Chordata | EDP of Bagarius yarrelli (goonch) |
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1.C.40.1.1 | Bacterial permeability inducing protein, BPIP precursor, of 487 aas and 1 N-terminal TMS. |
Eukaryota | Metazoa, Chordata | BPIP precursor of Homo sapiens |
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1.C.40.1.2 | LBP (lipopolysaccharide binding protein) precursor | Eukaryota | Metazoa, Chordata | LBP precursor of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.40.1.3 | CETP (cholesterylester transfer protein) precursor | Eukaryota | Metazoa, Chordata | CETP precursor of Oryctolagus cuniculus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.40.1.4 | Phospholipid transfer protein (PLTP) precursor (lipid transfer protein II) | Eukaryota | Metazoa, Chordata | PLTP of Homo sapiens (493 aas; P55058) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.40.1.5 | NRF5 protein of 551 aas. Plays a role in the uptake of a range of
molecules including phosphatidylserine, lipids and xenobiotic compounds
from the intestine to surrounding tissues (Choy and Thomas 1999). Possesses lipid transfer
activity and mediates transport of lipids from theintestine to the reproductive
tract. Binds phosphatidylserine and plays a role in the efficient clearance of
cell corpses by mediating phosphatidylserine appearance on phagocytic
cells, thus promoting phagocytic engulfment of apoptotic cells (Zhang et al. 2012). Vital
for embryonic development. Gene deletion leads to extension of the life span (Brejning et al. 2014). |
Eukaryota | Metazoa, Nematoda | NRF5 of Caenorhabditis elegans |
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1.C.40.1.6 | BPI-like protein of 458 aas and 2 TMSs. |
Eukaryota | Metazoa, Chordata | BPI-like protein of Homo sapiens |
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1.C.40.1.7 | Bactericidal/permeability-increasing protein, BPI of 472 aas and 2 TMSs.
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Eukaryota | Metazoa, Chordata | BPI of Larimichthys crocea (Large yellow croaker) (Pseudosciaena crocea) |
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1.C.40.1.8 | Cholesteryl ester transfer protein, CETP of 493 aas and 1 TMS. Involved
in the transfer of neutral lipids, including cholesteryl esters and
triglycerides, among lipoprotein particles. Allows the net movement of
cholesteryl esters from high density lipoproteins/HDL to
triglyceride-rich very low density lipoproteins/VLDL, and the equimolar
transport of triglyceride from VLDL to HDL (Drayna et al. 1987; Morton and Izem 2014).
Regulates reverse cholesterol transport, by which excess
cholesterol is removed from peripheral tissues and returned to the liver
for elimination (Qiu et al. 2007). |
Eukaryota | Metazoa, Chordata | CETP of Homo sapiens |
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1.C.40.2.1 | Takeout-like protein-1, To1, of 240 aas and 1 N-terminal TMS. Takeout proteins are insect juvenile hormone-binding proteins and arthropod allergens, which transport lipid hormones to target tissues during insect development (Alva and Lupas 2016). |
Eukaryota | Metazoa, Arthropoda | To1 of Epiphyas postvittana (Light brown apple moth) |
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1.C.40.2.2 | Takeout-like protein, To3 of 261 aas and 1 N-terminal TMS |
Eukaryota | Metazoa, Arthropoda | To3 of Danaus plexippus (Monarch butterfly) |
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1.C.41.1.1 | The tripartite haemolysin BL, consisting of HblA, HblC and HblD (Sastalla et al. 2013). These proteins are secreted via the general secretory pathway (Fagerlund et al. 2010). The 3D structure is known (PDB# 2NRJ; Gupta et al. 2023 |
Bacteria | Bacillota | HBL of Bacillus cereus |
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1.C.41.1.2 | Pore-forming haemolysin YhlA of 331 aas (Chen et al. 1996). |
Bacteria | Pseudomonadota | YhlA of Edwardsiella tarda |
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1.C.41.1.3 | The non-hemolytic pore-forming cyto-enterotoxin, Nhe (Fagerlund et al., 2008; Sastalla et al. 2013), a three-partite toxin. Pore formation and subsequent lysis of target cells caused by Nhe is an orchestrated process comprising three steps: (i) formation of NheB/C oligomers in solution, (ii) attachment of the oligomers to the cell membrane, (iii) binding of NheA to the oligomers (Fox et al. 2020). The benefit of these complexes is more stable cell binding as well as stronger and earlier cytotoxic effects. High molecular mass hetero-oligomers (~620 kDa), probably consist of one NheC and up to 15 NheB. NheBC induces membrane permeability. Formation of stable transmembrane channels with a conductance of about 870 pS and a diameter of about 2 nm due to the application of NheBC could be demonstrated in lipid bilayer experiments (Zhu et al. 2015). Thus, the NheBC complex increases the membrane permeability prior to the emergence of full pores containing also NheA. NHE can induce apoptosis (Liu et al. 2016) and activates the NLRP3 inflammasome (Fox et al. 2020). Bacillus cereus extracellular vesicles act as shuttles for biologically active multicomponent enterotoxins (Buchacher et al. 2023).
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Bacteria | Bacillota | Nhe of Baccilus cereus |
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1.C.41.1.4 | MakABE tricomponent cytotoxin. Tetrameric MakA cytotoxin of 369 aas and 2 or 3 TMSs in a 1 (moderately hydrophobic, N-terminal) + 2 TMS (central, very hydrophobic) arrangement. The protein-lipid interactions at low pH induce oligomerization of the MakA cytotoxin (Nadeem et al. 2022). The alpha-pore-forming toxins (α-PFTs) from pathogenic bacteria damage host cell membranes by pore formation. Nadeem et al. 2022 demonstrated the mechanism of MakA/B/E tripartite toxin, MakA is involved in membrane pore formation similar to other α-PFTs. In contrast, MakA in isolation forms tube-like structures in acidic endosomal compartments of epithelial cells in vitro. Nadeem et al. 2022 unraveled the dynamics of tubular growth, which occurs in a pH-, lipid-, and concentration-dependent manner. Within acidified organelle lumens or when incubated with cells in acidic media, MakA forms oligomers and remodels membranes into high-curvature tubes leading to loss of membrane integrity. A 3.7 Å cryo-EM structure of MakA filaments (7P3RA-D) revealed a unique protein-lipid superstructure. MakA forms a pinecone-like spiral with a central cavity and a thin annular lipid bilayer embedded between the MakA transmembrane helices in its active alpha-PFT conformation. MakB of 355 aas and possibly 2 central TMSs is a motility-associated killer factor (6W1W_A,B; 6TAO_A,B). MakA and MakB appear to be distantly related to each other (~20% identical over most of their lengths). MakE was not found in the NCBI database. V. cholerae MakA is a cholesterol-binding pore-forming toxin that induces non-canonical autophagy (Jia et al. 2022). |
Bacteria | Pseudomonadota | MakABE of Vibrio cholerae |
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1.C.41.1.5 | Toxin homolog of 355 aas and 2 TMSs. |
Bacteria | Bacteroidota | Toxin of Chryseobacterium viscerum |
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1.C.41.2.1 | Nematicidal pesticide pore-forming crystal protein α-toxin, Cry6Aa (Cry6A; CryVIa) of 475 aas. It is structurally similar to HlyE (TC# 1.C.10.1.1) (Dementiev et al. 2016). The X-ray struction of residues 1 - 396 at 1.9 Å resolution shows a structure similar to to those of Cly toxins (Huang et al. 2016). |
Bacteria | Bacillota | Cry6Aa of Bacillus thuringiensis |
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1.C.41.2.10 | Binary cytotoxin component of 321 aas. |
Bacteria | Pseudomonadota | Binary cytotoxin component of Pseudomonas syringae |
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1.C.41.2.2 | Uncharacterized toxin of 407 aas, |
Bacteria | Proteobacteria | Toxin of Pseudoalteromonas piscicida |
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1.C.41.2.3 | Uncharacterized toxin of 383 aas. |
Bacteria | Bacillota | Toxin of Clostridium kluyveri |
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1.C.41.2.4 | Uncharacterized toxin of 389 aas |
Eukaryota | Fungi, Basidiomycota | Toxin of Schizophyllum commune |
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1.C.41.2.5 | Uncharacterized toxin of 420 aas |
Fungi, Ascomycota | Toxin of Hypocrea virens (Gliocladium virens) (Trichoderma virens) |
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1.C.41.2.6 | Putative toxin of 415 aas and 1 TMS |
Bacteria | Pseudomonadota | Toxin of Pseudomonas cichorii |
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1.C.41.2.7 | The two component pore-forming toxin (PFT), YaxA-YaxB, where YaxA is 410 aas with 1 central TMS, and YaxB is 344 aas with no TMS. X-ray structures are available (Bräuning et al. 2018). While a yaxAB mutant (ΔyaxAB) is capable of colonizing mice at the same level as the wild type, the mutation slightly delays the course of infection and results in differing pathology in the spleen. Wagner et al. 2013 found that yaxAB encode a cytotoxin capable of lysing mammalian cells, that both YaxA and YaxB are required for cytotoxic activity, and that the two proteins associate. YaxAB-mediated cell death occurs via osmotic lysis through the formation of distinct membrane pores. In silico tertiary structural analysis identified predicted structural homology between YaxA and proteins in pore-forming toxin complexes from Bacillus cereus (HBL-B) and Escherichia coli (HlyE). Thus, it appears that YaxAB function as virulence factors by inducing cell lysis through the formation of pores in the host cell membrane (Wagner et al. 2013). YaxAB represents a family of binary α-PFTs with orthologues in human, insect, and plant pathogens. Bräuning et al. 2018 presented crystal structures of YaxA and YaxB, together with a cryo-electron microscopy map of the YaxAB complex. Their structures revealed a pore predominantly composed of decamers of YaxA-YaxB heterodimers. Both subunits bear membrane-active moieties, but only YaxA is capable of binding to membranes by itself. YaxB can subsequently be recruited to membrane-associated YaxA and induced to present its lytic transmembrane helices. Pore formation can progress by further oligomerization of YaxA-YaxB dimers (Bräuning et al. 2018). The 3D structure is known (PDB# 6GY6 and 6EL1; Gupta et al. 2023). YaxA has a sequence identity of 22% with YaxBm and both proteins have α-helical folds comprising a two-helix coiled-coil stalk and five-helix bundle head domain that is similar to that of ClyA family (Bräuning et al. 2018). |
Bacteria | Pseudomonadota | YaxAB of Yersinia enterocolitica |
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1.C.41.2.8 | Two component cytotoxin consisting of XaxA of 408 aas and XaxB of 350 aas. Xenorhabdus nematophila, a member of the Enterobacteriaceae, kills many species of insects by strongly depressing the immune system and colonizing the entire body. The peptide cytotoxin, XaxAB, has been purified from X. nematophila broth, and the cytolytic effect on insect immunocytes and the hemolytic effect on mammalian red blood cells have been described (Vigneux et al. 2007). This toxin, Xenorhabdus alpha-xenorhabdolysin (Xax), triggers apoptosis in both insect and mammalian cells. Vigneux et al. 2007 also cloned and sequenced xaxAB, and showed that hemolytic activity was observed only if the two proteins were added in the appropriate order. The membrane inserted complex forms a 1-1.3 MDa large pore complexes to perforate the host cell membrane. Schubert et al. 2018 reported the cryo-EM structure of the XaxAB pore complex and the crystal structures of the soluble monomers of XaxA and XaxB. The structures reveal that XaxA and XaxB are built similarly and appear as heterodimers in the 12-15 subunit containing pore, classifying XaxAB as bi-component α-PFT. Major conformational changes in XaxB, including the swinging out of an amphipathic helix, are responsible for membrane insertion. XaxA acts as an activator and stabilizer for XaxB that forms the actual transmembrane pore. A novel structural model for the mechanism of Xax intoxication was proposed (Schubert et al. 2018). Kopanja et al. 2018 determined the influence of an ostreolysin A/pleurotolysin B complex (OlyA/PlyB) on the morphology of murine neuronal NG108-15 cells. The 3D structure at 4 Å resolution has been solved (PDB# 6GY6; Gupta et al. 2023). |
Bacteria | Pseudomonadota | XaxAB of Xenorhabdus nematophila |
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1.C.41.3.1 | Putative toxin of 396 aas and 1 or 2 central and closely packed TMSs. |
Bacteria | Bacillota | Putative toxin of Lachnospiraceae bacterium (gut metagenome) |
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1.C.41.3.2 | Putative toxin of 405 aas and 2 central, closely spaced TMSs. |
Bacteria | Bacteroidota | Putative toxin of Phocaeicola vulgatus |
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1.C.41.3.3 | Putative toxin of 372 aas and 2 TMSs. |
Bacteria | Bacteroidota | Putative toxin of Portibacter sp. |
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1.C.41.3.4 | Putative toxin of 400 aas and 2 central TMSs. |
Bacteria | Spirochaetota | Putative toxin of Treponema sp. |
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1.C.42.1.1 | Bacillus anthracis protective antigen (PA). Many cationic compounds inhibit in nM - mM concentration ranges (Yamini et al. 2016). Both symmetry and size of cyclodextrin inhibitors and the toxin pore are important for effective inhibition (Yannakopoulou et al., 2011). A cryo electron microscopic structure of the anthrax protective antigen translocon and the N-terminal domain of anthrax lethal factor (aLF) inserted into a nanodisc model lipid bilayer has been solved revealing a cap, a narrow stalk and a transmembrane channel (Gogol et al. 2013). Poly(amindo)amine (PAMAM) dentrimers block activity (Förstner et al. 2014). The 3-d structure of PA, showing the channel and the φ-clamp, and providing information about the multi-step mechanism by which low pH is sensed and the membrane-spanning channel is formed has been published (Jiang et al. 2015). The export of the lethal factor and edema factor from the endosome into the host cytosol is dependent on the proton motive force (pmf) (Krantz et al. 2006; Colby and Krantz 2015). Translocation of anthrax toxin's lethal factor is initiated by entry of its N terminus into the protective antigen channel (Zhang et al. 2004). The endopeptidase activity of anthrax lethal factor (aLF) prevents the destruction of B.anthracis spores intracellularly by host macrophages, meanwhile disabling the signaling pathways extracellularly that leads to host lethality. This activity has been used for nanopore detection (Li et al. 2022). |
Bacteria | Bacillota | PA of Bacillus anthracis |
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1.C.42.1.2 | C2II channel-forming toxin component. Channel-formation is inhibited by azolopyridinium salts (Bronnhuber et al. 2014). |
Bacteria | Bacillota | C2II of Clostridium botulinum |
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1.C.42.1.3 | Iota toxin component Ib | Bacteria | Bacillota | Iotatoxin Ib of Clostridium perfringens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.42.1.4 | The Vegetative insecticidal protein 1A (Vip1) |
Bacteria | Bacillota | Vip1 of Bacillus thuringiensis |
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1.C.42.1.5 | The vegetative insecticidal protein 1A (Vip1A) (96aas) |
Bacteria | Bacillota | Vip1A of Bacillus thuringiensis |
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1.C.42.1.7 | Clostridium spirofore toxin component Sa (Sas) of 459 aas. |
Bacteria | Bacillota | Sas of Clostridium spirofore |
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1.C.43.1.1 | Lysenin of 297 aas and 1 N-terminal TMS, a sphingomyelin-specific pore-forming toxin from earthworms; causes contraction of rat vascular smooth muscle. (Sekizawa et al., 1997; Shogomori and Kobayashi, 2007). Trp-20 is required for cation selective channel assembly (Kwiatkowska et al., 2007). Adenosine phosphates control the activity of lysenin channels inserted into planar lipid membranes with respect to their macroscopic conductance and voltage-induced gating. Addition of ATP, ADP, or AMP decreased the macroscopic conductance of lysenin channels in a concentration-dependent manner, with ATP being the most potent inhibitor and AMP the least (Bryant et al. 2016). lysenin can specifically interact with sphingomyelin, and may confer innate immunity against parasites by attacking the membranes of the parasites to form pores (Pang et al. 2019). Upon binding to sphingomyelin (SM)-containing membranes, lysenin undergoes a series of structural changes promoting the conversion of water-soluble monomers into oligomers, leading to its insertion into the membrane and the 2-step formation of a lytic beta-barrel pore (Kulma et al. 2019). Structural stabilization of the lysenin prepore starts at the site of initial interaction with the lipid membrane and is transmitted to the twisted beta-sheet of the N-terminal domain (Kulma et al. 2019). 3-d structures are available (PDB# 5EC5; 3ZXD; 3ZX7). The beta pore-forming toxins (beta-PFTs) are cytotoxic proteins produced as soluble monomers, which cluster and oligomerize at the membrane of the target host cells. Their initial oligomeric state, the prepore, is not cytotoxic. The beta-PFTs undergo a large structural transition to a second oligomeric state, the pore, which pierces the membrane of the host cell and is cytotoxic. Munguira et al. 2019 described the mechanism by which the rates of formation of the transmembrane pores correlate with the local levels of crowding for the beta-PFT lysenin. Lysenin forms stable pre-pore and pore nonameric rings (Jiao et al. 2021). |
Eukaryota | Metazoa, Annelida | Lysenin of Eisenia foetida |
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1.C.43.1.2 | Lysenin 2 or Fetidin of 300 aas and 1 N-terminal TMS. 90% identical to Lysenin 1. |
Eukaryota | Metazoa, Annelida | Lysenin 2 of Eisenia fetida |
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1.C.43.1.3 | Lysenin related protein 3 of 300 aas and 1 N-terminal TMS. |
Eukaryota | Metazoa, Annelida | Lysenin 3 of Eisenia fetida |
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1.C.43.1.4 | Uncharacterized homologue of Lysenin of 288 aas and 1 N-terminal TMS. |
Eukaryota | Metazoa, Platyhelminthes | UP of Macrostomum lignano |
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1.C.43.1.5 | Uncharacterized protein of 305 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of Sinobacterium caligoides |
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1.C.44.1.1 | β-purothionin (A-I) precursor | Eukaryota | Viridiplantae, Streptophyta | β-purothionin precursor of Triticum aestivum |
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1.C.44.1.2 | Viscotoxin B precursor | Eukaryota | Viridiplantae, Streptophyta | Viscotoxin B precursor of Viscum album | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.45.1.1 | Antifungal protein 1, RsAFP1 prercursor | Eukaryota | Viridiplantae, Streptophyta | RsAFP1 precursor of Raphanus sativus ( P69241) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.45.1.2 | Flower-specific g-thionin precursor | Eukaryota | Viridiplantae, Streptophyta | g-thionin of Nicotiana tabacum (P32026) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.45.1.3 |
g-2 purothionin, the antifungal lentil seed defensin, Lc-def (47aas plus of 27aa leader peptide) (Finkina et al., 2008) |
Eukaryota | Viridiplantae, Streptophyta | Precursor of Lc-def of Lens culinaris (B3F051)
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1.C.45.1.4 | The antifungal lentil seed defensin, Lc-def (47aas plus of 27aa leader peptide) (Finkina et al., 2008) |
Eukaryota | Viridiplantae, Streptophyta | Defensin Lc-def of Lens culinaris |
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1.C.45.1.5 | γ-thionin or defensin J1-2 of 74 aas |
Eukaryota | Viridiplantae, Streptophyta | Thionin of Capsicum annuum (bell pepper) |
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1.C.45.1.6 | Plant vacuolar defensin, Pdf1.1, of 80 aas. It plays an antifungal role, and is involved in abiotic stress tolerance as well as inhibition of root growth (Oomen et al. 2011). |
Eukaryota | Viridiplantae, Streptophyta | Pdf1.1 of Arabidopsis thaliana |
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1.C.45.1.7 | Knol1 domain-containing protein of 81 aas and 1 N-terminal TMS. |
Eukaryota | Viridiplantae, Streptophyta | Knot1 of Setaria italica (Foxtail millet) (Panicum italicum) |
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1.C.45.2.1 | Defensin-like protein 106 of 106 aas |
Eukaryota | Viridiplantae, Streptophyta | Defensin of Arabidopsis thaliana |
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1.C.45.2.2 | Defensin-like protein 107 of 81 aas |
Eukaryota | Viridiplantae, Streptophyta | Defensin of Arabidopsis thaliana |
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1.C.45.2.3 | Defensin-like protein of 74 aas |
Eukaryota | Viridiplantae, Streptophyta | Defensin of Ipomoea trifida (Morning glory) |
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1.C.45.3.1 | Nasonin-1 of 56 aas and 1 N-terminal TMS; has antibacterial activity. The 3-D structure is known (2KOZ). |
Eukaryota | Metazoa, Arthropoda | Nasonin-1 of Nasonia vitripennis (Parasitic wasp) |
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1.C.45.3.2 | Uncharacterized protein of 73 aas and 1 N-terminal TMS. |
Eukaryota | Viridiplantae, Streptophyta | UP of Arabidopsis lyrata subsp. lyrata (Lyre-leaved rock-cress) |
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1.C.45.4.1 | Defensin-like protein 195 of 89 aas and 1 N-terminal TMS, It is a serine (trypsin-like) protease inhibitor, and its NMR sturcture is available (Zhao et al. 2002). |
Eukaryota | Viridiplantae, Streptophyta | UP of Arabidopsis thaliana |
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1.C.45.4.2 | Defensin-like protein 195, brazzein, of 54 aas; It is a taste-modifying protein, sweet-tasting. It is 2000 sweeter than sucrose on a molar basis (Caldwell et al. 1998). It has a pH-specific antimicrobial activity against bacteria (B. subtilis, E. coli and S. aureus) and the fungus C. albicans (Yount and Yeaman 2004). |
Eukaryota | Viridiplantae, Streptophyta | Brazzein of Pentadiplandra brazzeana |
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1.C.45.5.1 | Big defensin-1, BD1, of 124 aas and 2 TMSs, an antimicrobial peptide (González et al. 2017). |
Eukaryota | Metazoa, Mollusca | BD1 of Argopecten purpuratus (Chilean northern scallop) |
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1.C.45.5.2 | Big defensin, BD, of 117 aas and 2 TMSs |
Eukaryota | Metazoa, Arthropoda | BD of Tachypleus tridentatus (Japanese horseshoe crab) |
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1.C.45.5.3 | Big defensin isoform XI of 169 aas and 2 TMSs. |
Eukaryota | Metazoa, Mollusca | BD of Crassostrea gigas |
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1.C.45.5.4 | Big defensin of 111 aas and 2 TMSs |
Eukaryota | Metazoa, Mollusca | BD of Anadara broughtonii (Blood clam) (Scapharca broughtonii) |
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1.C.45.5.5 | Big defensin of 162 aas and 2 TMSs |
Eukaryota | Metazoa, Brachiopoda | BD of Lingula unguis |
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1.C.46.1.1 | CNP precursor protein (CNP-22 and CNP-29) | Eukaryota | Metazoa, Chordata | CNP precursor protein of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.46.1.2 | Full snake Bradykinin-potentiating and C-type natriuretic peptides (265aas) | Eukaryota | Metazoa, Chordata | Bradykinin-potentiating peptide of Bothrops jararaca (Q9PW56) |
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1.C.46.2.1 | Cardiac Peptide (145aas) | Eukaryota | Metazoa, Chordata | Cardiac peptide of Salmo salar (Q78AW6) |
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1.C.46.2.2 | Full ventricular natriuretic peptide precursor | Eukaryota | Metazoa, Chordata | Full ventricular natriuretic peptide of Acipenser transmontanus (P83962) |
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1.C.46.2.3 | Sothern et al. 1995 Natriuretic peptide A of 151 aas, NPPA. The atrial NPPA is a hormone that plays a key role in mediating cardio-renal homeostasis, and is involved in vascular remodeling and regulating energy metabolism (Sothern et al. 1995). It acts by specifically binding and stimulating NPR1 to produce cGMP, which in turn activates effector proteins, such as PRKG1, that drive various biological responses (Rubattu et al. 2014).It regulates vasodilation, natriuresis, diuresis and aldosterone synthesis and is therefore essential for regulating blood pressure, controlling the extracellular fluid volume and maintaining the fluid-electrolyte balance (Sothern et al. 1995). |
Eukaryota | Metazoa, Chordata | NPPA of Homo sapiens |
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1.C.47.1.1 | Defensin precursor | Eukaryota | Metazoa, Arthropoda | Defensin precursor of Drosophila melanogaster | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.47.1.10 | Micasin of 81 aas and 1 N-terminal TMS. The active peptide has 38 aas, and the structure is known (2LR5). |
Eukaryota | Fungi, Ascomycota | Micasin of Arthroderma otae (Microsporum canis) |
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1.C.47.1.11 | INVERT_DEFENSIN domain-containing protein of 1309 aas. Function unknown. |
Eukaryota | Metazoa, Chordata | INVERT_DEFENSIN of Branchiostoma floridae (Florida lancelet) (Amphioxus) |
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1.C.47.1.2 | Phormicin precursor | Eukaryota | Metazoa, Arthropoda | Phormicin precursor of Protophormia terraenovae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.47.1.3 | Sapecin precursor | Eukaryota | Metazoa, Arthropoda | Sapecin precursor of Sarcophaga peregrina | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.47.1.4 | Tenecin precursor | Eukaryota | Metazoa, Arthropoda | Tenecin precursor of Tenebrio molitor | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.47.1.5 | Soft tick Defensin A (73aas; 1 TMS) |
Eukaryota | Metazoa, Arthropoda | Defensin A of Ornithodoros moubata (Q9BLJ3) |
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1.C.47.1.6 |
Defensin-A (37-aas) (Charlet et al., 1996; Zhu, 2008). |
Eukaryota | Metazoa, Mollusca | Defensin-A of Mytilis edulis (P81610) |
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1.C.47.1.7 | Gigasin-2 (95 aas) (Zhu, 2008). |
Eukaryota | Metazoa, Mollusca | Gigasin-2 of Crassostrea gigas (Q6H9L9) |
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1.C.47.1.8 | Atesin-3 (71aas) (Zhu, 2008). |
Eukaryota | Fungi, Ascomycota | Atesin-3 of Aspergillus terreus (B1NJ41). |
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1.C.47.1.9 | Scapularisin preproprotein of 101 aas and 1 TMS, IscW. |
Eukaryota | Metazoa, Arthropoda | IscW of Ixodes scapularis (Black-legged tick) (Deer tick) |
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1.C.47.2.1 | L-Plectasin (40aas, 1 TMS); precursor (90aas, 2 TMSs). 3-d structure known (3E7R_L; 1ZFUA) (Mygind et al., 2005; Zhu, 2008) (43% identical to 1.C.47.1.1). |
Eukaryota | Fungi, Ascomycota | L-Plectasin precursor of Pseudoplectania nigrella (Q53I06) |
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1.C.47.3.1 | Panscorpine (Scorpine; scorpin) of 94 aas |
Eukaryota | Metazoa, Arthropoda | Scorpine of Pandinus imperator |
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1.C.47.3.2 | Potassium channel toxin BmTXK-beta; BmKLK; BmTX K-beta; BmTXKbeta of 90 aas |
Eukaryota | Metazoa, Arthropoda | BmTXK of Mesobuthus martensii |
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1.C.47.3.3 | Beta-KTx-like peptide of 79 aas |
Eukaryota | Metazoa, Arthropoda | Beta-KTx-like peptide of Pandinus cavimanus (Tanzanian red clawed scorpion) |
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1.C.47.3.4 | Male-specific defensin of 79 aas |
Eukaryota | Metazoa, Arthropoda | Defensin of Haemaphysalis longicornis |
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1.C.47.4.1 | Nodule-specific protein of 90 aas and 1 N-terminal TMS (Shafee et al. 2017). |
Eukaryota | Viridiplantae, Streptophyta | Nodule-specific protein of Astragalus sinicus (Chinese milk vetch) |
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1.C.47.5.1 | Defensin-like cysteine-rich peptide of 83 aas and 1 N-terminal TM |
Eukaryota | Viridiplantae, Streptophyta | Peptide of Torenia fournieri |
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1.C.48.1.1 | Major prion protein precursor PrP (yielding peptide PrP[106-126]) | Eukaryota | Metazoa, Chordata | PrP of Ovis aries | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.48.1.2 | Major prion protein, PrP or PRNP, of 253 aas and 3 possible TMSs, N-terminal, middle, and C-terminal. Its primary physiological function is
unclear. It has cytoprotective activity against internal or environmental
stresses and may play a role in neuronal development and synaptic
plasticity. May be required for neuronal myelin sheath maintenance, but may
play a role in iron uptake and iron homeostasis. Soluble oligomers are
toxic to cultured neuroblastoma cells and induce apoptosis (Mani et al. 2003; Taylor et al. 2009; Wu et al. 2010). The mouse orthologue (P04925), particularly the A116V mutant, forms ion channels in lipid membranes (Sabareesan et al. 2016). It's cell biology has been reviewed (Sarnataro et al. 2017). |
Metazoa, Chordata | PrP of Homo sapiens |
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1.C.48.1.3 | Prion protein of 497 aas and 3 TMSs |
Metazoa, Chordata | Prion protein of Paralichthys olivaceus (Bastard halibut) (Hippoglossus olivaceus) |
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1.C.48.1.4 | Prion-like protein, Doppel (PRND) of 176 aas and 2 TMSs |
Metazoa, Chordata | Doppel of Homo sapiens |
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1.C.48.1.5 | Shadow of prion protein, SPRN or SHO, of 151 aas and 3 TMSs |
Metazoa, Chordata | SPRN of Homo sapiens |
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1.C.49.1.1 | Islet amyloid percursor, amylin | Eukaryota | Metazoa, Chordata | Amylin of Canis familiaris | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.49.1.2 | Calcitonin gene regulatory peptide I precursor, CGRPI of 128 aas and 1 - 3 TMSs. CGRP induces vasodilation, dilating a variety of vessels including the coronary, cerebral and systemic vasculature. Its abundance in the CNS points toward a neurotransmitter or neuromodulator role (Kitamura et al. 1992). It also elevates platelet cAMP and elevates calcium while polarizing the membrane potential by both cAMP-independent and -dependent mechanisms (Burns et al. 2004).
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Eukaryota | Metazoa, Chordata | CGRPI of Homo sapiens |
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1.C.5.1.1 | ε-toxin (epsilon toxin; ETx) type B precursor, EtxB, of 328 aas. Forms heptameric pores (Miyata et al. 2002). However, it has been reported to act on oligodendrocytes causing demyelination without forming pores (Wioland et al. 2015). The toxin acts on the brain, affecting vascular permeability, but also damaging neurons, astrocytes and oligodendrocytes (Freedman et al. 2016). The pore-forming regions are initially folded up on the surfaces of the soluble precursors. To create the transmembrane pores, these regions must extend and refold into membrane-inserted beta-barrels (Tilley and Saibil 2006). The crystal structure of epsilon-toxin revealed structural similarity to aerolysin from Aeromonas hydrophila.(Cole et al. 2004). Residues in the central position of each beta-strand of the amphipathic beta-hairpin loop that forms the transmembrane pore, control the size and ion selectivity of the channel (Knapp et al. 2020). The pre-pore morphology of ETX) has been provided (Ji et al. 2023). The ETX pore is formed in two stages: ETX monomers first attach to the membrane and form a pre-pore with no special conditions required, which then undergo a conformational change to form a transmembrane pore at temperatures above the critical point in the presence of receptors (Ji et al. 2023). Epsilon toxin stimulates calcium-activated chloride channels, generating extracellular vesicles in Xenopus oocytes (Cases et al. 2024). |
Bacteria | Bacillota | EtxB or ETX of Clostridium perfringens |
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1.C.5.1.2 | Rhodanese-related sulfurtransferase of 319 aas and 1 N-terminal TMS. |
Bacteria | Bacillota | Sulfur transferase of Paenibacillus popilliae |
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1.C.5.1.3 | Poly-gamma-glutamate biosynthesis protein of 295 aas and 0 TMSs. |
Bacteria | Bacillota | PGG biosynthesis protein of Clostridium botulinum |
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1.C.5.2.1 | Mosquitocidal toxin, Mtx3 | Bacteria | Bacillota | Mtx3 of Bacillus sphaericus (Q57028) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.5.2.2 | Mosquitocidal toxin, Mtx2 | Bacteria | Bacillota | Mtx2 of Bacillus sphaericus (Q45470) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.5.2.3 | Uncharacterized protein of 319 aas, Sip1A |
Bacteria | Bacillota | Sip1A of Lysinibacillus sphaericus |
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1.C.5.3.1 | Parasporal crystal protein C53 |
Bacteria | Bacillota | C53 of Bacillus thurengiensis (Q45728) |
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1.C.50.1.1 | Alzheimer''s disease (AD) amyloid β-protein (amino acids 1-42) (Abeta protein or AβP or Aβ42). Aβ pores may consist of tetrameric and hexameric beta-sheet subunits (Strodel et al. 2010). Residues 22 - 35 in the peptide binds cholesterol to form Ca2+-permeable pores (Di Scala et al. 2014). Cholesterol promotes the insertion of Abeta in the plasma membrane, induces alpha-helical structure formation, and forces the peptide to adopt a tilted topology that favours oligomerization. Bexarotene, an amphipathic drug for the treatment of neurodegenerative diseases, competes with cholesterol for binding to Abeta and prevents oligomeric channel formation (Di Scala et al. 2014). The beta-amyloid protein is involved in the activation of the nAChRalpha7 receptor (Hassan et al. 2019). Tryptophan enantiomers (d/l-Trp) introduced into artificial nanochannels regulate the chiral selective transport of Abeta proteins; the l-Trp channel shows selectivity for the transport of Abeta protein (Zhu et al. 2020). The prevalence, presentation, and progression of Alzheimer's disease (AD) differ between men and women, although β-amyloid (Aβ) deposition is a pathological hallmark of AD in both sexes. Aβ-induced activation of the neuronal glutamate receptor mGluR5 is linked to AD progression. However, mGluR5 exhibits distinct sex-dependent profiles (Abd-Elrahman et al. 2020). mGluR5 isolated from male mouse cortical and hippocampal tissues bound with high affinity to Aβ oligomers, whereas mGluR5 from female mice exhibited no such affinity. This sex-selective Aβ-mGluR5 interaction is not depend on estrogen, but rather Aβ interaction with cellular prion protein (PrPC), which was detected only in male mouse brain homogenates. The ternary complex between mGluR5, Aβ oligomers, and PrPC was essential to elicit mGluR5-dependent pathological suppression of autophagy in primary neuronal cultures. Pharmacological inhibition of mGluR5 reactivated autophagy, mitigated Aβ pathology, and reversed cognitive decline in male APPswe/PS1ΔE9 mice, but not in their female counterparts. Aβ oligomers also bound with high affinity to human mGluR5 isolated from postmortem donor male cortical brain tissue, but not that from female samples, suggesting that this mechanism may be relevant to patients. mGluR5 does not contribute to Aβ pathology in females, highlighting the complexity of mGluR5 pharmacology and Aβ signaling that supports the need for sex-specific stratification in clinical trials assessing AD therapeutics (Abd-Elrahman et al. 2020). Proteins associated with or anchored to the plasma membrane are associated with cerebrospinal fluid biomarkers of amyloid and tau pathology in AD (Remnestål et al. 2021). The architecture of the Alzheimer's A beta P ion channel pore has been determined (Arispe 2004). A transmembrane annular polymeric structure may be responsible for the ion channel properties of the membrane-bound A beta P (Arispe 2004). Arispe 2004 synthesized peptides that encompass the histidine dyad (H-H) hypothesized to line the pore and showed that peptides designed to most closely match the proposed pore are the most effective at blocking ion currents through the membrane-incorporated A beta P channel. Abeta) proteins can form ion pores in the cell membrane, and the structure of the transmembrane domain of Abeta ion channels is known. Substances that block or inhibit the formation of Abeta ion channels are known, and zinc ions are considered as potential inhibitors of AD (Kim et al. 2021). The spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease-related patterns (Jin et al. 2022). The folding/misfolding of membrane-permiable Amyloid beta (Abeta) peptides is likely associated with advancing stages of Alzheimer's disease (AD) by disrupting Ca2+ homeostasis (Ngo et al. 2023). The aggregation of four TMS Abeta(17-42) peptides suggested that the secondary structures of transmembrane Abeta peptides tends to have different propensities compared to those in solution. The residues favorably forming beta-structure were interleaved by residues rigidly adopting turn-structure. A combination of beta and turn regions likely forms a pore structure. Six morphologies of 4Abeta were found over the free energy landscape and clustering analyses. Among these, the morphologies include (1) Abeta binding onto the membrane surface and three transmembrane Abeta; (2) three helical and coil transmembrane Abeta; (3) four helical transmembrane Abeta; (4) three helical and one beta-hairpin transmembrane Abeta; (5) two helical and two beta-strand transmembrane Abeta; and (6) three beta-strand and one helical transmembrane Abeta (Ngo et al. 2023). |
Eukaryota | Metazoa, Chordata | AβP of Rattus norvegicus |
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1.C.50.1.2 | The Alzheimer’s disease amyloid precursor β-protein (Aβpeptide; precursor: App, γ-secretase) (42aas) (3-d structure is known from NMR spectroscopy (1Z0Q_A; Jang et al., 2007; Zheng et al., 2008)). This peptide is derived from the amyloid βA4 protein isoform f (NP_001129602)) which forms variable oligomeric toxic pores leading to cytosolic calcium elevation and Alzheimer's disease (Demuro et al., 2011). The monomer of Ass1-42 normally activates type-1 insulin-like growth factor receptors and enhances glucose uptake in neurons and peripheral cells by promoting the translocation of the Glut3 glucose transporter from the cytosol to the plasma membrane (Giuffrida et al. 2015). At nanomolar concentrations, APPsα is an allosteric activator of α7-nAcChR (see TC family 1.A.9), mediated by the C-terminal 16 aas (CTα16) (Korte 2019). The amyloid precursor protein is a conserved Wnt receptor (Liu et al. 2021). Disorders of protein misfolding, such as Alzheimer's and Parkinson's diseases, involve amyloidogenic peptides like amyloid-β, tau and α-synuclein, which form metastable toxic oligomeric species that interact with biological membranes and form ion-conducting nanopores (Vassallo 2025). |
Eukaryota | Metazoa, Chordata | Aβ-peptide from the amyloid βA4 protein isoform f of Homo sapiens (NP_001129602) |
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1.C.50.1.3 | Beta amyloid protein-like, isoform D of 888 aas |
Eukaryota | Metazoa, Arthropoda |
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1.C.50.1.4 | Amyloid protein 1 of 629 aas |
Eukaryota | Metazoa, Cnidaria | Amyloid protein 1 of Hydra vulgaris (Hydra) (Hydra attenuata) |
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1.C.51.1.1 | Pilosulin (Philosin I) (from MyrPI) | Eukaryota | Metazoa, Arthropoda | Philosin I of Myrmecia pilosula | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.52.1.1 | Dermaseptin B1 precursor |
Eukaryota | Metazoa, Chordata | Dermaseptin B1 of Phyllomedusa bicolor | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.52.1.10 | PBN1 precursor | Eukaryota | Metazoa, Chordata | PBN1 precursor of Phyllomedusa bicolor | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.52.1.11 | Preprofallaxidin-6 (green tree frog) (71% identical to 1.C.52.1.9). The NMR structure of the mature peptide (Fallaxidin 4.1a) reveals a helical structure in detergent solultions. Pore formation is established (Sherman et al. 2009). |
Eukaryota | Metazoa, Chordata | Fallaxidin of Litoria fallax (B5LUQ8) |
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1.C.52.1.12 | Phylloseptin-7 (orange legged leaf frog) (81% identical to 1.C.52.1.10). | Eukaryota | Metazoa, Chordata | Phylloseptin of Phyllomedusa hypochondrialis (P84572) |
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1.C.52.1.13 | Raniseptin-1 (55% identical to 1.C.52.1.1). | Eukaryota | Metazoa, Chordata | Raniseptin-1 of Hypsiboas raniceps (P86037) |
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1.C.52.1.14 | Kininogen-1 (71% identical to 1.C.52.1.10). | Eukaryota | Metazoa, Chordata | Kininogen-1 of Phyllomedusa sauvagei (Q800F1). |
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1.C.52.1.15 | Vespakinin-M precursor (also homologous to Melittin) | Eukaryota | Metazoa, Arthropoda | Vespakinin of Vespa magnifica (Q0PQX8) |
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1.C.52.1.16 | Brevienin-1E of 71 aas |
Eukaryota | Metazoa | Brevenin-iE of Pelophylex esulentus |
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1.C.52.1.17 | Ranakinin-N of 58 aas |
Eukaryota | Metazoa, Chordata | Ranakinin-N of Hylarana nigrovittata |
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1.C.52.1.18 | Prepromelittin amphibian defense peptide |
Eukaryota | Metazoa, Chordata | Prepromelittin of Rana andersonii (E3SZK1) |
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1.C.52.1.19 | Rufosusi-spotted torrent frog Amolopin-3a anti-microbial peptide |
Eukaryota | Metazoa, Chordata | Amolopin-3a of Amolops loloensis (A6XFB5) |
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1.C.52.1.2 | Brevinin 2EF precursor | Eukaryota | Metazoa | Brevinin-2EF of Rana esculenta | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.52.1.20 | Demaseptin-1 |
Eukaryota | Metazoa, Chordata | Dermaseptin-1 of Phyllomedusa hypochondrialis (P84596) |
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1.C.52.1.21 | Brevinin-2HS of 70 aas and 2 TMSs. |
Eukaryota | Metazoa, Chordata | Brevinin-2HS of Odorrana schmackeri (Schmacker's frog) (Rana schmackeri) |
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1.C.52.1.22 | Rhacophorin-2 of 72 aas and 2 TMSs. |
Eukaryota | Metazoa, Chordata | Rhacophori-2 of Rhacophorus feae (Thao whipping frog) |
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1.C.52.1.23 | Hainanensin-1 of 67 aas and 2 TMSs |
Eukaryota | Metazoa, Chordata | Hainanensin-1 of Odorrana hainanensis (Odor frog) (Rana hainanensis) |
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1.C.52.1.24 | Amurin-1 of 70 aas and 2 TMSs |
Eukaryota | Metazoa, Chordata | Amurin-1 of Rana amurensis (Korean brown frog) |
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1.C.52.1.25 | Viridimin-1 of 66 aas and 2 TM |
Eukaryota | Metazoa, Chordata | Viridimin-1 of Amolops viridimaculatus (Dahaoping sucker frog) |
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1.C.52.1.26 | Amolopin-1a of 70 aas |
Eukaryota | Metazoa, Chordata | Amolopin-1a of Amolops loloensis (rufous-spotted torrent frog) |
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1.C.52.1.27 | Andersonin of 72 aas |
Eukaryota | Metazoa, Chordata | Andersonin of Odorrana andersonii (golden crossband frog) |
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1.C.52.1.28 | Lividin-1 of 68 aas |
Eukaryota | Metazoa, Chordata | Lividin-1 of Odorrana livida (green cascade frog) |
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1.C.52.1.29 | Kunyuenin of 62 aas |
Eukaryota | Metazoa, Chordata | Kunyuenin of Rana kunyuensis |
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1.C.52.1.3 | Gaegurin-4 precursor | Eukaryota | Metazoa, Chordata | Gaegurin-4 of Rana rugosa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.52.1.30 | Japonicin-1Ja of 61 aas |
Eukaryota | Metazoa, Chordata | Japonicin-1Ja of Rana japonica (Japanese reddish frog) |
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1.C.52.1.31 | Limnonectin-1Fa of 62 aas |
Eukaryota | Metazoa, Chordata | Limnonectin-1Fa of Limnonectes fujianensis (Fujian large-headed frog) |
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1.C.52.1.32 | Jingdongin-1 of 63 aas |
Eukaryota | Metazoa, Chordata | Jingdongin-1 of Amolop jingdongensis (Chinese torrent frog) |
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1.C.52.1.33 | Frenatin-3 of 68 aas |
Eukaryota | Metazoa, Chordata | Frenatin-2 of Litoria infrafrenata (Giant tree frog) (White-lipped tree frog) |
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1.C.52.1.34 | Antimicrobial peptide odorranain B4 of 63 aas. A 15 aa disulfide bonded peptide, ORB-1 (LKGCWTKSIPPKPCF), too short to pass through a membrane, forms anion selective channels (Hu et al. 2015). |
Eukaryota | Metazoa, Chordata | odorranain B4 of Odorrana grahami (Yunnanfu frog) (Rana grahami) |
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1.C.52.1.35 | Pore-forming Ocellatin-PT1 of 66 aas (Gusmão et al. 2017). |
Eukaryota | Metazoa, Chordata | Ocellatin-PT1 of Leptodactylus pustulatus (Ceara white-lipped frog) |
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1.C.52.1.36 | Dybowskin-1ST antimicrobial peptide of 59 aas. It has an N-terminal TMS with a largely hydrophilic central region with an α-helical structure. It promotes wound healing and effectively inhibits the growth of Escherichia coli and Staphylococcus aureus (Liu et al. 2021).
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Eukaryota | Metazoa, Chordata | antimicrobial peptide of Rana dybowskii (Dybovsky's frog) (Korean brown frog) |
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1.C.52.1.37 | Dermaseptin S1, Drs1, of 79 aas and 1 or 2 TMSs with the first N-terminal TMS being more hydrophobic than the second C-terminal TMS. The central region is very hydrophilic. It is 90% identical to Dermaseptin B1 (TC# 1.C.52.1.1) at the sequence level. It shows antimicrobial activity with potent activity against Gram-positive and Gram-negative bacteria, fungi and protozoa (Mor et al. 1991, Mor and Nicolas 1994). It also stimulates the microbicidal activity of polymorphonuclear leukocytes (Ammar et al. 1998) and may act by disturbing membrane functions with its amphipathic structure (Mor and Nicolas 1994). |
Eukaryota | Metazoa, Chordata | Dermaseptin S1 of Phyllomedusa sauvagei (Sauvage's leaf frog)
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1.C.52.1.4 | Esculentin-1b precursor | Eukaryota | Metazoa | Esculentin-1b of Rana esculenta | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.52.1.5 | Temporin G precursor | Eukaryota | Metazoa, Chordata | Temporin G precursor of Rana temporaria | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.52.1.6 | Temporin B precursor | Eukaryota | Metazoa, Chordata | Temporin B precursor of Rana temporaria | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.52.1.7 | Ranatuerin-2P precursor | Eukaryota | Metazoa, Chordata | Ranatuerin-2P precursor of Rana pipiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.52.1.8 | Tryptophyllin-1 precursor | Eukaryota | Metazoa, Chordata | Tryptophyllin-1 precursor of Pachymedusa dacnicolor | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.52.1.9 | Caerin 1.1.5 precursor; similar to maculatin 1.1 of Litoria genimaculata (1.C.76.1.1) (Fernandez et al., 2008; Mechler et al., 2007). | Eukaryota | Metazoa, Chordata | Caerin 1.1.5 precursor of Litoria caerulea |
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1.C.52.2.1 | Ceratotoxin A, CtxA, of 72 aas and 2 TMSs. It forms one of the largest pores among the group of ceratotoxins (Mayer et al. 2019). |
Eukaryota | Metazoa, Arthropoda | CtxA of Ceratitis capitata (medfly) (P36190) |
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1.C.52.2.2 | Ceratotoxin-B of 29 aas, corresponding to the C-terminal region of Ceratotoxin A. |
Eukaryota | Metazoa, Arthropoda | Ceratotoxin-B of Ceratitis capitata (Mediterranean fruit fly) |
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1.C.52.2.3 | Ceratotoxin 2 of 40 aas and 1 N-terminal TMS. |
Eukaryota | Metazoa, Arthropoda | Ceretotoxin 2 of Ceratitis rosa (Natal fruit fly) |
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1.C.53.1.1 | Cyclic bacteriocin, Group I, Lactocyclicin Q (LycQ, 63 aas; 1 or 2 TMSs) (Sawa et al., 2009; van Belkum et al., 2011) |
Bacteria | Bacillota | LcyQ of Lactococcus sp-strain QU12 (B9ZZY0) |
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1.C.53.1.2 | The Lactocyclin homologue of 83 aas and 2 TMSs. |
Bacteria | Bacillota | Lactocyclicin homologue of Streptococcus mutans (C6STH0) |
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1.C.53.1.3 | Uncharacterized protein of 85 aas and 2 TMSs |
Bacteria | Bacillota | UP of Streptococcus macacae |
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1.C.53.1.4 | Bacteriocin cerein 7B family protein of 91 aas and 2 TMSs |
Bacteria | Bacillota | Bacteriocin of Streptococcus sobrinus |
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1.C.53.1.5 | Putative toxic protein of 91 aas and 2 TMSs |
Bacteria | Pseudomonadota | Toxin of Pseudoxanthomonas sp. |
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1.C.53.1.6 | Uncharacterized protein of 117 aas and 2 TMSs |
Bacteria | Pseudomonadota | UP of Xenorhabdus bovienii |
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1.C.53.1.7 | Uncharacterized protein of 96 aas and 1 TMS. |
Bacteria | Pseudomonadota | UP of Yokenella regensburgei |
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1.C.53.1.8 | Uncharacterized protein of 72 aas and 2 TMSs. |
Bacteria | Pseudomonadota | UP of Xanthomonas albilineans |
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1.C.53.2.1 | DUF1269 domain containing protein of 152 aas and 2 TMSs. |
Bacteria | Bacteroidota | DUF1269 protein of Flavobacterium limnosediminis |
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1.C.53.2.10 | Membrane protein, Rv1234, of 175 aas and 2 TMSs. It is a non-essential protein that is induced during dormancy. A homologue in Micrococcus luteus, called Hyp730 (TC# 1.C.53.2.11), has been studied. Structural homology comparisons showed that Hyp730 is highly conserved and non-redundant in G+C rich Actinobacteria and other bacteria, and might be involved, under stress conditions, in an energy-saving process involving respiration during dormancy (Fannin et al. 2021). |
Bacteria | Actinomycetota | Rv1234 of Mycobacterium tuberculosis |
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1.C.53.2.11 | Functionally uncharacterized protein of 175 aas and 2 TMSs, Hyp730. It is a non-essential protein that is induced during dormancy. Structural homology comparisons showed that Hyp730 is highly conserved and non-redundant in G+C rich Actinobacteria and might be involved, under stress conditions, in an energy-saving process in respiration during dormancy (Fannin et al. 2021). |
Bacteria | Actinomycetota | Hyp730 of Micrococcus luteus |
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1.C.53.2.2 | General stress protein of 179 aas and 2 TMSs. |
Bacteria | Cyanobacteriota | GSP of Plectolyngbya sp. WJT66-NPBG17 (algae metagenome) |
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1.C.53.2.3 | ChaB family protein of 257 aas and 2 TM |
Bacteria | Cyanobacteriota | ChaB of Cylindrospermum stagnale |
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1.C.53.2.4 | Magnesium transporter of 154 aas and 2 TMSs. |
Bacteria | Actinomycetota | Mg2+ transporter of Brevibacterium rongguiense |
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1.C.53.2.5 | DUF1269 domain-containing protein of 175 aas and 2 TMSs. |
Bacteria | Acidobacteriota | DUF1269 domain protein of Granulicella sp. 5B5 |
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1.C.53.2.6 | Uncharacterized protein of 163 aas and 2 TMSs. |
Bacteria | Cyanobacteriota | UP of Gloeothece citriformis |
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1.C.53.2.7 | Uncharacterized protein of 160 aas and 2 TMSs. |
Bacteria | Actinomycetota | UP of Nonomuraea phyllanthi |
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1.C.53.2.8 | Signal transduction histidine kinase LytS of 227 aas and 2 TM |
Bacteria | Cyanobacteriota | Putative his kinase of Gloeocapsopsis dulcis |
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1.C.53.2.9 | Uncharacterized protein of 257 aas and 2 TMSs |
Bacteria | Actinomycetota | UP of Varibaculum massiliense |
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1.C.54.1.1 | Shiga toxin B Chain (StxB; verotoxin B chain) precursor, ST-B |
Viruses | ST-B of E. coli (P69178) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.55.1.1 | VirE2 anion-selective channel | Bacteria | Pseudomonadota | VirE2 of Agrobacterium tumefaciens (P0A3W8) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.56.1.1 | The HrpZ cation-selective channel protein of 341 aas. |
Bacteria | Pseudomonadota | HrpZ of Pseudomonas syringae |
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1.C.56.1.2 | HrpZ of 293 aas |
Bacteria | Pseudomonadota | HrpZ of Pseudomonas brassicacearum |
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1.C.56.1.3 | HrpZ of 314 aas |
Bacteria | Pseudomonadota | HrpZ of Pseudomonas viridiflava |
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1.C.56.1.4 | HrpZ of 336 aas |
Bacteria | Pseudomonadota | HrpZ of Marinomonas mediterranea |
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1.C.57.1.1 | Cytotoxin B, TcdB. The minimal pore-forming region is within amino acid residues 830 and 990 including glutamate-970 and glutamate-976. These two residues are essential for pore formation (Genisyuerek et al., 2011). Other residues important for toxicity have been identified (Zhang et al. 2014). Residues in the translocation domain of TcdB that form the pore and function in toxin translocation have been identified (Hamza et al. 2016). |
Bacteria | Bacillota | Cytotoxin B (TcdB) of Clostridium difficile |
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1.C.57.1.2 | Cytotoxin A | Bacteria | Bacillota | Cytotoxin A of Clostridium difficile | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.57.1.3 | Lethal toxin | Bacteria | Bacillota | Lethal toxin (cytotoxin L) of Clostridium sordellii | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.57.1.4 | α-toxin | Bacteria | Bacillota | α-toxin of Clostridium novyi | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.57.1.5 | Cytotoxin C, TpeL (Amimoto et al., 2007) | Bacteria | Bacillota | TpeL of Clostridium difficile (A2PYQ6) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.57.1.6 | MCF toxin of 2993 aas |
Bacteria | Pseudomonadota | MCF toxin of Photorhabdus asymbiotica subsp. asymbiotica (Xenorhabdus luminescens) |
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1.C.57.2.1 | Toxin B | Bacteria | Pseudomonadota | Toxin B of E. coli plasmid p0157 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.57.2.2 | Cytotoxic adherence factor TC0437 | Bacteria | Chlamydiota | TC0437 of Chlamydia muridarum | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.57.2.3 | LifA/Efa1-related large cytotoxin of 3218 aas. |
Bacteria | Chlamydiota | LifA of Chlamydia muridarum |
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1.C.57.3.1 | Pasteurella multocida toxin (PMT); dermonecrotic toxin (DMT); mitogenic toxin (ToxA) (Baldwin et al., 2004) | Bacteria | Pseudomonadota | PMT of Pasteurella multocida (P17452) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.57.3.2 | Cytotoxic necrotizing factor type 1, Cnf1 (Oswald et al., 1994) | Bacteria | Pseudomonadota | Cnf1 of E. coli (AAN03786) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.57.3.3 | Cytotoxic necrotizing factor type 2, Cnf2 (Oswald et al., 1994) | Bacteria | Pseudomonadota | Cnf2 of E. coli (A55260) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.57.3.4 | RTX (repeat in toxin) cytotoxin of 5206 aas, also called the "multifunctional-autoprocessing RTX" (MARTXVv) toxin, or Vibrio vulnificus cytotoxin (VVC). It exists in at least four distinct variants of the rtxA1 gene that encode toxins with different arrangements of effector domains that arose by recombination. VVC, in addition to being a pore-forming toxin, may be a transmembrane toxin with the ability to induce apoptosis in human vascular endothelial cells and tumor cells (Zhao et al. 2009). The protein has an α,β-hydrolase domain (residues ~2900 - 3120). |
Bacteria | Pseudomonadota | RTX cytotoxin of Vibrio vulnificus (BAC97056) |
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1.C.57.3.5 | Multifunctional-autoprocessing repeats-in-toxin, RtxA or Rtx, of 4558 aas. It is the precursor of a multifunctional toxin that causes destruction of the actin cytoskeleton by covalent cross-linking of actin and inactivation of Rho GTPases when translocated into the host cytoplasm (Satchell 2015). Upon translocation into the host cell, it undergoes autoprocessing in cis mediated by the peptidase C80 domain (also named CPD domain). The protease activity is activated upon binding inositol hexakisphosphate (InsP6), present at the host cell membrane, delivering the cysteine protease domain-containing toxin F3 chain to the host cytosol (Sheahan et al. 2007, Shen et al. 2009). It forms a pore in the plasma membrane of a eukaryotic cell to deliver the toxin (Woida and Satchell 2018). |
Bacteria | Pseudomonadota | RtxA of Vibrio cholerae |
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1.C.57.4.1 | Putative toxin A of 294 aas |
Bacteria | Spirochaetota | Toxin A of Brachyspira intermedia |
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1.C.58.1.1 | Microcin E492 (Bieler et al., 2006). Exhibits anti-bacterial and anti-tumor activities due to pore formation (Lagos et al. 2009). |
Bacteria | Pseudomonadota | Microcin E492 precursor of Klebsiella pneumoniae |
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1.C.58.1.2 | Microcin C24 | Bacteria | Pseudomonadota | Microcin C24 of E. coli | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.58.1.3 | Microciin of 92 aas and 1 TMS. |
Bacteria | Pseudomonadota | Microcin of Biostraticola sp. |
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1.C.58.1.4 | Uncharacterized protein of 95 aas and 1 TMS. |
Bacteria | Pseudomonadota | UP of Raoultella terrigena |
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1.C.58.1.5 | Uncharacterized protein of 105 aas and 1 TMS. |
Bacteria | Pseudomonadota | UP of Yersinia intermedia |
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1.C.58.1.6 | Uncharacterized protein of 96 aas and 1 TMS. |
Bacteria | Pseudomonadota | UP of Morganella morganii |
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1.C.58.1.7 | Uncharacterized protein of 68 aas and 1 TMS. |
Bacteria | Pseudomonadota | UP of Erwinia oleae |
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1.C.59.1.1 | CPE (Clostridium perfringens Enterotoxin) has been used for suicide gene therapy for selective treatment of claudin-3-and-4-overexpressing tumors (Walther et al., 2011). It can be used as an oncoleaking/tumor eradication agent as this pore-forming protein exerts specific and rapid toxicity towards claudin-3- and -4-overexpressing cancers (Pahle et al. 2015). The crystal structure of Clostridium perfringens enterotoxin displays features of beta-pore-forming toxins (Kitadokoro et al., 2011). The N-terminal region (nCPE) mediates the cytotoxic effect through pore formation in the plasma membrane of the mammalian host cell. The C-terminal region (cCPE) binds to the second extracellular loop of a subset of claudins, Claudin-3 and claudin-4, with high affinity (Veshnyakova et al., 2010). cCPE is not cytotoxic but is a potent modulator of tight junctions. The toxin forms highly cation-selective channels in lipid bilayers (Benz and Popoff 2018). Mepacrine inhibits CPE-induced electrophysiology effects in artificial lipid bilayers lacking CPE receptors by blocking subunit oligomerization and pore formation (Freedman et al. 2017). |
Bacteria | Bacillota | Enterotoxin of Clostridium perfringens (P01558) |
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1.C.59.2.1 | Neurotoxin of 623 aa |
Bacteria | Bacillota | Haemagglutinin/neurotoxin precursor of Clostridium botulinum (P46085) |
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1.C.59.3.1 | The β-barrel pore-forming toxin (PFP), Monalysin. The soluble monomer is cleaved to yield oligomeric pores. The structure of a cleaved form lacking the transmembrane domain has been solved by x-ray crystalography and cryo-EM (PDB#4MJT; Leone et al. 2015). The structure displays an elongated shape, resembling those of beta-pore-forming toxins such as aerolysin, but it lacks the receptor binding domain. Pro-monalysin forms a stable doughnut-like 18-mer complex composed of two disk-shaped nonamers held together by N-terminal swapping of the pro-peptides. This is in contrast with the monomeric pro-form of the other beta-PFTs that are receptor-dependent for membrane interaction. The membrane-spanning region of pro-monalysin is fully buried in the center of the doughnut, suggesting that upon pro-peptide cleavage, the two disk-shaped nonamers can - and have to - dissociate to leave the transmembrane segments free to deploy and lead to pore formation. In contrast with other toxins, the delivery of 18 subunits at once, nearby the cell surface, may be used to by-pass the requirement for a receptor-dependent concentration to reach the threshold for oligomerization into the pore-forming complex (Leone et al. 2015). |
Bacteria | Pseudomonadota | Monalysin of Pseudomonas entomophila (pathogen of Drosophila) |
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1.C.59.3.2 | Monalysin homologue of 245 aas |
Bacteria | Pseudomonadota | Monalysin homologue of Pseudomonas putida |
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1.C.59.3.3 | Putative toxin of 264 aas |
Bacteria | Myxococcota | Putative toxin of Cystobacter fuscus |
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1.C.59.4.1 | Putative toxin, SmlA of 283 aas. Deleting the encoding gene gives rise to slime molds that can only form small aggregates. May regulate the secretion or processing of a secreted factor that regulates aggregate size. |
Eukaryota | Evosea | SmlA of Dictyostelium discoideum (Slime mold) |
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1.C.59.4.2 | Uncharacterized protein of250 aas |
Eukaryota | Evosea | UP of Dictyostelium discoideum (Slime mold) |
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1.C.59.4.3 | Uncharacterized protein of 271 aas, SmlA |
Eukaryota | Evosea | UP of Polysphondylium pallidum (Cellular slime mold) |
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1.C.59.4.4 | Uncharacterized protein of 324 aas |
Eukaryota | Evosea | UP of Cavenderia fasciculata (Slime mold) (Dictyostelium fasciculatum) |
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1.C.59.5.1 | uncharacterized protein of 408 aas, DwiI. |
Eukaryota | Metazoa, Arthropoda | DwiI of Drosophila willistoni (Fruit fly) |
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1.C.59.5.2 | DUF1679 domain-containing protein of 354 aas |
Bacteria | Pseudomonadota | DUF1679 ptotein of Henriciella litoralis |
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1.C.59.5.3 | Uncharacterized protein of 677 aas. |
Bacteria | Actinomycetota | UP of Mycobacterium marinum |
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1.C.59.5.4 | DUF1679 domain-containing protein of 488 aa |
Bacteria | Pseudomonadota | DUF1679 protein of Sphingomonas panacis |
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1.C.59.5.5 | Uncharacterized protein of 414 aas |
Eukaryota | Metazoa, Nematoda | UP of Trichuris suis |
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1.C.59.5.6 | DUF1679 domain-containing protein of 323 aa |
Bacteria | Bacteroidota | DUF1679 protein of Cyclobacterium amurskyense |
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1.C.59.5.7 | Uncharacterized protein of 418 aas |
Eukaryota | Metazoa, Arthropoda | UP of Zeugodacus cucurbitae (melon fly) |
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1.C.59.5.8 | Uncharacterized protein of 428 aas |
Eukaryota | Metazoa, Arthropoda | UP of Cimex lectularius |
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1.C.59.5.9 | Aminoglycoside phosphotransferase family protein of 330 aa |
Bacteria | Deinococcota | AGPase of Deinococcus ficus |
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1.C.6.1.1 | M1-1 protoxin precursor killer toxin K1 of 316 aas and 1 TMS (Vondrejs et al. 1996; Becker and Schmitt 2017). |
Eukaryota | YKT-K1 of Saccharomyces cerevisiae |
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1.C.6.1.2 | Pre-killer Toxin of 329 aas and 1 N-terminal TMS, PMKT (PMKS-004207) (Santos et al. 2007; Belda et al. 2017). The mature toxin is a dimer of the α-subunit (63 aas) and the β-subunit (77 aas). . |
Eukaryota | Fungi, Ascomycota | PMKS-004207 of Pichia membranifaciens |
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1.C.6.1.3 | Uncharacterized homologue of killer toxin of 310 aas and 1 N-terminal TMS. |
Eukaryota | Fungi, Ascomycota | UP of Kazachstania africana (Yeast) (Kluyveromyces africanus) |
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1.C.6.1.4 | Uncharacterized killer toxin homologue of 307 aas and 1 N-rweminl TMS. |
Eukaryota | Fungi, Ascomycota | UP of Naumovozyma dairenensis (Saccharomyces dairenensis) |
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1.C.6.1.5 | Uncharacterized killer toxin homologue of 303 aas and 1 N-terminal TMS. |
Eukaryota | Fungi, Ascomycota | UP of Naumovozyma castellii (Yeast) (Saccharomyces castellii) |
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1.C.6.1.6 | Uncharacterized protein of 156 aas and 1 N-terminal TMS. |
Eukaryota | Fungi, Ascomycota | UP of Vanderwaltozyma polyspora |
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1.C.6.2.1 | Uncharacterized small killer toxin homologue of 173 aas and 3 or 4 TMSs in a 1 + 2 or 3 TMS arrangement. |
Eukaryota | Fungi, Ascomycota | UP of Torulaspora delbrueckii (Yeast) (Candida colliculosa) |
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1.C.6.2.2 | Uncharacterized killer toxin homologue of 189 aas and 4 TMSs in a 1 + 3 TMS arrangement. |
Eukaryota | Fungi, Ascomycota | UP of Debaryomyces fabryi |
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1.C.60.1.1 | Cytolysin, CylLL/CylLS (Hällgren et al. 2009). |
other sequences | CylLL and CylLS of Enterococcus species |
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1.C.60.1.10 | Type 2 lantibiotic of 61 aas and 1 TMS |
Bacteria | Bacillota | Lantibiotic of Lactobacillus reuteri |
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1.C.60.1.11 | Type 2 lantibiotic, SP_1948 family of 132 aas and 1 TMS. |
Bacteria | Bacillota | Lantibiotic of Pilibacter termitis |
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1.C.60.1.12 | Type 2 lantibiotic of 56 aas and 1 TMS |
Bacteria | Bacillota | Lantibiotic of Pilibacter termitis |
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1.C.60.1.13 | Type 2 lantibiotic, partial, of 47 aas and 1 TMS |
Bacteria | Bacillota | Lantibiotic of Geobacillus yumthangensis |
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1.C.60.1.14 | Type 2 lantibiotic of 60 aas and 1 TMS |
Bacteria | Bacillota | Lantibiotic of Ruminococcus gnavus |
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1.C.60.1.2 | Type 2 lantibiotic of 62 aas and 1 TMS |
Bacteria | Bacillota | Lantibiotic of Eubacterium plexicaudatum ASF492 |
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1.C.60.1.3 | Type 2 lantibiotic of 53 aas and 1 TMS |
Bacteria | Bacillota | Lantibiotic of Bacillus thuringiensis |
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1.C.60.1.4 | Mersacidin/lichenicidin family type 2 lantibiotic, partial, of 74 aas and 1 TMS. |
Bacteria | Bacillota | Lantibiotic of Bacillus cereus |
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1.C.60.1.5 | Type 2 lantibiotic of 106 aas and 1 TMS |
Bacteria | Bacillota | Lantibiotic of Lactobacillus gastricus |
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1.C.60.1.6 | Type 2 lantibiotic, SP_1948 family of 78 aas and 1 TMS |
Bacteria | Actinomycetota | Lantibiotic of Mycobacteroides abscessus |
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1.C.60.1.7 | Type 2 lantibiotic of 70 aas and 1 TMS |
Bacteria | Actinomycetota | Lantibiotic of an unclassified Actinomyces specie |
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1.C.60.1.8 | Type 2 lantibiotic of 69 aas and 1 TMS. |
Bacteria | Bacillota | Lantibiotic of Robinsoniella sp. |
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1.C.60.1.9 | Uncharacterized protein of 62 aas and 1 TMS |
Bacteria | Bacillota | UP of Paenibacillus zanthoxyli |
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1.C.60.2.1 | Uncharacterized protein of 71 aas and 1 TMS |
Bacteria | Bacillota | UP of Lachnospira pectinoschiza |
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1.C.60.2.2 | Uncharacterized protein of 59 aas and 1 TMS |
Bacteria | Bacillota | UP of Planococcus maitriensis |
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1.C.60.2.3 | Uncharacterized protein of 63 aas and 1 TMS. |
Bacteria | Bacillota | UP of Lachnospira pectinoschiza |
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1.C.60.2.4 | Class II lanthipeptide, LchA2/BrtA2 family of 60 aas and 1 TMS. |
None | Bacillati, Bacillota | LchA2 of Paenibacillus zeisoli |
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1.C.60.2.5 | Class II lanthipeptide, LchA2/BrtA2 family of 60 aas with 1 TMS. |
None | Bacillati, Actinomycetota | Lanthipeptide of Microbacterium sp. |
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1.C.60.3.1 | Plantaricin C of 82 aas and 1 TMS (Kim et al. 2020). |
None | Bacillati, Bacillota | Plantaricin C of Clostridiales bacterium FE2011 |
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1.C.60.3.2 | Plantaricin C family lantibiotic of 81 aas and 1 TMS. |
None | Bacillati, Bacillota | Plantaricin C of Clostridiales bacterium FE2011 |
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1.C.61.1.1 | Streptolysin S, SagA of 53 aas |
Bacteria | Bacillota | SagA of Streptococcus pyogenes |
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1.C.61.1.2 | Streptolysin S family bacteriocin of 55 aas (Molloy et al. 2011). |
Bacteria | Bacillota | Streptolysin S of Streptococcus iniae |
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1.C.61.1.3 | Clostridolysin BstA family, TOMM peptide of 52 aas |
Bacteria | Bacillota | Clostridolysin, BstA of Clostridiaceae bacterium |
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1.C.61.1.4 | Streptolysin S family bacteriocin of 50 aas |
Bacteria | Bacillota | Streptolysin-like protein of Clostridium gasigenes |
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1.C.62.1.1 | Pleurocidin | Eukaryota | Metazoa, Chordata | Pleurocidin precursor of Pseudopleuronectes americanus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.62.1.2 | Animicrobial peptide, Piscidin 1, of 68 aas. Forms pore, but preferentially forms disrupting surface structures (Perrin et al. 2016). |
Eukaryota | Metazoa, Chordata | Piscidin 1 of Oreochromis niloticus (Nile tilapia) (Tilapia nilotica) |
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1.C.62.1.3 | Piscidin 2 of 77 aas |
Eukaryota | Metazoa, Chordata | Picidin 2 of Oreochromis niloticus (Nile tilapia) (Tilapia nilotica) |
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1.C.62.1.4 | Piscidin 3 of 76 aas, TP3. |
Eukaryota | Metazoa, Chordata | Piscidin 3, TP3 of Oreochromis niloticus (Nile tilapia) (Tilapia nilotica) |
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1.C.63.1.1 | Spider venom α-latrotoxin of 1401 aas, α-LTX. It induces massive exocytosis after binding to a surface receptor, latrophilin (LPH). In this process, it first induced membrane depolarization by inhibition of repolarizing K+ channels followed by the appearance of Ca2+ transients. In a second phase, the toxin induced a large inward current and a prominent increase in intracellular calcium ions, reflecting pore formation (Lajus et al. 2006). |
Eukaryota | Metazoa, Arthropoda | α-latrotoxin from Latrodectus mactans |
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1.C.63.1.2 | α-latroinsectotoxin precursor (α-LIT) (1411aas) (Shatursky et al., 2007) | Eukaryota | Metazoa, Arthropoda | α-LIT of Latrodectus mactans (Q02989) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.63.1.3 | α-latrocrustotoxin-Lt1a-like protein of 722 aas. |
Eukaryota | Metazoa, Arthropoda | Lt1a of Parasteatoda tepidariorum |
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1.C.63.1.4 | Delta-latroinsectotoxin-Lt1a of 1214 aas and 2 TMSs near the N-terminus. It is an insecticidal presynaptic neurotoxin that induces massive neurotransmitter release at insect (but not vertebrate) neuromuscular junctions. Native toxin forms cation-permeable pores (with high permeability to calcium) in lipid membranes of locust muscle membrane and artificial lipid bilayers (Chen et al. 2021, Dulubova et al. 1996). It may bind to insect neurexin-1 homolog, insect adhesion G protein-coupled receptor L1 homolog, and insect receptor-type tyrosine-protein phosphatase S homolog, and induces neurotransmitter exocytosis both by forming tetrameric pores in membranes and signaling via G protein-coupled receptor. Oligomerization is a process independent of divalent cations (Chen et al. 2021).
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None | Metazoa, Arthropoda | Delta-latroinsectotoxin-Lt1a of Latrodectus tredecimguttatus (Mediterranean black widow spider) |
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1.C.64.1.1 | Fst peptide toxin of 33 aas and 1 TMS. It's 3-d structure is known (2KV5) and is identical to the Fst toxin from Enterococcus faecalis (Nonin-Lecomte et al. 2021). |
Bacteria | Bacillota | Fst of plasmid pAD1 of Enterococcus faecalis |
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1.C.64.1.10 | Putative toxic peptide of 33 aas and 1 TMS |
Bacteria | Bacillota | Toxic peptide of Lactococcus lactis |
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1.C.64.1.12 | Toxic peptide of 29 aas and 1 TMS (plasmid-encoded). |
Bacteria | Bacillota | toxin of Lacticaseibacillus rhamnosus |
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1.C.64.1.13 | Small polypeptide toxin of 35 aas and 1 TMS, LdrD. Its 3-d structure is known (PDB # 5LBJ) (Nonin-Lecomte et al. 2021). |
Bacteria | Pseudomonadota | LdrD of Escherichia coli (strain K12) |
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1.C.64.1.14 | Type I toxin-antitoxin system Fst family toxin, PepA1 or SprA1, of 31 aas and 1 TMSs. It's 3-d structure is known (PDB # 4B19) (Nonin-Lecomte et al. 2021) |
Bacteria | Bacillota | PEPA1 of Staphylococcus aureus |
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1.C.64.1.15 | Type I toxin-antitoxin system Fst family toxin of 32 aas and 1 TMS. |
Bacteria | Bacillota | Toxin of Staphylococcus sp. |
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1.C.64.1.2 | Toxic peptide of 31 aas and 1 TMS |
Bacteria | Bacillota | Toxic peptide of Enterococcus hirae |
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1.C.64.1.3 | Putative toxic peptide of 32 aas and 1 TMS. |
Bacteria | Bacillota | Peptide of Streptococcus agalactiae
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1.C.64.1.4 | Putative toxic peptide of 32 aas and 1 TMS |
Bacteria | Bacillota | Toxic peptide of Streptococcus mutans |
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1.C.64.1.5 | Toxic peptide of 35 aas and 1 TMS |
Bacteria | Bacillota | Toxic peptide of Lactobacillus gasseri |
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1.C.64.1.7 | type I toxin-antitoxin system Fst family toxin of 29 aas and 1 TMS |
Bacteria | Bacillota | Toxin of Lactobacillus casei |
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1.C.64.1.8 | Type I toxin-antitoxin system, Fst family toxin, of 31 aas and 1 TMS. |
Bacteria | Bacillota | Toxin of Staphylococcus epidermidis |
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1.C.64.1.9 | Uncharacterized protein of 31 aas and 1 TMS |
Bacteria | Bacillota | UP of Streptococcus pyogenes |
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1.C.65.1.1 | The plant host cell membrane pore-forming protein of type III protein secretion systems, HrpF | Bacteria | Pseudomonadota | HrpF of Xanthomonas campestris pv. vesicatoria | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.65.1.2 | The plant host membrane pore-forming translocator of type III secretion systems, PopF1 (Meyer et al., 2006) | Bacteria | Pseudomonadota | PopF1 of Ralstonia solanacearum (Q8XPT2) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.65.1.3 | The plant host membrane pore-forming translocater of type III secretion systems, PopF2 (Meyer et al., 2006) | Bacteria | Pseudomonadota | PopF2 of Ralstonia solanacearum (Q8XRF4) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.65.1.4 | The plant host membrane pore-forming translocater of type III secretion systems, NopX (NolX) | Bacteria | Pseudomonadota | NopX of Sinorhizobium fredii (Q5Y4S2) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.65.2.1 | The putative type III translocator, HrpK | Bacteria | Pseudomonadota | HrpK of Pseudomonas syringae (AAF71489) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.66.1.1 | Puroindoline-a | Eukaryota | Viridiplantae, Streptophyta | Puroindoline-a of Triticum aestivum (P33432) (called hordoindolines if from Hordeum vulgare; avenin or avenoindoline if from Avena sativa; grain softness proteins and γ-gliadins from various plants) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.67.1.1 | The pore-forming hemolysin, SphH | Bacteria | Spirochaetota | SphH of Leptospira interrogans (AAB68647) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.67.1.2 | Uncharacterized protein of 380 aas homologous to pyrophosphatases such as sphingomyelinases. |
Eukaryota | Evosea | UP of Entamoeba histolytica |
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1.C.68.1.1 | Oxyopinin 1 (2a) | Eukaryota | Metazoa, Arthropoda | Oxyopinin 1 of Oxyopes kitabensis (P83248) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.68.1.2 | Oxyopinin-2c of 37 aas. Disrupts biological membranes, particularly those rich in phosphatidylcholine. Has antimicrobial activity against E.coli, B.subtilis and S.aureus, and hemolytic activity against sheep, pig and guinea pig red blood cells. Has insecticidal activity against S.frugiperda ovarian cells by opening non-selective ion channels. Enhances the insecticidal activity of spider venom neurotoxic peptides (Corzo et al. 2002). |
Eukaryota | Metazoa, Arthropoda | Oxyopinin-2c of Oxyopes kitabensis |
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1.C.69.1.1 | Beta-2 toxin | Bacteria | Bacillota | Beta-2 toxin of Clostridium perfringens (BAB62455) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.69.1.2 | Beta2-toxin of 265 aas, Cpb2 |
Bacteria | Bacillota | Cpb2 of Clostridium perfringens |
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1.C.69.1.3 | Uncharacterized protein of 249 aas |
Bacteria | Bacillota | UP of Bacillus cereus |
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1.C.7.1.1 | Diphtheria toxin (DT) |
Viruses | Heunggongvirae, Uroviricota | DT of corynebacteriophage beta | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.7.1.2 | Uncharacterized protein of 519 aas |
Bacteria | Actinomycetota | UP of Streptomyces roseoverticillatus |
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1.C.7.2.1 | Diphtheria toxin,DT, translocation domain protein of 908 aas |
Eukaryota | Fungi, Ascomycota | DT of Metarhizium robertsii (Metarhizium anisopliae) |
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1.C.7.2.2 | Heat-labile enterotoxin, A chain, of 1081 aa |
Eukaryota | Fungi, Ascomycota | Enterotoxin of Metarhizium guizhouense |
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1.C.70.1.1 | Pore-forming CAMP factor of 255 aas. The 3-d structure is known (Zafar et al. 2011). See description of the structure in the family description. |
Bacteria | Bacillota | CAMP factor of Streptococcus agalactiae (CAD47659) |
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1.C.70.1.2 | Pore-forming CAMP factor of 257 aas. |
Bacteria | Bacillota | CAMP factor of Streptococcus pyogenes |
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1.C.70.1.3 | CAMP factor family pore-forming toxin (PFT)PFT of 415 aas with one N-terminal TMS.
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None | Bacillati, Bacillota | PFT of Anaerococcus hydrogenalis |
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1.C.70.1.4 | CAMP factor family pore-forming toxin of 459 aas and one N-terminal TMS. |
Bacteria | Bacillota | CAMP factor family pore-forming toxin of Finegoldia magna |
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1.C.70.1.5 | Uncharacterized protein of 392 aas and 1 N-terminal TMS. |
Bacteria | Bacillota | UP of Peptoniphilus phoceensis |
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1.C.70.1.6 | CAMP factor family pore-forming toxin of 271 aas and 1 N-terminal TMS.
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None | Bacillati, Actinomycetota | CAMP factor family pore-forming toxin of Cutibacterium acne (Propionibacterium acnes)
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1.C.71.1.1 | The Cyt1Aa δ endotoxin | Bacteria | Bacillota | Cyt1Aa of Bacillus thuringiensis subsp. israelensis (P0A382) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.71.1.2 | The Cyt2Aa δ endotoxin of 259 aas. Cyt2Aa2 binds and aggregates on the lipid membrane leading to the formation of non-specific holes and disruption of the cell membrane (Tharad et al. 2016). The crystal structure is available (PDB 3RON). |
Bacteria | Bacillota | Cyt2Aa of Bacillus thuringensis (Q04470) |
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1.C.71.1.3 | Type 2Ba cytolytic δ-endotoxin of 263 aas, Cyt2Ba. Kills the larvae of dipteran insects by making pores in the epithelial cell membrane of the insect midgut. The x-ray structure has been solved (PDB 2RCI) (Cohen et al. 2008). |
Bacteria | Bacillota | Cry2Ba of Bacillus thuringiensis |
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1.C.71.1.4 | Uncharacterized toxin of 164 aas. |
Bacteria | Bacillota | Toxin of Clostridium kluyveri |
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1.C.71.2.1 | The volvatoxin A2 precursor | Eukaryota | Fungi, Basidiomycota | Volvatoxin A2 precursor of Volvariella volvacea (Q6USC4) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.71.2.2 | Delta endotoxin, CytB of 206 aas |
Eukaryota | Fungi, Basidiomycota | CytB of Gloeophyllum trabeum (Brown rot fungus) |
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1.C.71.2.3 | Delta endotoxin CytB-like protein, ENDO, of 198 aas. |
Eukaryota | Fungi, Basidiomycota | CytB of Rhizoctonia solani |
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1.C.71.2.4 | Uncharacterized toxin of 178 aas |
Eukaryota | Fungi | Toxin of Fomitopsis pinicola (Brown rot fungus) |
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1.C.72.1.1 | Pertussis toxin | Bacteria | Pseudomonadota | Pertussis toxin of Bordetella pertussis A (S1) + B (S2-S5) Subunit S1 (P04977) Subunit S2 (P04978) Subunit S3 (P04979) Subunit S4 (P0A3R5) Subunit S5 (P04981) |
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1.C.72.2.1 | The ADP-ribosyltransferase toxin, ArtAB (Saitoh et al., 2005) (ArtA but not ArtB is demonsratively homologous to subunits in pertussis toxin) | Bacteria | Pseudomonadota | ArtAB of Salmonella enterica serovar Typhimurium ArtA (Q404H4) ArbB (Q404H3) |
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1.C.72.3.1 | The Subtilase cytotoxin, SubAB. Pentameric SubB, but not SubA, is homologous to ArtB of Salmonella enterica. SubA (AB5 subtilase) cytotoxin inactivates the endoplasmic reticulum chaperone, BiP (Paton et al., 2006; Beddoe et al., 2010). |
Bacteria | Pseudomonadota | Subtilase cytotoxin AB (SubAB) of E. coli |
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1.C.72.4.1 | Heat labile enterotoxin AB, EltAB, ItpAB, ToxAB, LT-AB, cholera toxin (258 aas and 124 aas, respectively). The biological activity of the toxin is produced by the A chain, which activates intracellular adenyl cyclase. The A2 domain of LTA has cell penitration function (Liu et al. 2016). LT holotoxin can enter intestinal epithelial cells and cause diarrhea. The A2 domain might be useful as a transport vehicle for other proteins (Liu et al. 2016). A biotinylated cholera toxin becomes a fusogenic lectin upon cross-linking with streptavidin. This reengineered protein brings about hemifusion and fusion of vesicles as demonstrated by mixing of fluorescently labeled lipids between vesicles as well as content mixing of liposomes filled with fluorescently labeled dextran (Wehrum et al. 2022). |
Bacteria | Pseudomonadota | EltAB of E. coli 078:H11 |
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1.C.72.4.2 | Heat labile enterotoxin IIB, A (α)-chain of 685 aas/B chain of |
Bacteria | Spirochaetota | Enterotoxin of Leptospira borgpetersenii |
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1.C.73.1.1 | Pore-forming exotoxin A (chain A; ExlA) (Rasper and Merrill 1994; Méré et al., 2005). Pore-formation has been demonstrated (Zalman and Wisnieski 1985). Secretion depends on ExlB, a Two Partner Secretion (TPS; TC# 1.B.20) system, as well as type IV pili. The protein has three domains: an N-terminal hemolyin domain, a central RGD motif domain, and a C-terminal domain required for cell lysis. Pore-formation precedes lysis (Basso et al. 2017). ExlA triggers cadherin cleavage by promoting calcium influx which activates ADAM10 for proteolysis (Reboud et al. 2017). ExlA possesses pore-forming activity and is cytolytic for most human cell types. It belongs to a class of poorly characterized bacterial toxins, sharing a similar protein domain organization and a common secretion pathway (Huber 2022). |
Bacteria | Pseudomonadota | Exotoxin A (ExlA) of Pseudomonas aeruginosa (P11439) |
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1.C.73.1.2 | The cholix toxin. The NAD-dependent ADP-ribosyltransferase (ADPRT) catalyzes transfer of the ADP-ribosyl moiety of oxidized NAD onto eukaryotic elongation factor 2 (eEF-2), thus arresting protein synthesis. It may use the eukaryotic pro-low-density lipoprotein receptor-related protein 1 (LRP1) to enter mouse cells, Cholix toxin shares structural and functional properties with Pseudomonas aeruginosa exotoxin A and Corynebacterium diphtheriae diphtheria toxin (Lugo and Merrill 2015). |
Bacteria | Pseudomonadota | Cholix toxin of Vibrio cholera |
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1.C.73.1.3 | Exotoxin A of 241 aas |
Bacteria | Myxococcota | Exotoxin A of Cystobacter fuscus |
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1.C.73.2.1 | Uncharacterzed protein of 679 aas |
Bacteria | Pseudomonadota | UP of Yersinia frederiksenii |
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1.C.73.2.2 | Exotoxin of 806 aas |
Bacteria | Pseudomonadota | Exotoxin of Yersinia similis |
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1.C.73.3.1 | Uncharacterized protein of 698 aas |
Bacteria | Actinomycetota | UP of Mycobacterium gastri |
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1.C.73.3.2 | Uncharacterized toxin of 736 aas. |
Bacteria | Acidobacteriota | Toxin of Chloracidobacterium thermophilum |
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1.C.73.3.3 | Putative toxin of 937 aa |
Bacteria | Planctomycetota | Toxin of Blastopirellula marina |
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1.C.73.3.4 | Putative toxin of 679 aas |
Bacteria | Cyanobacteriota | Toxin of Gloeocapsa sp. PCC 7428 |
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1.C.74.1.1 | Cobra cardiotoxin-1 (cytotoxin CM-6), CTX1. It is a basic protein that binds to cell membranes and depolarizes cardiomyocytes. It also possesses lytic activity on many cells, including red blood cells (Chien et al. 1994). Cytotoxicity is due to pore formation and to another mechanism independent of membrane-damaging activity (Wang et al. 2006). |
Eukaryota | Metazoa, Chordata | CTX1 of Naja naja (P60305) |
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1.C.74.1.2 | α-bungarotoxin isoform A31 (α-BTX A31) (blocks activity of the nicotinic acetylcholine receptor (TC #1.A.9) | Eukaryota | Metazoa, Chordata | αBTX A31 of Bungarus multicinctus (P60615) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.74.1.3 | β-cardiotoxin, CTX14, of 84 aas. |
Eukaryota | Metazoa, Chordata | CTX14 pf Ophiophagus hannah (King cobra) (Naja hannah) |
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1.C.74.1.4 | Long neurotoxin 43, LNTX43 of 108 aa |
Eukaryota | Metazoa, Chordata | LNTX-43 of Drysdalia coronoides (White-lipped snake) (Hoplocephalus coronoides) |
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1.C.74.1.5 | Bucain of 65 aas |
Eukaryota | Metazoa, Chordata | Bucain of Bungarus candidus (Malayan krait) |
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1.C.74.1.6 | 3 finger muscarinic toxin, Mt1 of 66 aas. Shows a non-competitive interaction with adrenergic and muscarinic receptors. Binds to alpha-2b (ADRA2B) (IC50=2.3 nM), alpha-1a (ADRA1A), alpha-1b (ADRA1B), and alpha-2c (ADRA2C) adrenergic receptors. Reversibly binds to M1 (CHRM1) muscarinic acetylcholine receptors, probably by interacting with the orthosteric site. |
Eukaryota | Metazoa, Chordata | MT1 of Dendroaspis angusticeps (Eastern green mamba) (Naja angusticeps) |
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1.C.74.1.7 | α-elapitoxin 2a, Nno2a of 73 aas |
Eukaryota | Metazoa, Chordata | Nno2a of Naja oxiana (Central Asian cobra) (Oxus cobra) |
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1.C.74.1.8 | Muscarinic toxin MT7 of 88 aas and 1 TMS. Forms a complex with the M1 muscarinic receptor with subnanomorlar affinity with a very slow dissociation rate. The 3-D crystal structure is known and reveals how it inhibits agonist-mediated GTP-γ-S binding and downstream signaling (Maeda et al. 2020). |
Eukaryota | Metazoa, Chordata | MT7 of Dendroaspis angusticeps (Eastern green mamba) (Naja angusticeps) |
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1.C.74.1.9 | Cytotoxin 1f of 15 aas. It shows cytolytic activity on many different cells by forming a pore in lipid membranes. In vivo, it increases heart rate or kills the animal by cardiac arrest. In addition, it binds to heparin with high affinity, interacts with Kv channel-interacting protein 1 (KCNIP1) in a calcium-independent manner, and binds to integrin alpha-V/beta-3 (ITGAV/ITGB3) with moderate affinity. |
Eukaryota | Metazoa, Chordata | Cytotoxin 1f of Naja atro (Chinese cobra) |
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1.C.75.1.1 | The Serratia pore-forming hemolysin/toxin of 1608 aas, ShlA. ShlA expression allows Serratia to trigger a Ca2+ signal that reshapes cytoskeleton dynamics and ends up pushing the Serratia-containing vacuoles out of the cell in an exocytic-like process (Di Venanzio et al. 2016). Thus, pore-forming toxins can allow bacteria to exit without compromising host cell integrity. ShlA triggers cadherin cleavage by promoting calcium influx which activates ADAM10 for proteolysis (Reboud et al. 2017). |
Bacteria | Pseudomonadota | ShlA of Serratia marcescens (P15320) |
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1.C.75.1.2 | Haemolysin of 3456 aas. Hemagglutinin repeat-containing protein. |
Bacteria | Pseudomonadota | Haemolysin of Enterobacter agglomerans (Erwinia herbicola) (Pantoea agglomerans) |
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1.C.75.1.3 | Two-partner secretion system hemagglutinin TpsA2 of 2521 aas |
Bacteria | Pseudomonadota | Haemagglutinin of Pseudomonas aeruginosa |
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1.C.75.1.4 | Filamentous hemagglutinin protein of 1599 aas. It is a two-partner secretion exoprotein, HrpA. |
Bacteria | Pseudomonadota | Filamentous hemagglutinin of Neisseria meningitidis |
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1.C.75.1.5 | Haemolysin XhlA of 1470 aas with 1 N-terminal TMS (Cowles and Goodrich-Blair 2005). |
Bacteria | Pseudomonadota | XhlA of Xenorhabdus nematophila (Achromobacter nematophilus) |
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1.C.75.1.6 | Exotoxin, ChlA of 1628 aas (Brumbach et al. 2007). |
Bacteria | Pseudomonadota | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.75.1.7 | Filamentous haemagglutinin family outer membrane protein of 2818 aas. |
Bacteria | Pseudomonadota | Haemagglutinin of Burkholderia ambifaria |
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1.C.75.1.8 | Cytopathogenic toxin, CptA, of 1991 aas and an N-terminal signal TMS. Sneathia amnii is a poorly characterized emerging pathogen that has been implicated in amnionitis and urethritis. Gentile et al. 2020 found that S. amnii damages fetal membranes, and they identified and purified the cytotoxic exotoxin, CptA, that lyses human red blood cells and damages cells from fetal membranes. It binds to red blood cell membranes and forms pores with a diameter of 2.0-3.0 nanometers, resulting in osmolysis. There is an association between Sneathia vaginalis and preterm birth (O'Brien et al. 2023). The Gram-negative anaerobe produces a large exotoxin, the cytopathogenic toxin A (CptA), that forms pores in human epithelial cells and red blood cells. In silico analysis predicts that a large amino-terminal region of the protein is globular and separated from the carboxy-terminal tandem repeats by a disordered region. O'Brien et al. 2023 found that a recombinant protein consisting of the predicted structured amino-terminal portion of CptA and devoid of the repeat region was sufficient to permeabilize epithelial cells and red blood cells. The repeat region was capable of binding to epithelial cells but did not permeabilize them or lyse red blood cells. CptA is the only S. vaginalis virulence factor that has been examined mechanistically (O'Brien et al. 2023). |
Bacteria | Fusobacteriota | CptA of Sneathia amnii |
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1.C.76.1.1 | Maculatin 1.1 (21 aas); similar to caerin (1.C.52.1.9) (Fernandez et al., 2008; Mechler et al., 2007). Maculatins self assemble in parallel to form pores in phospholipid bilayers (Sani et al. 2020). |
Eukaryota | Metazoa, Chordata | Maculatin 1.1 of Litoria genimaculata (P82066) |
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1.C.76.1.2 | Maculatin-2.1 of 18 aas and 1 TMS. Maculatins self assemble in parallel to form pores in phospholipid bilayers (Sani et al. 2020). |
Eukaryota | Metazoa, Chordata | Maculatin-2.1 of Litoria genimaculata (Green-eyed tree frog) |
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1.C.76.1.3 | Aurein-1.2 of 13 aas and 1 TMS. It shows antimicrobial activity against B. cereus, L. lactis, L. innocua, M. luteus, P. multocida, S. aureus, S. epidermidis and S. uberis, and it has anticancer activity (Rozek et al. 2000). It probably acts by disturbing membrane functions with its amphipathic structure. The 3d structure in a micelle is known (Wang et al. 2005). Flower-like nanomicelles have been used for the oral delivery of several antitumor drugs (Hu et al. 2023). |
Eukaryota | Metazoa, Chordata | Aurein-1.2 of Litoria aurea (bell frog) |
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1.C.76.1.4 | Citropin-1.2 of 16 aas and 1 TMS. |
Eukaryota | Metazoa, Chordata | Citropin-1.2 of Litoria citropa (Australian blue mountains tree frog) |
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1.C.76.1.5 | Uperin-2.3 of 19 aas and 1 TMS. It shows medium antibacterial activities against B. cereus, L. mesenteriodes and S. uberis. |
Eukaryota | Metazoa, Chordata | Uperin-2.3 of Uperoleia inundata (Floodplain toadlet) |
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1.C.77.1.1 | α-synuclein (140 aas). In addition to β-amyloid, the cellular prion protein, PrPC binds α-synuclein, which is responsible for neurodegenerative synucleopathies (Urrea et al. 2017). β-barrel channels such as α-hemolysin may serve as sensitive probes of α-synuclein (α-syn) interactions with membranes as well as model systems for studies of channel-assisted protein transport (Gurnev et al. 2014). α-synuclein interacts with membranes to affect Ca2+ signalling, and the oligomeric β-sheet-rich α-synuclein leads to Ca2+ dysregulation and Ca2+-dependent cell death (Angelova et al. 2016). |
Eukaryota | Metazoa, Chordata | α-synuclein of Homo sapiens (EAX06036) |
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1.C.77.1.2 | β-synuclein of 134 aas. The expression of β-synuclein can be regulated by Ca2+-dependent protein kinase G (PKG)-activation via stimulation of NMDA receptors (TC# 1.A.10) and voltage-operated Ca2+ channels (TC# 1.A.1) in the endoplasmic reticulum in the dorsal striatum (Yang and Choe 2014). Also forms a complex with the Slick/Slack channel, presumably to regulate its channel activity (Rizzi et al. 2015). |
Eukaryota | Metazoa, Chordata | beta-synuclein of Homo sapiens |
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1.C.77.1.3 | γ-synuclein, of 127 aas, (also designated synuclein-γ (SNCG) is implicated in both neurodegenerative diseases and cancer. Overexpression of SNCG in cancer cells is linked to tumor progression and chemoresistance (Liu et al. 2016). |
Eukaryota | Metazoa, Chordata | gamma-synuclein of Homo sapiens |
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1.C.78.1.1 | Pesticidal crystal protein (insecticidal δ-endotoxin), Cry15Aa | Bacteria | Bacillota | Cry15Aa of Bacillus thuringiensis (Q45729) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.78.1.2 | Crystal protein, CryET33 | Bacteria | Bacillota | CryET33 of Bacillus thuringiensis (Q9KKG8) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.78.1.3 | Parasporin 1470D | Bacteria | Bacillota | Parasporin of Bacillus thuringiensis (Q6L5X8) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.78.1.4 | CRY51Aa insecticidal aerolysin-type β-pore-forming toxin of 309 aas. The crystal structure is available (Xu et al. 2015). Cry35 and Cry51 belong to protein families (Toxin_10, ETX_MTX2) sharing a common β-pore forming structure and function with known mammalian toxins such as epsilon toxin (ETX) (Moar et al. 2016). |
Bacteria | Bacillota | Cry51Aa of Bacillus thuringiensis |
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1.C.79.1.1 | Histatin 3 precursor of 51 aas and 1 N-terminal TMS. Histatins are salivary proteins that are major precursors of the protective proteinaceous
structure on tooth surfaces (enamel pellicle). In addition, histatins
exhibit antibacterial and antifungal activities. His3-(20-43)-peptide
(histatin-5) is especially effective against C. albicans and C. neoformans, and inhibits Lys-gingipain and Arg-gingipain (rgpB) from
P. gingivalis (Gusman et al. 2001; Tsai et al. 1996). The His3-(20-43)-peptide is a potent inhibitor of
metalloproteinases MMP2 and MMP9. It may kill cells by volume dysregulation and ion imbalance triggered by osmotic stress (Puri and Edgerton 2014). Histatins also promote wound healing (Torres et al. 2018). |
Eukaryota | Metazoa, Chordata | Histatin 3 of Homo sapiens (P15516) |
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1.C.79.1.2 | Statherin (isoform a) precursor; inhibits precipitation of CaPO4H salts (secreted by parotid and submandibular glands) | Eukaryota | Metazoa, Chordata | Statherin of Homo sapiens (P02808) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.79.1.3 | histatin-1, Htn1 of 57 aas and 1 N-terminal TMS. functions as a tooth enamel constituent and as an antibacterial agent (Crosara et al. 2018). |
Eukaryota | Metazoa, Chordata | Histatin-1 of Homo sapiens |
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1.C.79.1.4 | Histatherin, HstN, isoform X2of 99 aas and 1 TMS/ |
Eukaryota | Metazoa, Chordata | HstN of Bos taurus |
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1.C.79.2.1 | Uncharacterized protein of 60 aas and 1 or 2 TMSs. |
Eukaryota | Metazoa, Chordata | UP of Rhinopithecus roxellan |
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1.C.79.3.1 | Uncharacterized protein of 55 aas and 1 TMS. |
Bacteria | Pseudomonadota | UP of Paraburkholderia caballeronis |
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1.C.8.1.1 | Botulinum neurotoxin types A-G. Poly(amindo)amine (PAMAM) detrimers block activity (Förstner et al. 2014). BoNTs inhibit synaptic exocytosis; intoxication requires the di-chain protein to undergo conformational changes in response to pH and redox gradients across the endosomal membrane with consequent formation of a protein-conducting channel by the heavy chain (HC) that translocates the light chain (LC) protease into the cytosol, colocalizing it with the substrate SNARE proteins (Montal 2009). Botulinum toxin type A inhibits salivary secretion, possibly by alterring RNA synthesis (Mao et al. 2020). pH-dependent structural changes in Botulinum Neurotoxin E have been decumented (Lalaurie et al. 2022). |
Bacteria | Bacillota | Botulinum neurotoxin precursor, type A of Clostridium botulinum |
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1.C.8.1.2 | Tetanus neurotoxin, TetX, of 1315 aas; secreted (Gupta et al. 2023). Tetanus toxin acts by inhibiting neurotransmitter release. It binds to peripheral neuronal synapses, is internalized, and moves by retrograde transport up the axon into the spinal cord where it can move between postsynaptic and presynaptic neurons. It inhibits neurotransmitter release by acting as a zinc endopeptidase that catalyzes the hydrolysis of the '76-Gln-|-Phe-77' bond of synaptobrevin-2. |
Bacteria | Bacillota | Tetanus neurotoxin precursor of Clostridium tetani |
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1.C.8.1.3 | Clostridium botulinum neurotoxin (BoNT) type E (The 3d structure is known (Kumaran et al., 2009)). BoNT consists of a light chain (L) and a heavy chain (H) linked by a disulfide bond, where the heavy chain is divided into a translocation domain and an acceptor binding domain (Hc). Tan et al. 2023 explored a recombinant L-HN fragment (EL-HN) composed of the L and HN domains of BoNT/E. Neurotoxicity of L-HN fragments was assessed in mice, and the receptor synaptic vesicle glycoprotein 2C (SV2C) was explored. The 50% mouse lethal dose of the nicked dichain EL-HN fragment (EL-HN-DC) was 0.5 mug, and its neurotoxicity was the highest among the L-HN's of the four serotypes of BoNT(A/B/E/F). The cleavage efficiency of EL-HN-DC toward synaptosome- associated protein 25 (SNAP25) in vitro was 3-fold higher than that of the single chain at the cellular level, and showed 200-fold higher animal toxicity. The EL-HN-DC fragment might enter cells via binding to SV2C to efficiently cleave SNAP25. Thus, the EL-HN fragment showed good biological activity and could be used as a drug screening model and to further explore the molecular mechanism of its transmembrane transport (Tan et al. 2023). |
Bacteria | Bacillota | BoNTE of Clostridium botulinum (Q00496) |
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1.C.8.1.4 | Non-toxic nonhemagglutinin type C of 1196 aas. Assembles with botulinum neurotoxin type C (BoNT/C) and protects it against pH-mediated inactivation or protease activity at pH 2.6 (the pH of the animal gastrointestinal tract) but not at pH 6.0. The non-toxic component is necessary to maintain toxicity. |
Viruses | Heunggongvirae, Uroviricota | Nonhemagglutinin type C of Clostridium botulinum C phage (Clostridium botulinum C bacteriophage) |
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1.C.80.1.1 | Pore-forming fimbrial (pilin) major subunit of 179 aas (Kumari et al. 2015). |
Bacteria | Pseudomonadota | Fimbrial major subunit of Xenorhabdus nematophilus (AAM91931) |
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1.C.80.1.2 | Minor F1c fimbrial subunit, SfaD of 179 aas. |
Bacteria | Pseudomonadota | SfaD of E. coli |
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1.C.80.1.3 | Putative fimbrial adhesin |
Bacteria | Pseudomonadota | Putative adhesin of E. coli |
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1.C.80.1.4 | Putative fimbrial adhesin |
Bacteria | Pseudomonadota | Adhesin of E. coli |
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1.C.81.1.1 | Arenicin-1 precursor (202 aas). The processed pore-forming β-hairpin antimicrobial peptide corresponds to residues 182-202 (Andrä et al., 2008; Shenkarev et al., 2011). Low-conductivity pores were detected in the phosphatidylethanolamine-containing lipids and high-conductivity pores in anionic lipids. The measured conductivity levels agreed with the model in which arenicin antimicrobial activity was mediated by the formation of toroidal pores assembled of two, three, or four β-structural peptide dimers and lipid molecules (Shenkarev et al., 2011). |
Eukaryota | Metazoa, Annelida | Arenicin-1 of Arenicola marina (lugworm) (Q5SC60) |
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1.C.81.1.10 | Gastrokine-1, GKN1 of 199 aas and 2 TMSs, one N-terminal and one C-terminal. It has mitogenic activity and may be involved in maintaining the integrity of the gastric mucosal epithelium (Martin et al. 2003). |
Eukaryota | Metazoa, Chordata | GKN1 of Homo sapiens |
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1.C.81.1.2 | Prepronicomicin-1 of 239 aas |
Eukaryota | Metazoa, Annelida | Prepronicomicin-1 of Nicomache minor |
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1.C.81.1.3 | Leukocyte cell-derived chemotaxin 1-like protein of 240 aa |
Eukaryota | Metazoa, Brachiopoda | Leukocyte cell-derived chemotaxin 1-like peptide of Lingula anatina |
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1.C.81.1.4 | Uncharacterized protein of 285 aas and 1 TMS. |
Eukaryota | Metazoa | UP of Exaiptasia pallida |
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1.C.81.1.5 | Leucocyte cell-derived chemotaxin protein 1 of 359 aas |
Eukaryota | Metazoa, Chordata | Leucocyte cell-derived chemotaxin protein 1 of Callorhinchus milii |
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1.C.81.1.6 | Uncharacteerized protein of 331 aas |
Eukaryota | Metazoa, Cnidaria | UP of Stylophora pistillata |
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1.C.81.1.7 | Gastrokine-3-like protein of 181 aas and 1 - 5 TMSs. GKN3 is a host cell receptor for Japanese Encephalitis virus entry into neurons (Mukherjee et al. 2018).
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Eukaryota | Metazoa, Chordata | Gastrokine-3-like protein of Xenopus laevis |
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1.C.81.1.8 | Leukocyte cell-derived chemotaxin protein 1 isoform 2 precursor of 333 aa |
Eukaryota | Metazoa, Chordata | Chemotaxis protein of Homo sapiens |
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1.C.81.2.3 | Integral membrane protein 2C, Itm2C (BRI3, Hucep-14, NPD018), of 267 aas with 1 strongly hydrophobic TMS near the N-terminus. It is a negative regulator of amyloid-beta peptide production, and may inhibit the processing of APP by blocking its access to alpha- and beta-secretase (Gong et al. 2008). Binding to the beta-secretase-cleaved APP C-terminal fragment is negligible, suggesting that ITM2C is a poor gamma-secretase cleavage inhibitor. It may also play a role in TNF-induced cell death and neuronal differentiation (Matsuda et al. 2009). |
Eukaryota | Metazoa, Chordata | Itm2C of Homo sapiens |
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1.C.82.1.1 | Pore-forming peptide HP(2-20) (Park et al., 2008). (derived from the ribosomal protein L1 N-terminus). The 3-D structure is known (1P0G_A). |
Bacteria | Campylobacterota | HP(2-20) of Helicobacter pylori (Q9ZK21) |
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1.C.82.1.2 | 50S ribosomal protein L1 of 230 aas |
Bacteria | Pseudomonadota | L1 of Snodgrassella alvi |
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1.C.83.1.1 | Cyclic bacteriocin, Group II, Gassericin A (GaaA; 91 aas; 2 TMSs) (van Belkum et al., 2011) |
Bacteria | Bacillota | Gassericin of Lactobacillus gasseri (O24790) |
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1.C.83.1.2 | Butyrivibriocins AR10, BviA (Kalmokoff and Teather 1997; Kalmokoff et al. 2003; Maqueda et al. 2008). |
Bacteria | Bacillota | Butyrivibriocin AR10 (BviA) of Butyrivibrio fibrisolvens |
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1.C.84.1.1 | Leakage-promoting cyclic peptide, Subtilosin (43aas) |
Bacteria | Bacillota | Subtilosin of Bacillus subtilis (O07623) |
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1.C.84.1.2 | Subilosin A |
Bacteria | Bacillota | Subtilosin A of Streptococcus constellatus (Gemella morbillorum) |
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1.C.85.1.1 | β-defensin-1 | Eukaryota | Metazoa, Chordata | β-defensin-1 of Homo sapiens (P60022) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.85.1.10 | Canine β-defensin 107, cBD107, of 70 aas and 1 N-terminal TMS (van Damme et al. 2009). |
Eukaryota | Metazoa, Chordata | cBD107 of Canis lupus familiaris (Dog) (Canis familiaris) |
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1.C.85.1.11 | Porcine β-defensin-2 of 69 aas and 1 N-terminal TMS. Porcine beta defensin 2 (pBD2) caused the bacterial membranes to be broken, bulging, and perforated (Zhang et al. 2020). pBD2 may have multiple modes of action, but the main mechanism by which pBD2 kills S. aureus is the destruction of the membrane. It is 63% identical to human β-defensin-1. |
Eukaryota | Metazoa, Chordata | pBP2 of Sus scrofa |
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1.C.85.1.2 | β-defensin-2 | Eukaryota | Metazoa, Chordata | β-defensin 2 of Homo sapiens (O15263) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.85.1.3 | β-defensin-3 of 67 aas and 1 N-terminal TMS. Canine BD103 (van Damme et al. 2009) is 79% identical. |
Eukaryota | Metazoa, Chordata | β-defensin-3 of Homo sapiens (P81534) |
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1.C.85.1.4 | β-defensin-14 | Eukaryota | Metazoa, Chordata | β-defensin-14 of Mus musculus (Q7TNV9) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.85.1.5 | Epididymus sperm-associated antigen (EP2E) |
Eukaryota | Metazoa, Chordata | EP2E of Homo sapiens (Q9H4P9) |
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1.C.85.1.6 | β-defensin-2 of 71 aas and 1 TMS |
Eukaryota | Metazoa, Chordata | Defensin β2 of Mus musculus |
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1.C.85.1.7 | β-defensin 11 of 69 aas and 1 TMS |
Eukaryota | Metazoa, Chordata | Defb11 of Rattus norvegicus |
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1.C.85.1.8 | β-Defensin 3 (BD3) of 63 aas and 1 TMS (Colavita et al. 2015). Sass et al. 2008 have proposed that interference with the organisation of membrane-bound multienzyme complexes such as the electron transport chain and the cell wall biosynthetic complex rather than on formation of defined transmembrane pores is responsible for death of Staphylococcus aureus (Sass et al. 2008). However, BD3 selectively inhibits mouse Kv1.6 and human KCNQ1/KCNE1 channels with IC50 values of 0.6 μM and 1.2 μM, respectively (Zhang et al. 2018).
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Eukaryota | Metazoa, Chordata | BD3 pf Mus musculus |
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1.C.85.1.9 | Canine β-defensin-1, cBD1, of 41 aas and 1 N-terminal TMS. Production of beta-defensins constitutes an important role in skin defense, and variable expression of three cBDs in different organ systems of the dog has been observed. In skin, three beta-defensins, cBD1, cBD103 and cBD107, were extensively expressed (van Damme et al. 2009). There is a possible defect in the innate immune response of dogs with atopic dermatitis. cDB1 may be a marker for Leishmania infantum infection in dogs (da Silva et al. 2017). |
Eukaryota | Metazoa, Chordata | Defensin 1 of Canis lupus familiaris (Dog) (Canis familiaris) |
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1.C.85.2.1 | Myotoxin-4 or Crotamine-4. It specifically modifies voltage-sensitive Na+channels, inhibits K+ channels and exhibits analgesic effects. This snake myotoxin family member is a cationic peptide with multiple functions. It acts as a cell-penetrating peptide (CPP), and has antimicrobial activities, causes hind limb paralysis, and gives rise to severe muscle necrosis by a non-enzymatic mechanism. As a cell-penetrating peptide, crotamine has high specificity for actively proliferating cells, and it interacts inside the cell with subcellular and subnuclear structures, like vesicular compartments, chromosomes and centrioles (Hayashi et al. 2008). The toxin selectively inhibits Kv1.1/KCNA1, Kv1.2/KCNA2 and Kv1.3/KCNA3 channels with IC50 values of 369, 386 and 287 nM, respectively (Peigneur et al. 2012). Crotamine shows antibacterial activity against E. coli and B. subtilis, and antifungal activity against Candida spp., Trichosporon spp. and C. neoformans. It kills bacteria through membrane permeabilization (Kerkis et al. 2004). |
Eukaryota | Metazoa, Chordata | Myotoxin-4 of Crotalus durissus terrificus (P24334) |
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1.C.85.2.2 | Crotamine-IV-2 toxin of 42 aas and 0 TMSs. Croamines are cationic peptides that possess multiple
functions. hey act as cell-penetrating peptides (CPPs), as potent
voltage-gated potassium channel inhibitors and as antimicrobial
agents (Hayashi et al. 2008). As an antimicrobial peptide, crotamine shows
antibacterial activity against E.coli and B.subtilis, and antifungal
activity against Candida spp., Trichosporon spp. and C. neoformans. It
kills bacteria through membrane permeabilization (Hayashi et al. 2008). It selectively inhibits Kv1.1/KCNA1, Kv1.2/KCNA2 and Kv1.3/KCNA3 channels (Peigneur et al. 2012). It is also hemolytic (Oguiura et al. 2011). |
Eukaryota | Metazoa, Chordata | Croamine-IV-2 of Crotalus durissus cumanensis |
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1.C.85.2.3 | β-defensin-like protein of 63 aas and 1 TMS |
Eukaryota | Metazoa, Chordata | defensin-like protein of Bothrops matogrossensis (Pitviper) (Bothrops neuwiedi matogrossensis) |
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1.C.85.2.4 | Crotamine-like precursor of 76 aas and 1 TMS. |
Eukaryota | Metazoa, Chordata | Crotamine-like peptide of Thamnodynastes strigatus (Coastal house snake) |
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1.C.85.3.1 | Epithelial Gallinacin-1α. The full length antimicrobial peptide precursor is CHP2. Attacks bacteria and fungi. |
Eukaryota | Metazoa, Chordata | Gallinacin 1α of Gallus gallus (P46157) |
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1.C.85.3.2 | β-defensin prepropeptide of 59 aas and 2 TMSs. |
Eukaryota | Metazoa, Chordata | β-defensin of Meleagris gallopavo (turkey) |
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1.C.85.3.3 | Avian beta-defensin, 5beta of 66 aas and 1 TMS. |
Eukaryota | Metazoa, Chordata | Beta-defensin of Columba livia (domestic pigeon) |
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1.C.85.4.1 | Helofensin-1 lethal toxin of 183 aas (PMID 19837656). This toxin possesses an inhibitory effect on electrical stimulation of the isolated hemi-diaphragm of mice. Neither hemorrhagic nor hemolytic activities were detected, but Huang et al. 2016 reported it to be a membrane active protein.
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Eukaryota | Metazoa, Chordata | Helofensin-1 of Heloderma suspectum cinctum (Banded Gila monster) |
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1.C.85.4.2 | Helofensin-3 (90% identical to helofensin-1) of 182 aas. A lethal toxin. |
Eukaryota | Metazoa, Chordata | Helofensin-3 of Heloderma suspectum cinctum (Banded Gila monster) |
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1.C.85.4.3 | Uncharacterized protein of 172 aas |
Eukaryota | Metazoa, Cnidaria | UP of Nematostella vectensis (Starlet sea anemone) |
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1.C.86.1.1 | Pore-forming Trialysin (Martins et al., 2008) | Eukaryota | Metazoa, Arthropoda | Trialysin of Triatoma infestans (Q8T0Z4) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.87.1.1 | Pore-forming Vibrio outer protein Q, VopQ, or Vibrio effector protein, VepA of 492 aas (Sreelatha et al. 2013). |
Bacteria | Pseudomonadota | VopQ of Vibrio parahaemolyticus |
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1.C.87.1.2 | VopQ orthologue of 554 aas |
Bacteria | Proteobacteria | VopQ of Vibrio harveyi |
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1.C.87.1.3 | VopQ orthologue of 479 aas |
Bacteria | Pseudomonadota | VopQ of Photobacterium sp. AK15 |
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1.C.88.1.1 | Chrysophsin 1, Chy1 | Eukaryota | Metazoa, Chordata | Chy1 of Chrysophrys major (P83545) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.88.1.2 | Chrysophsin 2, Chy2 | Eukaryota | Metazoa, Chordata | Chy2 of Chrysophrys major (P83546) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.88.1.3 | Chrysophsin 3, Chy3 | Eukaryota | Metazoa, Chordata | Chy3 of Chrysophrys major (P83547) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.89.1.1 | β-neoendorphin-dynorphin precursor (Proenkephalin B; Preprodynorphin) | Eukaryota | Metazoa, Chordata | Dynorphin of Homo sapiens (P01213) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.89.1.2 | Proenkephalin A (264aa precursor of opioid peptides) | Eukaryota | Metazoa, Chordata | Proenkephalin A of Homo sapiens (P01210) |
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1.C.89.1.3 | Prepronociceptin of 176 aa |
Eukaryota | Metazoa, Chordata | Preprociceptin of Homo sapiens |
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1.C.9.1.1 | Vacuolating cytotoxin precursor, VacA of 1287 aas that forms a hexameric pore in the membranes of target cells after processing (Pyburn et al. 2016). The 88 kDa secreted VacA protein, composed of an N-terminal p33 domain and a C-terminal p55 domain, assembles first into water-soluble oligomers before inserting into membranes. Details for the insertion process are known (Pyburn et al. 2016). The biology of VacAs has been reviewed (Foegeding et al. 2016). VacA preferentially associates with lipid rafts, and the affinity of VacA for rafts is independent of its capacity to oligomerize or form membrane channels (Raghunathan et al. 2018). Cryoelectron microscopy has been used to resolve 10 structures of VacA assemblies, including monolayer (hexamer and heptamer) and bilayer (dodecamer, tridecamer, and tetradecamer) oligomers (Zhang et al. 2019). The models of the 88-kDa full-length VacA protomer derived from the near-atomic resolution maps are highly conserved among different oligomers and show a continuous right-handed beta-helix made up of two domains with extensive domain-domain interactions. The specific interactions between adjacent protomers in the same layer stabilizing the oligomers are well resolved. For double-layer oligomers, short- and/or long-range hydrophobic interactions between protomers across the two layers were found. These structures and other previous observations led to a mechanistic model wherein VacA hexamer correspond to the prepore-forming state, and the N-terminal region of VacA, responsible for the membrane insertion would undergo a large conformational change to bring the hydrophobic transmembrane region to the center of the oligomer for the membrane channel formation (Zhang et al. 2019). VacA enters cells, localizes to mitochondria, and induces mitochondrial membrane permeability changes due to toxin channel activity (Willhite and Blanke 2004). |
Bacteria | Campylobacterota | VacA of Helicobacter pylori |
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1.C.9.1.3 | Vacuolating cytotoxin domain-containing protein of 2120 aas and 1 N-terminal TMS. |
Bacteria | Campylobacterota | VacA-like protein of Helicobacter mustelae |
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1.C.90.1.1 | Cyclic bacteriocin, Group I, carnocyclin, (CdlA; 64 aas; 1 TMS) (van Belkum et al., 2011) (3-d solution structure: 2KJF_A; forms anion selective pores; Similar to As-48 (1.C.28.1.1)) (Martin-Visscher et al., 2009) |
Bacteria | Bacillota | CdlA of Carnobacterium maltaromaticum (B2MVM5) |
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1.C.90.1.2 | Cyclic bacteriocin, Group I, Garvicin ML (GarML; 63 aas; 1 or 2 TMSs) |
Bacteria | Bacillota | GarML of Lactococcus garvieae (D2KC49) |
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1.C.90.1.3 | Cyclic bacteriocin, Group I Uberolysin, UblA (70 aas; 1 TMS) (van Belkum et al., 2011) |
Bacteria | Bacillota | UblA of Streptococcus uberis (A5H1G9) |
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1.C.90.2.1 | Putative bacteriocin (73 aas; 2 TMSs) |
Bacteria | Bacillota | Putative bacteriocin of Staphylococcus aureus (Q99X21) |
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1.C.90.2.2 | Putative bacteriocin (118 aas; 3 TMSs) |
Bacteria | Bacillota | Putative bacteriocin of Bacillus thuringiensis (A0RKJ6) |
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1.C.90.3.1 | Putative bacteriocin (69 aas; 1 TMS) |
Bacteria | Bacillota | Putative bacteriocin of Clostridium perfringens (Q0SUX0) |
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1.C.90.3.2 | Putative bacteriocin (67 aas; 1 TMS) |
Bacteria | Bacillota | Putative bacteriocin of Clostridium perfringens (B1BXT7) |
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1.C.90.3.3 | Putative bacteriocin (87 aas; 2 TMSs) |
Bacteria | Bacillota | Putative bacteriocin of Enterococcus faecium (C9BRP5) |
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1.C.90.3.4 | Putative bacteriocin (98 aas; 2 TMSs) |
Bacteria | Bacillota | Putative bacteriocin of Streptococcus pneumoniae (A5MY21) |
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1.C.91.1.1 | The tetrameric Stefin B pore-forming protein (98aas); structure known (20CT_A) |
Eukaryota | Metazoa, Chordata | Stefin B of Homo sapiens (P04080) |
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1.C.92.1.1 | C-reactive protein 1.1 precursor, CRP1.1 | Eukaryota | Metazoa, Arthropoda | CRP1.1 of Limulus polyphemus (P06205) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.92.1.2 | Serum amyloid P component precursor, SAP (223aas) | Eukaryota | Metazoa, Chordata | SAP of Homo sapiens (P02743) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.C.92.1.3 | Neuronal pentraxin receptor-1 (NPR1) of 432 aas and 1 or 2 N-terminal TMSs. May be involved in mediating uptake of synaptic material during synapse remodeling or in mediating the synaptic clustering of AMPA glutamate receptors at a subset of excitatory synapses. NPR is a potent inducer of both excitatory and inhibitory heterologous synapses; knockdown of NPR in cultured neurons decreases the density of both excitatory and inhibitory synapses (Lee et al. 2017). NPR1 is an auxiliary subunit of AMPA receptors (Matthews et al. 2021). |
Eukaryota | Metazoa, Chordata | NPR1 of Homo sapiens |
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1.C.93.1.1 | Lacticin Q (Yoneyama et al., 2009). Form toroida pores in taget membranes (Draper et al. 2015). |
Bacteria | Bacillota | Lacticin Q of Lactococcus lactis (A4UVR2) |
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1.C.94.1.1 | Processed pore-forming thuricin S (allows propidium iodide to enter the cell) (Chehimi et al., 2010). |
Bacteria | Bacillota | Thuricin S of Bacillus thuringiensis (P84763) |
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1.C.94.1.2 | Full-length thuricin S homologue (thuricin17, thuricin H, TucA1, ThnA1) of 58 aas and 1 TMS, or of 40 aas (B5U2V4) and 1 TMS. |
Bacteria | Bacillota | Thuricin S homologue of Bacillus thuringiensis (C3FAQ6) |
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1.C.94.2.1 | Uncharacterized protein, Thuricin CD or Trnβ, of 49 aas and 1 TMS. |
Bacteria | Bacillota | UP of Bacillus cereus |
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1.C.94.2.2 | ThuricinCD or Trnα of 47 aas and 1 TMS |
Bacteria | Bacillota | Trnα of Bacillus cereus |
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1.C.95.1.1 | Pore-forming ESAT-6 (EsxA) (95 aas) (Nuñez-Garcia et al. 2018). Secreted from the bacterial cytoplasm via a ESX protein secretion system (Type VII; TC# 3.A.24.5.1). |
Bacteria | Actinomycetota | ESAT-6 of Mycobacterium tuberculosis (bovis) (P0A564). |
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1.C.95.1.10 | Uncharacterized protein of 134 aas. |
Bacteria | Pseudomonadota | UP of Paracoccus aminophilus |
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1.C.95.1.11 | Uncharacterized protein of 211 aas. |
Bacteria | Actinomycetota | UP of Nakamurella lactea |
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1.C.95.1.12 | Uncharacterized protein of 97 aas. |
Bacteria | Bacillota | UP of Holdemania filiformis |
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1.C.95.1.13 | Uncharacterized WXG100 family type VII secretion targetof 100 aas. |
Bacteria | Actinomycetota | UP of Salinispora arenicola |
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1.C.95.1.2 | ESAT-6-like protein, EsxA of 95 aas (Callahan et al. 2010). |
Bacteria | Actinomycetota | ESAT-6-like protein of Corynebacterium diphtheriae |
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1.C.95.1.3 | ESAT-6-like protein. a WXG100 (YukE) family type VII secretion target. |
Bacteria | Actinomycetota | ESAT-6 protein of Gordonia rhizosphera |
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1.C.95.1.4 | ESAT6-like protein of 95 aas. |
Bacteria | Actinomycetota | ESAT-6-like protein of Amycolatopsis nigrescens |
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1.C.95.1.5 | ESAT-6-like protein of 96 aas. |
Bacteria | Actinomycetota | ESAT-6 of Intrasporangium chromatireducens |
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1.C.95.1.6 | ESAT-6-like protein of 101 aas |
Bacteria | Actinomycetota | UP of Nesterenkonia sp. F |
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1.C.95.1.7 | ESAT-6-like protein of 103 aas. |
Bacteria | Actinomycetota | ESAT-6-like protein of Williamsia marianensis |
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1.C.95.1.8 | Uncharacterized protein of 96 aas |
Bacteria | Actinomycetota | UP of Paeniglutamicibacter antarcticus |
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1.C.95.1.9 | Uncharacterized WXG100 family type VII secretion target of 102 aas. |
Bacteria | Bacillota | UP of Herbivorax saccincola |
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1.C.95.2.1 | EsxE/EsxF pair of proteins of 90 and 103 aas, respectively (Tak et al. 2021). Mycobacterium tuberculosis secretes the tuberculosis necrotizing toxin (TNT) to kill host cells. The WXG100 proteins EsxE and EsxF are essential for TNT secretion. EsxE and EsxF form a water-soluble heterodimer (EsxEF) that assembles into oligomers and long filaments, binds to membranes, and forms stable membrane-spanning channels. Electron microscopy of EsxEF reveals mainly pentameric structures with a central pore (Tak et al. 2021). Mutations of both WXG motifs and of a GXW motif do not affect dimerization, but abolish pore formation, membrane deformation and TNT secretion. The WXG/GXW mutants are locked in conformations with altered thermostability and solvent exposure, indicating that the WXG/GXW motifs are molecular switches controlling membrane interaction and pore formation. EsxF is accessible on the bacterial cell surface, suggesting that EsxEF form an outer membrane channel for toxin export. Thus, our study reveals a protein secretion mechanism in bacteria that relies on pore formation by small WXG proteins. |
None | Bacillati, Actinomycetota | EsxE/EsxF of Mycobacterium tuberculosis |
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1.C.96.1.1 | The haemolytic lectin, CEL-III (Uchida et al. 2004). CEL-III heptamerizes via a large structural transition from alpha-helices to a beta-barrel during the transmembrane pore-formation process (Unno et al. 2014). |
Eukaryota | Metazoa, Echinodermata | CEL-III of Cucumaria echinata (Q868M7) |
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1.C.96.1.2 | Putative pore-forming lectin toxin of 481 aas. |
Eukaryota | Metazoa, Cnidaria | Putative toxin of Acropora millepora (Staghorn coral) |
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1.C.96.1.3 | Putative uncharacterized α-1,2-mannosidase of 608 aas |
Bacteria | Actinomycetota | UP of Streptomyces rubidus |
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1.C.96.1.4 | Uncharacterized protein of 278 aas |
Bacteria | Pseudomonadota | UP of Delftia tsuruhatensis |
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1.C.96.2.1 | Uncharacterized protein of 514 aas |
Bacteria | Pseudomonadota | UP of Moritella sp. PE36 |
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1.C.96.2.2 | Uncharacterized protein of 255 aas and 0 TMSs |
Pseudomonadota | UP of Photorhabdus temperata |
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1.C.96.2.3 | Uncharacterized protein of 249 aa |
Bacteria | Bacillota | UP of Brevibacillus laterosporus |
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1.C.96.2.4 | Uncharacterized protein of 271 aas |
Bacteria | Pseudomonadota | UP of Polaromonas glacialis |
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1.C.96.3.1 | Uncharacterized protein of 376 aas |
Bacteria | Actinomycetota | UP of Streptomyces griseofuscus |
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1.C.96.3.2 | Uncharacterized protein of 413 aas |
Bacteria | Actinomycetota | UP of Murinocardiopsis flavida |
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1.C.96.3.3 | Uncharacterized protein of 373 aas |
Bacteria | Actinomycetota | UP of Nocardiopsis sp. |
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1.C.97.1.1 | Pleurotolysin A/B pore-forming toxin. Pleurotolysin A (PlyA; also called ostreolysin A, OlyA) binds first in a sphingomyelin-dependent process; Pleurotolysin B (PlyS) binds to A in the membrane and inserts (Kondos et al., 2011). The binary cytolytic pore-forming complex forms non-selective ion conducting pores of variable size (Schlumberger et al. 2013) to promote fruiting (Ota et al. 2014). Conformational changes accompanying pore formation have been reported (Lukoyanova et al. 2015). In these systems, the aegerolysin-like proteins provide the membrane cholesterol/sphingomyelin selectivity and recruit oligomerised pleurotolysin B molecules, to create a membrane-inserted pore complex. The resulting protein structure has been imaged with electron microscopy, and it has a 13-meric rosette-like structure, with a central lumen that is ~4-5 nm in diameter. The opened transmembrane pore is non-selectively permeable for ions and smaller neutral solutes, and is a cause of cytolysis of a colloid-osmotic type (Ota et al. 2014). Ostreolysin A6 (OlyA6) is a protein produced by the oyster mushroom (Pleurotus ostreatus). It binds to membrane sphingomyelin/cholesterol domains, and together with its protein partner, pleurotolysin B (PlyB), it forms 13-meric transmembrane pore complexes. OlyA6 binds 1000 times more strongly to the insect-specific membrane sphingolipid, ceramide phosphoethanolamine (CPE). In concert with PlyB, OlyA6 has potent and selective insecticidal activity against the western corn rootworm. Milijaš Jotić et al. 2021 analysed the histological alterations of the midgut wall columnar epithelium of western corn rootworm larvae fed with OlyA6/PlyB, which showed vacuolisation of the cell cytoplasm, swelling of the apical cell surface into the gut lumen, and delamination of the basal lamina underlying the epithelium. Cryo-EM was used to explore the membrane interactions of the OlyA6/PlyB complex using lipid vesicles composed of artificial lipids containing CPE, and western corn rootworm brush border membrane vesicles. Multimeric transmembrane pores were formed in both vesicle preparations, similar to those described for sphingomyelin/cholesterol membranes. Thus, the molecular mechanism of insecticidal action of OlyA6/PlyB arises from specific interactions of OlyA6 with CPE, and the consequent formation of transmembrane pores in the insect midgut (Milijaš Jotić et al. 2021). |
Eukaryota | Fungi, Basidiomycota | Pleurotolysin A/B of Pleurotus ostreatus |
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1.C.97.1.2 | Erylysin A/B pore-forming toxin (Shibata et al., 2010). Erylysin B is 96% identical to Pleurotolysin B) |
Eukaryota | Fungi, Basidiomycota | Erylysin A/B of Pleurotus eryngii |
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1.C.97.1.3 | MACPF protein homologue of Erylysin B |
Eukaryota | Evosea | MACPF protein of Dictyostelium discoideum (Q54I05) |
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1.C.97.1.4 | Hypothetical protein homologous to Erylysin B of 924aas with a MACPF domain. |
Eukaryota | Fungi, Ascomycota | Hypothetical protein of Chaetomium globosum (Q2GRU1) |
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1.C.97.1.5 | Uncharacterized protein of 557 aas |
Eukaryota | Fungi, Ascomycota | UP of Aspergillus oryzae |
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1.C.97.1.6 | Uncharacterized protein homologous to Erylysin B (892aas) Residues 85-337aas of Erylysin B align with residues 242-477 of the Chlorobium sequence. |
Bacteria | Chlorobiota | Hypothetical protein of Chlorobium limicola (B3EDT0) |
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1.C.97.1.7 | Uncharacterized protein of 1165 aas |
Bacteria | Pseudomonadota | UP of Tistrella mobilis |
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1.C.97.1.8 | Uncharacterized protein of 800 aas with an N-terminal 280 aa soluble PQ-rich domain that shows similarity with TC# 1.B.27.1.9 and a C-terminal domain rich in predicted β-structure that shows similarity to Pleurotolysin snf its homologues. |
Eukaryota | Fungi, Ascomycota | UP of Hypocrea virens (Gliocladium virens) (Trichoderma virens) |
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1.C.97.1.9 | Uncharacterized protein of 668 aas |
Eukaryota | Fungi, Basidiomycota | UP of Piriformospora indica |
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1.C.97.2.1 | Putative hemolysin of 224 aas |
Eukaryota | Fungi, Ascomycota | Putative hemolysin of Ajellomyces dermatitidis (Blastomyces dermatitidis) |
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1.C.97.2.2 | Uncharacterized protein of 282 aas |
Eukaryota | Fungi, Ascomycota | UP of Coccidioides posadasii (Valley fever fungus) |
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1.C.97.2.3 | Uncharacterized protein of 244 aas |
Eukaryota | Fungi | UP of Ajellomyces capsulatus (Darling's disease fungus) (Histoplasma capsulatum) |
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1.C.97.2.4 | Uncharacterized protein of 190 aas |
Eukaryota | Fungi, Ascomycota | UP of Cyphellophora europaea |
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1.C.97.3.1 | Hemolysin of 198 aas |
Eukaryota | Fungi, Ascomycota | Hemolysin of Neurospora crassa |
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1.C.97.3.2 | Pore-forming ostreolysin (Berne et al., 2005). 97% identical to Erylysin A (1.C.97.1.2). |
Eukaryota | Fungi, Basidiomycota | Ostreolysin of Pleurotus osteatus (P83467) |
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1.C.97.3.3 | Aegerolysin (135aas) (Homologous to Pleurotolysin A). Aegerolysin-like proteins provide the membrane cholesterol/sphingomyelin selectivity and recruit oligomerized pleurotolysin B molecules to create a membrane-inserted pore complex (Ota et al. 2014). |
Bacteria | Bacteroidota | Aegerolysin of Spirosoma linguale (D2QTE8) |
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1.C.97.3.4 | Aegerolysin (121aas) (Homologous to Pleurotolysin A) |
Bacteria | Pseudomonadota | Aegerolysin of Pseudomonas aeruginosa (A6UXQ8) |
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1.C.97.3.5 | Putative hemolysin of 140 aas |
Eukaryota | Fungi, Ascomycota | Hemolysin of Penicillium oxalicum (Penicillium decumbens) |
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1.C.97.3.6 | Putative hemolysin of 199 aas |
Eukaryota | Fungi, Ascomycota | Putative hemolysin of Ajellomyces capsulatus (Darling's disease fungus) (Histoplasma capsulatum) |
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1.C.97.3.7 | Putative hemolysin of 222 aas |
Viruses | Bamfordvirae, Nucleocytoviricota | Putative hemolysin of Trichoplusia ni ascovirus 2c |
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1.C.97.3.8 | Putative hemolysin of 204 aas |
Eukaryota | Viridiplantae, Streptophyta | Putative hemolysin of Selaginella moellendorffii (Spikemoss) |
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1.C.98.1.1 | The heterotrimeric CDT, CdtA/B/C toxin complex. CdtA and CdtC may form a heterodimeric complex required for CdtB delivery. Localized to the cell outer membrane. Contains a ricin B-type lectin domain (Smith and Bayles 2006). All three have an N-terminal TMS, and possibly a second one near their C-termini. |
Bacteria | Pseudomonadota | Trimeric CdtA/B/C of E. coli |
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1.C.98.1.2 | Cytolethal distending pore-forming toxin B (CdtB) of 317 aas and 2 TMSs of Drosophila primaeva (Magyar et al. 2025). |
None | Metazoa, Arthropoda | CdtB of Drosophila primaeva |
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1.C.99.1.1 | Cation (K+, Na+)-selective pore-forming Orf8a (Sars8a) peptide of 39 aas and 1 N-terminal TMS (Hsu et al. 2015, Scott and Griffin 2015). Because of its pore forming capacity, this protein could also be assigned to TC subclass 1.A (Barrantes 2021). |
Viruses | Orthornavirae, Pisuviricota | Orf8a of severe acute respiratory syndrome causing corona virus (SARS-CoV) (Q7TA23) |
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1.C.99.1.2 | Pore-forming protein of 122 aas with 1 N-terminal TM |
Viruses | Orthornavirae, Pisuviricota | Pore-former of Bat β-coronavirus |
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1.C.99.1.3 | Non structural protein 8 of 121 aas and 1 N-terminal TM |
Viruses | Orthornavirae, Pisuviricota | Protein 8 of Bat coronavirus 279/2005 (BtCoV) |
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1.C.99.1.4 | ORF8 protein of 121 aas and 1 N-terminal TMS. Orf8 is a short 29-amino-acid single-passage transmembrane peptide that forms cation-selective channels when assembled in lipid bilayers (Barrantes 2021). A cell-based system combined with flow cytometry can be used to evaluate antibody responses against SARS-CoV-2 transmembrane proteins in patients with COVID-19 (Martin et al. 2022). |
Viruses | Orthornavirae, Pisuviricota | ORF8 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) |
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1.C.99.1.5 | Uncharaacterized protein, Sars8b of 84 aas and 0 TMSs. This protein may be N-terminally truncated. |
Viruses | Orthornavirae, Pisuviricota | Sars8b of Severe acute respiratory syndrome-related coronavirus (SARS) |
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1.C.99.2.1 | Uncharacterized protein of 101 aas and 1 or 2 TMSs, with one TMS at the N-terminus, and possibly another at the C-terminus. |
Viruses | Orthornavirae, Pisuviricota | UP of SARS coronavirus WH20 |
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1.C.99.2.2 | Orf7a of 121 aas and 2 or 3 TMSs, one at the N-terminus, one at the C-terminus, and a peak of moderate hydrophobicity in the middle. N-terminal fragments of 29 aas, 39 aas and 43 aas can be found in the NCBI protein database (Acc# QIG55990, QIS30140, and QIZ64621, respectively). Bone marrow stromal antigen 2 (BST-2; tetherin) is an antiviral response protein that inhibits transport of viral particles after budding within infected cells. RNA viruses such as SARS-CoV-2 use various strategies to disable BST-2. ORF7a TMS interactions play a key role along with extracellular and juxtamembrane domains in modulating BST-2 function (Mann et al. 2023). |
Viruses | Orthornavirae, Pisuviricota | Orf7a of severe acute respiratory syndrome coronavirus 2 |
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1.C.99.2.3 | X4-like protein of 120 aas and 2 TMSs, N- and C-terminal. |
Viruses | Orthornavirae, Pisuviricota | X4-like protein of Rhinolophus bat coronavirus HKU32 |
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1.D.118.1.1 | The bone marrow stromal antigen 2, BST2. of 180 aas and 1 TMS. The pore-forming B18 peptide is derived from this protein (residues 80 - 97) (Lyu et al. 2020). |
Eukaryota | Metazoa, Chordata | BST-2 of Homo sapiens |
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1.D.118.1.2 | Bone marrow stromal antigen 2, BSA2, of 158 aas and 1 N-terminal TMS. |
Eukaryota | Metazoa, Chordata | BSA2 of Phascolarctos cinereus |
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1.D.118.1.3 | Uncharacterized protein of 424 aas and 2 TMSs, one N-terminal and one central. The first domain seems to be homologous to BSA2 (TC# 1.D.118 .1.1). |
Eukaryota | Metazoa, Chordata | UP of Sorex araneus (European shrew) |
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1.D.194.1.1 | Intestinalin (P30), a 30 aa peptide derived from the first 30 aas of LysC, derived from Clostridium intestinale strain URNW. The GenBank accession # given with this entry corresponds to the entire LysC protein as the 30 aa peptide does not yet have an accession #. The protein is predicted by the WHAT program to have an N-terminal TMS although this region does not show strong hydrophobicity. It forms large pores due to oligomerization of the 30 aa peptide. |
Bacteria | Bacillota | Intestinalin of Clostridium intestinale |
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1.D.194.1.2 | Peptidoglycan recognition protein family protein of 150 aa |
Bacteria | Bacillota | PG recognition protein of Bacillus cereus group |
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1.D.194.1.3 | N-acetylmuramoyl-L-alanine amidase of 204 aas and 1 N-terminal TM |
Bacteria | Armatimonadota | Amidase of Armatimonadetes bacterium |
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1.D.194.1.4 | Peptidoglycan recognition protein 5 |
Eukaryota | Metazoa, Chordata | PRP5 of Micropterus dolomieu |
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1.D.24.1.1 | Polytheonamide B from a bacterium symbiont of Theonella swinhoei pTSMAC1. It is of 145 aas with 1 TMS near the C-terminus of the protein. Antimicrobial peptide active against Gram-positive bacteria (MIC=4->125 ug/ml) (Freeman et al. 2012).It may act by forming transmembrane ion channels, since the peptide rapidly depolarizes the bacterial cytoplasmic membrane, simultaneously decreasing the membrane potential and intracellular potassium contents. The name 'proteusin' was inspired by Proteus, a Greek shape-shifting sea god. Compared to polytheonamide B, polytheonamide A has an additional sulfoxide moiety at Met-141, which arises from spontaneous oxidation during polytheonamide isolation. The potent cytotoxicity of PolyA against MCF-7 cancer cells originates from its two ion transport functions. Compound 1 depolarizes the plasma membrane and neutralizes acidic lysosomes. Xue et al. 2023 described how these two functions can be uncoupled by designing and synthesizing new analogues. |
Bacteria | Polytheonamide of Theonella swinhoei |
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1.D.24.1.2 | NHLP leader peptide family, RiPP precursor of 118 aas and possibly 1 C-terminal TMS. |
Bacteria | Cyanobacteriota | RIPP precursor of Scytonematopsis contorta HA4267-MV1 (algae metagenome) |
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1.D.24.1.4 | NHLP leader peptide family RiPP precursor pf 142 aas woth 1 C-terminal TMS. |
Bacteria | Cyanobacteriota | RiPP of Nostoc sp. KVJ20 |
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1.D.24.1.5 | NHLP leader peptide family RiPP precursor of 196 aas with one or two C-terminal TMSs. |
Bacteria | Pseudomonadota | RiPP of Tistrella mobilis |
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1.D.24.1.6 | Uncharacterized protein of 252 aas and 2 or 3 C-terminal TMSs. |
Bacteria | Candidatus Wallbacteria | UP of Candidatus Wallbacteria bacterium HGW-Wallbacteria-1 (groundwater metagenome) |
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1.D.24.1.7 | Uncharacterized protein of 184 aas and possibly as many as 2 semi-hydrophobic TMSs |
Bacteria | Gemmatimonadota | UP of Gemmatimonadales bacterium |
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1.D.24.2.1 | Thiocyanate hydrolase subunit gamma of 237 aas with 1 C-terminal TMS. |
Bacteria | Actinomycetota | TCH of Mycobacterium sp. GA-0227b |
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1.D.253.1.1 | Protein constituents of the Proteosomal β-barrel-nanopore complex: A peptide trimeric (GGS)n linker was used to connect the relevant protein domains (Zhang et al. 2021). See TC family (1.D.253)) description for details. |
Proteosomal β-barrel-nanopore complex derived of proteins from dissimilar sources. |
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1.E.1.1.1 | Lysis protein S; also called ''pinholin'' or pinholin S(21)68, of 71 aas and 2 TMSs. It forms small heptameric pores that depolarize the membrane (Park et al., 2007; Pang et al., 2009). This holin is of topological Class II, forming 2 TMSs, with the N- and C-termini inside (Park et al. 2006). TMS1 partially externalizes from the lipid bilayer regulates channel-formation and interacts with the membrane surface, whereas TMS2 remains buried in the lipid bilayer in the active conformation and forms the pore (Ahammad et al. 2019). Pinholin S(21)68 triggers the lytic cycle of bacteriophage phi21 in infected Escherichia coli. Activated transmembrane dimers oligomerize into small holes and uncouple the proton gradient. Structural models have been proposed for (1) the oligomeric pinhole (right-handed heptameric TMD2 bundle), (2) the active dimer (right-handed Gly-zipped TMD2/TMD2 dimer), and (3) the full-length pinholin protein before being triggered (Gly-zipped TMD2/TMD1-TMD1/TMD2 dimer in a line) (Steger et al. 2020). The TMSs are α-helical rather than pi or 310-helices which have been observed in other channel forming proteins (Drew et al. 2021). Pinholin S(21) mutations induce structural, topological and conformational changes (Ahammad et al. 2021). The helical tilt angle and dynamic properties of the transmembrane domains of pinholin S2168 have been determined using mechanical alignment EPR spectroscopy (Khan et al. 2023). |
Viruses | Heunggongvirae, Uroviricota | Lysis protein S (71 aas; P27360) |
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1.E.1.1.2 |
Lysis protein S. Identical to EssD, a holin from lambdoid prophage DLP12 with two TMSs (Srividhya and Krishnaswamy 2007). |
Bacteria | Pseudomonadota | Lysis protein S (71aas; P77237) |
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1.E.1.1.3 | Holin of 68 aas and 1 TMS. Deleting the lysis module, encoding the holin, lysin and two spanins, increases outer membrane vesicle (OMV) production, suggesting that during evolution this operon has been domesticated to regulate vesiculation, possibly through the elimination of non-recyclable peptidoglycan fragments (Pasqua et al. 2021). The expression of the lysis module is negatively regulated by environmental stress stimuli as high osmolarity, low pH and low temperature (Pasqua et al. 2021). |
Viruses | Heunggongvirae, Uroviricota | Holin of E. coli phage H-19B (68 aas; AAD04658) |
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1.E.1.1.4 | Lysis S family holin protein |
Bacteria | Pseudomonadota | Lysis S holin of E. coli |
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1.E.1.1.5 | Hypothetical protein, HP |
Bacteria | Pseudomonadota | HP of Cronobacter sakazakii |
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1.E.1.1.6 | Holin of 62 aas and 1 TMS |
Bacteria | Pseudomonadota | Putative holin of Hamiltonella defensa |
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1.E.1.1.7 | Lysis S family protein with fused N-terminal holin domain of 2 - 3 TMSs; 720 aas |
Bacteria | Pseudomonadota | Holin-Lysis S fusion protein of E. coli |
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1.E.1.1.8 | Holin of 86 aas and 1 TMS. |
Bacteria | Pseudomonadota | Holin of Pectobacterium polonicum |
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1.E.1.1.9 | Putative uncharacterized holin of 75 aas and 1 or 2 TMSs. Shows extensive similarity to members of TC family 1.E.25. |
Bacteria | Pseudomonadota | Holin of Salmonella enterica |
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1.E.10.1.1 | Lysis holin protein (late protein GP14) (Tedin et al. 1995). |
Viruses | Heunggongvirae, Uroviricota | GP14 (131 aas; spP11188) |
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1.E.10.1.2 |
Pneumococcal phage SV1 holin 1. |
Viruses | Heunggongvirae, Uroviricota |
Pneumococcal phage SV1 holin 1 |
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1.E.10.1.3 | Holin HolSMP (Orf43) (Shi et al. 2012). |
Viruses | Heunggongvirae, Uroviricota | HolSMP of Streptococcus suis phage SMP |
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1.E.10.1.4 | Anti-holin (gene 14) of 132 aas and 2 TMSs. It determines the precise timing of host cell lysis. Antiholins may also be stabilizing elements that ensure robust cell lysis under fluctuating physiological conditions (Mondal and Kolomeisky 2025). |
Viruses | Heunggongvirae, Uroviricota | Antiholin of Bacillus phage B103 (Bacteriophage B103) |
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1.E.11.1.1 | Holin 145 (Bon et al. 1997) |
Viruses | Heunggongvirae, Uroviricota | Holin (145 aas) |
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1.E.11.1.10 | Holin of 100 aas and 2 TMSs |
Bacteria | Actinomycetota | Holin of Atopobium parvulum |
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1.E.11.1.11 | Holin of 120 aas and 2 N-terminal TMSs. This holin has been used to generate pores in "ghosts" of this bacterium (Riangrungroj et al. 2023). |
Bacteria | Bacillota | Holin of Lactiplantibacillus plantarum subsp. plantarum |
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1.E.11.1.12 | Holin of 82 aas and 2 TMSs. |
Bacteria | Bacillota | Holin of Firmicutes bacterium HGW-Firmicutes-17 |
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1.E.11.1.2 | Holin | Viruses | Heunggongvirae, Uroviricota | Holin (88 aas) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.E.11.1.3 |
Holin of 85 aas, Ejh (Diaz et al. 1996). A synthetic peptide based on Ejh has been reconstituted and shown to be active (Haro et al. 2003). Ejh has been used to promote release of polyhydroxyalkanoate granules from bacterial cells (Martínez et al. 2011). |
Viruses | Heunggongvirae, Uroviricota | Holin EJh (85 aas) |
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1.E.11.1.4 | Holin |
Bacteria | Bacillota | Holin of of Streptococcus pyongenes |
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1.E.11.1.5 | Holin HolTW (Loessner et al. 1998). |
Viruses | Heunggongvirae, Uroviricota | Holin HolTS of Staphylococcus phage TWORT |
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1.E.11.1.6 | Putative holin |
Bacteria | Bacillota | Putative holin of Listeria innocua |
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1.E.11.1.7 | Putative holin; phage phiLC3 holin family |
Bacteria | Bacillota | Putative holin of Streptococcus sanguinis |
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1.E.11.1.8 | Holin (Orf33) of 167 aas from Stahylococcus phage K. Phage K lysis differentially affects planctonic and biofilm cells (Cerca et al. 2007; Curtin and Donlan 2006). 95% identical to HolGH15 of phage GH15 of S. aureus which has broad host range antibacterial activity against many pathogens (Song et al. 2016). |
Viruses | Heunggongvirae, Uroviricota | Orf33 of Stahylococcus phage K; HolGH15 of Staphylococcus phage GH15 |
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1.E.11.1.9 | Holin of the phage phi LC3 family of 91 aas and 2 TMSs |
Bacteria | Actinomycetota | Holin of Collinsella aerofaciens |
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1.E.11.2.1 |
Holin of Clostridium phage phiCP390 (Seal et al. 2011). This holin is identical to the holin of phage phiCP26F (gp23; F2VHY0). |
Viruses | Heunggongvirae, Uroviricota | Holin of Clostridium perfringens phage PhiCP390 |
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1.E.11.2.2 | Putative holin |
Bacteria | Bacillota | Putative holin of Clostridium perfringens |
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1.E.11.2.3 | Putative holin |
Bacteria | Bacillota | Putative holin of Geobacillus kustophilus |
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1.E.11.2.4 | Uncharacterized holin phage phi LC3 of 63 aas and 2 TMSs. |
Bacteria | Bacillota | Putative holin of Ruminiclostridium papyrosolvens |
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1.E.11.2.5 | Holin of 83 aas and 2 TMSs, Phage_holin_1. |
bacterium | Holin of a eubacterium |
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1.E.11.3.1 | Putative holin of 49 aas and 1 TMS. TMS 1 corresponds to TMS 2 in the holins of TC subfamilies 1.E.11.1 and 1.E.11.2. |
Bacteria | Pseudomonadota | Putative holin of Pseudomonas putida |
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1.E.11.3.10 | Uncharacterized protein of 60 aas and 1 TMS |
Bacteria | Pseudomonadota | UP of Chromatiales bacterium 21-64-14 (mine drainage metagenome) |
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1.E.11.3.11 | Uncharacterized protein of 62 aas and 1 TMS |
Bacteria | Pseudomonadota | UP of Chromatium okenii |
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1.E.11.3.2 | Putative holin of 50 aas and 1 TMS |
Bacteria | Pseudomonadota | Putative holin of Pseudomonas syringae |
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1.E.11.3.3 | Putative uncharacterized holin of 32 aas and 1 TMS. |
Bacteria | Pseudomonadota | UP of Halomonas sp. HL-48 (microbial mat metagenome) |
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1.E.11.3.4 | Uncharacterized protein of 48 aas and 1 TMS. |
Bacteria | Pseudomonadota | UP of Marinobacter sp. T13-3 (gas well metagenome) |
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1.E.11.3.5 | Uncharacterized protein of 63 aas and 1 TMS (N-terminal) |
Bacteria | Pseudomonadota | UP of Mangrovitalea sediminis |
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1.E.11.3.6 | Uncharacterized protein of 41 aas and 1 TMS |
Bacteria | Pseudomonadota | UP of Nitrincola nitratireducens |
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1.E.11.3.7 | Uncharacterized protein of 48 aas and 1 TMS. |
Bacteria | Pseudomonadota | UP of Halioglobus sediminis |
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1.E.11.3.8 | Uncharacterized protein of 49 aas and 1 TMS |
Bacteria | Pseudomonadota | UP of Alcanivorax nanhaiticus |
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1.E.11.3.9 | Uncharacterized protein of 54 aas and 1 TMS |
Bacteria | Pseudomonadota | UP of Gynuella sunshinyii |
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1.E.11.4.1 | Holin of 176 aas and 2 N-terminal TMSs. |
Bacteria | Bacillota | Holin of Lactiplantibacillus plantarum |
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1.E.12.1.1 | Holin (114 aas) (Henrich et al. 1995). |
Viruses | Heunggongvirae, Uroviricota | Holin of Lactobacillus gasseri phage Adh |
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1.E.12.1.2 | Holin |
Bacteria | Bacillota | Holin of Lactobacillus crispatus |
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1.E.12.1.3 | Putative holin |
Bacteria | Bacillota | Putative holin of Lachnospireceae bacterium |
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1.E.12.2.1 | Holin of the LL-H family |
Bacteria | Bacillota | Holin of Lactobacillus iners |
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1.E.12.2.2 | Uncharacterized protein (133 aas) |
Bacteria | Firmicutes | Uncharacterized protein of Lactobacillus hominis |
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1.E.12.2.3 |
Putative holin of Lactobacillus phage Lv-1 |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Lactobacillus phage Lv-1 |
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1.E.12.2.4 | Putative holin of 133 aas |
Bacteria | Bacillota | Putative holin of Lactobacillus sp. |
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1.E.12.2.5 | Putative holin of 137 aas |
Bacteria | Bacillota | Putative holin of Lactobacillus amylovorus |
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1.E.12.2.6 | Putative holin of the LL-H family (124 aas). |
Bacteria | Bacillota | Putative holin of Lactobacillus iners |
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1.E.12.2.7 | Putative holin of the LL-H family (134 aas) |
Bacteria | Bacillota | Putative holin of Lactobacillus fermentum |
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1.E.13.1.1 | Holin of 117 aas and 3 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Holin of Lactococcus lactis phage P008 |
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1.E.13.1.2 | Holin (Chandry et al. 1997). |
Viruses | Heunggongvirae, Uroviricota | Holin of Lactococcus phage SK1 |
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1.E.13.1.3 | Phage holin |
Bacteria | Bacillota | Holin of Lactococcus garvieae |
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1.E.13.2.1 | Uncharaacterized protein of 187 aas and 3 TMSs. |
Eukaryota | Metazoa, Nematoda | UP of Toxocara canis (dog roundworm) |
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1.E.14.1.1 | LrgA holin-like protein (Bayles, 2003; Yang et al., 2005; Ranjit et al. 2011). Functions in biofilm formation (Ranjit et al. 2011). Calcium-chelating alizarin and other anthraquinones inhibit biofilm formation and modulate the expression of the cid/lrg genes (encoding the holin/antiholin system) (Lee et al. 2016). CidA and LrgA function as holins to support endolysin-induced lysis, and the lrgAB operon also facilitates pyruvate uptake during microaerobic and anaerobic growth (Laabei and Duggan 2022). The Staphylococcus aureus CidA and LrgA proteins are functional holins involved in the transport of by-products of carbohydrate metabolism (Endres et al. 2022). |
Bacteria | Bacillota | LrgA of Staphylococcus aureus (147 aas; gbU52961) |
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1.E.14.1.10 | LrgA holin, involved in biofilm formation, oxidative stress and competence for DNA transfer. Regulated at the transcriptional level by the two component regulatory system, LytST (Ahn et al. 2012). |
Bacteria | Bacillota | LrgA of Streptococcus mutants |
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1.E.14.1.11 | LrgA-type holin of 136 aas and 4 TMSs |
Bacteria | Deinococcota | Putative holin of Deinococcus deserti |
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1.E.14.1.12 | LrgA family holin of 118 aas and 4 TMSs |
Bacteria | Bacillota | Holin of Bacillus toyonensis |
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1.E.14.1.13 | Holin of 114 aas and 3 TMSs |
Bacteria | Bacteroidota | Holin of Capnocytophaga ochracea |
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1.E.14.1.14 | LrgA family holin of 129 aas and 4 TMSs |
Bacteria | Bacillota | Holin of Exiguobacterium sibiricum |
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1.E.14.1.15 | LrgA paralogue of 120 aas |
Bacteria | Bacillota | LrgA of Streptococcus mutans |
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1.E.14.1.16 | Putative holin of 128 aas and 4 TMSs, CidA or YwbH. Functions in acetic acid promotion of biofilm formation (Chen et al. 2015). Increases the activity of extracellular
murein hydrolases probably by mediating their export via hole formation. May be inhibited by LrgB/YwbG (2.A.122.1.5). |
Bacteria | Bacillota | CidA of Bacillus subtilis |
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1.E.14.1.17 | Putative holin (or anti-holin) of 146 aas and 4 TMSs, YsbA or LrgA. YsbA is important for acetic acid induced biofilm formation (Chen et al. 2015) and for pyruvate utilization (van den Esker et al. 2016). van den Esker et al. 2016 proposed that YsbA is a pyruvate transporter. Thus, there is some question about the function of this protein and other members of this family. |
Bacteria | Bacillota | YsbA of Bacillus subtilis |
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1.E.14.1.2 |
Holin, CidA (Bayles, 2003; Yang et al., 2005; Ranjit et al. 2011). Functions in biofilm formation in part by mediating release of cytoplasmic DNA during cell lysis to contribute to the biofilm matrix (Ranjit et al. 2011; Fischer et al. 2013). This protein contributes to cell lysis of dying cells (Patton et al. 2005). Calcium-chelating alizarin and other anthraquinones inhibit biofilm formation and modulate the expression of the cid/lrg genes (encoding the holin/antiholin system) (Lee et al. 2016). CidA and LrgA function as holins to support endolysin-induced lysis, and the lrgAB operon also facilitates pyruvate uptake during microaerobic and anaerobic growth (Laabei and Duggan 2022). The Staphylococcus aureus CidA and LrgA proteins are functional holins involved in the transport of by-products of carbohydrate metabolism (Endres et al. 2022). |
Bacteria | Bacillota | CidA of Staphylococcus aureus (P60646) |
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1.E.14.1.3 | Marine hydrolase exporter (MHE) (Desvaux et al. 2005). |
Bacteria | Fusobacteriota | MHE of Fusobacterium mortiferum (C3WD05) |
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1.E.14.1.4 | 4 TMS LrgA putative holin/anti-holin. This protein has also been suggested to be a component of a 3-hydroxypropionate exporter, functioning together with YohK (TC# 2.A.1.122.1.1) (Nguyen-Vo et al. 2020). |
Bacteria | Pseudomonadota | LrgA of E. coli (F4V3T5) |
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1.E.14.1.5 | 4 TMS murein hydrolase exporter, LrgA-like protein |
Archaea | Euryarchaeota | LrgA-like protein of Thermococcus gammatolerans (C5A1Q2) |
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1.E.14.1.6 | 4 TMS Hypothetical protein (HP) |
Archaea | Euryarchaeota | HP of Pyrococcus furiosus (Q8TZY1) |
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1.E.14.1.7 | 4 TMS LrgA-like protein |
Bacteria | Chloroflexota | LrgA-like protein of Chloroflexus aggregans (B8GAY6) |
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1.E.14.1.8 | 4 TMS holin protein |
Bacteria | Bacillota | Holin of Pediococcus acidilactici (D2EIF4) |
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1.E.14.1.9 | CidA holin-like protein |
Bacteria | Pseudomonadota | CidA of E. coli (E7UC95) |
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1.E.14.2.1 | Putative archaeal holin of 145 aas and 4 TMSs |
Archaea | Euryarchaeota | Putative holin of Methanocaldococcus (Methanococcus) vulcanius |
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1.E.14.2.2 | Putative archaeal holin of 145 aas and 4 TMSs |
Archaea | Euryarchaeota | Holin of Methanocaldococcus vulcanius |
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1.E.14.2.3 | Putative holin of 194 aas and 5 TMSs |
Archaea | Euryarchaeota | Putative holin of Methanocaldococcus sp. |
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1.E.15.1.1 | ArpQ holin-like protein | Bacteria | Bacillota | ArpQ (58 aas; gbZ50854) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.E.16.1.1 | Cph1 holin (Functionally characterized (Martín et al. 1998)). |
Viruses | Heunggongvirae, Uroviricota | Cph1 holin (134 aas; gbZ47794) |
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1.E.16.1.2 | gp18 holin of Listeria phage P40 |
Viruses | Heunggongvirae, Uroviricota | gp18, Listeria phage P40 |
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1.E.16.1.3 | Phage related holin |
Bacteria | Bacillota | Holin of Lactobacillus ruminis |
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1.E.16.1.4 | Toxin secretion phage lysis holin |
Bacteria | Bacillota | Holin of Streptococcus mitis |
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1.E.17.1.1 | BlyA holin-like protein. When expressed in E. coli, it can release a latent ClyA (HlyE; 1.C.10.1.1) cytolysin from the cell (Ludwig et al. 2008). |
Bacteria | Spirochaetota | BlyA of cp32 prophage from Borrelia burgdorferi (Q44828) |
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1.E.17.1.2 | BlyA family holin |
Bacteria | Spirochaetota | BlyA-like protein of Borrelia garinii |
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1.E.17.1.3 | BlyA family holin |
Bacteria | Spirochaetota | BlyA-like protein of Borrelia sp. SV1 |
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1.E.17.1.4 | BlyA family holin |
Bacteria | Spirochaetota | BlyA-like protein of Borrelia hermsii |
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1.E.17.1.5 | Putative holin of 59 aas and 1 TMS |
Bacteria | Spirochaetota | Putative holin of Borrelia burgdorferii |
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1.E.17.1.6 | BlyA Family holin of 65 aas and 1 TMS. |
Bacteria | Spirochaetota | Holin of Borrellia garinii |
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1.E.17.2.1 | Holin, BlyA family member of 61 aas and 1 TMS |
Bacteria | Spirochaetota | Holin of Borrelia crocidurae |
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1.E.17.2.2 | Bly family holin of 55 aas and 1 TMS. |
Bacteria | Spirochaetota | Bly family holin of Borrelia hermsii |
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1.E.18.1.1 | The L. lactis phage r1t holin, Orf49 | Viruses | Heunggongvirae, Uroviricota | Orf49 holin of L. lactis phage r1t (spQ38134) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.E.18.1.10 | Putative holin, GP2, of 135 aas and 4 TMSs |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Rhodococcus phage E3 |
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1.E.18.1.11 | Putative holin of 80 aas and 2 TMSs |
Bacteria | Actinomycetota | Holin of Agrococcus pavilionesis |
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1.E.18.1.12 | Holin of 78 aas and 2 TMSs. |
Archaea | Euryarchaeota | Holin of uncultured Methanobrevibacter sp. |
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1.E.18.1.2 |
The Mycobacteriophage Ms6 hol gene product, Gp4. May be an antiholin, counteracting the effect of the holin Gp5 (Catalão et al. 2011). |
Viruses | gp4 of Mycobacteriophage Ms6 |
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1.E.18.1.3 | Protein of unknown function |
Bacteria | Bacillota | Uncharacterized protein of Anaerostipes caccae (67 aas) |
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1.E.18.1.4 | Holin |
Bacteria | Actinomycetota | Holin of Corynebacterium ulcerans |
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1.E.18.1.5 | Putative holin, gp37 |
Viruses | Heunggongvirae, Uroviricota | gp37 of mycobacterial phage Che9d |
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1.E.18.1.6 | Putative holin |
Bacteria | Actinomycetota | Putative holin of Propionibacterium acnes |
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1.E.18.1.7 | Putative holin |
Bacteria | Actinomycetota | Putative holin of Renibacterium salmoninarium |
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1.E.18.1.8 | Putative holin |
Bacteria | Bacillota | Putative holin of Eubacterium saphenum |
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1.E.18.1.9 | Uncharacterized 4 TMS holin of 168 aas with two 2 TMS repeats. |
Bacteria | Actinomycetota | UP of Rhodococcus opacus |
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1.E.19.1.1 | Holin (161 aas) |
Bacteria | Actinomycetota | Holin of Mobiluncus mulieris |
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1.E.19.1.10 | Phage-related holin of 142 aas and 4 TMSs |
Bacteria | Mycoplasmatota | Holin of Acholeplasma laidlawii |
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1.E.19.1.11 | Holin of 141 aas and 2 TMSs |
Bacteria | Chloroflexota | Holin of Dehalococcoides ethenogenes |
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1.E.19.1.12 | Holin of 137 aas and 2 TMSs (Jin et al. 2013). |
Viruses | Heunggongvirae, Uroviricota | Holin of Geobacillus phage GBSV1 |
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1.E.19.1.13 | Toxin secretion/holin system; holin of 124 aas |
Bacteria | Mycoplasmatota | Holin of Mycoplasma sp. |
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1.E.19.1.14 | Putative holin of 142 aas |
Bacteria | Chloroflexota | Putative holin of Herpetosiphon aurantiacus |
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1.E.19.1.15 | Putative holin of 141 aas and 3 TMSs |
Bacteria | Bacteroidota | Putative holin of Alistipes shahii |
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1.E.19.1.16 | Holin of 138 aas and 3 TMSs (Kong and Ryu 2015). |
Viruses | Heunggongvirae, Uroviricota | Holin of Bacillus phage PBC1 |
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1.E.19.1.17 | Holin of 139 aas and 2 TMSs. |
Bacteria | Bacteroidota | Holin of Bacteroides fragilis |
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1.E.19.1.18 | Holin of a tactivirus of 131 aas and 3 TMSs. |
Viruses | Bamfordvirae, Preplasmiviricota | Holin of Tectiviridae sp. |
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1.E.19.1.2 | Uncharacterized protein |
Bacteria | Bacillota | Uncharacterized protein of Lachnospiraceae bacterium |
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1.E.19.1.3 | Putative holin of 152 aas and 3 TMSs |
Bacteria | Bacillota | Putative holin of Brevibacillus brevis |
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1.E.19.1.4 | Uncharacterized protein |
Viruses | Heunggongvirae, Uroviricota | Uncharacterized protein of Bacillus phage IEBH |
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1.E.19.1.5 | Uncharacterized protein (142 aas) |
Bacteria | Bacillota | Uncharacterized protein of Clostridium bolteae |
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1.E.19.1.6 | Holin |
Bacteria | Actinomycetota | Holin of Corynebacterium diphtheriae |
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1.E.19.1.7 | Putative holin of 139 aas nd 3 TMSs |
Bacteria | Thermotogota | Putative holin of Petrotoga mobilis |
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1.E.19.1.8 | Prophage lambda Sa04 protein |
Bacteria | Bacillota | Sa04 protein of Megasphaera elsdenii |
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1.E.19.1.9 | Holin (129 aas) |
Bacteria | Fusobacteriota | Fusobacterium sp. ZP-0 |
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1.E.19.2.1 | Holin of 170 aas and 3 TMSs |
Bacteria | Bacillota | Holin of Macrococcus caseolyticus |
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1.E.19.2.2 | Staphylococcus aureus phage P68 holin, hol15 (Takác et al. 2005). |
Viruses | Heunggongvirae, Uroviricota | Hol15 of Staphylococcal phage P68 |
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1.E.19.2.3 | phage-like holin, YqxH1 (135 aas) |
Bacteria | Bacillota | YqxH1 of Bacillus amyloliquefaciens |
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1.E.19.3.1 | The C. difficile holin, TcdE. TcdE acts as a holin-like protein to facilitate the release of C. difficile toxins A and B to the extracellular environment, but, unlike most phage holins, it does not cause the non-specific release of cytosolic contents. TcdE is thus a bacterial holin that releases toxins into the environment by a phage-like system (Tan et al. 2001; Govind and Dupuy 2012). Different isoforms have differing activities in toxin release (Govind et al. 2015). An autolysin, Cwp19 (L7PGA3), may also play a role in toxin release (El Meouche and Peltier 2018). Adaptation of this phage-derived holin/endolysin system to toxin transport has been discussed (Mehner-Breitfeld et al. 2018). Thus, TcdE exists as three isoforms, differing with respect to their N-terminal extensions. The longest TcdE isoform has a moderate effect on cell growth, whereas the shortest isoform strongly induces lysis. The effect of the longest isoform was inhibitory for cell lysis, implying a regulatory function of the N-terminal 24 residues. Mehner-Breitfeld et al. 2018 analyzed the PaLoc sequence of 44 C. difficile isolates and found that four of these encode only the short TcdE isoform, and the most closely related holins from C. difficile phages only possess one of these initiation codons, indicating that the N-terminal extensions of TcdE evolved in C. difficile. |
Bacteria | Bacillota | TcdE of Clostridium difficile |
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1.E.19.3.2 | Holin of 141 aas and 3 TMSs, TcsE (Sirigi Reddy et al. 2013). |
Bacteria | Bacillota | TcsE of Clostridium sordellii |
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1.E.19.4.1 |
Holin of Clostridium phage phi3626. The function has been demonstrated (Zimmer et al. 2002). The charge distribution of this 2 TMS protein suggestions that the β-turn between TMSs 1 and 2, with 7 lys and arg residues, is in the cytoplasm and the N- and C-termini are in the periplasm (Zimmer et al. 2002). |
Viruses | Heunggongvirae, Uroviricota | Holin of Clostridium phage phi3626 |
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1.E.19.4.2 | Toxin secretion holin of 137 aas and 3 TMSs. |
Bacteria | Actinomycetota | Holin of Atopobium minutum |
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1.E.19.4.3 | Putative holin of 158 aas and 3 TMSs. |
Bacteria | Actinomycetota | Putative holin of Gardnerella vaginalis |
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1.E.19.4.4 | Uncharacterized holin of 161 aas and 4 TMSs. |
Archaea | Candidatus Bathyarchaeota | Putative holin of Candidatus Bathyarchaeota archaeon |
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1.E.19.4.5 | Phage holin family protein of 146 aas and 3 TM |
Archaea | Euryarchaeota | Holin of Methanoculleus sp. |
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1.E.19.5.1 | Holin of 162 aas and 3 TMSs |
Bacteria | Thermodesulfobacteriota | Putative holin of Desulfovibrio vulgaris |
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1.E.19.5.2 | Holin of 199 aas and 3 TMSs. |
Bacteria | Thermodesulfobacteriota | Holin of Maridesulfovibrio frigidus |
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1.E.19.5.3 | Phage holin family protein of 166 aas and 3 TMSs.
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Bacteria | Thermodesulfobacteriota | Holin of Bilophila wadsworthia |
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1.E.19.6.1 | Putative holin of 178 aas and 4 TMSs |
Bacteria | Bacteroidota | Holin of Pedobacter saltans |
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1.E.19.6.2 | Putative holin of 181 aas and 3 TMSs |
Bacteria | Bacteroidota | Holin of Capnocytophaga sputigena |
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1.E.19.6.3 | Putative holin of 170 aas and 3 TMSs |
Bacteria | Bacteroidota | Holin of Cyclobacterium marinum (Flectobacillus marinus) |
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1.E.2.1.1 | Lysis protein S of phage lambda, holin S105. The lambda-holin protein can mediate a caspase-independent non-apoptotic mode of cell death (Agu et al. 2007). Topological class I with three TMSs. The N-terminus is outside and the C-terminus is inside (Graschopf and Bläsi 1999; Gründling et al. 2000). Nearly identical to the holin of Shigella phage Sf6 (Dover et al. 2016). It lambda protein has a three-helix topology with an unstructured C-terminal domain, as well as at least one interface on TMS1 which is exposed to the lumen of the hole, and a highly constrained steric environment suggestive of a tight helical packing interface at TMS2 (Morris et al. 2023). |
Viruses | Heunggongvirae, Uroviricota | Lysis protein S (105 aas; spP03705) |
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1.E.2.1.10 | Holin of 108 aas; the gene is in a prophage genome adjacent to genes encouding a lysozyme inhibitor and a lytic protein. |
Bacteria | Pseudomonadota | Holin of E. coli |
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1.E.2.1.11 | Holin (N-terminal 100 aas) fused to a D-alanyl-D-alanine carboxypeptidase (C-terminal 138 aas). The protein is 238 aas in length with 3 N-terminal TMSs. |
Bacteria | Pseudomonadota | Fusion holin of Serratia odorifera |
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1.E.2.1.12 | Putative holin of 96 aas and 3 TMSs. |
Bacteria | Pseudomonadota | Holin of Acinetobacter proteolyticus |
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1.E.2.1.13 | Holin, lambda family, of 108 aas and 3 TMSs, ChiW (Hamilton et al. 2014). It is involved (possibly indirectly) in chitinase secretion (Costa et al. 2019). |
Bacteria | Pseudomonadota | Holin of Serratia marcescens |
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1.E.2.1.14 | Holin of 110 aas and 3 TMSs (Czajkowski 2019). |
Bacteria | Pseudomonadota | Holin of Pectobacterium zantedeschiae |
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1.E.2.1.2 | Lysis protein 13, gp65 of enterobacterial phage P22. |
Viruses | Heunggongvirae, Uroviricota | Lysis protein 13 (108 aas; spP09962) |
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1.E.2.1.3 | Hypothetical lysis protein | Bacteria | Pseudomonadota | Hypothetical lysis protein (118 aas; spP44188) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.E.2.1.4 | Hol-1 of lysogenic Xenorhabdus nematophila (Brillard et al., 2003) | Bacteria | Pseudomonadota | Hol-1 of lysogenic Xenorhabdus nematophila (CAB58444) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.E.2.1.5 |
Putative holin |
Bacteria | Pseudomonadota | Putative holin of Pseudomonas syringae |
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1.E.2.1.6 | Putative holin |
Bacteria | Pseudomonadota | Putative holin of Klebsiella oxytoca |
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1.E.2.1.7 | Putative holin |
Bacteria | Pseudomonadota | Putative holin of Pantoea sp. |
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1.E.2.1.8 | Putative holin |
Bacteria | Pseudomonadota | Putative holin of Actinobacillus succinogenes |
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1.E.2.1.9 | Putative phage-like holin of 112 aas and 3 TMSs |
Bacteria | Pseudomonadota | putative holin of Hamiltonella defensa subsp. Acyrthosiphon pisum |
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1.E.2.2.1 | Helicobacter phage 1961P holin_3 superfamily protein |
Viruses | Heunggongvirae, Uroviricota | Helicobacter phage 1961P holin |
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1.E.2.2.2 | Putative holin |
Bacteria | Campylobacterota | Putative holin of Campylobacter concisus |
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1.E.2.2.3 | Putative holin |
Bacteria | Campylobacterota | Putative holin of Campylobacter jejuni |
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1.E.2.2.4 | Putative holin |
Bacteria | Campylobacterota | Putative holin of Arcobacter butzleri |
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1.E.2.3.1 | Phage-holin-3 superfamily (CDD) member of 72 aas and possibly 1-2 TMSs. Therre were no obvious homologues in the NCBI database as of 3/3/14. However, rseidues 9 - 54 in this protein match residues 9 - 54 in TC# 1.E.2.1.1 with 35% identity and 46% similarity with no gaps. |
Bacteria | Cyanobacteriota | Putative holin of Cyanothece sp. PCC 7425 |
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1.E.2.3.2 | Uncharacterized protein of 71 aas and 1 or 2 TMSs |
Bacteria | Cyanobacteriota | UP of Nostoc linckia |
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1.E.2.3.3 | Uncharacterized protein of 83 aas and 1 TMS. |
Bacteria | Cyanobacteriota | UP of Oculatella sp. FACHB-28 |
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1.E.2.3.4 | Uncharacterized protein of 72 aas and 1 or 2 TMSs. |
Bacteria | Cyanobacteriota | UP of Calothrix brevissima |
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1.E.2.3.5 | Uncharacterized protein of 61 aas and 1 or 2 TMSs. |
Bacteria | Cyanobacteriota | UP of Leptolyngbya sp. FACHB-321 |
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1.E.2.3.6 | Uncharacterized protein of 68 aas and 1 or 2 TMSs. |
Bacteria | Bacteroidota | UP of Flavobacterium sp. CLA17 |
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1.E.2.3.7 | Uncharacterized protein of 64 aas and 1 TMS |
Bacteria | Cyanobacteriota | UP of Desertifilum sp. SIO1I2 |
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1.E.2.3.8 | Uncharacterized protein of 71 aas and 1 or 2 TMSs. |
Bacteria | Cyanobacteriota | UP of Trichocoleus sp. FACHB-591 |
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1.E.2.4.1 | Putative holin of 93 aas and 3 TMSs (Zampara et al. 2020). |
Viruses | Heunggongvirae, Uroviricota | Holin of Campylobacter phage F375 |
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1.E.2.4.2 | Uncharacterized protein of 101 aas and 3 TMSs in a 1 + 2 TMS arrangement. |
Bacteria | Campylobacterota | UP of Campylobacter sp. LR286c |
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1.E.2.4.3 | Phage holin family protein of 111 aas and 3 TMSs in a 1 + 2 TMS arrangement. |
Bacteria | Campylobacterota | Holin of Helicobacter japonicus |
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1.E.2.4.4 | Uncharacterized protein of 113 aas and 3 TMSs in a 1 + 2 TMS arrangement. |
Bacteria | Campylobacterota | UP of Campylobacter troglodytis |
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1.E.20.1.1 | Holin, Hol (Nakayama et al. 2000) |
Bacteria | Pseudomonadota | Hol of Pseudomonas aeruginosa PAO1 |
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1.E.20.1.2 | Pyocin R2_PP holin |
Bacteria | Pseudomonadota | Pyocin R2-PP holin of Pseudomonas aeruginosa |
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1.E.20.1.3 | SH3 type 3 domain-containing protein |
Bacteria | Pseudomonadota | SHE type 3 domain-containing protein of Brucella sp. |
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1.E.20.1.4 | Holin of 115 aas and 3 TMSs, pyocin R2 holin. Functions in DNA release within biofilms (Wang et al. 2016). A gene cluster encoding a bacteriophage-derived pyocin and its lysis cassette was upregulated in phenozine producing strains. A holin encoded in this gene cluster was found to contribute to the release of eDNA in biofilm matrices, demonstrating that the influence of the phenozine, 2-OH-PCA, on eDNA production is due in part to cell autolysis as a result of pyocin production and release (Wang et al. 2016). |
Bacteria | Pseudomonadota | Holin of Pseudomonas chlororaphis |
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1.E.20.1.5 | Uncharacterized protein of 104 aas and 2 or 3 TMSs |
Archaea | UP of Candidatus Pacearchaeota archaeon |
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1.E.20.1.6 | Uncharacterized protein of 104 aas and 3 TMSs. |
Archaea | Euryarchaeota | UP of Methanofollis liminatans |
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1.E.21.1.1 | Putative holin |
Bacteria | Chloroflexota | Putative holin of Dehalococcoides sp GT |
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1.E.21.1.2 | Uncharacterized protein |
Bacteria | Bacillota | Uncharacterized protein of Facklamia hominis |
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1.E.21.1.3 | Holin |
Viruses | Heunggongvirae, Uroviricota | Holin of Entereococcal phage BC-611 |
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1.E.21.1.4 | Putative holin of 88 aas and 3 TMSs |
Bacteria | Bacillota | Putative holin of Lysinibacillus fusiformi |
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1.E.21.2.1 | Holin, hol118 of 96 aas and 3 TMSs (Kuo et al. 2009). A stably engineered holin-expressing suicidal attenuated strain of Listeria monocytogenes has been used to deliver proteins and DNA to mammalian intestinal epithelial cells (Kuo et al. 2009). |
Viruses | Heunggongvirae, Uroviricota | hol118 of Listeria monocytogenes phage A118 |
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1.E.21.2.2 | Putative holin |
Bacteria | Actinomycetota | Putative holin of Bifidobacterium dentium |
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1.E.22.1.1 | Holin |
Bacteria | Pseudomonadota | Holin of Neisseria gonorrhoeae |
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1.E.22.1.2 | Holin |
Bacteria | Pseudomonadota | Holin of Neisseria meningitidis |
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1.E.22.2.1 | Putative holin of 63 aas and 1 TMS. |
Bacteria | Bacillota | Putative holin of Calditerricola satsumensis |
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1.E.22.3.1 | Putative holin of 80 aas and 1 TMS. |
Bacteria | Actinomycetota | Putative holin of Saccharomonospora cyanea |
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1.E.22.3.2 | Putative holin of 64 aas and 1 TMS. |
Bacteria | Actinomycetota | Putative holin of Mycobacterium avium |
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1.E.22.3.3 | Putative holin of 77 aas and 1 TMS |
Bacteria | Actinomycetota | Putative holin of Rhodococcus fascians |
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1.E.22.3.4 | Putative holin of 77 aas and 1 TMS |
Bacteria | Actinomycetota | Putative holin of Corynebacterium ulceribovis |
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1.E.23.1.1 | The Bacillus morphognesis and germination protein; putative holin, YwcE (Real et al., 2005) |
Bacteria | Bacillota | YwcE of Bacillus subtilis (P39603) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.E.23.1.2 | Uncharacterized protein |
Bacteria | Bacillota | Uncharacterized protein of Bacillus clausii |
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1.E.23.1.3 | Putative holin, YwcE |
Bacteria | Bacillota | Putative holin of Bacillus amyloliquefaciens |
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1.E.23.1.4 | Putative holin of 98 aas and 3 TMSs |
Bacteria | Bacillota | Putative holin of Pontibacillus halophilus |
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1.E.23.1.5 | Putative holin of 94 aas and 3 TMSs. |
Bacteria | Bacillota | Holin of Aneurinibacillus aneurinilyticus |
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1.E.23.2.1 | Putative holin |
Bacteria | Bacillota | Putative holin of Halobacillus halophilus |
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1.E.23.2.2 | Putative holin of 97 aas and 3 TMSs |
Bacteria | Bacillota | Holin of Lentibacillus amyloliquefaciens |
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1.E.24.1.1 | The phage Dp-1 holin (74 aas) (Sheehan et al., 1997) | Viruses | Heunggongvirae, Uroviricota | Holin of Dp-1 Bacteriophage (O03978) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.E.24.1.2 | The enterococcal chromosomal holin (68 aas) | Bacteria | Bacillota | Holin of Enterococcus faecalis (Q830I1) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.E.24.1.3 |
Phage PhiAM2 holin (74 aas) (Identical to Lactococcus phage ul36 gpOfr74B holin (Labrie et al. 2004)). |
Viruses | Heunggongvirae, Uroviricota | Holin of PhiAM2 Bacteriophage (Q9G090) |
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1.E.24.1.4 | Holin of 74 aas and 2 TMSs (Roces et al. 2016). It is identical to the holin of Lactococcal Prophage TP712 (Escobedo et al. 2019). |
Bacteria | Bacillota | Holin of Lactococcus lactis subsp. cremoris (A2RJJ3); identical to the holin of |
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1.E.24.1.5 | Putative chromosomal holin (87 aas) | Bacteria | Actinomycetota | Holin of Bifidobacterium adolescentis (A7A6X9) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.E.24.2.1 | Holin family protein |
Bacteria | Bacillota | Holin family protein of Solobacterium moorei |
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1.E.24.3.1 | Uncharacterized protein |
Bacteria | Actinomycetota | Uncharacterized protein of Collinsella tanakaei |
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1.E.25.1.1 | Pseudomonas phage F116 holin |
Viruses | Heunggongvirae, Uroviricota | Holin of Pseudomonas phage F116 |
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1.E.25.1.2 | Variovorax paradoxus holin |
Bacteria | Pseudomonadota | Holin of Variovorax paradoxus |
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1.E.25.1.3 | hypothetical protein |
Bacteria | Pseudomonadota | Holin of Bordetella bronchiseptica |
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1.E.25.1.4 | Uncharacterized protein |
Bacteria | Pseudomonadota | Uncharacterized protein of Acidovorax citrulli |
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1.E.25.1.5 | Putative holin |
Bacteria | Pseudomonadota | Putative holin of Laribacter hongkongensis |
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1.E.25.1.7 | Holin of 83 aas and 1 TMS |
Bacteria | Pseudomonadota | Holin of Acinetobacter nosocomialis |
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1.E.25.2.1 | Serratia NucE (RegA) holin (Berkmen et al. 1997). |
Bacteria | Pseudomonadota | NucE of Serratia marcescens (gbU11698) |
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1.E.25.2.2 | Putative holin, NucE |
Bacteria | Pseudomonadota | NucE of Erwinia tasmaniensis |
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1.E.25.2.3 | Putative holin of 100 aas and 2 N-terminal TMSs |
Bacteria | Pseudomonadota | Holin of Pectobacterium atrosepticum |
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1.E.25.2.4 | Putative holin and DUF4254 domain-containing protein of 94 aas and 1 or 2 N-terminal TMSs. |
Bacteria | Pseudomonadota | Holin of Raoultella terrigena |
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1.E.25.2.5 | Putative holin of 97 aas and 1 or 2 TMSs. |
Bacteria | Pseudomonadota | Holin of Yersinia frederiksenii |
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1.E.25.2.6 | Putative holin of 73 aas and 2 TMSs. |
Bacteria | Pseudomonadota | Holin of Pectobacterium zantedeschiae |
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1.E.25.2.7 | Putative holin of 89 aas and 1 or 2 TMSs (Czajkowski 2019). |
Viruses | Heunggongvirae, Uroviricota | Holin of Dickeya phage BF25/12 |
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1.E.26.1.1 | Holin (105 aas) |
Bacteria | Bacillota | Holin of Clostridium phytofermentans |
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1.E.26.1.10 | Putative holin of 186 aas |
Bacteria | Bacillota | Putative holin of Paenibacillus polymyxa |
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1.E.26.1.11 | Uncharacterized protein of 172 aas |
Bacteria | Bacillota | UP of Lactobacillus brevis |
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1.E.26.1.12 | Putative holin of 109 aas and 1 TMS |
Bacteria | Thermomicrobiota | Putative holin of Nitrolancea hollandica |
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1.E.26.1.13 | Putative holin of 113 aas and 1 TMS |
Bacteria | Bacillota | Putative holin of Paenibacillus polymyxa |
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1.E.26.1.2 | SE-1 phage holin of 123 aas and 1-3 TMSs (Yuan et al. 2016). |
Bacteria | Bacillota | Holiin of SE-1 phage infecting Erysipelothrix rhusiopathiae |
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1.E.26.1.3 | Phage holin of the LL0H family (110 aas) |
Bacteria | Bacillota | Holin of Streptococcus pneumoniae |
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1.E.26.1.4 | Putative holin of 1112 aas and 1 TMS |
Bacteria | Bacillota | Putative holin of Caldicellulosiruptor owensensis |
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1.E.26.1.5 | Putative holin of 109 aas and 2 TMSs |
Bacteria | Thermotogota | Putative holin of Marinitoga piezophila |
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1.E.26.1.6 | Holin of S. mutans phage M102 (van der Ploeg 2007). |
Viruses | Heunggongvirae, Uroviricota | Holin of phage M102 |
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1.E.26.1.7 | Putative holin of 109 aas and 1 TMS. |
Bacteria | Bacillota | Putative holin of Caldicellulosiruptor hydrothermalis |
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1.E.26.1.8 | Holin_LLH superfamily member |
Bacteria | Bacillota | holin of Desulfotomaculum gibsoniae |
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1.E.26.1.9 | Putative holin of 112 aas, Gp072 |
Viruses | Heunggongvirae, Uroviricota | Gp072 of Lactococcus phage KSY1 |
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1.E.26.10.1 | Uncharacterized protein of 107 aas |
Bacteria | Mycoplasmatota | UP of Acholeplasma laidlawii |
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1.E.26.11.1 | Putative holin of 140 aas and 1 or 2 TMSs |
Bacteria | Deinococcota | Putative holin of Meiothermus ruber |
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1.E.26.11.2 | Putative holin of 140 aas and 1 TMS |
Bacteria | Deinococcota | Putative holin of Thermus sp. RL |
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1.E.26.11.3 | Holin of Thermus phage P23-77 of 140 aas and 1 TMS |
Viruses | Holin of Thermus phage P23-77 |
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1.E.26.2.1 | Holin of Lactobacillus phage LF1 |
Viruses | Heunggongvirae, Uroviricota | Holin of Lactobacillus phage LF1 |
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1.E.26.2.2 | Holin P163 (Gindreau and Lonvaud-Funel 1999). |
Viruses | Holin P163 of Leuconostoc phage 10MC |
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1.E.26.2.3 | Putative holin of 117 aas |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Lactobacillus phage JCL1032 |
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1.E.26.2.4 | Uncharacterized protein of 140 aa |
Bacteria | Bacillota | UP of Lactobacillus acidophilus |
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1.E.26.2.5 | Holin, Hyb50 of 254 aas. This holin causes lysis by itself, but with the lytic enzyme, Lyb50, lysis occurs more rapidly (Wang et al. 2008). Smaller amounts of Lyb50 can reach the periplasm without the holin (Guo et al. 2015). |
Viruses | Heunggongvirae, Uroviricota | Holin of Lactobacillus phage phiPYB5 |
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1.E.26.3.1 | Holin of the LL-H family (105 aas) |
Bacteria | Bacillota | Holin LL-H of Peptoniphilus harei |
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1.E.26.3.2 | Uncharacterized protein of 126 aas and 1 TMS |
Bacteria | Bacillota | UP of Clostridium acetobutylicum |
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1.E.26.3.3 | Phage-like holin of 127 aas and 1 N-terminal TMS. |
Bacteria | Bacillota | Holin of Peptoniphilus indolicus |
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1.E.26.3.4 | Phage holin, LL-H family of 123 aas and 1 TMS. |
Bacteria | Bacillota | Holin of Clostridium pasteurianum BC1 |
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1.E.26.4.1 | Putative holin of 153 aas and 1 N-terminal TMS |
Bacteria | Bacillota | Holin of Lactococcus lactis |
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1.E.26.5.1 | Putative holin of 118 aas and 1 TMS |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Thermus phage P74-26 |
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1.E.26.6.1 | Uncharacterized protein of 145 aas and 1 TMS |
Bacteria | Bacillota | UP of Clostridium kluyveri |
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1.E.26.6.2 | Putative holin of 166 aas |
Bacteria | Bacillota | Putative porin of Desulfosporosinus meridiei |
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1.E.26.6.3 | Uncharaccterized protein of 177 aas |
Bacteria | Bacillota | UP of Thermoanaerobacterium saccharolyticum |
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1.E.26.7.1 | Uncharacterized protein of 96 aas |
Bacteria | Bacillota | UP of Clostridium acidurici |
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1.E.26.7.2 | Putative holin of 162 aas and 1 or 2 TMSs |
Bacteria | Fusobacteriota | Putative holin of Fusobacterium varium |
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1.E.26.7.3 | Putative holin of 162 aas and 1 or 2 TMSs |
Bacteria | Fusobacteriota | Putative holin of Fusobacterium ulcerans |
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1.E.26.7.4 | Putative holin of 167 aas and 1 or 2 TMSs |
Bacteria | Fusobacteriota | Putative holin of Sebaldella termitidis |
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1.E.26.7.5 | Putative holin of 134 aas and 1 TMS |
Bacteria | Bacillota | Putative holin of Faecalibacterium prausnitzii |
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1.E.26.8.1 | Uncharacterized protein of 172 aas |
Bacteria | Bacillota | UP of Clostridium pasteurianum |
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1.E.26.8.2 | Phage holin of 161 aas and 1 TMS. |
Viruses | Heunggongvirae, Uroviricota | Holin of Clostridium phage phiSM101 |
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1.E.26.8.3 | Holin of 139 aas and 1 TMSs. |
Bacteria | Bacillota | Holin of Clostridium kluyveri |
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1.E.26.9.1 | Holin of 114 aas |
Bacteria | Bacillota | Holin of Lactobacillus johnsonii |
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1.E.26.9.2 | Phage holin of 118 aas with one of two TMSs, one N-terminal and the other (of lesser hydrophobicity) at residue 45. |
Bacteria | Bacillota | Phage holin of Lactobacillus sp. |
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1.E.27.1.1 | holin BhlA (70 aas). A member of the DUF2762 family. Its holin function has been demonstrated (Aunpad and Panbangred 2012). |
Bacteria | Bacillota | BhlA of Bacillus pumilus |
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1.E.27.1.2 | Bacillus subtilis phage SP beta-holin-like protein (70 aas). |
Bacteria | Bacillota | Phage SP beta-holin |
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1.E.27.1.3 | Phage-like protein (80 aas). |
Bacteria | Bacillota | Phage-like protein of Clostridium botulinum |
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1.E.27.1.4 | Holin protein BhlA (Anthony et al. 2010). |
Bacteria | Bacillota | BhlA of Bacillus licheniformis |
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1.E.27.1.5 | Bacteriocin UviB of 64 aas. This protein is in the DUF2762 Superfamily. |
Bacteria | Bacillota | UviB of Clostridium perfringens
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1.E.27.1.6 | Uncharacterized protein of 76 aas |
Bacteria | Bacillota | UP of Bacillus cereus |
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1.E.27.1.7 | Uncharacterized protein of 78 aas |
Bacteria | Bacillota | UP of Bacillus thuringiensis |
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1.E.27.1.8 | Plasmid-encoded UviB-like holin of 65 aas with 1 TMS, TpeE. This protein mediates non-lytic protein translocation (Brüser and Mehner-Breitfeld 2022). Holins generate large membrane lesions that permit the passage of endolysins across the cytoplasmic membrane of prokaryotes, ultimately resulting in cell wall degradation and cell lysis. However, there are examples known for non-lytic holin-dependent secretion of proteins by bacteria, indicating that holins may transport proteins without causing large membrane lesions. Phage-derived holins can be used for a non-lytic endolysin translocation to permeabilize the cell wall for the passage of secreted proteins. In addition, clostridia, which do not possess the Tat pathway for transport of folded proteins, most likely employ non-lytic holin-mediated transport also for secretion of toxins and bacteriocins that are incompatible with the general Sec pathway. The small holin TpeE mediates non-lytic toxin secretion in Clostridium perfringens. TpeE contains only one short transmembrane helix that is followed by an amphipathic helix, which is reminiscent of TatA, the membrane-permeabilizing component of the Tat translocon for folded proteins. Brüser and Mehner-Breitfeld 2022 reviewed the known cases of non-lytic holin-mediated transport and then focus on the structural and functional comparison of TatA and TpeE, resulting in a mechanistic model for holin-mediated transport. This model is strongly supported by a so far not recognized naturally occurring holin-endolysin fusion protein. |
Bacteria | Bacillota | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.E.28.1.1 | Mu1/6 holin. Can replace other holins in promoting cell lysis and death (Farkasovská et al. 2004). |
Viruses | Heunggongvirae, Uroviricota | Holin of Streptomyces aureofaciens phage Mu1/6 |
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1.E.28.1.2 | Uncharacterized protein |
Bacteria | Actinomycetota | Uncharacterized protein of Streptomyces sp. SMB |
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1.E.28.1.3 | Uncharacterized protein |
Bacteria | Actinomycetota | Uncharacterized protein of Pseudonocardia dioxanivorans |
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1.E.28.2.1 | Putative holin |
Bacteria | Actinomycetota | Putative holin of Saccharomonaspora cyanea |
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1.E.29.1.1 |
p36 holin of Clostridial phage Phi C2. Functional in E. coli (Goh et al. 2007). |
Viruses | Caudovirales | p36 holin of phage Phi C2 |
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1.E.29.1.2 | Holin of Clostridial phage Phi CD119 (Goh et al. 2007). |
Viruses | Heunggongvirae, Uroviricota | Holin of clostridial phage Phi CD119 |
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1.E.29.1.3 | Putative holin of 94 aas and 3 TM |
Bacteria | Bacillota | Putative holin of Lactobacillus plantarum |
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1.E.29.1.4 | Putative holin of 87 aas and 3 TM |
Bacteria | Bacillota | Putative holin of Tetagenococcus halophilus |
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1.E.29.1.5 | Putative holin of 89 aas and 2 or 3 TMSs |
Bacteria | Bacillota | Holin of Turicibacter sanguinis |
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1.E.29.2.1 | Holin, Hol44 of Oenococcus phage fOg44 (118 aas; 3 TMSs) |
Viruses | Hol44 of phage fOg44 |
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1.E.29.2.2 | Putative holin |
Bacteria | Bacillota | Putative holin of Leuconostoc kimchii |
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1.E.29.2.3 | Holin (97aas) |
Bacteria | Bacillota | Holin of Leuconostoc gasicomitatum |
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1.E.29.2.4 | Lactobacillus phage phi g1e holin (Oki et al. 1997). |
Viruses | Heunggongvirae, Uroviricota | Lactobacillus phage phi g1e holin |
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1.E.29.2.5 | Putative holin of 78 aas and 3 TMSs |
Bacteria | Bacillota | Putative holin of Pelotomaculum thermopropionicum |
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1.E.29.2.6 | Putative holin of 81 aas and 3 TMSs. |
Bacteria | Bacillota | Holin of Sporosarcina newyorkensis |
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1.E.29.2.7 | Holin of 79 aas and 2 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Holin of Bacillus phage J5a |
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1.E.29.3.1 | Putative holin of 81 aas and 3 TMSs |
Bacteria | Bacillota | Putative holin of Brevibacillus laterosporus |
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1.E.29.3.2 | Putative holin of 69 aas and 2 or 3 TMSs |
Bacteria | Bacillota | Holin of Paenibacillus sp. |
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1.E.29.3.3 | Putative holin of 101 aas and 2 or 3 TMSs. |
Bacteria | Bacillota | Holin of Cohnella phaseoli |
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1.E.3.1.1 | Lysis protein TM (gene Y product), 93aas; 3 TMSs, N out; C in (predicted). This holin has been functionally characterized (To et al. 2013). It's function is counteracted by the anti-holin, LysA. |
Viruses | Heunggongvirae, Uroviricota | Lysis protein TM (P51773) |
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1.E.3.1.2 | Enterobacterial phage holin family 2 protein, GpY from phage P2 |
Bacteria | Pseudomonadota | GpY of phage P2 |
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1.E.3.1.3 | holin protein of E. coli phage PhiKT |
Viruses | Heunggongvirae, Uroviricota | Holin of phage PhiKT |
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1.E.3.1.4 | Phage holin of family 2 |
Bacteria | Pseudomonadota | Phage holin of Burkholderia ambifaria |
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1.E.3.1.5 |
Putative holin of 96 aas and 3 TMSs |
Bacteria | Pseudomonadota | Putative holin of Achromobacter xylosoxidans |
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1.E.3.2.1 | Uncharacterized protein |
Bacteria | Actinomycetota | Uncharacterized protein of Mycobacterium avium |
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1.E.3.2.2 | Uncharacterized protein (92 aas) |
Bacteria | Actinomycetota | Unchazracterized protein of Mycobacterium abscessus |
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1.E.3.3.1 | Hypothetical protein; putative porin of 89 aas and 3 TMSs. |
Archaea | Thermoproteota | Hypothetical protein of Pyrolobus fumarii |
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1.E.30.1.1 | Holin Gp-K of bacteriophage PM2 of marine Pseudoalteromonas species (Krupovic et al. 2007). |
Viruses | Bamfordvirae, Preplasmiviricota | Gp-K of phage PM2 (Q9XJR0) |
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1.E.30.1.2 | Putative holin |
Bacteria | Pseudomonadota | Putative holin of Vibrio parahaemolyticus |
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1.E.30.1.3 | Putative holin |
Bacteria | Pseudomonadota | Putative holin of Vibrio splendidus |
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1.E.31.1.1 | Lactococcus lactis phage Phi31 holin of the Holin SPP1 or Phage_holin family (Durmaz and Klaenhammer 2007). |
Viruses | Heunggongvirae, Uroviricota | Holin of phage Phi31 |
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1.E.31.1.10 | Putative holin |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Brochithrix phage A9 |
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1.E.31.1.11 | XhlB holin of 109 aas; belongs to the SPP1 family. |
Bacteria | Bacillota | XhlB of Staphylococcus epidermidis |
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1.E.31.1.12 | XhlB holin of 87 aas and 2 TMSs (Aunpad and Panbangred 2012). |
Bacteria | Bacillota | XhlB holin of Bacillus pumilus |
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1.E.31.1.13 | Two component holin, requiring two non-homologous small proteins, the gene 26 product (O48472; 82 aas, 2 TMSs, a member of family TC# 1.E.31) and the gene 24.1 product (O48470; 83 aas; 1 C-terminal TMS, not homologous to members of family 1.E.31) (Fernandes and São-José 2017). |
Viruses | Heunggongvirae, Uroviricota | Holin of Bacillus phage SPP1 |
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1.E.31.1.14 | Two component holin, requiring two non-homologous small proteins, one of 87 aas and 2 TMSs (E0U1U5), a member of family TC# 1.E.31, and another gene product, XhlA, of 89 aas with 1 C-terminal TMS (P39798), not homologous to members of family 1.E.31 (Fernandes and São-José 2017). |
Bacteria | Bacillota | Holin of Bacillus phage PBSX |
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1.E.31.1.15 | Holin-like protein of 81 aas and 2 TMSs. The holin and autolyin interact directly (Jin et al. 2013). |
Viruses | Heunggongvirae, Uroviricota | Holin of Geobacillus virus E3 |
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1.E.31.1.16 | Holin V of 99 aas and 2 TMSs. Its function as a holin protein was confirmed as its expression in E. coli impaired cell growth and viability while holV expression in B. thuringiensis led to bacterial lysis, which was enhanced by coexpressing the holin with its cognate endolysin (Leprince et al. 2022). |
Viruses | HolV of Bacillus phage Vp4 |
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1.E.31.1.2 |
Prophage L54a holin of the SPP1 family |
Bacteria | Bacillota | Holin of Staphylococcus aureus |
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1.E.31.1.3 | Holin of 74 aas and 2 TMSs |
Bacteria | Bacillota | Holin of Bacillus pumilus |
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1.E.31.1.4 | Holin |
Bacteria | Bacillota | Holin of Streptococcus gallolyticus |
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1.E.31.1.5 | Holin |
Bacteria | Actinomycetota | Holin of Bifidobacterium calenulatum |
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1.E.31.1.6 | Holin XhlB of 87 aas and 2 TMSs (Krogh et al. 1998; Babar et al. 2022). |
Bacteria | Bacillota | Holin XhlB of Bacillus subtilis prophage PBSX |
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1.E.31.1.7 | Holin XpaG2 (Kyogoku and Sekiguchi 1996). |
Bacteria | Bacillota | X[aG2 pf Bacillus licheniformis |
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1.E.31.1.8 | Holin-like protein |
Bacteria | Actinomycetota | Holin-like protein of Bifidobacterium longum |
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1.E.31.1.9 | Putative holin |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Bacillus phage BPS13 |
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1.E.31.2.1 | Putative holin of 77 aas and 2 TMSs |
Bacteria | Bacillota | Putative holin of Bacillus thuringiensis |
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1.E.31.2.2 | Putative holin of 77 aas and 2 TMS |
Bacteria | Bacillota | Putative holin of Bacillus cereus |
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1.E.31.2.3 | Holin |
Bacteria | Bacillota | Holin of Bacillus cereus |
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1.E.31.2.4 | Putative holin |
Bacteria | Bacillota | Putative holin of Brevibacterium laterosporus |
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1.E.31.3.1 | Putative holin (Orf041) of Staphylococcal phage 2683 |
Viruses | Heunggongvirae, Uroviricota | Holin of Staphylococcus aureus phage 2683 |
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1.E.31.3.2 | Putative firmicute holin |
Bacteria | Bacillota | Putative holin of Solibacillus silvestris |
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1.E.32.1.1 | Putative holin, HolA |
Viruses | Heunggongvirae, Uroviricota | HolA of Actinomyces phage Ar-1 |
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1.E.32.1.2 | Putative holin |
Bacteria | Actinomycetota | Putative holin of Streptomyces cattleya |
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1.E.32.1.3 | Putative holin |
Bacteria | Actinomycetota | Putative holin of Thermobispora bispora |
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1.E.32.2.1 | Putative holin |
Bacteria | Actinomycetota | Putative holin of Segniliparus rotundus |
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1.E.33.1.1 | Putative holin of 95 aas and 3 TMSs |
Bacteria | Pseudomonadota | Putative holin of Sideroxydans lithotrophicus |
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1.E.33.1.2 | DUF4063 family protein of 77 aas and 2 TMSs, N- and C-terminal. |
Bacteria | Pseudomonadota | DUF4063 family protein of Arsenophonus nasoniae |
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1.E.33.1.3 | Holin of 109 aas and 2 or 3 TMSs |
Bacteria | Thermodesulfobacteriota | Holin of Desulfovibrio sp. A2 |
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1.E.33.1.4 | Hypothetical protein of 119 aas and 2 or 3 TMSs |
Bacteria | Thermodesulfobacteriota | Hypothetical protein of Biophila wadsworthia |
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1.E.33.1.5 | Putative holin of 92 aas and 3 TMSs |
Bacteria | Pseudomonadota | Putative holin of Cardiobacterium hominis |
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1.E.33.1.6 | Putative holin of 87 aas and 3 TMSs |
Bacteria | Pseudomonadota | Putative holin of Sideroxydans lithotrophicus |
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1.E.33.1.7 | Putative holin of 107 aas and 2 TMSs |
Bacteria | Pseudomonadota | Putative holin of Rhodanobacter sp. |
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1.E.34.1.1 | Putative holin |
Bacteria | Actinomycetota | Putative holin of Nocardia cyriacigeorgica |
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1.E.34.1.10 | Uncharacterized protein of 126 aas and 2 TMSs |
Bacteria | Pseudomonadota | UP of Novosphingobium pentaromativorans |
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1.E.34.1.11 | Uncharacterized protein of 134 aas and 2 TMSs. |
Archaea | Euryarchaeota | UP of Methanocella arvoryzae |
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1.E.34.1.12 | Uncharacterized protein of 123 aas and 2 TMSs. |
Archaea | Euryarchaeota | UP of Methanomicrobiales archaeon |
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1.E.34.1.13 | Phage holin family protein of 149 aas and 2 TM |
Bacteria | Actinomycetota | Holin of Microlunatus phosphovorus |
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1.E.34.1.14 | Phage holin family protein of 150 aas and 2 TM |
Bacteria | Chloroflexota | Holin of Chloroflexi bacterium |
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1.E.34.1.15 | Phage holin family protein of 138 aas and 2 TMSs (Nabhani et al. 2021). |
Bacteria | Pseudomonadota | Holin of Rhizobium phaseoli Palo, a T7-like podophage of Rhizobium phaseoli |
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1.E.34.1.2 | Putative holin |
Bacteria | Actinomycetota | Putative holin of Saccharomonospora viridis |
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1.E.34.1.3 | Putative holin (DUF1469 family) |
Bacteria | Actinomycetota | Putative holin of Gordonia otitidis |
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1.E.34.1.4 | Putative holin |
Bacteria | Actinomycetota | Putative holin of Intrasporangium calvum |
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1.E.34.1.5 | Uncharacterized protein of 170 aas and 2 TMSs |
Bacteria | Actinomycetota | UP of Saccharopolyspora erythraea |
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1.E.34.1.6 | Uncharacterized protein of 156 aas and 2 TMSs |
Bacteria | Actinomycetota | UP of Stackebrandtia nassauensis |
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1.E.34.1.7 | Uncharacterized protein of 133 aas and 2 TMSs |
Bacteria | Pseudomonadota | UP of Rhodobacter sphaeroides |
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1.E.34.1.8 | DUF1469 protein of 307 aas and 2 TMSs. The DUF1469 domain is residues 30 - 150 where the two TMSs are. |
Bacteria | Actinomycetota | DUF1469 domain protein of Micrococcus luteus (Micrococcus lysodeikticus) |
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1.E.34.1.9 | Uncharacterized protein of 199 aas and 2 TMSs |
Bacteria | Deinococcota | UP of Deinococcus maricopensis |
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1.E.34.2.1 | YqjE (DUF1469) of 134 aas and 2 TMSs. |
Bacteria | Pseudomonadota | YqjE of E coli |
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1.E.34.2.2 | Uncharacterized protein of 127 aas and 2 TMSs. |
Bacteria | Pseudomonadota | UP of Gallionella capsiferriformans (Gallionella ferruginea capsiferriformans) |
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1.E.34.2.3 | Uncharacterized protein of 119 aas and 2 TMSs |
Bacteria | Pseudomonadota | UP of Oxalobacter formigenes |
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1.E.34.2.4 | Uncharacterized protein of 131 aas and 2 TMSs |
Bacteria | Pseudomonadota | UP of Thiomonas intermedia (Thiobacillus intermedius) |
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1.E.34.2.5 | Phage holin family protein of 129 aas and 2 TMSs. |
Bacteria | Thermodesulfobacteriota | Holin of Desulfovibrio sp. X2 |
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1.E.34.3.1 | Uncharacterized DUF1469 protein of 128 aas and 2 TMSs. |
Bacteria | Cyanobacteriota | UP of Prochlorococcus marinus |
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1.E.34.4.1 | Uncharacterized protein of 125 aas and 2 TMSs |
Bacteria | Bacteroidota | UP of Porphyromonas gingivalis |
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1.E.34.4.2 | Uncharacterized protein of 116 aas and 2 TMSs |
Bacteria | Bacteroidota | UP of Prevotella marshii |
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1.E.34.4.3 | Uncharacterized protein of 113 aas and 2 TMSs |
Bacteria | Bacteroidota | UP of Belliella baltica |
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1.E.35.1.1 | Gp7 protein, putative holin of 85 aas and 1 TMS (Catalão et al. 2012). |
Viruses | Heunggongvirae, Uroviricota | Gp7 of mycobacterial phage Bethlehem |
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1.E.35.1.2 | Gp29 putative holin of 91 aas and 1 TMS (Catalão et al. 2012). |
Viruses | Heunggongvirae, Uroviricota | Gp29 of mycobacterial phage ShiLan |
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1.E.35.1.3 | Gp31 putative holin of 77 aas and 1 TMS (Catalão et al. 2012). |
Viruses | Heunggongvirae, Uroviricota | Gp31 of mycobacterial phage Che8 |
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1.E.36.1.1 | Putative holin, Gp33 of 127 aas and 2 TMSs |
Viruses | Heunggongvirae, Uroviricota | Gp33 of Mycobacterial phage Cjw1 |
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1.E.36.1.10 | Uncharacterized protein of 145 aas and 4 TMSs. |
Bacteria | Actinomycetota | UP of Demequina flava |
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1.E.36.1.2 | Putative holin Gp36 of 84 aas and 2 TMSs (Catalão et al. 2012). |
Viruses | Heunggongvirae, Uroviricota | Gp36 of mycobacterial phage PBI1 |
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1.E.36.1.3 |
Putative holin Gp10 of 137 aas and 2 or 3 TMSs |
Viruses | Heunggongvirae, Uroviricota | Gp10 of mycobacterial phage Timshel |
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1.E.36.1.4 | Putative holin, Gp29 of 134 aas and 2 TMSs |
Viruses | Heunggongvirae, Uroviricota | Gp29 of mycobacterial phage Charlie |
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1.E.36.1.5 | Putative holin Gp14 of 144 aas and 2 TMSs |
Viruses | Heunggongvirae, Uroviricota | Gp14 of mycobacterial phage EricB |
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1.E.36.1.6 | Putative holin of 146 aas and 2 TMSs |
Bacteria | Actinomycetota | Putative holin of Mycobacterium massiliense |
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1.E.36.1.7 | Mycobacterial phage D29 holin of 141 aas, Gp11. Gp11 shows a lipid concentration-dependent conformational switch from an α-helix to a β-sheet structure (Lella and Mahalakshmi 2013). Toxicity has been studied showing that TMS 1 (but not TMS 2) and a C-terminal coiled-coil region are essential for activity because the latter is necessary for holin aggregation, insertion into the membrane and bacterial cell death (Kamilla and Jain 2015). A role for TMS 2 in pore formation has been proposed (Lella and Mahalakshmi 2016). The first TMS has been engineered to form a nanopore (Lella and Mahalakshmi 2016). The D29 and Chy1 phage holins are identical in amino acid sequence (Gan et al. 2016). |
Viruses | Heunggongvirae, Uroviricota | Holin, gp11 of Mycobacterial phage D29. |
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1.E.36.1.8 | Putative holin of 138 aas and 2 TMSs |
Bacteria | Actinomycetota | Putative holin of Mycobacterium abscessus |
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1.E.36.1.9 | Holin of 136 aas and 2 TMSs, gp255. |
Viruses | Heunggongvirae, Uroviricota | gp255 of Mycobacterium phage Pleione |
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1.E.36.2.1 | Putative holin of 69 aas and 2 TMSs |
Bacteria | Actinomycetota | Putative holin of Actinomyces neuii |
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1.E.36.2.2 |
Putative holin of 67 aas and 2 TMSs, Gp31 of mycobacterial phage Brujita |
Viruses | Heunggongvirae, Uroviricota | Gp31 of mycobacterial phage Brujita |
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1.E.36.2.3 | Putative holin of 67 aas and 2 TMSs |
Viruses | Heunggongvirae, Uroviricota | Gp27 of mycobacterial phage Che9c |
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1.E.36.2.4 | Putative holin of 68 aas and 2 TMSs |
Bacteria | Actinomycetota | Putative holin of Mobiluncus mulieris |
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1.E.36.3.1 | Holin of 64 aas and 2 TMSs, HolB (Delisle et al. 2006; Leprince et al. 2022). |
Viruses | Heunggongvirae, Uroviricota | HolB of phage Ar-1 or Vp4 (deep blue) |
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1.E.36.3.2 | TMEM125 family member of 65 aas and 2 TMSs. |
Viruses | Duplodnaviria | TMEM125 protein of Podoviridae sp. |
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1.E.36.4.1 | Putative holin of 178 aas and 2 TMSs, Gp48 |
Viruses | Heunggongvirae, Uroviricota | Gp48 and mycobacterial phage Ares |
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1.E.36.4.2 | Holin of 173 aas and 2 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Holin of Mycobacterium phage Jolie1 |
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1.E.36.5.1 |
Putative holin of 106 aas and 2 TMSs, Gp54 (Catalão et al. 2012). |
Viruses | Heunggongvirae, Uroviricota | Gp54 of Mycobacterial phage Omega |
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1.E.36.5.2 | Putative holin of 98 aas and 2 TMSs, Gp71 |
Viruses | Heunggongvirae, Uroviricota | Gp71 of mycobacterial phage Corndog |
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1.E.36.6.1 | Putative holin, Gp17 of 144 aas and 4 TMSs |
Viruses | Heunggongvirae, Uroviricota | Gp17 of Mycobacterial phage Daisy |
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1.E.36.6.2 | Putative holin of 113 aas and 4 TMSs |
Bacteria | Actinomycetota | Putative holin of Nocardia farcinica |
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1.E.36.6.3 | Putative holin, Gp16 of 135 aas and 4 TMSs |
Viruses | Caudovirales | Gp16 of mycobacterial phage Acadian |
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1.E.36.6.4 | Putative holin, Gp32 of 150 aas and 4 TMSs |
Viruses | Heunggongvirae, Uroviricota | Gp32 of Mycobacterial phage Larva |
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1.E.36.6.5 | Putative holin, Gp31 of 128 aas and ~3 TMSs |
Viruses | Heunggongvirae, Uroviricota | Gp31 of Mycobacterial phage TM4 |
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1.E.37.1.1 | Enterobacterial phage T1 holin, Gp13 of 71 aas and 1 TMS (Catalão et al. 2012). |
Viruses | Caudovirales | Gp13 of enterobacterial phage T1 |
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1.E.37.1.2 | Gp9 holin (putative) of phage phiE49; 55 aas; 1 TMS |
Viruses | Heunggongvirae, Uroviricota | Gp9 holin of E. coli phage phiE49 |
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1.E.37.1.3 | Holin of 71 aas and 1 TMS at about residue 30. |
Viruses | Heunggongvirae, Uroviricota | Holin of Klebsiella phage Shelby |
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1.E.37.1.4 | Holin of 71 aas and 1 TMS at about residue 40. |
Viruses | Heunggongvirae, Uroviricota | Holin of Klebsiella phage Shelby |
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1.E.38.1.1 | Putative holin of 92 aas and 2 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Staphylococcus aureus phage P68 |
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1.E.39.1.1 |
Putative holin Gp29 of 116 aas and 2 TMSs (Catalão et al. 2012). |
Viruses | Heunggongvirae, Uroviricota | Gp29 of mycobacterial phage Angel |
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1.E.39.1.2 | Holin of 116 aas and 2 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Holin of Mycobacterium phage Avocado |
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1.E.39.1.3 | Holin of 84 aas and 2 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Holin of Rhodococcus phage Trina |
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1.E.39.1.4 | Putative holin of 84 aas and 2 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Holin of Rhodococcus phage REQ1 |
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1.E.39.1.5 | Putative holin of 70 aas and 1 TMS. |
Bacteria | Actinomycetota | Putative holin of Amycolatopsis rifamycinica |
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1.E.39.2.1 | Holin of 106 aas and 3 TMSs (Zhou et al. 2018). |
Viruses | Heunggongvirae, Uroviricota | Holin of Acinetobacter phage vB_AbaM_AB3P2 |
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1.E.4.1.1 | LydA protein | Bacteria | Pseudomonadota | LydA protein (109 aas; pirS18681) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.E.4.1.2 | LydC of enterobacterial phage P1 |
Viruses | Heunggongvirae, Uroviricota | LydC of phage P1 |
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1.E.4.1.3 | Hypothetical protein (113 aas) |
Bacteria | Pseudomonadota | Hypothetical protein of Burkholderia phytofirmans |
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1.E.4.1.4 | Holin of 134 aas and 4 TMSs. The lysis genes encode the holin, peptidase M15A or endolysin, lysB and lysC. Each gene and combinations were cloned into Escherichia coli and the lytic effects were measured. Co-expression of holin and peptidase M15A showed the highest lysis activity. Expression of holin, lysB/C or holin, peptidase M15A, lysB and lysC lysed the E. coli membrane whereas peptidase M15A alone did not. The predicted transmembrane structures of holin and lysB/C indicated they could insert into the bacterial membrane to form pores, affecting cell permeability and causing lysis (Khakhum et al. 2016). |
Viruses | Heunggongvirae, Uroviricota | Holin of Burkholderia phage ST79 |
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1.E.40.1.1 | The Gp37 4 TMS (221 aas) putative holin |
Viruses | Heunggongvirae, Uroviricota | Gp37 of mycobacterial phage PBI1 |
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1.E.40.1.2 | The Gp44 putative holin of 164 aas and 4 TMSs |
Viruses | Heunggongvirae, Uroviricota | Gp44 of mycobacterial phage Patience |
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1.E.40.1.3 |
Gp28 putative holin of 161 aas and 4 TMSs |
Viruses | Heunggongvirae, Uroviricota | Gp28 of mycobacterial phage Che9c |
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1.E.40.1.4 |
Gp29 putative holin of 160 aas and 4 TMSs |
Viruses | Heunggongvirae, Uroviricota | Gp29 of mycobacterial phage BigNuz |
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1.E.40.2.1 | Putative holin of 121 aas and 4 TMSs |
Bacteria | Cyanobacteriota | Putative holin of Fischerella sp. JSC11 |
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1.E.40.2.2 | Putative holin of 121 aas and 4 TMSs. The holin functions of a homolog of 54% identity to this holin have been well documented for cyanophage PaV-LD from the cyanobacterium, Planktothrix agardhii (Meng et al. 2022). |
Bacteria | Cyanobacteriota | Putative holin of Microcoleus vaginatus |
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1.E.40.2.3 | Putative holin of 121 aas and 4 TMSs |
Bacteria | Cyanobacteriota | Putative holin of Anabaena variablis |
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1.E.40.3.1 | Putative holin of 121 aas and 4 TMSs |
Bacteria | Pseudomonadota | Putative holin of Burkholderia rhizoxinica |
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1.E.40.3.2 |
Putative holin of 113 aas and 4 TMSs |
Bacteria | Pseudomonadota | Putative holin of Ralstonia solanacearum |
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1.E.40.3.3 | Putative holin of 145 aas and 4 TMSs |
Bacteria | Verrucomicrobiota | Putative holin of Opititus terrae |
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1.E.40.3.4 | Putative holin of 120aas and 4 TMSs |
Bacteria | Bacillota | Putative holin of Amphibacillus xylanus |
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1.E.40.3.5 |
Putative holin of 128 aas and 4 TMSs |
Bacteria | Bacillota | Putative holin of Gemella morbillorum |
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1.E.40.3.6 | Putative holin |
Bacteria | Spirochaetota | Holin of Leptospira interrongans |
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1.E.40.3.8 | Putative holin of 146 aas and 4 TMSs (Palmer et al. 2020). |
Bacteria | Chloroflexota | Holin of Chloroflexi bacterium G233 |
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1.E.40.4.1 | Putative holin of 115 aas and 4 TMSs |
Bacteria | Bacillota | Putative holin of Ammonifex degensii |
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1.E.40.4.2 | Putative holin of 117 aas and 4 TMSs |
Bacteria | Bacillota | Putative holin of Paeibucillus mucilagiosus |
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1.E.40.4.3 |
Putative holin with 122 aas and 4 TMSs. Shows limited sequence similiarity with 1.E.19.4.1. |
Bacteria | Bacillota | Putative holin of Clostridium perfringens |
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1.E.40.4.4 | Uncharacterized protein of 161 aas and 4 TMSs. |
Bacteria | Bacillota | UP of Pediococcus damnosus |
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1.E.40.5.1 |
Largely hydrophilic protein with an N-terminal putative 4 TMS holin domain (720 aas). The large hydrophilic domain may be a Type I phosphodiesterase/nucleotide pyrophosphatase. |
Bacteria | Chloroflexota | Puative holin fusion protein of Caldilinia aeophila |
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1.E.40.5.2 | Phage holin family proteinof 141 aas and 4 TMSs. |
Archaea | Euryarchaeota | Holin of Methanobrevibacter arboriphilus |
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1.E.40.6.1 | Holin of 139 aas and 4 TMSs. |
Bacteria | Actinomycetota | Holin of Cellulosimicrobium cellulans (Arthrobacter luteus) |
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1.E.41.1.1 | Putative holin |
Bacteria | Deinococcota | Putative holin of Meiothermus silvanus |
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1.E.42.1.1 | Holin-like antibacterial protein of 34aas and 1 TMS. Antibacterial and holin activities have been demonstrated (Rajesh et al. 2011). |
Unclassified | Antibacterial protein of unknown source (B5M446) |
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1.E.42.1.2 |
Putative holin-like toxin of 34aas and 1 TMS |
Bacteria | Bacillota | Holin-like toxin of Leuconostoc carnosum (K0DCD3) |
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1.E.42.1.3 | Predicted holin-like toxin of 45aas and 1 TMSs |
Bacteria | Bacillota | Holin-like toxin of Lactobacillus casei (Q03BM3) |
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1.E.42.1.4 | Uncharacterized protein of 34aas and 1 TMS |
Bacteria | Actinomycetota | Putative protein of Scardovia inopinata (D6KVW0) |
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1.E.42.1.5 | Putative holin of 80 aas and 1 C-terminal TMS. |
Bacteria | Bacillota | Holin of Enterococcus faecalis |
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1.E.42.1.6 | Putative holin of 48 aas and 1 C-terminal TMS |
firmicute | Viridiplantae, Streptophyta | Holin of Abiotrophia defectiva |
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1.E.42.1.7 | Holin-like toxin of 49 aas and 1 TMS. |
Bacteria | Bacillota | Holin of Staphylococcus pseudintermedius |
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1.E.43.1.1 | YeaQ of 82 aas and 3 TMSs |
Bacteria | Pseudomonadota | YeaQ of Klebsiella pneumoniae (A6TAG3) |
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1.E.43.1.10 | Putative holin of 83 aas and 3 TMSs |
Bacteria | Bacteroidota | Putative holin of Bacteroides vulgatus |
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1.E.43.1.11 | Putative transglycosylase-associated holin of 115 aas and 3 TMSs |
Bacteria | Pseudomonadota | holin of Burkholderia pseudomallei |
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1.E.43.1.12 | Transglycosylase, putative holin of 126 aas and 3 TMSs. |
Bacteria | Planctomycetota | Putative holin of Planctopirus limnophila |
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1.E.43.1.13 | Putative holin of 97 aas and 3 TMSs. |
Bacteria | Bdellovibrionota | Holin of Bdellovibrio bacteriovorus |
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1.E.43.1.14 | Putative holin of 80 aas and 2 TMSs (Hug et al. 2016). |
Bacteria | Candidatus Peregrinibacteria | Holin of Candidatus Peribacter riflensis |
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1.E.43.1.15 | GlsB/YeaQ/YmgE family stress response membrane protein. |
Bacteria | Cyanobacteriota | UP of Nostoc sp. PCC 7107 |
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1.E.43.1.16 | Antiholin/holin protein of 135 aas and 3 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Pectobacterium phage MA12 |
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1.E.43.1.2 |
Transglycosylase-associated protein of 86 aas and 3 TMSs |
Bacteria | Chloroflexota | T-A protein of Thermobaculum terrenum (D1CIE6) |
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1.E.43.1.3 |
Putative holin of 144 aas and 4 TMSs |
Bacteria | Pseudomonadota | Putative holin of E. coli (B6IAY2) |
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1.E.43.1.4 |
Uncharacterized protein of 104 aas and 3 TMSs |
Bacteria | Planctomycetota | UP of Blastopirellula marina (A3ZS55) |
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1.E.43.1.5 | Putative holin of 124 aas and 3 or 4 TMSs. |
Bacteria | Pseudomonadota | Putative holin of Pseudomonas aeruginosa (Q9I549) |
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1.E.43.1.6 | Putative holin |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Pseudomonas phage phiCTX |
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1.E.43.1.7 |
Transglycosylase associated protein of 146 aas and 3 or 4 TMSs |
Bacteria | Deinococcota | T-A protein of Deinococcus radiodurans (Q9RRU6) |
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1.E.43.1.8 | Bacteria | Actinomycetota | Uncharacterized protein of Gordonia polyisoprenivorans (H6N4M5) |
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1.E.43.1.9 |
Membrane protein of 82 aas and 3 TMSs |
Bacteria | Bacillota | Membrane protein of Bacillus cereus (J8Z3M3) |
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1.E.43.2.1 |
Hypothetical protein of 134 aas and 4 TMSs |
Archaea | Euryarchaeota | HP of Natronobacterium gregoryi (G4G4E5) |
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1.E.43.2.2 |
Hypothetical Protein of 110 aas and 3 TMSs |
Archaea | Thermoproteota | HP of Pyrolobus fumarii (G0EH17) |
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1.E.43.2.3 | Putative holin of 119 aas and 4 TMSs. |
Archaea | Euryarchaeota | Putative holin of Methanobacterium paludis |
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1.E.43.2.4 | Putative holin of 142 aas and 3 TMSs. |
Archaea | Euryarchaeota | putative holin of Haloferax denitrificans |
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1.E.43.2.5 | Putative holin of 112 aas and 3 TMSs. |
Archaea | Euryarchaeota | Putative holin of Methanoculleus marisnigri |
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1.E.43.2.6 | Putative holin of 124 aas and 4 TMSs. |
Archaea | Thermoproteota | Putative holin of Pyrobaculum aerophilum |
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1.E.43.2.7 | Putative holin of 123 aas and 4 TMSs. There appears to be a 2 TMS repeat unit, so that TMSs 1 - 2 are homolous to TMSs 3 - 4. |
Archaea | Euryarchaeota | Putative holin of Methanobacterium lacus |
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1.E.43.2.8 | Uncharacterized protein of 168 aas and 4 TMSs, YckC3. |
Bacteria | Thermodesulfobacteriota | YckC3 of Desulfovibrio gigas |
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1.E.43.2.9 | Putative holin of 103 aas and 3 TMSs. |
Bacteria | Pseudomonadota | Putative holin of Klebsiella pneumoniae |
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1.E.44.1.1 | Putative holin of 61 aas and 2 TMSs. Very similar to a putative holin of phage PhiLC3. |
Viruses | Heunggongvirae, Uroviricota | Putative holin of phage Tua2009 (phage r1t). |
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1.E.44.1.2 | Putative holin of 78 aas and 2 TMSs. |
Bacteria | Bacillota | Putative holin of Lactococcus lactis |
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1.E.44.1.3 | Putative holin of 64 aas and 1 TMS. |
Bacteria | Bacillota | Holin of Lactococcus lactis |
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1.E.45.1.1 | Putative holin of 64 aas and 2 TMSs |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Xanthomonas phage Xp15 |
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1.E.46.1.1 | Putative holin of prophage Hp1 of 69 aas and 1 or 2 TMSs. |
Bacteria | Bacillota | Putative holin of Clostridium hathewayi |
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1.E.47.1.1 | Putative holin of 159 aas and 2 TMSs |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Caulobacter phage CorMagneto |
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1.E.47.1.2 | Putative holin of 157 aas and 2 TMSs |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Caulobacter phage CorColossus |
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1.E.48.1.1 | Putative holin of 107 aas and 1 C-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Salmonella phage SSU5 |
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1.E.48.1.2 | Hypothetical protein of 108 aas and 1 C-terminal TMS. |
Bacteria | Pseudomonadota | Putative holin of Photorhabdus asymbiotica |
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1.E.48.1.3 | Putative holin |
Bacteria | Pseudomonadota | Putative holin of Klebsiella sp. MS 92-3 |
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1.E.49.1.1 | Hypothetical protein of 101 aas and 4 TMSs. |
Bacteria | Spirochaetota | HP of Treponema denticola |
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1.E.49.1.2 |
Hypothetical protein of 108 aas and 4 TMSs. |
Bacteria | Spirochaetota | HP of Treponema phagedenis |
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1.E.49.1.3 | Putative holin of 105 aas and 4 TMSs in a 2 + 2 TMS arrangement. |
Bacteria | Spirochaetes | Putative holin of Treponema denticola |
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1.E.49.1.4 | Putative phage holin of 41 aas and 1 TMS |
Viruses | Heunggongvirae, Uroviricota | Putative holin of phage phi td1 |
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1.E.49.1.5 | Putative holin of 105 aas and 4 TMSs |
Bacteria | Spirochaetota | Holiin of Treponema socranskii |
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1.E.5.1.1 | P35 holin of phage PRD1 (Rydman and Bamford 2003; Ziedaite et al. 2005). This holin is up to 98% identical to the holins of plasmid-dependent tectiviruses (Quinones-Olvera et al. 2024). Cell death can be dependent on holins LrgAB repressed by a novel ArsR family regulator CdsR (Zhang et al. 2024). |
Viruses | Bamfordvirae, Preplasmiviricota | P35 protein of Bacteriophage PRD1 (Q3T4L9) |
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1.E.5.1.2 | Phage holin |
Bacteria | Pseudomonadota | Phage holin of of Providencia stuartii |
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1.E.5.1.3 | Putative holin |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Xanthomonas phage vB_XSVEM_DIBBI |
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1.E.5.1.4 | Putative holin (106 aas) |
Bacteria | Pseudomonadota | Putative holin of Pantoea stewartii |
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1.E.5.1.5 | Uncharacterized protein |
Bacteria | Pseudomonadota | Uncharacterized protein of Methyloversatilis universalis |
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1.E.5.1.6 | putative phage holin pg30 |
Viruses | Heunggongvirae, Uroviricota | gp30 of Burkholderia phage Bcep43 |
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1.E.5.1.7 | Uncharacterized protein of 112 aas and 3 TMSs |
Bacteria | UP of Parcubacteria group bacterium |
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1.E.5.2.1 | Phage-related protein (105 aas) |
Bacteria | Campylobacterota | Phage-related protein of Nitratiruptor sp. strain SB155-2 |
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1.E.5.2.2 | Uncharacterized protein |
Bacteria | Pseudomonadota | Uncharacterized protein of Vibrio mimicus |
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1.E.5.2.3 | Putative holin |
Viruses | Heunggongvirae, Uroviricota | Putative holin of proteobacterial phage |
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1.E.5.2.4 | Uncharacterized protein |
Bacteria | Pseudomonadota | Uncharacterized protein of Nitrosomonas eutropha |
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1.E.5.2.5 | Putative holin of 134 aas and 3 TMSs. |
Bacteria | Pseudomonadota | Holin of E. coli |
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1.E.5.2.6 | Putative holin of 107 aas and 3 TMSs. |
Bacteria | Pseudomonadota | Hol of Citrobacter sp. TSA-1 |
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1.E.5.2.7 | Phage holin family protein of 138 aas and 3 TMSs in a 1 + 2 TMS arrangement. |
Bacteria | Pseudomonadota | Holin of Marinomonas shanghaiensis |
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1.E.5.2.8 | Holin, HolY of 103 aas and 3 TMSs. It is found in a holin-endolysin cassette in Y. enterocolitica, and has been adapted via evolution to export a large bacterial toxin (Sänger et al. 2023). |
Bacteria | Pseudomonadota | HolY of Yersinia enterocolitica |
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1.E.5.2.9 | Holin, Stm0015, of 114 aas and 3 TMSs. This holin, together with a peptidoglycan hydrolase, Stm0016, comprises a secretion system (type 10) for an exo-chitinase of 699 aas (Stm0018) (partially homologous to the protein listed under TC# 9.B.29.2.7 (Chi1)). |
Archaea | Thermoproteota | Holin of Salmonella enterica (subsp. Typhimurium) |
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1.E.5.3.1 | Uncharacterized protein |
Bacteria | Thermodesulfobacteriota | Uncharacterized protein of Desulfovibrio vulgaris |
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1.E.5.3.2 | Putative holin |
Bacteria | Synergistota | Putative holin of Aminobacterium colombiense |
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1.E.5.3.3 | Uncharacterized protein |
Bacteria | Synergistota | Uncharacterized protein of Dethiosulfovibrio peptidovorans |
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1.E.5.3.4 | Putative holin |
Bacteria | Synergistota | Putative holin of Jonquetella anthopi |
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1.E.5.3.5 | Putative holin |
Bacteria | Synergistota | Putative holin of Pyramidobacter piscolens |
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1.E.5.4.1 | Phage holin family protein of 108 aas and 3 TMSs. |
Bacteria | Pseudomonadota | Holin of Rhizobium sp. |
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1.E.5.4.2 | Phage holin family protein of 108 aas and 2 or 3 TMSs. |
Bacteria | Pseudomonadota | Holin of Chitinibacter tainanensis |
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1.E.5.4.3 | Phage holin family protein of 111 aas and 3 TMSs. |
Bacteria | Pseudomonadota | Holin of Azospirillum oryzae |
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1.E.5.4.4 | Phage holin family protein of 117 aas and 3 TMSs. |
Bacteria | Pseudomonadota | Holin of Elstera litoralis |
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1.E.5.4.5 | Putative holin of 117 aas and 3 TMSs. |
Bacteria | Pseudomonadota | Holin of Halomonas qiaohouensis |
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1.E.5.4.6 | Uncharacterized putative holin protein of 108 aas and 3 TMSs. |
Bacteria | Pseudomonadota | UP of Parvibaculum sp. |
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1.E.5.4.7 | Uncharacterized putative holin of 121 aas and 3 TMSs. |
Bacteria | Pseudomonadota | UP of Hoeflea sp. |
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1.E.5.5.1 | Holin of 96 aas with 3 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Holin of Serratia phage Serbin |
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1.E.50.1.1 | Putative type II holin |
Viruses | Heunggongvirae, Uroviricota | Putative type II holin of Burkholderia phage BcepMigI |
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1.E.50.1.2 | Hypothetical protein |
Bacteria | Pseudomonadota | HP of Polaromonas naphthalenivorans |
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1.E.50.1.3 | Putative holin of 80 aas and 1 TMS |
Bacteria | Pseudomonadota | Holin of Methylibium sp. T29-B |
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1.E.51.1.1 | Putative holin, Gp64 od 41 aas and 1 TMS. |
Viruses | Heunggongvirae, Uroviricota | Gp64 of Listeria phage A118 |
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1.E.51.1.2 | Putative holin, Gp60 of 41 aas and 1 TMS. |
Viruses | Heunggongvirae, Uroviricota | Gp60 of Listeria phage A500 |
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1.E.51.1.3 | Putative holin of 41 aas and 1 TMS |
Bacteria | Bacillota | Putative holin of Listeria monocytogenes |
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1.E.52.1.1 | Putative holin, BlyA family |
Bacteria | Bacillota | Putative holin of Ruminococcus obeum |
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1.E.52.1.2 | Uncharacterized protein |
Bacteria | Bacillota | Uncharacterized protein of Ruminococcus bromii |
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1.E.52.2.1 | Putative holin of 99 aas and 2 TMSs |
Bacteria | Actinomycetota | Putative holin of Collinsella intestinalis |
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1.E.52.3.1 | Putative holin of 54 aas and 1 TMS |
Bacteria | Bacillota | Putative holin of Johnsonella ignava |
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1.E.52.3.2 |
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Bacteria | Pseudomonadota | Flp pilin compenent of Cupriavidus taiwanensis |
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1.E.52.3.3 | Flp/Fap pilin component |
Bacteria | Myxococcota | Pilin compenent of Anaeromyxobacter dehalogenans |
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1.E.53.1.1 | Toxic protein, HokC or Gef of the Hok/Gef family. When injected into melanoma cells, gef caused the appearance of pore-like structures in the cell membrane (Boulaiz et al. 2003). |
Bacteria | Pseudomonadota | HokC or Gef of E. coli (P0ACG4) |
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1.E.53.1.10 | PndA of 43 aas |
Bacteria | Pseudomonadota | PndA of E. coli |
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1.E.53.1.11 | SrnB |
Bacteria | Pseudomonadota | SrnB of E. coli |
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1.E.53.1.2 | HokA toxic peptide |
Bacteria | Pseudomonadota | HokA of E. coli |
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1.E.53.1.3 | Pore-forming toxic peptide, HokB (Brielle et al. 2016). Involved in persistence, controlled by ppGpp (Harms et al. 2016). Causes collapse of the membrane potential leading to dormancy and persistance (Verstraeten et al. 2015). The pore-forming activity leads to leakage of intracellular ATP, which correlates with the induction of persistence. There is a link between persistence and pore activity, as the number of HokB-induced persister cells was strongly reduced using a channel blocker (Wilmaerts et al. 2018). |
Bacteria | Pseudomonadota | HokB of E. coli |
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1.E.53.1.4 | HokD of 70 aas |
Bacteria | Pseudomonadota | HokD of E. coli |
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1.E.53.1.5 | HokE |
Bacteria | Pseudomonadota | HokE of Klebsiella oxytoca |
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1.E.53.1.6 | HokG |
Bacteria | Pseudomonadota | HokG of Klebsiella oxytoca |
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1.E.53.1.7 | Small toxic membrane protein, Stm of 71 aas |
Bacteria | Pseudomonadota | Stm of Salmonella enterica |
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1.E.53.1.8 | Putative Hok protein of 69 aas |
Bacteria | Pseudomonadota | Putative Hok protein of Candidatus Regulla insecticola |
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1.E.53.1.9 | Regulatory protein for HokC, MocC |
Bacteria | Pseudomonadota | MocC of E. coli |
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1.E.53.2.1 | Hok/Gef family protein of 164 aas |
Bacteria | Pseudomonadota | Hok protein of E. coli |
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1.E.53.2.2 | Uncharacterized protein of 128 aas and 1 - 4 TMSs. |
Bacteria | Pseudomonadota | UP of Bordetella pertussis |
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1.E.53.2.3 | Tar ligand binding domain-containing protein, partial. of 72 aas and 1 TM |
Bacteria | Pseudomonadota | Tar ligand binding protein of Salmonella enterica |
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1.E.53.3.1 | Uncharacterized protein of 143 aas and 1 central TMS. |
Bacteria | Pseudomonadota | UP of Massilia aquatica |
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1.E.54.1.1 | Gene Transfer Agent (GTA) holin of 164 aas with 3 TMSs in a 1 + 2 TMS arrangement. Involved in GTA release from cells in stationary phase (Westbye et al. 2013). |
Bacteria | Pseudomonadota | GTA holin of Rhodobacter capsulatus |
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1.E.54.1.2 | Putative holin of 195 aas and possibly 4 TMSs in a 1 (N-terminal) + 2 (central) +1 (C-terminal). |
Bacteria | Pseudomonadota | Putative holin of Rhodospirillum photometricum |
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1.E.54.1.3 | Putative holin of 186 aas and 2 or 3 TMSs, one of low hydrophobicity at the N-terminus, and 2 sharper peaks for higher hydrophobicity centrally located. |
Bacteria | Pseudomonadota | Holin homologue of Saccharophagus degradans |
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1.E.54.1.4 | Putative holin of 181 aas of the DUF3154 family. |
Bacteria | Pseudomonadota | Putative holin of Rubelimicrobium thermophilum |
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1.E.54.1.5 | Putative holin of 177 aas and 2 - 4 TMSs. |
Bacteria | Pseudomonadota | Putative holin of Rhodospirillum photometricum |
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1.E.54.2.1 | Putative holin of 134 aas and 3 TMSs, one N-terminal and two central. |
Bacteria | Thermodesulfobacteriota | Putative holin of Desulfovibrio desulfuricans |
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1.E.54.2.2 | Putative holin of 136 aas and 2 TMSs. |
Bacteria | Pseudomonadota | Putative holin of Vibrio splendidus |
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1.E.54.2.3 | Putative holin of 113 aas and 2 TMSs |
Bacteria | Pseudomonadota | Putative holin of Puniceispirillum marinum |
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1.E.54.2.4 | Putative holin of 150 aas and 2 TMSs |
Bacteria | Pseudomonadota | Putative holin of Pseudoalteromonas tunicata |
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1.E.54.2.5 | Putative holin of 196 aas and 2 or 3 TMSs. |
Viruses | Caudovirales | Putative holin of Salmonella phage ViI |
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1.E.54.2.6 | Putative holin of 121 aas and 2 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Pelagibacter phage HTVC011P |
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1.E.54.4.1 | Gp21 protein of 145 aas and 2-3 TMSs |
Viruses | Gp21 of Cellulophaga phage phi48:2 |
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1.E.54.4.2 | Putative holin of 148 aas and 2 TMSs |
Bacteria | Pseudomonadota | Putative holin of Pseudoalteromonas haloplanktis |
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1.E.54.4.3 | Uncharacterized protein of 149 aas and 2 putative TMSs |
Bacteria | Thermodesulfobacteriota | UP of Desulfatibacillum alkenivorans |
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1.E.54.4.4 | Uncharacterized protein of 168 aas and 2 - 3 TMSs |
Bacteria | Pseudomonadota | UP of Teredinibacter turnerae |
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1.E.54.4.5 | Uncharaterized protein of 145 aas and 2 TMSs |
Bacteria | Pseudomonadota | UP of Vibrio azureus |
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1.E.54.4.6 | Uncharacterized protein of 132 aas and 2 TMSs |
UP of Pseudoalteromonas piscicida |
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1.E.54.4.7 | Uncharacterized protein of 87 aas and 2 TMSs |
Bacteria | Pseudomonadota | UP of Aliivibrio salmonicida (Vibrio salmonicida) |
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1.E.54.5.1 | Uncharacterized protein of 137 aas and 3 TMSs |
Bacteria | Pseudomonadota | UP of Novosphingobium aromaticivorans |
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1.E.54.5.2 | Uncharacterized protein of 144 aas and 2 - 3 TMSs |
Bacteria | Pseudomonadota | UP of Marinobacter nanhaiticus |
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1.E.55.1.1 | GTA holin of 85 aas and 2 TMSs (Matson et al. 2005). |
Bacteria | Spirochaetota | GTA holin of Brachyspira hyodysenteriae |
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1.E.55.1.2 | VSH-1 holin of 92 aas and 2 TMSs. |
Bacteria | Spirochaetota | Holin of Brachyspira pilosicoli |
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1.E.55.1.3 | Putative holin of 97 aas and 2 TMSs. |
Bacteria | Spirochaetota | Putative holin of Brachyspira (Serpulina) intermedia |
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1.E.55.1.4 | Putative holin of 92 aas and 2 TMSs |
Bacteria | Spirochaetota | Putative holin of Brachyspira pilosicoli |
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1.E.55.2.1 | Putative holin of 142 aas and 3 TMSs |
Bacteria | Pseudomonadota | Putative holin of Pseudomonas syringae |
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1.E.55.2.2 | Putative porin of 143 aas and 3 TMSs |
Bacteria | Pseudomonadota | Putative porin of Pseudomonas putida |
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1.E.55.2.3 | Putative holin of 133 aas and 3 TMSs |
Bacteria | Pseudomonadota | Putative holin of Photorhabdus temperata |
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1.E.55.2.4 | Putative holin of 126 aas and 2 TMSs |
Bacteria | Pseudomonadota | Putative holin of E. coli |
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1.E.55.2.5 | Putative holin of 143 aas and 3 TMSs |
Bacteria | Actinomycetota | Putative holin of Mycobacterium abscessus |
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1.E.55.3.1 | Putative holin of 105 aas and 4 TMSs |
Bacteria | Bacillota | Putative holin of Staphylococcus pasteuri |
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1.E.55.3.2 | Uncharacterized protein of 105 aas and 4 TMSs |
Bacteria | Bacillota | UP of Macrococcus caseolyticus |
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1.E.56.1.1 | Putative holin (DUF745 protein) of 102 aas and 3 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Holin of Salmonella phage SPN1S |
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1.E.56.1.10 | Putative holin of 92 aas and 3 TMSs |
Bacteria | Pseudomonadota | Putative holin of Pseudomonas poae |
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1.E.56.1.11 | Putative holin of 85 aas and 3 TMSs |
Bacteria | Pseudomonadota | Putative holin of Acinetobacter baumannii |
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1.E.56.1.12 | Class I holin of 105 aas and 3 TMSs |
Viruses | Heunggongvirae, Uroviricota | Class 1 hoin of Pseudomonas phage AF |
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1.E.56.1.2 | Holin of 106 aas and 3 TMSs. Similar to the holins of phage KS5 and AP3 which have been used to combat infection by B. cenocepacia in a Galleria mellonella moth wax model. AP3 treatment of larvae infected with B. cenocepacia revealed an increase (P < 0.0001) in larval survival (Roszniowski et al. 2016). |
Bacteria | Pseudomonadota | Holin of Burkholderia cenocepacia |
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1.E.56.1.3 | Putative holin of 93 aas and 3 TMSs |
Viruses | Heunggongvirae, Uroviricota | Holin of Enterobacterial phge mEp390 |
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1.E.56.1.4 | Uncharacterized protein of 93 aas and 3 TMSs |
Bacteria | Pseudomonadota | UP of Klebsiella variicola |
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1.E.56.1.5 | Putative holin of 91 aas and 3 TMSs |
Viruses | Heunggongvirae, Uroviricota | Enterbacterial phage PhiP27 |
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1.E.56.1.6 | Putative holin of 93 aas and 3 TMSs |
Bacteria | Pseudomonadota | Putative holin of E. coli |
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1.E.56.1.7 | Putative holin of 94 aas and 3 TMSs |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Pseudomonas phage Phi297 |
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1.E.56.1.8 | Putative holin of 94 aas and 3 TMSs |
Bacteria | Pseudomonadota | Putative holin of Laribacter hongkongensis |
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1.E.56.1.9 | Putative holin, gp28, of 88 aas and 3 TMSs |
Viruses | Heunggongvirae, Uroviricota | gp28 of Burkholderia phage KS14 |
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1.E.57.1.1 | Mycobacteriophage Ms6 Gp5 holin of 124 aas and 1 N-terminal TMS (of the DUF2746/Pha00327 family) (Catalão et al. 2011). |
Viruses | Gp5 holin of Mycobacteriophage Ms6 |
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1.E.57.1.2 | Gp32 of Mycobacteriophage Che12 of 108 aas and 1 TMS. |
Viruses | Heunggongvirae, Uroviricota | Gp32 of Mycobacerial phage Che12 |
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1.E.57.1.3 | Putative holin of 110 aas and 1 N-terminal TMS. |
Bacteria | Actinomycetota | Putative holin of Leifsonii xyli |
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1.E.57.1.4 | Putative holin of 117 aas and 1 TMS, Gp33 |
Viruses | Heunggongvirae, Uroviricota | Gp33 of Mycobacterial phage DS6A |
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1.E.57.1.5 | Putative holin of 129 aas and 1 TMS |
Bacteria | Actinomycetota | Putative holin of Gordonia sihwensis |
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1.E.57.1.6 | Putative holin of 157 aas and 1 TMS |
Bacteria | Actinomycetota | Holin of Acinomyces turicensis |
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1.E.57.2.1 | Putative holin of 146 aas and 1 TMS, Gp26 |
Viruses | Heunggongvirae, Uroviricota | Gp26 of Tsukamurella phage TPA2 |
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1.E.57.2.2 | Putative holin of 145 aas and 1 TMS |
Viruses | Heunggongvirae, Uroviricota | Holin of Gordonia phage GTE5 |
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1.E.57.2.3 | Putative holin of 139 aas and 1 TMS |
Bacteria | Actinomycetota | Holin of Gordonia sihwensis |
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1.E.57.2.4 | Putative holin of 122 aas and 1 TMS |
Bacteria | Actinomycetota | Holin of Segniliparus rugosus |
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1.E.57.2.5 | Putative holin of 117 aas and 1 TMS |
Bacteria | Actinomycetota | Hoin of Rhodocuccus opacus |
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1.E.57.3.1 | Putative holin of 173 aas and 1 TMS |
Bacteria | Actinomycetota | Holin of Corynebacterium callunae |
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1.E.57.3.2 | Putative holin of 140 aas and 1 TMS |
Bacteria | Actinomycetota | Holin of Corynebacterium aurimucosum (Corynebacterium nigricans) |
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1.E.57.3.3 | Putative holin of 118 aas and 1 TMS |
Bacteria | Actinomycetota | Holin of Corynebacterium pyruviciproducens |
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1.E.58.1.1 | Erwinia Phage Phi-Ea1h Holin of 119 aas and 1 TMS. This holin may export a lysozyme (Lyz; Q9FZS7) and possibly an EPS depolymerase (Q9G072) (Kim and Geider 2000). This protein has not signficant homologues in the NCBI database as of 3/3/14 as revealed by a protein BLAST search. |
Viruses | Heunggongvirae, Uroviricota | Holin of Erwinia Phage Phi-Ea1h |
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1.E.59.1.1 | Putative holin/viroporin of 81 aas and 2 TMSs |
Viruses | Putative holin of Acholeplasma phage L2 |
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1.E.59.1.2 | Uncharacterized protein of 75 aas and 2 TMSs. |
Bacteria | Mycoplasmatota | UP of Acholeplasma brassicae |
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1.E.6.1.1 | 17.5 lysis protein, gb17.5 (67 aas); the phage T7 holin (Nguyen and Kang 2014). This holin is 94% identical to the holin from E. coli phage CICC 80001 (Xu et al. 2015). |
Viruses | Heunggongvirae, Uroviricota | gb17.5 of E. coli phage T7 |
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1.E.6.1.2 | Putative lysis protein |
Viruses | Heunggongvirae, Uroviricota | Putative lysis protein of Vibrio phage ICP3 |
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1.E.6.1.3 | Type II holin |
Viruses | Heunggongvirae, Uroviricota | Type II holin of Pseudomonas phage gh-1 |
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1.E.6.2.1 | Putative holin |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Caulobacter phage Cd1 |
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1.E.6.2.2 | Putative holin-like phage protein |
Bacteria | Pseudomonadota | Putative holin-like phage protein of Candidatus Glomeribacter gigasporarum |
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1.E.6.2.3 | Hypothetical protein |
Bacteria | Pseudomonadota | Hypothetical protein of Comamonas testosteroni |
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1.E.6.2.4 | Putative class II holin |
Viruses | Heunggongvirae, Uroviricota | Class II holin of Enterbacterial phage LKA1 |
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1.E.6.2.5 | Holin of 77 aas and 1 central TMS from E. coli phage ECBP5, Orf46. This protein is nearly identical to the pin-holin characterized for E. coli phage KBNP1315 (Lee et al. 2015). It infects a pathogenic avian E. coli strain (Lee et al. 2015). |
Viruses | Heunggongvirae, Uroviricota | Holin of phage ICBP5 or KBNP1315. |
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1.E.6.2.6 | Putative holin of 60 aas and 1 TMS |
Viruses | Heunggongvirae, Uroviricota | Holin of Pectobacterium phage PP1 |
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1.E.6.2.7 | Putative holin of 64 aas and 1 TMS |
Bacteria | Pseudomonadota | Holin of Lysobacter dokdonensis |
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1.E.6.2.8 | Putative holin of 107 aas and 2 TMSs. |
Bacteria | Pseudomonadota | Holin of Stenotrophomonas maltophilia |
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1.E.6.2.9 | Holin of 62 aas |
Viruses | Heunggongvirae, Uroviricota | Holin of Ralstonia phage RsoP1IDN |
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1.E.6.3.1 | Phage pinholin (Summer et al. 2010). |
Viruses | Heunggongvirae, Uroviricota | Pinholin of Xyella phage Xfas53 |
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1.E.6.3.2 | putative pinholin |
Bacteria | Pseudomonadota | Pinholin of Stenophomonas maltophilia |
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1.E.6.3.3 | Putatuve pinholin |
Bacteria | Pseudomonadota | Pinholin of Delftia acidovorans |
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1.E.6.3.4 | Putative pinholin |
Bacteria | Pseudomonadota | Pinholin of Comamonas testosteroni |
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1.E.6.3.5 | Putative pinholin |
Bacteria | Pseudomonadota | Pinholin of Laribacter honkongensis |
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1.E.6.3.6 | Holin of 61 aas and 1 C-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.E.60.1.1 | Putative holin of 45 aas and 1 TMS. |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Mycobacterium virus Acadian |
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1.E.60.1.2 | Putative holin of 45 aas and 1 TMS. |
Viruses | Heunggongvirae, Uroviricota | Putative holin of Mycobacterium phage Rich |
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1.E.60.1.3 | Uncharacterized protein of 89 aas and 2 TMSs. |
Archaea | Euryarchaeota | UP of Halorientalis persicus |
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1.E.60.1.4 | Putative holin of 85 aas and 2 TMSs. |
Archaea | Euryarchaeota | Putative holin of Halogranum amylolyticum |
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1.E.61.1.1 | Holin (gene 44) of Pseudomonas phage phiKMV of 66 aas and 1 TMS. The holin accumulates harmlessly in the cytoplasmic membrane
until it reaches a critical concentration that triggers the formation
of nanometer-scale pores (pinholes) causing host cell membrane
depolarization and a protein, endolysin orcytolysin refolding and release into the periplasmic
space (Briers et al. 2011). The 66 aa holin from Pseudomonas phage AIIMS-Pa-Ai (genbank acc # QPP21131.1) is identical to this one (Rathor et al. 2022). An identical protein in the region of overlap has 77 aas (Rathor et al. 2022).
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Viruses | Heunggongvirae, Uroviricota | Holin of phage phiKMV |
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1.E.61.1.2 | Holin homologue of 79 aas and 1 TMS. |
Bacteria | Pseudomonadota | Holin of Pseudomonas tolaasii |
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1.E.62.1.1 | Putative holin of 49 aas and 1 N-terminal TMS |
Viruses | Heunggongvirae, Uroviricota | Holin of Bacillus phage VioletteMad |
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1.E.62.1.2 | Putative holin; member of the YvrJ family |
Bacteria | Bacillota | YvrJ family protein of Caldanaerobius fijiensis |
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1.E.62.1.3 | Putative holin, member of the YvrJ family, of 60 aas and 1 N-terminal TMS |
Bacteria | Bacillota | YvrJ family protein of Carnobacterium alterfunditum |
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1.E.62.1.4 | YvrJ family protein of 50 aas and 1 TMS |
Bacteria | Bacillota | YvrJ protein of Peptoanaerobacter stomatis |
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1.E.62.1.5 | Uncharacterized YvrJ family protein of 60 aas and 1 TMS |
Bacteria | Bacillota | UP of Pelotomaculum schinkii |
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1.E.62.1.6 | Uncharacterized YvrJ family protein of 48 aas and 1 TMS |
Bacteria | Bacillota | UP of Kurthia zopfii |
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1.E.62.1.7 | Uncharacterized YvrJ family protein of 71 aas and 1 N-terminal TMS |
Bacteria | Synergistota | YvrJ family protein of Aminomonas paucivorans |
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1.E.62.1.8 | Uncharacterized YvrJ family member of 49 aas and 1 TMS |
Bacteria | Bacillota | UP of Selenomonas ruminantium |
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1.E.63.1.1 | Characterized holin, Gp19 or HolSD of 76 aas and 2 TMSs (Lu et al. 2019). |
Viruses | Heunggongvirae, Uroviricota | Gp19 or HolSD of Streptomyces phage phiSASD1 |
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1.E.63.1.10 | Putative holin of 75 aas and 2 TMSs |
Bacteria | Actinomycetota | Holin of Streptomyces aidingensis |
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1.E.63.1.11 | Putative holin of 78 aas and 2 TMSs |
Bacteria | Actinomycetota | Holin of Saccharothrix variisporea |
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1.E.63.1.12 | Gp19 holin of 76 aas and 2 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Gp19 of Streptomyces phage phiSASD1 |
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1.E.63.1.2 | Uncharacterized holin homologue of 78 aas and 2 TMSs. |
Bacteria | Actinomycetota | Holin of Actinoplanes italicus |
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1.E.63.1.3 | Putative holin of 100 aas and 2 TMSs. |
Bacteria | Actinomycetota | Holin of Micromonospora aurantiaca |
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1.E.63.1.4 | Putative holin of 83 aas and 2 TMSs |
Bacteria | Actinomycetota | Holin of Salinispora pacifica |
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1.E.63.1.5 | Putative holin of 77 aas and 2 TMSs. |
Bacteria | Actinomycetota | Holin of Thermoactinospora rubra |
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1.E.63.1.6 | Putative holin of 83 aas and 2 TMSs |
Bacteria | Actinomycetota | Holin of Amycolatopsis sp. CFH S0078 |
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1.E.63.1.7 | Putative holin of 70 aas and 2 TMSs |
Bacteria | Actinomycetota | Holin of Streptomyces albidoflavus |
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1.E.63.1.8 | Putative holin of 73 aas and 2 TMSs/ |
Bacteria | Actinomycetota | Holin of Catenulispora sp. |
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1.E.63.1.9 | Putative holin of 77 aas and 2 TMSs. |
Bacteria | Actinomycetota | Holin of Ornithinicoccus sp. YJ01 |
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1.E.64.1.1 | Enterobacterial phage P7 holin, LydD of 84 aas and 2 TMSs . |
Viruses | Heunggongvirae, Uroviricota | LydD holin of Phage P7 |
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1.E.64.1.2 | Holin of 84 aas and 2 TMSs. |
Bacteria | Pseudomonadota | Holin of Pantoea sp. PSNIH6 |
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1.E.64.1.4 | Uncharacterized protein of 77 aas and 2 TMSs. This protein interconnects 1.E.64.1, 1.E.64.2 and 1.E.53.2.6. |
Bacteria | Pseudomonadota | UP of Methylobacterium sp. WL12 |
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1.E.64.1.5 | Uncharacterized protein of 68 aas and 2 TMSs. |
Bacteria | Pseudomonadota | UP of Mesorhizobium sp. (plant metagenome) |
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1.E.64.2.1 | Uncharacterized putative holin of 73 aas and 2 TMSs. |
Bacteria | Proteobacteria | Putative holin of Hyphomicrobiales bacterium |
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1.E.64.2.2 | Uncharacterized protein of 73 aas and 2 TMSs. |
Bacteria | Pseudomonadota | UP of Rhizobium leguminosarum |
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1.E.64.2.3 | Uncharacterized protein, putative holin of 77 aas and 2 TMSs. |
Bacteria | Pseudomonadota | UP of Pleomorphomonas carboxyditropha |
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1.E.64.2.4 | Uncharacterized protein of 72 aas and 2 TMSs. |
Bacteria | Pseudomonadota | UP of Achromobacter pulmoni |
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1.E.64.2.5 | Fusion protein with a holin domain at the N-terminus and a lysozyme domain at the C-terminus. The holin domain includes 2 TMSs, while there is a single TMS at the N-terminus of the lysozyme domain. |
Bacteria | Pseudomonadota | Holin-Lysozyme fusion protein of Leisingera daeponensis |
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1.E.64.2.6 | Uncharacterized protein of 77 aas asnd 2 TMSs. |
Bacteria | Pseudomonadota | UP of Pseudomonas sp. GV047 |
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1.E.64.2.7 | Putative class II holin of 69 aas and 2 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Holin of Alteromonas phage vB_AmeP_R8W |
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1.E.64.3.1 | Holin of Acinetobacter phage Loki of 80 aas and 2 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Holin of Acinetobacter baumannii phage Loki |
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1.E.64.3.10 | Uncharacterized protein of 84 aas and 2 TMSs. |
Bacteria | Pseudomonadota | UP of Zavarzinia aquatilis |
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1.E.64.3.2 | Burkholderia phage BcepNazgul holin of 127 aas and 3 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Holin of Burkholderia phage BcepNazgul |
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1.E.64.3.3 | Uncharacterized protein of 93 aas and 2 probable TMSs. |
Bacteria | Pseudomonadota | UP of Achromobacter dolens |
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1.E.64.3.4 | Putative holin of 79 aas and 2 TMSs. This protein is 86% idetical and the same length as the holin from phage vB_SenS_ST1UNAM which has lytic activity against Salmonella typhimurium (Rodea M et al. 2024). |
Viruses | Heunggongvirae, Uroviricota | Holin of Salmonella phage Akira |
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1.E.64.3.5 | Putative holin of 114 aas and 3 TMSs. |
Bacteria | Pseudomonadota | Holin of Klebsiella oxytoca |
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1.E.64.3.6 | Uncharacterized protein of 90 aas and 2 TMSs. |
Bacteria | Pseudomonadota | UP of Acinetobacter baumannii |
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1.E.64.3.7 | Uncharacterized protein (putative holn) of 88 aas and 2 TMSs. |
Bacteria | Pseudomonadota | UP of Cupriavidus alkaliphilus |
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1.E.64.3.8 | Uncharacterized protein of 90 aas and 2 TMSs. |
Bacteria | Pseudomonadota | UP of Sphingomonas sp. RIT328 |
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1.E.64.3.9 | Uncharacterized protein of 87 aas and 2 TMSs. |
Bacteria | Pseudomonadota | UP of Achromobacter marplatensis (Achromobacter spiritinus) |
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1.E.65.1.1 | Holin protein of 80 aas and 1 C-terminal TMS. |
Bacteria | Bacillota | Holin of prophage PBSX in Enterococcus faecium |
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1.E.65.1.2 | Holin XhlA/B of 74 aas and one C-terminal TMS. |
Bacteria | Bacillota | Holin of Lactococcus lactis subsp. lactis (Streptococcus lactis) |
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1.E.65.1.3 | Holin of 67 aas and one C-terminal TMS |
Bacteria | Bacillota | Holin of Brevibacillus laterosporus |
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1.E.65.1.4 | Hemolysin XhlA of 83 aas and 1 C-terminal TMS.
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Bacteria | Bacillota | Hemolysin XhlA family protein of Desulfosporosinus fructosivorans |
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1.E.65.1.5 | Hemolysin XhlA family protein of 87 aas and 1 C-terminal TMS. |
Bacteria | Bacillota | XhlA of Desulfosporosinus fructosivorans |
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1.E.65.1.6 | Uncharacterized protein of 107 aas and 1 C-terminal TMS. |
Bacteria | Bacillota | UP of Thermoactinomyces daqus |
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1.E.65.1.7 | Uncharacterized protein of 119 aas and one C-terminal TMS. |
Bacteria | Pseudomonadota | UP of Pseudomonas brassicacearum |
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1.E.66.1.1 | Gp25 protein of E. coli phage Mu of 99 aas. It functions as a holin but has been called a releasin (Chamblee et al. 2022). Its gene is Mup25. |
Viruses | Heunggongvirae, Uroviricota | Gp25 of phage Mu |
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1.E.66.1.10 | DUF2730 family protein of 111 aas and 1 TMS |
Bacteria | Pseudomonadota | DUF2730 protein of Rhizobium pusense |
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1.E.66.1.11 | DUF2730 family protein of 131 aas and 1 TM |
Bacteria | Pseudomonadota | DUF2730 protein of Microvirga sp. |
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1.E.66.1.12 | Uncharacterized protein of 103 aas and 1 TMS. |
Bacteria | Pseudomonadota | UP of Neptunomonas japonica |
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1.E.66.1.13 | DUF2730 family protein of 113 aas and 1 TM |
Bacteria | Pseudomonadota | DUF2730 protein of Halomonas profundi |
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1.E.66.1.14 | DUF2730 family proteinof 116 aas and 1 TM |
Bacteria | Pseudomonadota | DUF2730 protein of Pseudoalteromonas flavipulchra |
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1.E.66.1.15 | Uncharacterized protein of 140 aas and 1 TMS |
Bacteria | Pseudomonadota | UP of Alteromonadaceae bacterium |
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1.E.66.1.16 | DUF2730 family protein of 144 aas and 1 TM |
Bacteria | Pseudomonadota | DUF2730 protein of Roseospira marina |
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1.E.66.1.17 | Uncharacterized protein of 136 aas |
Bacteria | Pseudomonadota | UP of Inquilinus limosus |
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1.E.66.1.2 | Uncharacterized DUF2730 protein of 102 aas and 1 N-terminal TMS. |
Viruses | Duplodnaviria | UP of Myoviridae sp. |
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1.E.66.1.3 | Mu-like phage gp25 protein of 80 aas and 1 N-terminal TMS. |
Bacteria | Proteobacteria | Gp25 of Glaesserella parasuis |
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1.E.66.1.4 | Putative Mu-like phage gp25 protein of 107 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | gp25-like protein of Avibacterium paragallinarum |
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1.E.66.1.5 | Uncharacterized protein of 112 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of Pleomorphomonas diazotrophica |
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1.E.66.1.6 | Uncharacterized protein of 153 aas and 2 N-terminal TMSs. This protein shows sequence similarity with other members of this family in the C-terminal domain, not in the first TMS. |
Bacteria | Pseudomonadota | UP of Salipiger sp. |
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1.E.66.1.7 | DUF2730 family protein of 109 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | DUF2730 of Grimontia hollisae |
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1.E.66.1.8 | DUF2730 family protein of 104 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | DUF2730 protein of Rhodobiaceae bacterium |
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1.E.66.1.9 | DUF2730 protein of 100 aas and 1 TMS |
Bacteria | Pseudomonadota | DUF2730 protein of Ignatzschineria sp. |
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1.E.66.2.1 | DUF2730 family protein of 141 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | DUF2730 protein of Azospirillum thiophilum |
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1.E.66.2.2 | Uncharacterized protein of 134 aas and 1 TMS. |
Bacteria | Pseudomonadota | UP of Thalassolituus sp. |
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1.E.66.2.3 | Uncharacterized protein of 136 aas and 1 TMS |
Bacteria | Pseudomonadota | UP of Caenispirillum bisanense |
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1.E.66.3.1 | Uncharacterized protein of 127 aas and 1 TMS |
Viruses | UP of Bacteriophage sp. |
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1.E.66.3.2 | Uncharacterized protein of 122 aas |
Viruses | Duplodnaviria | UP of Siphoviridae sp |
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1.E.66.3.3 | Uncharacterized protein of 127 aas |
Bacteria | Thermodesulfobacteriota | UP of Desulfovibrio fairfieldensis |
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1.E.66.3.4 | Uncharacterized protein of 128 aas |
Bacteria | Myxococcota | UP of Deltaproteobacteria bacterium |
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1.E.66.3.5 | DUF2730 family protein of 127 aa |
Bacteria | Pseudomonadota | DUF2730 protein of Methylocystaceae bacterium |
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1.E.66.3.6 | DUF2730 family protein of 128 aa |
Bacteria | Thermodesulfobacteriota | DUF2730 protein of Desulfovibrio mexicanus |
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1.E.66.4.1 | Uncharacterized protein of 117 aas and 1 TMS |
Bacteria | Acidobacteriota | UP of Holophagales bacterium |
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1.E.66.4.2 | Uncharacterized protein of 124 aas and 1 TMS |
Bacteria | Pseudomonadota | UP of Halomonas salina |
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1.E.66.4.3 | DUF2730 family protein of 115 aas and 1 TMS |
Bacteria | Pseudomonadota | DUF2730 protein of Acidihalobacter prosperus |
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1.E.66.4.4 | Uncharacterized protein of 116 aas |
Viruses | Duplodnaviria | UP of Myoviridae sp. |
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1.E.66.4.5 | Uncharacterized protein of 116 aas |
Bacteria | Thermodesulfobacteriota | UP of Desulfoluna spongiiphila |
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1.E.67.1.1 | Holin of Pseudomonas lytic phage HZ2201 of 72 aas and 2 TMSs. This phage shows antibiofilm efficacy against P. aeruginosa (Fei et al. 2023). See family description for details. This protein is (nearly) identical to the holin from phage PaP3 except for 22 N-terminal amino acids with a third TMS in the latter protein (GenBank acc # NP_775222.1) that are lacking in 1.E.67.1.1. It is likely that the 1.E.67.1.1 protein is N-terminally truncated, as all other members of the family are longer with 3 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Holin of P. aeruginoisa phage HZ2201 |
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1.E.67.1.2 | Holin of 119 aas and 3 TMSs (Fei et al. 2023). See family description for details. |
Viruses | Heunggongvirae, Uroviricota | Holin of Vibrio phage 1.204.O._10N.222.46.F12 |
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1.E.67.1.3 | Holin of 89 aas and 3 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Holin of phage MedPE-SWcel-C56 |
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1.E.67.1.4 | Putative holin of 96 aas and 3 TMSs. |
Bacteria | Pseudomonadota | Holin of Alishewanella sp. WH16-1 |
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1.E.67.1.5 | Uncharacterized protein of 98 aas and 3 TMSs. |
Bacteria | Pseudomonadota | UP of Rheinheimera soli |
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1.E.67.1.6 | Uncharacterized putative holin protein of 122 aas and 3 N-terminal TMSs. |
Viruses | Heunggongvirae, Uroviricota | UP of Pseudomonas phage GP100 |
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1.E.68.1.1 | Holin of 72 aas and 1 N-terminal TMS. This protein is nearly identical to and the same length as the holin of Shigella phage SGF2 (Lu et al. 2023). |
Viruses | Heunggongvirae, Uroviricota | Holin of Escherichia phage phiEco32 |
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1.E.68.1.2 | Uncharacterized putative holin of 72 aas and 1 N-terminal TMS. It is ~ 70% identical to TC# 1.E.68.1.1. |
Viruses | Heunggongvirae, Uroviricota | UP of Escherichia phage 4E8 |
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1.E.69.1.1 | Holin of 131 aas with two C-terminal TMSs. |
Viruses | Heunggongvirae, Uroviricota | Holin of Caudoviricetes sp. (hot spring metagenome) |
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1.E.69.1.2 | Putative holin of 75 aas with 2 C-terminal TMSs. |
Archaea | Putative holin of Nitrososphaerales archaeon |
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1.E.7.1.1 | Holin of 78 aas and 1 - 3 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Holin Haemophilus influenzae phage HP1; spP51727) |
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1.E.7.1.2 | Holin of 74 aas and 1 TMS. |
Bacteria | Pseudomonadota | Holin of Haemophilus somnus |
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1.E.7.1.3 | Holin of 68 aas and 1 TMS. |
Bacteria | Pseudomonadota | Holin of Mannheimia haemolytica |
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1.E.7.1.4 | Holin of 75 aas and 1 TMS |
Bacteria | Pseudomonadota | Holin of Rodentibacter trehalosifermentans |
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1.E.7.2.1 | phage pg24 protein of 80 aas and 1 TMS |
Viruses | Heunggongvirae, Uroviricota | gp24 of Burkholderia phage phi644-2 |
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1.E.7.2.2 | Holin of 83 aas and 1 TMS. |
Bacteria | Pseudomonadota | Holin of Azomonas agilis |
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1.E.7.2.3 | Holin of 96 aas and 1 TMS |
Bacteria | Pseudomonadota | Holin of Thauera butanivorans |
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1.E.7.2.4 | Holin of 66 aas and 1 TMS |
Viruses | Duplodnaviria | Holin of Siphoviridae sp. (Human Metagenome) |
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1.E.7.2.5 | Holin of 80 aas and 1 TMS |
Bacteria | Pseudomonadota | Holin of Comamonas odontotermitis |
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1.E.7.2.6 | Holin of 67 aas and 1 TMS |
Bacteria | Pseudomonadota | Holin of Enterobacter cloacae |
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1.E.7.2.7 | Holin of 78 aas and 2 TMSs |
Bacteria | Pseudomonadota | Holin of Acinetobacter soli |
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1.E.70.1.1 | Holin of 107 aas and 3 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Holin of Natrialba phage PhiCh1 |
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1.E.70.1.2 | Uncharacterized protein of 99 aas and 3 TM |
Archaea | Euryarchaeota | UP of Halorubrum saccharovorum |
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1.E.70.1.3 | Holin of 107 aas and 3 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Holin of Halobacterium phage ChaoS9 |
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1.E.70.1.4 | Uncharacterized protein of 104 aas and 3 TMSs. |
Archaea | Euryarchaeota | UP of Haloparvum sedimenti |
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1.E.71.1.1 | Phage holin family protein of 92 aas and 2 TMSs. |
Archaea | Candidatus Bathyarchaeota | Holin of Candidatus Bathyarchaeota archaeon |
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1.E.71.1.2 | Uncharacterized protein of 93 aas and 2 TMSs. |
Bacteria | Acidobacteriota | UP of Candidatus Sulfotelmatobacter sp. (soil metagenome) |
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1.E.71.1.3 | Uncharacterized protein of 123 aas and 2 TMSs. |
Bacteria | Acidobacteriota | UP of Candidatus Acidoferrales bacterium |
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1.E.71.1.4 | Putative transcrijptional regulator of 85 aas and 2 TMSs. |
Archaea | Nitrososphaerota | Uncharacterized protein of Nitrososphaerota archaeon |
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1.E.71.1.5 | Uncharacterized protein of 94 aas and 2 N-terminal TMSs. |
Bacteria | Thermodesulfobacteriota | UP of Thermodesulfobacteriota bacterium |
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1.E.8.1.1 | Lysis protein, T, of 218 aas and 1 TMS. T holin activity is regulated by the largely periplasmic anti-holin RI (P13304) and the cytoplasmic antiholin RIII which act synergistically (Chen and Young 2016). RI is degraded by DegP (Tran et al., 2007). Mutations in all 3 topological domains if RI (the N-terminal cytoplasmic domain, the single TMS, and the C-terminal periplasmic domain) can abrogate holin function (Moussa et al. 2014). |
Viruses | Heunggongvirae, Uroviricota | Lysis protein or holin (P06808) of Phage T4 |
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1.E.8.1.2 |
T-holin (196 aas) of phage RB43. |
Viruses | Heunggongvirae, Uroviricota | T-holin of phage RB43 |
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1.E.8.1.3 | Putative holin of 208 aas and 1 TMS. |
Viruses | Heunggongvirae, Uroviricota | Holin of pectobacterial phage My1 |
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1.E.8.1.4 | Putative holin (lysis protein) of enterobacterial phage T5 (218 aas; 1 TMS) (Catalão et al. 2012). |
Viruses | Heunggongvirae, Uroviricota | Putative holin of phage T5 |
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1.E.8.1.5 | T holin lysis mediator of 215 aas and 1 TMS. Phage KP27 protects against multidrug resistant strains of Klebsiella (Maciejewska et al. 2016). |
Viruses | Heunggongvirae, Uroviricota | Holin of Klebsiella phage KP27 |
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1.E.8.1.6 | Holin of 240 aas and 2 N-terminal TMSs. It interacts (via its C-terminus) with antiholin (via its C-terminus); this interaction blocks the holin homomultimerization and delays host cell lysis. It also interacts (via its N-terminus) with the lysis inhibition accessory protein rIII; this interaction stabilizes the holin-antiholin complex thereby resulting in a robust block of the hole formation. |
Viruses | Heunggongvirae, Uroviricota | Holin of Acinetobacter phage AbTZA1 |
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1.E.9.1.1 | Immunity protein | Viruses | Heunggongvirae, Uroviricota | Immunity protein (83 aas; spP08986) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.E.9.1.10 | Putative holin |
Bacteria | Gemmatimonadota | Putative holin of Gemmatimonas aurantiaca |
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1.E.9.1.11 | Putative holin |
Bacteria | Chlorobiota | Putative holin of Chlorobium tepidum |
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1.E.9.1.12 | Putative holin |
Bacteria | Chlorobiota | Putative holin of Chlorobaculum parva |
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1.E.9.1.2 | Putative holin |
Bacteria | Acidobacteriota | Putative holin of Granulicella mallensis |
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1.E.9.1.3 | Putative holin |
Bacteria | Acidobacteriota | Putative holin of Terriglobus saanensis |
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1.E.9.1.4 | 2 TMS protein of 87 aas |
Bacteria | Bacillota | Protein of 87 aas of Clostridium hylemonae (C0BVR9) |
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1.E.9.1.5 |
3 TMS phage protein, Gp75, of 105 aas. TMSs 2-3 are homologous to TMSs 1-2 in 1.E.9.1.4. |
Viruses | Heunggongvirae, Uroviricota | Gp75 of Mycobacterium phage Bethlehem (Q5J5E8) |
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1.E.9.1.6 | Immunity protein |
Bacteria | Bacteroidota | Immunity protein of Niastella koreensis |
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1.E.9.1.7 | Immunity protein |
Bacteria | Cyanobacteriota | Immunity protein of Prochlorococcus marinus |
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1.E.9.1.8 | Signal peptide transmembrane protein |
Bacteria | Pseudomonadota | Signal peptide membrane protein of Burkholderia xenovorans |
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1.E.9.1.9 | Putative holin |
Bacteria | Pseudomonadota | Putative holin of Acidithiobacillus ferrivorans |
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1.F.1.1.1 | The SNARE fusion complex, fusing neurotransmitter vesicles with the presynaptic membrane. Ca2+ acts on the synaptic vesicle synaptotagmin1 (synaptotagmin I; SytI, Syt1, SSVP65, SYT) to trigger rapid exocytosis (Chapman, 2008). Syt1 is a major Ca2+ sensor for fast neurotransmitter release. It contains tandem Ca2+-binding C2 domains (C2AB), a single transmembrane α-helix and a highly charged 60-residue- long linker in between. The linker region of Syt1 is essential for its two signature functions: Ca2+-independent vesicle docking and Ca2+-dependent fusion pore opening. The linker contains the basic-amino acid-rich N-terminal region and the acidic amino acid-rich C-terminal region (Lai et al. 2013). The intrinsically disordered region between Syt I's transmembrane helix and the first C2 domain interats with vesicular lipids and modulates Ca2+ binding to C2 (Fealey et al. 2016). t-SNARE and v-SNARE interact in their C-terminal TMSs to promote pore opening (Wu et al. 2016). Both sides of a trans-SNARE complex can drive pore opening suggesting an indentation model in which multiple SNARE C-termini cooperate in opening the fusion pore by locally deforming the inner leaflets (D'Agostino et al. 2016). The TMSs of SNARE proteins regulate the fusion process (Wu et al. 2017). The cysteine-rich domain of SNAP-23 regulates its membrane association and exocytosis from mast cells (Agarwal et al. 2019). Snc1 is trafficked between the endosomal system and the Golgi apparatus via multiple pathways, providing evidence for protein quality control surveillance of a SNARE protein in the endo-vacuolar system (Ma and Burd 2019). MemDis is a novel prediction method, utilizing a convolutional neural network and long short-term memory networks for predicting disordered regions in transmembrane proteins (Dobson and Tusnády 2021). Curcuminoids (bisdemethoxycurcumin and curcumin) modulate the release of neurotransmitters during exocytosis (Li et al. 2016). Oxidative stress-induced inhibition of VAMP8 trafficking to lysosomes is associated with the development of neurodegenerative diseases due to blocked autophagosome-lysosome fusion (Ohnishi et al. 2022). Calcium (Ca2+) plays a critical role in triggering all three primary modes of neurotransmitter release (synchronous, asynchronous, and spontaneous). Synaptotagmin1, a protein with two C2 domains, is the first isoform of the synaptotagmin family that was identified and demonstrated as the primary Ca2+ sensor for synchronous neurotransmitter release (Zhou 2023). Other isoforms of the synaptotagmin family as well as other C2 proteins such as members of the double C2 domain protein family were found to act as Ca2+ sensors for different modes of neurotransmitter release. A new model, release-of-inhibition, for the initiation of Ca2+-triggered synchronous neurotransmitter release has been proposed. Synaptotagmin1 binds Ca2+ via its two C2 domains and relieves a primed pre-fusion machinery. Before Ca2+ triggering, synaptotagmin1 interacts Ca2+ independently with partially zippered SNARE complexes, the plasma membrane, phospholipids, and other components to form a primed pre-fusion state that is ready for fast release. However, membrane fusion is inhibited until the arrival of Ca2+ reorients the Ca2+-binding loops of the C2 domain to perturb the lipid bilayers, help bridge the membranes, and/or induce membrane curvatures, which serves as a power stroke to activate fusion (Zhou 2023). Synaptobrevin2 (Syb2) monomers and dimers differentially engage in regulating the trans-SNARE assembly during membrane fusion. The differential recruitment of two syb2 structures at the membrane fusion site has consequences in regulating individual nascent fusion pore properties. A few syb2 transmembrane domain residues control monomer/dimer conversion. Thus, syb2 monomers and dimers are differentially recruited at the release sites for regulating membrane fusion events (Patil et al. 2024).
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Eukaryota | Metazoa, Chordata | The ten component SNARE fusion complex of Homo sapiens, fusing neurotransmitter vesicles with the presynaptic membrane. |
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1.F.1.1.2 | Yeast vacuolar snare complex including the vesicle-associated membrane protein 2 (Snc2p; 115aas; 1-C-terminal TMS) (Chernomordik et al., 2005), the vacuole morphogenesis protein, Vam3 (PTH1) of 283 aas, the vacuolar v-snare, Nyv1 of 253 aas, and the t-snare, Vti1 of 217 aas. Considering these last three proteins, SNARE TMSs serve as non-specific membrane anchors in vacuole fusion, but fusion requires the SNARE complexes in the plasma and vacuolar membranes. Lipid-anchored Vti1 was fully active, lipid-anchored Nyv1 (R-SNARE) permitted the fusion reaction to proceed up to hemifusion, but lipid-anchored Vam3 interfered with fusion before hemifusion. Vam7 (a soluble SNARE; 316 aas) and Sec18 (758 aas) remodel SNARE compexes to allow lipd-anchored R-SNARE (NYV1, 253 aas), acting with Q-SNARE (VTS1; 523 aas), to support vacuole fusion (Jun et al. 2007).Thus, these proteins have non-specific membrane anchors, but each of these proteins makes different contributions to the hemifusion intermediate and opening of the fusion pore (Semenov et al. 2014). The 181-198 region of Qa-snare, immediately upstream of the SNARE heptad-repeat domain, is required for normal fusion activity with HOPS. This region is needed for normal SNARE complex assembly (Song and Wickner 2017). Sec17 and Sec18 act twice in the fusion cycle, binding to trans-SNARE complexes to accelerate fusion, and then to hydrolyze ATP to disassemble cis-SNARE complexes (Song et al. 2017). Fusion with wild-type SNARE domains is controlled by juxtamembrane domains, transmembrane anchors, and Sec17 (Orr et al. 2022). |
Eukaryota | Fungi, Ascomycota | The vacuolar snare complex of Saccharomyces cerevisiae |
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1.F.1.1.3 | The worm SNARE complex and it's regulators for vesicle neurotransmetter and neuropeptide release (Gracheva et al. 2007). The core SNARE complex consists of Syntaxin, SNAP and Synaptobrevin and mediates the synaptic vesicle cycle (Rathore et al. 2010). Synaptotagmin I is a Ca2+ sensor triggering vesicle fusion (Yu et al. 2013). Regulators include Snapin dimers (Yu et al. 2013), Complexin, a presynaptic protein that interacts with the SNARE complex (the C-terminal domain binds lipids to inhibit exocytosis) (Hobson et al. 2011; Wragg et al. 2013), Unc-18, which binds syntaxin and regluates synaptic vesicle (neurotransmitter) docking (Graham et al. 2011), Unc13 which also regulates docking of the synaptic vesicles to the plasma membrane by interacting with syntaxin, CAPS or Unc31, a Ca2+-activated protein for secretion that is required for dense core vesicle docking for neuropeptide release (Lin et al. 2010), and Tomosyn or Tom-1, a negative regluator of both neurotransmitter and neuropeptide release (Gracheva et al. 2007). |
Eukaryota | Metazoa, Chordata | Synaptic vesicle fusion apparatus of Caenorhabditis elegans |
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1.F.1.1.4 | The mouse synaptobrevin 2 (syb2)/VAMP2/Syntaxin (Syx)/SNAP-25 complex is involved in vesicle fusion pore formation (Chang et al. 2015). The synaptobrevin juxtamembrane regions plus the TMS may catalyze pore formation by forming a membrane-spanning complex that increases curvature stress at the circumference of the hemifused diaphragm of the prepore intermediate state (Tarafdar et al. 2015). The TMS of VAMP2 plays a critical role in membrane fusion, and the structural mobility provided by the central small amino acids is crucial for exocytosis by influencing the molecular re-arrangements of the lipid membrane that are necessary for fusion pore opening and expansion (Hastoy et al. 2017). SNARE TMSs may function as parts of the fusion pores during Ca2+-triggered exocytosis for release of both neurotransmitters and hormones (Chiang et al. 2018). The intracellular periodontal pathogen, P. gingivalis, exploits a recycling pathway involving VAMP2 to exit from infected cells (Takeuchi et al. 2016). VAMP2 can bind to different sets of lipids in different organellar-mimicking membranes. Considering that the cellular trafficking pathway of most eukaryotic integral membrane proteins involves residence in multiple organellar membranes, this study highlights how the lipid-specificity of the same integral membrane protein may change depending on the membrane context (Panda et al. 2023). |
Eukaryota | Metazoa, Chordata | Fusion pore forming subunits of Mus musculus
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1.F.1.1.5 | The RABGET1 (RABEX5) - STX6-VAMP3-VTI1B complex mediates fusion between recycling endosomes and Streptococcus (GAS)-containing autophagosome-like vacuoles (Nozawa et al. 2017). Macroautophagy/autophagy plays a critical role in immunity by directly degrading invading pathogens such as Group A Streptococcus (GAS), through a process that has been named xenophagy. Autophagic vacuoles directed against GAS, termed GAS-containing autophagosome-like vacuoles (GcAVs), use recycling endosomes (REs) as a membrane source. This complex mediates fusion between GcAVs and REs. STX6 (syntaxin 6) is recruited to GcAVs and forms a complex with VTI1B and VAMP3 to regulate the GcAV-RE fusion that is required for xenophagy. STX6 targets the GcAV membrane through its tyrosine-based sorting motif and transmembrane domain, and localizes to TFRC (transferrin receptor)-positive punctate structures on GcAVs through its H2 SNARE domain. STX6 is required for the fusion between GcAVs and REs to promote clearance of intracellular GAS by autophagy. VAMP3 and VTI1B interact with STX6 which become localized on the TFRC-positive puncta on GcAVs for RE-GcAV fusion. Knockout of RABGEF1 impairs the RE-GcAV fusion and STX6-VAMP3 interaction. Thus, RABGEF1 mediates RE fusion with GcAVs through the STX6-VAMP3-VTI1B complex. Oligodendroglial macroautophagy has been reported to be essential for myelin sheath turnover to prevent neurodegeneration and death (Aber et al. 2022). |
Eukaryota | Metazoa, Chordata | FABGET1 - STX6-VAMP3-VTI1B complex of Homo sapiens |
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1.F.1.2.1 | Dysferlin/Caveolin 3/MG53 (TRIM72) complex. Mediates vesicle fusion and membrane repair in muscle cells (Fuson et al. 2014). Dysferlin (DysF; Fer1L1) belongs to the Ferlin family. A deficiency of dysferlin, which binds lipids in a Ca2+-dependent process, causes vesicle accumulation near membrane lesions (Roostalu and Strähle 2012). The C2 domains of dysferlin plays roles in membrane localization, Ca2+ signaling and sarcolemmal repair (Muriel et al. 2022). Dysferlin, a transmembrane protein containing 7 C2 domains, C2A through C2G, concentrates in transverse tubules of skeletal muscle, where it stabilizes voltage-induced Ca2+ transients and participates in sarcolemmal membrane repair. Each of dysferlin's C2 domains except C2B regulate Ca(2+) signaling (Muriel et al. 2022). |
Eukaryota | Metazoa, Chordata | Dysferlin (DysF; Fer1L1)/Caveolin 3/MG53 (TRIM72) complex of Homo sapiens.
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1.F.1.2.2 | Myoferlin, MyoF, of 2016 aas and one C-terminal TMS, and possibly another near the N-terminus. It is a calcium/phospholipid-binding protein that plays a role in the plasmalemma repair mechanism of endothelial cells that permits rapid resealing of membranes disrupted by mechanical stress. It is also involved in endocytic recycling and pivotal physiological functions related to numerous cell membranes, such as the endocytosis cycle, vesicle trafficking, membrane repair, membrane receptor recycling, and protein secretion. MyoF is overexpressed in a variety of cancers (Dong et al. 2019; Gu et al. 2020). HBZ of the complex retrovirus, human T-cell leukemia virus type 1 (HTLV-1), upregulates myoferlin expression to facilitate HTLV-1 infection. Myoferlin functions in membrane fusion and repair as well as vesicle transport (Polakowski et al. 2023).
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Eukaryota | Metazoa, Chordata | Myoferlin of Homo sapiens |
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1.F.1.2.3 | E3 ubiquitin-protein ligase, Tripartite motif 11, TRIM11, of 468 aas and possibly 1 C-terminal TMS. It disaggregates and degrades misfolded tau. In Alzheimer's disease and other taupathies, tau protein misfolds and forms oligomers, which clump together to form filamentious aggregates. TRIM11 breaks up these aggregates and facilitates the proteasomal degradation of misfolded tau (Noble and Hanger 2023). TRIM11 is down regulated in Alzheimer's disease, and up-regulation helps to reverse the symptoms of Alzheimer's diseease. Upon overexpression, TRIM11 reduces HIV-1 and murine leukemia virus infectivity by suppressing viral gene expression (Uchil et al. 2008). |
Eukaryota | Metazoa, Chordata | TRIM11 of Homo sapiens |
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1.F.1.3.1 | Synaptobrevin homolog YKT6 of 198 aas and possibly one N-terminal TMS. It is a vesicular soluble NSF attachment protein receptor (v-SNARE) mediating vesicle docking and fusion to a specific acceptor cellular compartment. It functions in endoplasmic reticulum to Golgi transport, and is part of a SNARE complex composed of GOSR1, GOSR2 and STX5. It functions in early/recycling endosome to TGN transport as part of a SNARE complex composed of BET1L, GOSR1 and STX5 (Tai et al. 2004). It has S-palmitoyl transferase activity and is prenylated (McNew et al. 1997). Double prenylation of Ykt6 is required for lysosomal hydrolase trafficking (Sakata et al. 2021). |
Eukaryota | Metazoa, Chordata | Ykt6 of Homo sapiens |
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1.F.1.3.2 | Vesicle-associated membrane protein 7, VAMP7, of 220 aas and 2 TMSs, N- and C-terminal. It is involved in the targeting and/or fusion of transport vesicles to their target membrane during transport of proteins from the early endosome to the lysosome. Iy is required for heterotypic fusion of late endosomes with lysosomes and homotypic lysosomal fusion. Required for calcium regulated lysosomal exocytosis, and involved in the export of chylomicrons from the endoplasmic reticulum to the cis Golgi. Required for exocytosis of mediators during eosinophil and neutrophil degranulation, and target cell killing by natural killer cells. Required for focal exocytosis of late endocytic vesicles during phagosome formation (Braun et al. 2004). VAMP7j is a splice variant of human VAMP7 that modulates neurite outgrowth by regulating L1CAM transport to the plasma membrane (Gasparotto et al. 2023). |
Eukaryota | Metazoa, Chordata | VAMP7 of Mus muculus |
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1.F.2.1.1 | Yeast 8 subunit exocyst complex involved in tethering before membrane fusion between vesicles and the plasma membrane (Zárský et al. 2013). Subunits include Sec3, 1336 aas, Sec5, 971 aas, Sec6, 805 aas, Sec8, 1065 aas, Sec10, 871 aas, Sec15, 910 aas, Exo70, 623 aas and Exo84, 753 aas. Exosomes can function as nano-shuttles bearing, for example, therapeutic biomolecules (Masjedi et al. 2024). |
Eukaryota | Fungi, Ascomycota | The exosome complex of Saccharomyces cerevisiae |
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1.F.2.1.2 | Human octameric exocyst complex consisting of Exo1, 2, 3, 4, 5, 6, 7, and 8. These subunits are of 894, 924, 756, 974, 708, 804, 735, and 725 aas, resepctively (Wu and Guo 2015). |
Eukaryota | Metazoa, Chordata | Exocyst complex of Homo sapiens |
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1.F.2.1.3 | Octameric Exocyst complex consisting of Sec3A (887 aas), Sec5A (1090 aas), Sec6 (752 aas), Sec8 (1053 aas), Sec10 (825 aas), Sec15 (790 aas), Exo70A (638 aas) and Exo84A (754 aas) (Zhang et al. 2010). |
Eukaryota | Viridiplantae, Streptophyta | Exocyst complex of 8 subunits of Arabidopsis thaliana |
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1.F.3.1.1 | EHD1 of 534 aas and 0 TMSs. |
Eukaryota | Metazoa, Chordata | EHD1 of Homo sapiens |
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1.F.3.1.2 | Intersectin-1 isoform X4 of 1631 aa |
Eukaryota | Metazoa, Arthropoda | Intersectin 1 of Dendroctonus ponderosae (mountain pine beetle) |
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1.F.3.1.3 | Intersectin-1-like isoform X2 of 1738 aas. |
Eukaryota | Metazoa, Chordata | Intersectin-1 of Scleropages formosus (Asian bonytongue) |
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1.F.3.1.4 | Guanine nucleotide exchange factor, VAV2, of 878 aas and possibly 3 TMSs in a 1 (N-terminus) + 2 TMSs (residues 220 - 280). VAV2 is a factor for the Rho family of Ras-related GTPases. It plays a role in angiogenesis. Its recruitment by phosphorylated EPHA2 is critical for EFNA1-induced RAC1 GTPase activation and vascular endothelial cell migration and assembly. Vav2 is also an amyloid precursor protein (APP)-interacting protein that regulates APP protein levels (Zhang et al. 2022). APP has TC# 1.C.50.1.2. |
Eukaryota | Metazoa, Chordata | VAV2 of Homo sapiens |
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1.F.3.1.5 | Miltosome-endosome contact site proteins, EHD1 (EHI105270; uniprot C4M131) of 507 aas and 0 TMSs, and ETMP1 (EHI175060; uniprot C4LZN1) of 256 aas and 1 or 2 TMSs at the C-terminus and possibly at about residue 80. Membrane contact sites (MCSs) are key regulators of interorganellar communication and have been widely demonstrated between various organelles, but studies on MCSs involving mitochondrion-related organelles (MROs), present in some anaerobic parasitic protozoans, remain scarce. Entamoeba histolytica, the etiological agent of amoebiasis, possesses an MRO called the mitosome. This organelle is crucial for cellular differentiation and disease transmission, thereby contributing to the amoeba's parasitic lifestyle. The interaction between the Entamoeba-specific transmembrane mitosomal protein (ETMP1) and EH domain-containing protein (EHD1) showcases a mitosome-endosome contact site in E. histolytica (Santos et al. 2022). Despite their divergent and reduced nature, MROs like mitosomes conserve mechanisms for interorganellar cross talk. Santos et al. 2022 suggested that lipid and ion transport, mitosome fission, and quality control are potential processes that are mediated by the ETMP1-EHD1-tethered mitosome-endosome contact site in E. histolytica. |
Eukaryota | Evosea | Mitosome-endosome contact site of Entamoeba histolytica |
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1.F.3.1.6 | A-Protein kinase ancoring protein of 2817 aas with 0 TMSs. Similarity of the sequence of this protein with other members of this family occur only at the C-terminus of the protein. A-kinase anchoring proteins (AKAPs) are key orchestrators of cAMP signaling that act by recruiting protein kinase A (PKA) in proximity of its substrates and regulators to specific subcellular compartments. Modulation of AKAPs function offers the opportunity to achieve compartment-restricted modulation of the cAMP/PKA axis, paving the way to new targeted treatments. For instance, blocking the AKAP activity of phosphoinositide 3-kinase γ (PI3Kγ) improves lung function by inducing cAMP-mediated bronchorelaxation, ion transport, and antiinflammatory responses. Here, we report the generation of a nonnatural peptide, D-retroinverso (DRI)-Pep #20, optimized to disrupt the AKAP function of PI3Kγ. DRI-Pep #20 mimicked the native interaction between the N-terminal domain of PI3Kγ and PKA, demonstrating nanomolar affinity for PKA, high resistance to protease degradation and high permeability to the pulmonary mucus barrier (Della Sala et al. 2024). |
Eukaryota | Metazoa, Chordata | Anchoring Protein Kinase A of Homo sapiens |
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1.G.1.1.1 | The Influenza Virus (Class I) Haemagglutinin (HA) (560aas; HA1-S-S-HA2) | Viruses | Orthornavirae, Negarnaviricota | HA of Influenza virus (Q1W0T1) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.G.1.1.2 | Influenza B/Hong Kong hemagglutinin/fusion protein precursor of 582 aas. |
Viruses | Orthornavirae, Negarnaviricota | Polyprotein of Influenza B/Hong Kong |
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1.G.1.1.3 | Hemagglutinin (partial) of 172 aas. The 3-d structure bound to a fusion inhibitor has been determined (PDB 3EYM). Several other structures of these and other peptides have also been determined (Apellániz et al. 2014). From the C-terminal part of 1.G.1.1.1 bearing a C-terminal TMS. |
Viruses | Orthornavirae, Negarnaviricota | Hemagglutinin of human influenza virus (fragment) |
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1.G.1.1.4 | H5 influenza virus haemagllutinin fusion protein of 568 aas and 2 TMSs, N- and C-terminal (Kononova et al. 2017). |
Viruses | Orthornavirae, Negarnaviricota | H5 of Influenza A virus (A/Duck/Hong Kong) |
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1.G.1.1.5 | H1 influenza virus haemagllutinin fusion protein of 566 aas and 2 TMSs, N- and C-terminal (Kononova et al. 2017). |
Viruses | Orthornavirae, Negarnaviricota | H1 of Influenza A virus (A/Turkey/MO/24093/99(H1N2)) |
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1.G.1.1.6 | Influenza A virus A fusion protein of 562 aas and 2 TMSs at the N- and C-termini. The membrane-bound configuration and lipid perturbing effects of hemagglutinin subunit 2 N-terminushave been studied by computer simulations (Michalski and Setny 2022). |
Viruses | Orthornavirae, Negarnaviricota | Fusion protein of influenzae A/mallard/Maryland |
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1.G.1.1.7 | Influenza A hemagglutinin of 562 aas. Hemagglutinin of Influenza A, but not of Influenza B and C viruses is acylated by ZDHHC2, 8, 15 and 20. |
Viruses | Orthornavirae, Negarnaviricota | Hemagglutinin of Influenza A virus (A/Ann Arbor/7/1967(H2N2)) |
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1.G.10.1.1 | The herpes envelope glycoprotein class III membrane fusion system including glycoproteins gB, gD, gH and gL. There are two fusion peptides of 8 aas each that form a bipartite system (Apellániz et al. 2014; Feng and Jia 2016). |
Viruses | Heunggongvirae, Peploviricota | Class III fusion system of human herpes virus 1 (strain 17) |
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1.G.11.1.1 | The poxvirus entry protein complex of Vaccinia virus WR. F9 and L1 are homologous, and G9 and J5 may be homologous as well. Loss of the 35-amino acid hydrophobic O3 protein is partially compensated by mutations in the transmembrane domains of other entry proteins (Tak et al. 2021). |
Viruses | Bamfordvirae, Nucleocytoviricota | Poxvirus entry complex of Vaccinia virus WR. |
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1.G.12.1.1 | Avian leukosis virus (RSV) envelope glycoprotein, gp95 or EnvA (606aas; 2 TMSs, N- aqnd C-terminal). Mediates pore formation preceded by a relatively stable hemifusion-like intermediate (Jha et al., 2011). A shorter version is of 138 aas and has two TMSs at the N- and C-termini. It's acc# is H7CEB0. The fusion peptide is 28 aas with a single TMS (Apellániz et al. 2014). |
Viruses | Pararnavirae, Artverviricota | EnvA of Rous sarcoma virus (Avian leukosis virus) (P03397) |
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1.G.12.2.1 | Cat envelope syncytin-Car1 protein, a fusogenic endogenous retrovirus-derived envelope protein of 473 aas and 2 TMSs, N- and C-terminal. |
Eukaryota | Metazoa, Chordata | Syncytin-Car1 of Felis catus |
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1.G.12.2.2 | Ebola virus glycoportein 2, GP2, of 676 aas and 2 TMSs, N- and C-terminal. The NMR structure of the internal fusion loop of 54 aas has been solved (2LCY) The fusion peptide is 17 aas long (Apellániz et al. 2014). The GP2 protein also encodes the GP2-δ peptide of 40 aas which is a viroporin (He et al. 2017). This nonstructural polypeptide, called the delta peptide, is produced in abundance during Ebola virus infection. Full length and conserved C-terminal delta peptide fragments permeabilize the plasma membranes of nucleated cells, increase ion permeability across confluent cell monolayers and permeabilize synthetic lipid bilayers. Permeabilization activity is dependent on the disulfide bond between the two conserved cysteines. The conserved C-terminal portion of the peptide is biochemically stable in human serum, and most serum-stable fragments have full activity (He et al. 2017). |
Viruses | Orthornavirae, Negarnaviricota | GP2 of Zaire Ebola virus |
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1.G.12.2.3 | Glycoprotein 2, GP2, of 320 aas and 2 TMSs, one N-terminal and one C-terminal. A 3-stage mechanism of action has been discussed and reviewed (Apellániz et al. 2014) (see family description). |
Viruses | Mononegavirales | GP2 of Llovia virus |
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1.G.12.2.4 | Full virion envolope spike glycoprotein, GP1.2, of 681 aas and 2 TMSs, N- and C-terminal. The intervan fusion peptide is 15 aas long (Apellániz et al. 2014). |
Viruses | Orthornavirae, Negarnaviricota | GP1.2 of Ravn Virus |
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1.G.12.2.5 | The small secreted glycoprotein GP2 of 364 aas, containing the viroporin, GP2-δ, the last 40 aas of GP2 of Zaire ebolavirus (He et al. 2017). This nonstructural polypeptide, called the delta peptide, is produced in abundance during Ebola virus infection. Full length and conserved C-terminal delta peptide fragments permeabilize the plasma membranes of nucleated cells, increase ion permeability across confluent cell monolayers and permeabilize synthetic lipid bilayers. Permeabilization activity is dependent on the disulfide bond between the two conserved cysteines. The conserved C-terminal portion of the peptide is biochemically stable in human serum, and most serum-stable fragments have full activity (He et al. 2017). This glycoprotein interacts with cholesterol to enhance membrane fusion and cell entry (Lee et al. 2021). |
Viruses | Orthornavirae, Negarnaviricota | GP2 of Ebola virus (EBOV) |
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1.G.13.1.1 | Membrane fusion protein p14 (fusion-associated small transmembrane (Fast) protein) of 125 aas and 1 TMS of reptilian reovirus has an approximately 38-residue myristoylated N-terminal ectodomain containing a moderately apolar N-proximal region, termed the hydrophobic patch. The structure of the 38 aa non-myristoylated N-terminal transmembrane/ectodomain has been determined by NMR (2XL0_A) (Corcoran et al. 2004). Mediates lipid mixing in a liposome fusion assay The soluble nonmyristoylated p14 ectodomain peptide consists of an N-proximal extended loop flanked by two proline hinges. The remaining two-thirds of the ectodomain is disordered, consistent with predictions based on CD spectra of the myristoylated peptide. The myristoylated p14 ectodomain peptide mediates lipid mixing in a liposome fusion assay. Structural plasticity, environmentally induced conformational changes, and kinked structures predicted for the p14 ectodomain and hydrophobic patch are all features associated with fusion peptides (Corcoran et al. 2004). It lacks a cleavable signal sequence and uses an internal reverse signal-anchor sequence to direct membrane insertion and protein topology. This topology results in the unexpected, cotranslational translocation of the essential myristylated N-terminal domain of p14 across the cell membrane (Corcoran and Duncan 2004). |
Viruses | Orthornavirae, Duplornaviricota | p14 of the reptilian orth-reovirus |
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1.G.13.1.2 | Small non-structured protein, p13 of 113 aas and 1 (or 2) TMSs. |
Viruses | Orthornavirae, Duplornaviricota | p13 of Broome virus |
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1.G.13.1.3 | P14 protein of 119 aas and 1 TMS. |
Viruses | Orthornavirae, Duplornaviricota | P14 of a reptilian orthoreovirus |
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1.G.13.2.1 | The p15 fusion-associated small transmembrane (FAST) protein is a nonstructural viral protein that induces cell-cell fusion and syncytium formation (Top et al. 2012). The small, myristoylated N-terminal ectodomain of p15 lacks any of the defining features of a typical viral fusion protein. NMR and CD spectroscopy indicated that this small fusion module (residues 68 - 87) comprises a left-handed polyproline type II (PPII) helix flanked by small, unstructured N- and C-termini (PDB# 2MNS_A). Individual prolines in the 6-residue proline-rich motif are tolerant to alanine substitutions, but multiple substitutions that disrupt the PPII helix eliminate cell-cell fusion activity. A synthetic p15 ectodomain peptide induces lipid mixing between liposomes. Lipid mixing, liposome aggregation, and stable peptide-membrane interactions are all dependent on both the N-terminal myristate and the presence of the PPII helix. A model for the mechanism of action of this viral fusion peptide, whereby the N-terminal myristate mediates initial, reversible peptide-membrane binding that is stabilized by subsequent amino acid-membrane interactions. These interactions induce a biphasic membrane fusion reaction, with peptide-induced liposome aggregation representing a distinct, rate-limiting event that precedes membrane merger. The PPII helix may function to force solvent exposure of hydrophobic amino acid side chains in the regions flanking the helix to promote membrane binding, apposition, and fusion (Top et al. 2012). A fusion-inducing lipid packing sensor (FLiPS) in the cytosolic endodomain in the p15 fusion-associated small transmembrane (FAST) protein is essential for pore formation during cell-cell fusion and syncytiogenesis (Read et al. 2015). The Myristoylated Polyproline Type Ii Helix Protein of 22 aas (residues 68 - 87 in P15) functions as a fusion peptide during cell-cell membrane fusion. The 3-d structure is known (PDB# 2LKW). |
Viruses | Orthornavirae, Duplornaviricota | Membrane fusion protein p15 of Baboon orthoreovirus |
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1.G.14.1.1 | Influenza C virus hemagglutinin-fusion pore-forming protein of 655 aas and 4 TMSS, one N-terminal and three C-terminal but separated by about 100 residues. Pore formation is blocked by human interferon-induced transmembrane proteins such as IFM3 (Q01628) (Desai et al. 2014). The only spike of influenza C virus, the hemagglutinin-esterase-fusion glycoprotein (HEF) combines receptor binding, receptor hydrolysis and membrane fusion activities in a single protein. Like other hemagglutinating glycoproteins of influenza viruses, HEF is S-acylated, but only with stearic acid at a single cysteine located at the cytosol-facing end of the transmembrane region. S-acylation is essential for replication of influenza viruses A, B and C by affecting budding and/or membrane fusion (Wang et al. 2016). |
Viruses | Orthornavirae, Negarnaviricota | Hemagglutinin-esterase-fusion glycoprotein of Influenza Virus |
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1.G.14.1.2 | Hemagglutinin-esterase protein of 423 aas and 2 TM |
Viruses | Orthornavirae, Pisuviricota | Heagglutinin-esterase of Equine coronavirus |
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1.G.14.1.3 | Fusion protein of 594 aas and 2 TMSs, N- and C-terminal. |
Viruses | Orthornavirae, Negarnaviricota | Fusion protein of Wenling hoplichthys paramyxovirus |
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1.G.15.1.1 | The major envelope protein, GP64, of 512 aas and 2 TMSs (N- and C-terminal). The two fusion peptides of this type III bipartite system are residues 75 - 88 and 145 - 160 (Apellániz et al. 2014). The GP64 transmembrane domain is essential for GP64 trafficking, membrane fusion, virion budding, and virus infectivity but could be replaced only by transmembrane domains from related viral membrane proteins (Li and Blissard 2008). |
Viruses | GP64 of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV). |
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1.G.15.1.2 | Envelope glycoprotein of 520 aas and 2 TMSs, N- and C-terminal. |
Viruses | Orthornavirae, Negarnaviricota | GP of Dhori virus |
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1.G.15.1.3 | Envelope glycoprotein (GP) of 519 aas and 2 TMSs. |
Viruses | Orthornavirae, Negarnaviricota | GP of Jos virus |
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1.G.15.1.4 | Envelope glycoprotein (GP) of 512 aas and 2 TMSs. |
Viruses | Orthornavirae, Negarnaviricota | GP of Thogoto virus |
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1.G.16.1.1 | The HIV Env protein of 68 aas containing the 20 aa fusion peptide (Apellániz et al. 2014). A longer Env protein (199 aas) has UniProt acc# E3SW33. |
Viruses | Pararnavirae, Artverviricota | HIV-FP of Immunodificiency Virus type 1 |
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1.G.16.1.2 | SIV fusion N-terminal peptide of 22 aas contained within this 86 aa peptide and one N-terminal TMS. Called Pg41 or Env. |
Viruses | Pararnavirae, Artverviricota | Env protein fragment of Simian Immunodeficiency Virus |
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1.G.16.1.3 | Envelope glycoprotein 160, GP160, Env protein of 854 aas. This is the intact protein from which GP41 is derived by proteolysis. Envelope glycoprotein gp160 oligomerizes in the host endoplasmic reticulum predominantly into trimers. Gp160 transits in the host Golgi, where glycosylation is completed. The precursor is then proteolytically cleaved in the trans-Golgi and thereby activated by cellular furin or furin-like proteases to produce gp120 and gp41. Transmembrane protein gp41 is a class I viral fusion protein (Chen 2019). The protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During fusion of viral and target intracellular membranes, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. Complete fusion occurs in host cell endosomes and is dynamin-dependent, however some lipid transfer might occur at the plasma membrane. The virus undergoes clathrin-dependent internalization long before endosomal fusion, thus minimizing the surface exposure of conserved viral epitopes during fusion and reducing the efficacy of inhibitors targeting these epitopes. Membranes fusion leads to delivery of the nucleocapsid into the cytoplasm (Klug et al. 2017). The C- and the N-terminal regions of the glycoprotein 41 ectodomain fuse membranes enriched and not enriched with cholesterol, respectively (Shnaper et al. 2004).
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Viruses | Pararnavirae, Artverviricota | GP160 of Homo sapiens |
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1.G.18.1.1 | The SARS-CoV has two fusion peptides, one of 19 aas (residues 770 - 788) and the other of 16 aas (residues 873 - 888) in the spike glycoprotein precursor of 1255 aas (Apellániz et al. 2014). The structure of a 34 aa fusion peptide has been determined (PDB 1ZVB). The very hydrophobic C-terminal TMS also appears to be required for fusion (Aliper and Efremov 2023). The Spike (S) glycoprotein cytoplasmic domain is palmitoylated and that palmitoylation has two membrane proximal cysteine clusters I and II that are important for S-mediated cell fusion (Petit et al. 2007). The SARS-CoV E protein has transmembrane domains that increase the mamalian cell membrane permeability (Liao et al. 2006). |
Viruses | Orthornavirae, Pisuviricota | Spike glycoprotein of SARS coronavirus |
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1.G.18.1.2 | The Coronavirus spike glycoprotein (S-glycoprotein; spike S2 protein of E2peplomer protein of 1363 aas. The fusion peptide isN-terminal and of 19 aas (Apellániz et al. 2014). It is a class I fusion protein. |
Viruses | Orthornavirae, Pisuviricota | S2 of bovine coronavirus (BCV) |
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1.G.18.1.3 | Spike (S) protein (partial) of 120 aas |
Viruses | Orthornavirae, Pisuviricota | S protein of feline coronavirus |
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1.G.18.1.4 | Spike glycoprotein of 1171 aas. |
Viruses | Orthornavirae, Pisuviricota | S-protein of Infectious bronchitis virus |
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1.G.18.1.5 | Spike glycoprotein of 1353 aas. |
Viruses | Orthornavirae, Pisuviricota | S-protein of Pipistrellus bat coronavirus HKU5 |
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1.G.18.1.6 | Surface glycoprotein of 1273 aas and at least two TMSs, N- and C-terminal, but several smaller peaks of hydrophobicity that could be TMSs occur inbetween these two. Wrapp et al. 2020. Cai et al. 2020 determined a 3.5-Å-resolution cryo-EM structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. They also provided biophysical and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. report two cryo-electron microscopy structures derived from a preparation of the full-length S protein, representing its prefusion (2.9-angstrom resolution) and postfusion (3.0-angstrom resolution) conformations, respectively. The spontaneous transition to the postfusion state is independent of target cells. The prefusion trimer has three receptor-binding domains clamped down by a segment adjacent to the fusion peptide. The postfusion structure is strategically decorated by N-linked glycans, suggesting possible protective roles against host immune responses and harsh external conditions (Cai et al. 2020). |
Viruses | Orthornavirae, Pisuviricota | Surface glycoprotein of severe acute respiratory syndrome coronavirus 2 |
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1.G.18.1.7 | The surface spike (S) protein of 1353 aas and at least 2 TMSs, N- and C-terminal, but several hydrophobic peaks observed with the central region of this protein could be TMSs. |
Viruses | Orthornavirae, Pisuviricota | S protein of betacoronavirus England 1 |
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1.G.19.1.1 | The rotavirus A membrane fusion protein complex including VP5 and 8, derived by proteolysis of VP4, as well as VP7, VP6 and VP2. VP5, 8 and 7 may play primary roles while VP6 and 2 play secondary roles (Gilbert and Greenberg 1998; Golantsova et al. 2004; Settembre et al. 2011; Elaid et al. 2014). These proteins from different viral strains may be very divergent in sequence. |
Viruses | Orthornavirae, Duplornaviricota | Fusion complex of rotavirus A |
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1.G.19.1.2 | Major outer capsid protein VP4, partial, of 696 aas and 0 - 2 TMSs. The GCRV-II virus major outer capsid protein VP4 promotes cell apoptosis by VDAC2-mediated calcium pathway facilitation (Zhao et al. 2025). |
Viruses | Orthornavirae, Duplornaviricota | VP4 of human rotavirus A |
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1.G.2.1.1 | The Paramyxovirus (Class I) fusion (F) protein (545 aas) | Viruses | Mononegavirales | Protein F of Paramyxovirus (Q5S8E4) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.G.2.1.2 | Fusion glycoprotein FO (Class I) (565 aas) (31% identical throughout its length with 1.H.2.1.1) (Lamb and Jardetzky 2007). Interacts with protein G and protein TM in J paramyxovirus to promote fusion (Li et al. 2015). |
Viruses | Orthornavirae, Negarnaviricota | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.G.2.1.3 | The respiratory syncytial virus (RSV) fusion (F) glycoprotein. The crystal strcuture is available (McLellan et al. 2013). The protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and plasma cell membrane fusion, the heptad repeat (HR) regions assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and plasma cell membranes which leads to delivery of the nucleocapsid into the cytoplasm. Fusion is pH independent and occurs directly at the outer cell membrane. The trimer of F1-F2 (protein F) interacts with glycoprotein G at the virion surface. Upon binding of G to heparan sulfate, the hydrophobic fusion peptide is unmasked and interacts with the cellular membrane, inducing the fusion between host cell and virion membranes. RSV fusion protein is able to interact directly with heparan sulfate and therefore actively participates in virus attachment. |
Viruses | Orthornavirae, Negarnaviricota | F-glycoprotein of respiatory syncytial virus |
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1.G.2.1.4 | The fusion glycoprotein F0 of 94 aas |
Viruses | Mononegavirales | F0 of Newcastle Disease Virus |
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1.G.2.1.5 | Fusion glycoprotein F0 of 550 aas |
Viruses | Orthornavirae, Negarnaviricota | Fusion glycoprotein of Measles virus |
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1.G.2.1.6 | Fusion glycoprotein of 529 aas (Apellániz et al. 2014). Loosely associated fusion peptide and TMS helices generate significant negative Gaussian curvature to membranes that possess spontaneous positive curvature, consistent with fusion peptide-TMS assembly facilitating the transition of the membrane from hemifusion intermediates to the fusion pore (Yao et al. 2016). |
Viruses | Mononegavirales | Fusion protein of influenza virus 5 (PIV5) |
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1.G.2.1.7 | Fusion glycoprotein F0 of 546 aas and 2 TMSs (N- and C-terminal) (Apellániz et al. 2014). The unique endocytic trafficking pathway of Hendra virus F protein is required for proper viral assembly and particle release (Cifuentes-Muñoz et al. 2017). |
Viruses | Mononegavirales | F0 of Hendra virus |
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1.G.2.1.8 | Fusion glycoprotein, F, of 111 aas and 1 C-terminal TMS as well as two small peaks of moderate hydrophobicity in the N-terminal and central regions of the protein. The trimeric fusion, F, glycoproteins of morbilliviruses are activated by furin cleavage of the precursor F0 into the F1 and F2 subunits, and an additional membrane-proximal cleavage occurs and modulates F protein function (von Messling et al. 2004). |
Viruses | Orthornavirae | Fusion GP of Canine morbillivirus |
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1.G.2.1.9 | The fusion (F) protein (602 aas and 3 very hydrophobic TMSs, one N-terminal, one at residue 120 and one C-terminal, plus 5 moderately hydrophobic peaks at residies 240 - 470, of the zoonotic Nipah virus, that together with the G (glyco)-protein (546 aas and 1 N-terminal TMS; Q9IH62) are essential for viral entry into human and animal cells (Coropceanu et al. 2022). |
Viruses | Riboviria | F-protein of Nepah virus |
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1.G.2.2.1 | Baseplate J/gp47 family protein of 374 aa |
Bacteria | Pseudomonadota | Gp47 family protein of Providencia stuartii |
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1.G.20.1.1 | Envelope poly-glycoprotein of 1135 aas and 3 - 5 TMSs, Gc-GP. Glycoprotein N (Hanta G!; N-terminal domain) and Glycoprotein C (Hanta G2; C-terminal domain) interact with each other after cleavage of the full length protein, present on the surface of the virion. They attach the virion to host cell receptors to induce virion internalization predominantly through clathrin-dependent endocytosis. Gc-GP also promotes fusion of the viral membrane with the host endosomal membrane after endocytosis of the virion (Jin et al. 2002). |
Viruses | Orthornavirae, Negarnaviricota | Gc-GP of Hantaan virus (Korean hemorrhagic fever virus) |
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1.G.20.1.2 | Polyprotein of 1432 aas and 5 - 7 TMSs. |
Viruses | Orthornavirae, Negarnaviricota | Polyprotein of I612045 virus |
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1.G.20.1.3 | M polyprotein, Gn-Gc-NSm, of 1403 aas and 5 - 7 TMSs. |
Viruses | Orthornavirae, Negarnaviricota | Gn-Gc-NSm of Shamonda virus |
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1.G.20.1.4 | The envelopment polyprotein, GP, of 1441 aas and 8 TMSs in a 1 (N-terminal) + 2 +4 + 1 (C-terminal) TMS arrangement. The precursor protein is processed to the glycoprotein (C-terminal) and glycoprotein (N-terminal) which interact with each other and are present at the surface of the virion. They are able to attach the virion to a cell receptor and to promote fusion of membranes after endocytosis of the virion (Plassmeyer et al. 2005; Pekosz et al. 1995; Hulswit et al. 2021). |
Viruses | Orthornavirae, Negarnaviricota | GP of Bunyavirus La Crosse |
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1.G.20.2.1 | Envelope glycoprotein of 1684 aas and 5 - 8 TMSs, Env-GP, including Gn and Gc (Xiao et al. 2011). Blocking transport out of multivesicular bodies still allowed virus entry while preventing vesicular acidification, required for membrane fusion, trapping virions in the MVBs (Shtanko et al. 2014). Entry is dependent on the CCHFV envelope GP (Suda et al. 2016). |
Viruses | Bunyaviridae | Env-GP of Crimean-Congo hemorrhagic fever virus (CCHFV) |
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1.G.20.2.2 | GPC glycoprotein of 1296 aas and 3 - 4 TMSs. May function in evasion or tolerance by the virus to the host immune response. |
Viruses | Orthornavirae, Negarnaviricota | GPC of the Erve virus |
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1.G.20.2.3 | M-protein, Gn-Gc-NSm, of 1549 aas and 5 - 7 TMSs. |
Viruses | Orthornavirae, Negarnaviricota | Gn-Gc-NSm of Simbu virus |
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1.G.21.1.1 | Fusogenic protein, Gp42 of 223 aas with 1 N-terminal TMS. |
Viruses | Heunggongvirae, Peploviricota | Gp42 of Epstein Barr Virus |
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1.G.21.1.2 | ORF44 of 241 aas and 2 N-terminal TMSs. |
Viruses | Heunggongvirae, Peploviricota | ORF44 of Callitrichine herpesvirus 3 (Marmoset lymphocryptovirus) |
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1.G.21.1.3 | C-type lectin sprotein A7 of 243 aas and 1 N-terminal TMS. |
Viruses | Heunggongvirae, Peploviricota | A7 of Alcelaphine herpesvirus 1 (strain C500) (AlHV-1) (Malignant catarrhal fever virus) |
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1.G.22.1.1 | The gO or gL glycoprotein fusogen of 278 aas and 3 TMSs, 1 N-terminal and 2 near the C-terminus (Feng and Jia 2016). The heterodimer glycoprotein H (742 aas; 2 TMSs, N- and C-terminal)-glycoprotein L is required for the fusion of viral and plasma membranes leading to virus entry into the host cell. Membrane fusion is mediated by the fusion machinery composed at least of gB (907 aas; 3 TMSs, 1 N-terminal and 2 near the C-terminus; similar to gB of 1.G.10.1.1) and the heterodimer gH/gL. |
Viruses | Heunggongvirae, Peploviricota | gO of Human cytomegalovirus (strain Merlin) (HHV-5) (Human herpesvirus 5) |
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1.G.22.1.2 | Rhesus cytomegalovirus glycoprotein B of 854 aas and 3 TMSs, 1 N-terminal and 2 near the C-terminus of the protein. GpB is an envelope glycoprotein that forms spikes at the surface of virion envelope. It is essential for the initial attachment to heparan sulfate moieties of the host cell surface proteoglycans and is involved in fusion of viral and cellular membranes leading to virus entry into the host cell. Following initial binding to its host receptors, membrane fusion is mediated by the fusion machinery composed at least of gB and the heterodimer gH/gL. It may be involved in the fusion between the virion envelope and the outer nuclear membrane during virion egress (Yue et al. 2003). |
Viruses | Heunggongvirae, Peploviricota | Gp3 of Rhesus cytomegalovirus |
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1.G.23.1.1 | The fusion complex of African swine fever virus (ASFV) consisting of two proteins, p199L and pE248R (Matamoros et al. 2020). See family description for details. |
Viruses | Bamfordvirae, Nucleocytoviricota | p199L/pE248R of African swine fever virus |
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1.G.3.1.1 | Tick-borne encephalitis virus (TBEV) (Class II) polyprotein of 3414 aas. Residues 281 - 776 include the envelop protein that includes the viral fusion protein (Zhang et al. 2017). |
Viruses | Orthornavirae, Kitrinoviricota | Tick-borne encephalitis virus polyprotein (P14336) |
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1.G.3.1.2 | Polyprotein (3391aas) (includes the membrane fusion protein, envelope protein E (495aas; 38% identical to residues 282-774 in 1.G.3.1.1) (Liao et al., 2010)). The fusion peptides are residues 98 - 113 in V7SFC4 and residues 378 - 393 in P14340 (Apellániz et al. 2014). |
Viruses | Orthornavirae, Kitrinoviricota | Polyprotein of Dengue virus (P14340) |
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1.G.3.1.3 | Polyprotein of 3432 aas of the Flavi-glycoprotein family. The type II fusion peptide is residues 392 - 407 (Apellániz et al. 2014). |
Viruses | Orthornavirae, Kitrinoviricota | Polyprotein of Japanese encephalitis virus |
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1.G.3.1.4 | Non-structural protein 2B of 131 aas and 2 TMSs. |
Viruses | Orthornavirae, Kitrinoviricota | NS2B of Usutu virus |
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1.G.3.1.5 | NS2B of 131 aas and 2 TMSs. |
Viruses | Orthornavirae, Kitrinoviricota | NS2B of Murray Valley encephalitis virus |
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1.G.3.1.6 | NS2A viroporin of 218 aas and 4 - 8 TMSs (Shrivastava et al. 2017). |
Viruses | Orthornavirae, Kitrinoviricota | NS2A of Dengue Virus |
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1.G.3.1.7 | Polyprotein of 3433 aas and about 20 - 24 TMSs. It includes the N2Sa protein which has been shown to be a viroporin (Leung et al. 2008). |
Viruses | Orthornavirae, Kitrinoviricota | N2Sa of Kunjin Virus |
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1.G.3.1.8 | Non-structural protein, NSP 2B, of 122 aas and 2 TMSs. It forms a viroporin (Shrivastava et al. 2020). |
Viruses | Orthornavirae, Kitrinoviricota | NSP2B of Dengue virus |
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1.G.3.1.9 | Zika viroporin, ZikV-M (the M protein) of 75 aas and 1 C-terminal TMS. Flaviviruses contain several important human pathogens. Among these, the Zika virus is an emerging etiological agent. One of its structural proteins, prM, plays an essential role in viral maturation and assembly, making it an attractive drug and vaccine development target. Tomar et al. 2022 have characterized ZikV-M as a potential viroporin candidate using three different bacterium-based assays which were used to identify potential ZikV-M blockers. Mutational analyses of conserved amino acids in the transmembrane domain of other flaviviruses, including West Nile and Dengue viruses, were performed to study their role in ion channel activity. Thus, ZikV-M is a potential ion channel that can be used as a drug target for high throughput screening and drug repurposing (Tomar et al. 2022). P2X7R is expressed in cancer and immune system cell surfaces. ATP plays a key role in numerous metabolic processes due to its abundance in the tumour microenvironment. P2X7R plays an important role in cancer by interacting with ATP. The unusual property of P2X7R is that stimulation with low doses of ATP causes the opening of a permeable channel for sodium, potassium, and calcium ions, whereas sustained stimulation with high doses of ATP favours the formation of a non-selective pore. The latter effect induces a change in intracellular homeostasis that leads to cell death. |
Viruses | Orthornavirae, Kitrinoviricota | ZikV-M viroporin of Zika Virus |
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1.G.4.1.1 | The Semliki Forest Virus (SFV) (Class II) Structural polyprotein (1253 aas; E1=816-1253 E2=334-774). The fusion peptide is residues 895 - 913 (Apellániz et al. 2014). The 6K viroporin transports monovalent cations and Ca2+ (Hyser and Estes 2015). Conformational change and protein-protein interactions of this fusion protein have been considered (Gibbons et al. 2004). |
Viruses | Orthornavirae, Kitrinoviricota | Structural polyprotein of Semliki Forest Virus (P03315) |
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1.G.4.1.2 | The Ross River virus 6K protein. The class II fusion peptide is residues 896 - 914 (Apellániz et al. 2014). The 6K protein transports monovalent cations and Ca2+ (Hyser and Estes 2015). |
Viruses | Orthornavirae, Kitrinoviricota | 6K protein of Ross River Virus (P08491) |
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1.G.4.1.3 | The Barmah Forest virus 6K protein (58 aas; present within the viral structural polyprotein (P89946)) | Viruses | Orthornavirae, Kitrinoviricota | 6K protein of Barmah Forest Virus (P89946) |
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1.G.4.1.4 | The Sindbis virus 6K protein (55 aas; present within the structural polyprotein (AAC83379)). Transports monovalent cations and Ca2+ (Hyser and Estes 2015). |
Viruses | Orthornavirae, Kitrinoviricota | 6K protein of Sindbis Virus (Q9YJX7) |
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1.G.4.1.5 | Salmonid α-virus 6K protein of 1319 aas and 6 TMSs in a possible 1 + 4 + 1 TMS arrangement (Elmasri et al. 2022). |
Viruses | Orthornavirae, Kitrinoviricota | 6K protein of Salmonid virus |
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1.G.4.1.6 | Structural polyprotein, E2-6K-E1 region of 923 aas and 5 TMSs in a 4 (central) + 1 (C-terminal) TMS arrangement (Huang and Fischer 2022). |
Viruses | Orthornavirae, Kitrinoviricota | E2-6K-E1 polyproptein of Chikungunya virus (CHIIKV). |
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1.G.5.1.1 | The Vesicular Stomatitis Virus (VSV) Glycoprotein G (423 aas) | Viruses | Orthornavirae, Negarnaviricota | Glycoprotein G of Vesicular Stomatitis Virus (P0C2X0) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1.G.5.1.2 | Glycoprotein G of 508 aas. |
Viruses | Orthornavirae, Negarnaviricota | G of Monopterus albus rhabdovirus |
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1.G.5.1.3 | Virion transmembrane glycoprotein of 662 aas |
Viruses | Orthornavirae, Negarnaviricota | VTG of Obodhiang virus |
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1.G.5.1.4 | Glycoprotein G of 524 aas. |
Viruses | Orthornavirae, Negarnaviricota | G of Rabies virus |
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1.G.6.1.1 | S protein of 226 aas and 4-5 TMSs; a member of the viral major surface antigen (vMSA) family |
Viruses | Pararnavirae, Artverviricota | S protein of Hepatitis B virus (HBV) (A7XED7) |
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1.G.7.1.1 | GAG polyprotein; contains matrix proteins p16, capsid protein p25 and nucleocapsid protein p14 (442aas). |
Viruses | Pararnavirae, Artverviricota | cell-cell fusion protein, p14 of Reovirus Visna lentivirus from the GAG polyprotein (degraded to p14 and other products) (P23425) |
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1.G.7.2.1 | The Atlantic salmon reovirus fusion-associated small transmembrane (FAST) cell fusogenic protein, p22, of 198 aas and 1 TMS (Ciechonska and Duncan 2014). It induces cell-cell fusion and syncytium formation (Racine et al. 2009). |
Viruses | Orthornavirae, Duplornaviricota | p22 of atlantic salmon reovirus |
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1.G.7.2.2 | Non-structural protein 5, S7, of 146 aas. |
Viruses | Orthornavirae, Duplornaviricota | S7 of Aquareovirus C (AQRV-C) |
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1.G.7.2.3 | The NS22 protein of 207 aas |
Viruses | Orthornavirae, Duplornaviricota | NS22 of the Fall chinook aquareovirus |
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1.G.7.2.4 | FAST protein of 188 aas |
Viruses | Orthornavirae, Duplornaviricota | FAST protein of Atlantic halibut reovirus |
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1.G.8.1.1 | Preglycoprotein polyprotein (GP) complex. Contains (1) regional peptide, (2) GPI, and (3) GP2. (2 N-terminal TMSs) (Igonet et al., 2011). |
Viruses | Orthornavirae, Negarnaviricota | GP2 of Lymphocytic choriomeningitis virus (P09991) |
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1.G.8.1.2 | Pre-glycoprotein polyprotein (precursor), GPC (York and Nunberg, 2009). |
Viruses | Arenaviridae | Pre-GPC of Junin virus (P26313) |
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1.G.8.1.3 | Glycoprotein precursor, partial, of 225 aas. |
Viruses | Orthornavirae, Negarnaviricota | GP precursor of Middle Pease River virus |
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1.G.8.1.4 | Glycoprotein precursor, partial of 235 aas. |
Viruses | Negarnaviricota | Gp precursor of Gairo mammarenavirus |
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1.G.8.1.5 | Glycoprotein precursor, GPC, of Lujo mammarenavirus of 454 aas and 2 - 5 TMSs with 1 - 3 TMSs N-terminal and 1 TMS C-terminal. Lujo virus (LUJV) belongs to the Old World (OW) genus Mammarenavirus (family Arenaviridae), a biosafety level (BSL) 4 agent (Cao et al. 2021). A high-throughput screening of an FDA-approved drug library was conducted using pseudotype viruses bearing LUJV envelope glycoprotein (GPC) to identify inhibitors of LUJV entry. Three hit compounds, trametinib, manidipine, and lercanidipine, were identified as LUJV entry inhibitors in the micromolar range. Mechanistic studies revealed that trametinib inhibited LUJV GPC-mediated membrane fusion by targeting C410 [located in the transmembrane domain], while manidipine and lercanidipine inhibited LUJV entry by acting as calcium channel blockers. All three hits extended their antiviral spectra to the entry of other pathogenic mammarenaviruses, and all three could inhibit the authentic prototype mammarenavirus, lymphocytic choriomeningitis virus (LCMV), and could prevent infection at the micromolar level (Cao et al. 2021). |
Viruses | Riboviria | GPC of Lujo mammarenavirus |
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1.G.9.1.1 | HERV-W_7q21.2 provirus ancestral Env polyprotein (ENV-W; gPr73; enverin; syncytin-1, HERV-7q envelope protein) (Blond et al., 1999; Mi et al., 2000). This endogenous retroviral envelope protein, encoded within the human genome, has retained its original fusogenic properties and participates in trophoblast fusion and the formation of a syncytium during placenta morphogenesis. It may induce fusion through binding of SLC1A4 and SLC1A5 (Blond et al. 2000; Lavillette et al. 2002; Sugimoto et al. 2013. Syncytin-1 interacts with the ASCT2 receptor (Štafl et al. 2021). It also participates in virus-free extracellular vesicle cargo loading and delivery (see TC# 8.A. 40.1.19) (Bui et al. 2023).
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Eukaryota | Metazoa, Chordata | HERV-W_7q21.2 of Homo sapiens (Q9UQF0) |
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1.G.9.1.2 | Syncytin 2 of 538 aas. Syncytins maintain cell-cell fusogenic activity based on ENV: gene-mediated viral cell entry but promote fusion of various cells during development in humans (Soygur and Sati 2016). Receptor usage of Syncytin-1: ASCT2, but not ASCT1, is a functional receptor and effector of cell fusion in the human placenta (Štafl et al. 2024). |
Eukaryota | Metazoa, Chordata | Syncytin 2 of Homo sapiens |
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1.G.9.1.3 | Syncytin-B of 618 aas with several TMSs, possibly as many as 6, with one N-terminal, one C-terminal, and 4 internal at residues 120, 170, 360 and 440. PiT1/SLC20A1 is the receptor for the endogenous retroviral envelope syncytin-B involved in mouse placenta formation (Mousseau et al. 2024). |
Eukaryota | Metazoa, Chordata | Syncytin-B of Mus musculus |
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1.G.9.2.1 | Envelope glycoprotein, Env, of 654 aas and 3 TMSs, one N-terminal, one C-terminal and one at about residue 473. |
Viruses | Pararnavirae, Artverviricota | Env of porcine endogenous retrovirus A |
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1.G.9.2.2 | The human T-lymphotropic virus type 1 (HTLV-1) glycoprotein gp21 of 121 aas and containing the N-terminal 25 aa fusion peptide with a single TMS. |
Viruses | Pararnavirae, Artverviricota | gp21 of the human T-lymphotropic virus type 1 (HTLV-1) |
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1.H.1.1.1 | Claudin 16 (CLDN16; Paracellin) (defects in CLDN16 are the cause of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) (primary hypomagnesemia) (Hou et al., 2007; Ikari et al., 2008). Forms a Mg2+/Ca2+-selective pore together with Claudin-3 and Claudin-19 (Brandao et al. 2012; Milatz et al. 2017). The tight junction archetecture and constituent proteins have been reviewed (Van Itallie and Anderson 2014). Claudin-16 and -19 form a stable dimer through cis-association of transmembrane domains 3 and 4, and mutations disrupting the claudin-16/19 cis-interaction increase tight junction ultrastructural complexity but reduce tight junction permeability (Gong et al. 2015). |
Eukaryota | Metazoa, Chordata | Cldn 16 of Homo sapiens |
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1.H.1.1.10 | Claudin 10a (Claudin-10a; isoform 1) has an anion-selective paracellular channel (Angelow et al., 2008) while Claudin 10b (Claudin-10b; isoform 2) has a cation-selective paracellular channel (Milatz and Breiderhoff 2017). |
Eukaryota | Metazoa, Chordata | Cldn10a of Mus musculus (Q9Z0S6) |
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1.H.1.1.11 | Claudin 2 (Claudin-2; CLDN2) (forms narrow, fluid filled, water-permeable cation-selective paracellular pores) (Angelow et al., 2008; Yu et al., 2009). It is a dimer in a high molecular weight protein complex (Van Itallie et al. 2011; Krug et al. 2014). Transports Na+, K+, Ca2+ smal organic molecules and water through the paracellular channel (Fromm et al. 2017). Site-specific distributions of claudin-2- and claudin-15-based paracellular channels drive their organ-specific functions in the liver, kidney, and intestine (Tanaka et al. 2017). Disruption of the gastrointestinal epithelial barrier is a hallmark of chronic inflammatory bowel diseases (IBDs), and in the intestines of patients with IBDs, the expression of CLDN2 is upregulated (Takigawa et al. 2017). Leu increases Ca2+ flux through cellular redistribution of Cldn-2 to the tight junction membrane (Gaffney-Stomberg et al. 2018). |
Eukaryota | Metazoa, Chordata | Cldn2 of Mus musculus (O88552) |
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1.H.1.1.12 | Claudin-15 of 227 aas and 4 TMSs, Cldn15. Suzuki et al. 2013 reported the crystal structure of mouse claudin-15 at a resolution of 2.4 angstroms. The structure revealed a characteristic β-sheet fold consisting of two extracellular segments anchored to a transmembrane four-helix bundle by a consensus motif. Potential paracellular pathways with distinctive charges on the extracellular surface provided insight into the molecular basis of ion homeostasis across tight junctions. Site-specific distributions of claudin-2- and claudin-15-based paracellular channels drive their organ-specific functions in the liver, kidney, and intestine (Tanaka et al. 2017). A model of the claudin-15-based paracellular channel has been presented (Alberini et al. 2017). |
Eukaryota | Metazoa, Chordata | Cldn15 of Mus musculus |
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1.H.1.1.13 | Claudin 17 (Cluadin-17; CLDN17) of 224 aas and 4 TMSs. Selectively permeable to anions (Krug et al. 2014). |
Eukaryota | Metazoa, Chordata | CLDN17 of Homo sapiens |
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1.H.1.1.14 | Claudin-1 (CLDN1) of 211 aas. Forms homoligomers as well as heterooligomers with Claudin-3 (Milatz et al. 2015). Claudins function as major constituents of the tight junction complexes that regulate the permeability of epithelia. While some claudin family members play essential roles in the formation of impermeable barriers, others mediate the permeability to ions and small molecules. Often, several claudin family members are coexpressed and interact with each other, and this determines the overall permeability. CLDN1 is required to prevent the paracellular diffusion of small molecules through tight junctions in the epidermis and is required for the normal barrier function of the skin (Kirschner et al. 2013). It influences stratum corneum (SC) proteins important for SC water barrier function, and is crucial for TJ barrier formation for allergen-sized macromolecules (Kirschner et al. 2013). |
Eukaryota | Metazoa, Chordata | Claudin-1 of Homo sapiens |
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1.H.1.1.15 | Claudin-3 (CLDN3) of 220 aas. Forms homooligomers as well as heterooligomers with CLNVN1 (Milatz et al. 2015). Also forms hetero-oligomers with Claudin-16 and Claudin-19 which are divalent cation (Ca2+ and Mg2+)-selective (Milatz et al. 2017). The crystal structure of claudin-3 at 3.6 A resolution reveals that the third TMS is bent compared with that of other subtypes, and strand formation - straight or curvy strands - observed in native epithelia results in different morphologies (Nakamura et al. 2019). . |
Eukaryota | Metazoa, Chordata | CLDN3 of Homo sapiens |
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1.H.1.1.16 | Claudin 5 of 218 aas and 4 TMSs. Plays an important role in the tight junctions that comprise the blood-brain barrier (BBB) (Irudayanathan et al. 2015). Polyinosinic-polycytidylic acid [Poly(I:C)], a synthetic analog of viral double-stranded RNA (dsRNA) commonly used to simulate viral infections, decreases the expression of claudin-5, and gives rise to increased endothelial permeability (Huang et al. 2016). DNA methylation plays an important role in regulating BBB repair after stroke, through regulating processes associated with BBB restoration and prevalently with processes enhancing BBB injury (Phillips et al. 2023). It may have 4 C-terminal TMSs. Wine-processed Chuanxiong Rhizoma enhances efficacy of aumolertinib against EGFR mutant non-small cell lung cancer xenografts in nude mouse brain (Niu et al. 2023). |
Eukaryota | Metazoa, Chordata | Claudin-5 of Homo sapiens |
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1.H.1.1.17 | Claudin 10b of 233 aas and 4 TMSs with a monovalent cation-selective paracellular channel (Milatz and Breiderhoff 2017). |
Eukaryota | Metazoa, Chordata | Claudin 10b of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.H.1.1.18 | Claudin 18-like protein of 411 aas and 5 or 6 TMSs in a 1 + 2 + 2 +1 or 1 + 1 + 2 + 1 TMS arrangement, respectively. |
Eukaryota | Metazoa, Chordata | Claudn-18-like protein of Scleropages formosus (Asian bonytongue) |
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1.H.1.1.19 | Claudin-9, CLDN9, of 217 aas and 4 or 5 TMSs. It plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity. It acts as a receptor for hepatitis C virus (HCV) entry into hepatic cells. It's expression in breast cancer has been evaluated, and its signifucabce with respect to its impact on drug resistance has been reported (Zhuang et al. 2023). |
Eukaryota | Metazoa, Chordata | CDN9 of Homo sapiens |
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1.H.1.1.2 |
Claudin 7 (anion selective; Angelow et al., 2008). 25% identity with Cldn 16; down regulated in breast cancer. In urothelial tumors, REG1A expression and loss of claudin 7 may be markers of prognosis that predict tumor recurrence (Yamuç et al. 2022). |
Eukaryota | Metazoa, Chordata | Cldn 7 of Homo sapiens |
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1.H.1.1.3 | Claudin 22 (function unknown; distantly related to most claudins) | Eukaryota | Metazoa, Chordata | Cldn 22 of Homo sapiens (Q8N7P3) |
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1.H.1.1.4 | Claudin 23 (function unknown; distantly related to most claudins including Cldn 22). Related to cancer invasion/metastasis; it may regulate these phenomena through activation of the MEK signalling pathway in pancreatic cancer (Wang et al., 2010). Shows reduced levels in atopic dermatitis (De Benedetto et al., 2011). |
Eukaryota | Metazoa, Chordata | Cldn 23 of Homo sapiens |
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1.H.1.1.5 | Claudin-19 (Cldn19) (interacts with Cldn3 and Cldn16 to form divalent cation (Mg2+ and Ca2+)-selective tight junctions; mutations in both proteins can give rise to hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), an inherited disorder (Hou et al., 2008). Claudins 16 and 19 belong to the PMP22-Claudin subfamily. The structure of Claudin 19 with Clostridium perfringens enterotoxin bound (3.7Å resolution) revelaed interactions with the two extracellular loops of the claudin giving rise to helix displacement as the mechanism of tight junction disruption (Saitoh et al. 2015). Claudin-16 and -19 form a stable dimer through cis-association of transmembrane domains 3 and 4, and mutations disrupting the claudin-16/19 cis-interaction increase tight junction ultrastructural complexity but reduce its permeability (Gong et al. 2015). |
Eukaryota | Metazoa, Chordata | Cldn19 of Homo sapiens (Q8N6F1) |
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1.H.1.1.6 | Claudin 4 (209aas) forms paracellular chloride channels in the kidney
collecting duct and requires Claudin 8 for tight junctions localization (Hou et al., 2010). |
Eukaryota | Metazoa, Chordata | Cldn4 of Homo sapiens (O14493) |
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1.H.1.1.7 | Claudin 8 (225aas) is required for localization of Claudin 4 (TC# 1.H.1.1.6) to the kidney tight junctions (Hou et al., 2010). Bartter's syndrome patients have a single nucleotide substitution of C for T at position 451 of the claudin-8 gene sequence that changes the amino acid residue from serine to proline at position 151 in the second extracellular domain of the claudin-8 gene (Chen et al., 2009). Interactions between epithelial sodium channel gamma-subunit and claudin-8 modulates paracellular sodium permeability in the renal collecting duct (Sassi et al. 2020). |
Eukaryota | Metazoa, Chordata | Cldn8 of Homo sapiens (P56748) |
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1.H.1.1.8 | PM22_Claudin family (CLDN_18A2.1; CRA_C; 264 aas). It is 88% identical to the human ortholog, CLDN18 of 261 aas and 4 TMSs (P56856). The human CLDN18.1 attenuates malignant properties including xenograft tumor growth in vivo as well as cell proliferation, migration, invasion and anchorage-independent colony formation in vitro (Luo et al. 2018). A transmembrane scaffold from CD20 helps recombinant expression of a chimeric claudin 18.2 in an in vitro coupled transcription and translation system (Wang et al. 2024). |
Eukaryota | Metazoa, Chordata | Claudin-18A2.1 of Mus musculus (P56857) |
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1.H.1.1.9 | Claudin 15 (with a cation selective paracellular channel (Angelow et al., 2008). Claudin-15 is highly expressed in the intestine where it forms efficient Na+ channels and Cl- barriers. The permeation process of Na+, K+, and Cl- ions inside a refined structural model of a claudin-15 paracellular channel was investigated using all-atom molecular dynamics simulations in a double-bilayer (Alberini et al. 2018). The channel allows the passage of the two physiological cations while excluding chloride with 30x selectivity. These features are generated by the action of several acidic residues, in particular, the ring of D55 residues which is located at the narrowest region of the pore, in correspondence with the energy minimum for cations and the peak for chloride. Claudin-15 thus regulates tight junction selectivity by invoking the experimentally determined role of the acidic residues (Alberini et al. 2018). Water and small cations can pass through the channel, but larger cations, such as tetramethylammonium, do not (Samanta et al. 2018). TMS 3 plays a role in claudin-15 strand flexibility (Fuladi et al. 2022). Specifically, the kink in TMS 3 skews the rotational flexibility of claudin-15 in the strands and limits their fluctuation (Fuladi et al. 2022). |
Eukaryota | Metazoa, Chordata | Cldn15 of Homo sapiens (P56746) |
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1.H.1.2.1 | Epithelial membrane protein2 EMP2. This protein interconnects the Claudin superfamily with the LACC (SUR7) family (1.A.81) of mating-dependent 4TMS Ca2+ channels in fungi and the 4TMS Ca2+ channel auxiliary subunit γ1-γ8 (CCAγ) family of animals (8.A.16). |
Eukaryota | Metazoa, Chordata | EMP2 of Mus musculus (Q8CGC1) |
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1.H.1.2.2 | Peripheral myelin protein 22, PMP22 of 160 aas and 4 TMSs. May be involved in growth regulation and myelinization in the peripheral nervous system (Magyar et al. 1997). PMP22 associates with MPZ via their transmembrane domains, and disrupting this interaction causes a loss-of-function phenotype similar to hereditary neuropathy associated with liability to pressure palsies(Pashkova et al. 2023). |
Eukaryota | Metazoa, Chordata | PMP22 of Homo sapiens |
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1.H.1.3.1 | Claudin family protein (related to Sur7; TC# 1.A.81) |
Eukaryota | Fungi, Basidiomycota | Sur7 family protein of Cryptococcus formans |
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1.H.1.4.1 | Putative 5 TMS Claudin family member, distantly related to Sur7 in family 1.A.81. |
Eukaryota | Fungi, Ascomycota | Claudin-like protein of Neurospora crassa |
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1.H.1.4.2 | Protein up-regulated during nitrogen stress 1, PUN1 (YLR414c). Colocalizes with Sur7 in punctate patches of the plasma membrane. |
Eukaryota | Fungi, Ascomycota | PUN1 of Saccharomyces cerevisiae |
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1.H.1.4.3 | Uncharacterized protein |
Eukaryota | Fungi, Ascomycota | UP of Aspergillus niger |
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1.H.1.4.4 | 4 TMS uncharacterized protein |
Eukaryota | Fungi, Ascomycota | UP of Saccharomyces cerevisiae |
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1.H.1.4.5 | Uncharacterized protein |
Eukaryota | Fungi, Ascomycota | UP of Aspergillus oryzae |
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1.H.1.4.6 | Ecm7, (448aas; 4 TMS), is a member of the PMP-22/EMP/MP20 Claudin superfamily of transmembrane proteins that includes gamma-subunits of voltage-gated calcium channels. It appears to interact with Mid1 and regulate the activity of the Cch1/Mid1 channel (TC# 1.A.1.11.10; Martin et al., 2011). Ecm7p is related to members of TC families 1.H.1, 1.H.2 and 1.A.81. |
Eukaryota | Fungi, Ascomycota | Ecm7 of Saccharomyces cerevisiae |
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1.H.1.5.1 | β-type IP39 protein of 264 aas and 4 TMSs in a 1 3 TMS arrangement. Euglenoid flagellates have striped surface structures comprising pellicles, which allow the cell shape to vary from rigid to flexible during the characteristic movement of the flagellates. In Euglena gracilis, the pellicular strip membranes are covered with paracrystalline arrays of a major integral membrane protein, IP39, a four TMS protein with the conserved sequence motif of the PMP-22/EMP/MP20/Claudin superfamily. Suzuki et al. 2013 reported the three-dimensional structure of Euglena IP39 determined by electron crystallography. Two-dimensional crystals of IP39 formed a striated pattern of antiparallel double-rows in which trimeric IP39 units are longitudinally polymerised, resulting in continuously extending zigzag-shaped lines. Structural analysis revealed an asymmetric molecular arrangement in the trimer, suggesting that at least four different interactions between neighbouring protomers are involved. A combination of such multiple interactions would be important for linear strand formation of membrane proteins in a lipid bilayer (Suzuki et al. 2013). |
Eukaryota | Euglenozoa | IP39 of Euglena gracilis |
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1.H.1.5.2 | α-type IP39 protein of 263 aas. Nearly identical to 1.H.1.5.1. The low resolution 3-d structure is available (Suzuki et al. 2013). |
Eukaryota | Euglenozoa | IP39 of Euglena gracilis |
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1.H.1.6.1 | Claudin-like protein (shows similarity to members of both 1.H.1 and 1.H.2). |
Eukaryota | Metazoa, Chordata | Claudin-like protein of Ciona intestinalis (sea squirt) (F6YNZ8) |
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1.H.1.6.2 | Epithelial membrane protein 1-like of 164 aas and 4 TMSs in a 1 + 3 TMS arrangement. |
Eukaryota | Metazoa, Mollusca | EMP1 of Pomacea canaliculata |
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1.H.1.7.1 | Sur7p Ca2+ channel (4TMSs); affects sphingolipid metabolism and is involved in sporulation (Young et al., 2002). Related proteins contribute to secretion, biofilm formation and macrophage killing (see 1.A.81.3.2; Bernardo and Lee, 2010). |
Eukaryota | Fungi, Ascomycota | Sur7p of Saccharomyces cerevisiae (P54003) |
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1.H.1.7.2 | 4TMS Sur7 family cortical patch protein. Contributes to secretion, biofilm formation and macrophage killing (Bernardo and Lee, 2010). |
Eukaryota | Fungi, Ascomycota | Sur7p of Candida albicans (Q5A4M8) |
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1.H.2.1.1 | Pickel; Megatrachea; Claudin 2 isoform A; forms septate junctions |
Eukaryota | Metazoa, Arthropoda | Pickel of Drosophila melanogaster (O76899) |
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1.H.2.1.2 | Pickel homologue |
Eukaryota | Metazoa, Arthropoda | Pickel homologue of Anopheles gambiae (F5HJC0) |
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1.H.2.1.3 | Claudin-like septate junction protein of 290 aas and 4 TMSs. |
Eukaryota | Metazoa, Platyhelminthes | Claudin of Clonorchis sinensis (Chinese liver fluke) |
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1.H.2.1.4 | Uncharacterized protein of 277 aas and 4 TMSs in a 1 + 3 TMS arrangement. |
Eukaryota | Metazoa, Arthropoda | UP of Varroa destructor (honeybee mite) |
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1.H.2.2.1 | CLC-5 protein of 281 aas and 4 TMSs in a 1 + 3 TMS arrangement. |
Eukaryota | Metazoa, Nematoda | CLC-5 of Caenorhabditis elegans (Q9NGJ7) |
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1.H.2.2.2 | Gap junction protein of 303 aas and 4 TMSs, Nsy-4. Involved in intercellular signalling, regulation of cell adhesion and morphology, and paracellular channel passage of small molecules. |
Eukaryota | Metazoa, Nematoda | Nsy-4 of Caenorhabditis elegans |
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1.H.2.2.3 | Claudin protein Clc2 or Clc4 of 252 aas and 4 TMSs |
Eukaryota | Metazoa, Nematoda | Clc-2 of Caenorhabditis elegans |
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1.H.2.3.1 | Uncharacterized CBN-CLC-4 protein of 194 aas and 4 TMSs in a 1 + 3 or 1 + 2 + 1 TMS arrangement. |
Eukaryota | Metazoa, Nematoda | UP of Caenorhabditis brenneri |
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1.H.2.3.2 | Uncharacterized protein of 176 aas and 4 TMSs in a 1 + 3 TMS arrangement. |
Eukaryota | Euglenozoa | UP of Trypanosoma brucei |
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1.H.3.1.1 | Amastin of 174 aas and 4 TMSs in a 1 + 3 TMS arrangement as is typical of members of the Amastin family (Slathia and Sharma 2018). |
Eukaryota | Euglenozoa | Amastin of Trypanosoma cruzi |
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1.H.3.1.10 | Uncharacterized protein of 270 aas and 4 distant TMSs in an apparent 2 + 2 TMS arrangement. |
Eukaryota | Euglenozoa | UP of Strigomonas culicis |
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1.H.3.1.11 | Uncharacterized protein of 199 aas and 4 TMSs in a 21 + 3 TMS arrangement. |
Eukaryota | Euglenozoa | UP of Leishmania guyanensis |
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1.H.3.1.12 | g-amastin of 216 aas and 4 TMSs in a 1 + 2 + 1 arrangement. |
Eukaryota | Euglenozoa | g-Amastin of Crithidia sp. |
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1.H.3.1.13 | Amastin-like protein of 250 aas and 4 TMSs in a 1 _ 2 + 1 TMS arrangement. |
Eukaryota | Euglenozoa | Amastin-like surface protein of Angomonas deanei |
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1.H.3.1.14 | Amastin-like protein of 249 aas and 4 TMSs in a 1 + 2 + 1 TMS arrangement. |
Eukaryota | Euglenozoa |
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1.H.3.1.15 | Uncharacterized protein of 190 aas and 4 TMSs |
Eukaryota | Euglenozoa | UP of Trypanosoma conorhini |
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1.H.3.1.16 | Uncharacterized protein of 194 aas and 4 TMSs in a 1 + 3 TMS arrangement. |
Eukaryota | Fungi, Basidiomycota | UP of Saitozyma podzolica |
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1.H.3.1.17 | Uncharacterized protein of 490 aas and 8 TMSs in a 1 + 3 + 1_ 2 + 1 TMS arrangement. This protein belongs to the Pfam family, PF02681 and the PAP2 (CL0525) clan. |
Eukaryota | Euglenozoa | UP of Leishmania major |
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1.H.3.1.18 | Amastin protein, TryB2, of 299 aas with a hydrophilic N-terminal domain followed by a 4 TMS .domain. |
Eukaryota | Euglenozoa | Amastin of Trypanosoma brucei brucei |
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1.H.3.1.19 | Amastin protein of 183 aas and 4 TMSs. |
Eukaryota | Euglenozoa | Amastin of Leishmania donovani
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1.H.3.1.2 | Amastin-like protein of 456 aas and 4 C-terminal TMSs in a 1 + 3 TMS arrangement. |
Eukaryota | Euglenozoa | Amastin of Trypanosoma brucei |
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1.H.3.1.3 | Amastin-like protein of 221 aas and 4 TMSs in a 1 + 3 TMS arrangement. |
Eukaryota | Euglenozoa | Amastin-like protein of Leishmania braziliensis |
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1.H.3.1.4 | Large amastin-like protein of 461 aas and 10 TMSs in a 2 + 1 + 4 + 3 TMS arrangement. This protein may have 2 N-terminal TMSs followed by two 4-TMS Amastin-like domains. The last 4 TMSs show the greatest sequence similarity with shorter amastins. |
Eukaryota | Euglenozoa | Large mmastin-like protein of Trypanosoma cruzi |
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1.H.3.1.5 | Putative amastin-like surface protein of 262 aas and 5 or 6 TMSs in a 2 + 3 or 3 + 3 TMS arrangement, respectively. |
Eukaryota | Euglenozoa | Amastin-like protein of Leishmania major |
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1.H.3.1.6 | Amastin-like protein of 203 aas and 4 TMSs in a 1 + 2 + 1 TMS arrangement. |
Eukaryota | Euglenozoa | Amastin-like protein of Leishmania braziliensis |
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1.H.3.1.7 | Uncharacterized protein of 331 aas and 7 TMSs in a 2 + 2 + 2 + 1 TMS arrangement. |
Euglenozoa | UP of Angomonas deanei |
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1.H.3.1.8 | Amastin-like protein of 380 aas and 8 TMSs in a 1 + 4 + 3 TMS arrangement, possibly with two tandem amastin-like domains. |
Eukaryota | Euglenozoa | Internally duplicated amastin domains in Bodo saltans |
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1.H.3.1.9 | Putative amastin protein of 431 aas and 9 TMSs in a 2 + 2 + 2 + 2 + 1 TMS arrangement. |
Eukaryota | Euglenozoa | Amastin-like protein of Phytomonas sp. |
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1.H.3.2.1 | Uncharacterized pali-domain containing protein of 523 aas and 4 TMSs at the N-terminus of the protein in a 1 + 3 TMS arrangement with a long C-terminal hydrophilic domain. |
Eukaryota | Fungi, Ascomycota | UP of Suhomyces tanzawaensis |
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1.H.3.2.2 | Uncharacterized protein of 580 aas and 4 TMSs in a 1 + 3 arrangement with a long C-terminal hydrophilic domain. |
Eukaryota | Fungi, Ascomycota | UP of Candida parapsilosis |
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1.H.3.2.3 | Uncharacterized protein of 553 aas and 4 TMSs in a 1 + 3 TMs arrangement followed by a long hydrophilic domain. |
Eukaryota | Fungi, Ascomycota | UP of Clavispora lusitaniae |
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1.H.3.2.4 | Putative pH signal transduction protein PalI of 561 aas and 4 N-terminal TMSs in a 1 + 3 TMS arrangement followed by a large hydrophilic domain. |
Fungi, Ascomycota | PalI protein of Aspergillus flavus |
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1.H.3.2.5 | Uncharacterized protein of 231 aas and 4 TMSs in a 1 + 3 TMS arrangement. |
Eukaryota | Fungi, Ascomycota | UP of Venustampulla echinocandica |
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1.H.3.2.6 | Uncharacterized protein of 309 aas and 4 TMSs in a 1 + 3 TMs arrangement with a C-terminal hydrophilic domain. |
Eukaryota | Fungi, Ascomycota | UP of Komagataella pastoris |
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1.H.3.2.7 | Tos7p of 515 aas and 4 N-terminal TMSs in a 1 + 3 TMS arrangement. Tos7 contributes to cell surface-related functions probably as an auxiliary component of the MCC/eisosome complex that interacts with and regulates the secretory pathway (Zhu et al. 2020). |
Eukaryota | Fungi, Ascomycota | Tos7 of Saccharomyces cerevisiae (baker's yeast) |
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1.H.3.3.1 | Uncharacterized protein of 367 aas and 4 TMSs in a 1 + 3 TMS arrangement. |
Eukaryota | UP of Monosiga brevicollis |
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1.H.3.3.2 | Uncharacterized protein of 597 aas and 4 N-terminal TMSs in a 1 + 3 TMS arrangement followed by a large hydrophilic domain that shows extensive sequence similarity with 1.W.6.4.1. |
Eukaryota | UP of Monosiga brevicollis |
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1.H.3.3.3 | Uncharacterized protein of 262 aas and either 4 or 6 TMSs in a 1 + 3 or 3 + 3 TMS arrangement, respectively. |
Eukaryota | UP of Salpingoeca rosetta |
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1.H.3.3.4 | Uncharacterized protein of 179 aas and 4 TMSs in a 1 + 2 + 1 TMS arrangement. |
Eukaryota | Metazoa, Nematoda | UP of Ancylostoma ceylanicum |
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1.H.3.3.5 | Uncharacterized protein of 195 aas and 4 TMSs in a 1 + 2 + 1 TMS arrangement. |
Eukaryota | Metazoa, Nematoda | UP of Steinernema carpocapsae |
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1.H.3.3.6 | Unharacterized protein of 209 aas and 4 TMSs in a 1 + 3 TMS arrangement. |
Eukaryota | Metazoa, Nematoda | UP of Caenorhabditis brenneri |
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1.H.3.4.1 | Uncharacterized protein of 251 aas and 4 TMSs in a 1 + 3 TMS arrangement |
Eukaryota | Euglenozoa | UP of Leptomonas pyrrhocoris |
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1.H.3.4.2 | Uncharacterized protein of 227 aas and 4 or 5 TMSs in a 1 + 2 + 1 or 1 + 3 + 1 TMS arrangement. |
Eukaryota | Euglenozoa | UP of Trypanosoma theileri |
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1.H.3.4.3 | Uncharacterized protein of 221 aas and 4 TMSs in a 1 + 3 TMS arrangement. |
Eukaryota | Euglenozoa | UP of Trypanosoma equiperdum |
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1.I.1.1.1 | Nuclear Pore Complex (NPC) (Tran and Wente, 2006). The structure of the NPC core (400kD) has been determined at 7.4 Å resolution revealing a curved Y-shaped architecture with the coat nucleoporin interactions forming the central ""triskeleton"". 32 copies of the coat neucloporin complex (CNC) structure dock into the cryoelectron tomographic reconstruction of the assembled human NPC, thus accounting for ~16 MDa of it's mass (Stuwe et al. 2015). Import of integral membrane proteins (mono- and polytopic) into the the inner nuclear membrane occurs by an active, transport factor-dependent process (Laba et al. 2015). Ndc1 and Pom52 are partially redundant NPC components that are essential for proper assembly of the NPC. The absence of Ndc1p and Pom152p results in aberrant pores that have enlarged diameters and lack proteinaceous material, leading to increased diffusion between the cytoplasm and the nucleus (Madrid et al. 2006). Pom152 is a transmembrane protein within the nuclear pore complex (NPC) of fungi that is important for NPC assembly and structure. Pom152 is comprised of a short amino-terminal region that remains on the cytosolic side of the nuclear envelope (NE) and interacts with NPC proteins, a transmembrane domain, and a large, glycosylated carboxy-terminal domain within the NE lumen. Here we show that the N-terminal 200 amino acids of Pom152 that include only the amino-terminal and transmembrane regions are sufficient for localization to the NPC (Brown et al. 2021). Atg39 selectively captures the inner nuclear membrane into lumenal vesicles for delivery to the autophagosome (Chandra et al. 2021). The inner nuclear membrane (INM) changes its protein composition during gametogenesis, sheding light on mechanisms used to shape the INM proteome of spores (Shelton et al. 2021). Several nucleoporins with FG-repeats (phenylalanine-glycine repeats) (barrier nucleoporins) possess potential amyloidogenic properties (Danilov et al. 2023). A multiscale structure of the yeast nuclear pore complex has been described, and its implications have been discussed (Akey et al. 2023). NPCs direct the nucleocytoplasmic transport of macromolecules, and Akey et al. 2023 provided a composite multiscale structure of the yeast NPC, based on improved 3D density maps from cryoEM and AlphaFold2 models. Key features of the inner and outer rings were integrated into a comprehensive model. The authors resolved flexible connectors that tie together the core scaffold, along with equatorial transmembrane complexes and a lumenal ring that anchor this channel within the pore membrane. The organization of the nuclear double outer ring revealed an architecture that may be shared with ancestral NPCs. Additional connections between the core scaffold and the central transporter suggest that under certain conditions, a degree of local organization is present at the periphery of the transport machinery. These connectors may couple conformational changes in the scaffold to the central transporter to modulate transport. Collectively, this analysis provides insights into assembly, transport, and NPC evolution (Akey et al. 2023). |
Eukaryota | Fungi, Ascomycota | Well-characterized nucleoporins of Saccharomyces cerevisiae |
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1.I.1.1.2 | Fungal Nuclear Pore Complex (NPC) with 29 components. Stuwe et al. 2015 presented the reconstitution of the ~425-kilodalton inner ring complex (IRC), which forms the central transport channel and diffusion barrier of the NPC, revealing its interaction network and equimolar stoichiometry. The Nsp1•Nup49•Nup57 channel nucleoporin heterotrimer (CNT) attaches to the IRC solely through the adaptor nucleoporin Nic96. The CNT•Nic96 structure reveals that Nic96 functions as an assembly sensor that recognizes the three-dimensional architecture of the CNT, thereby mediating the incorporation of a defined CNT state into the NPC. They proposed that the IRC adopts a relatively rigid scaffold that recruits the CNT to primarily form the diffusion barrier of the NPC, rather than enabling channel dilation (Stuwe et al. 2015). |
Eukaryota | Fungi, Ascomycota | NPC of Chaetomium thermophilum |
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1.I.1.1.3 | Nuclear Pore Complex, NPC, with 86 protein components. NPCs mediate nucleocytoplasmic transport and gain transport selectivity through nucleoporin FG domains. Chug et al. 2015 reported a structural analysis of the frog FG Nup62•58•54 complex. It comprises a ≈13 nanometer-long trimerization interface with an unusual 2W3F coil, a canonical heterotrimeric coiled coil, and a kink that enforces a compact six-helix bundle. Nup54 also contains a ferredoxin-like domain. Chug et al. 2015 further identified a heterotrimeric Nup93-binding module for NPC anchorage. The quaternary structure alternations in the Nup62 complex, which were previously proposed to trigger a general gating of the NPC, are incompatible with the trimer structure. Chug et al. 2015 suggested that the highly elongated Nup62 complex projects barrier-forming FG repeats far into the central NPC channel, supporting a barrier that guards the entire cross section. The Sun1/UNC84A protein and Sun2/UNC84B may function redundantly in early HIV-1 infection steps and therefore influence HIV-1 replication and pathogenesis (Schaller et al. 2017). The integral transmembrane nucleoporin Pom121 functionally links nuclear pore complex assembly to nuclear envelope formation (Antonin et al. 2005) and ensures efficient HIV-1 pre-integration complex nuclear import (Guo et al. 2018). Mechanosensing at the nuclear envelope by nuclear pore complex stretch activation involves cell membrane integrins (TC# 8.A.54) and SUN proteins, SUN1 and SUN2, in the nuclear membrane (Donnaloja et al. 2019). TMX2 is a thioredoxin-like protein that facilitates the transport of proteins across the nuclear membrane (Oguro and Imaoka 2019). Torsin ATPase deficiency leads to defects in nuclear pore biogenesis and sequestration of the myelokd leukemia factor 2, MLF2 (Rampello et al. 2020). Cdk1 (CDC2, CDC2.8A, CDKN1, P34CDC2) acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry (Lupberger et al. 2011). G4C2 repeat RNA initiates a POM121-mediated reduction in specific nucleoporins (Coyne et al. 2020) (Pom121: acc# A8CG34). Defects in nucleocytoplasmic transport and accumulation of specific nuclear-pore-complex-associated proteins play roles in multiple neurodegenerative diseases, including C9orf72 Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS/FTD). Using super-resolution structured illumination microscopy, Coyne et al. 2020 have explored the mechanism by which nucleoporins are altered in nuclei isolated from C9orf72 induced pluripotent stem-cell-derived neurons (iPSNs). Of the 23 nucleoporins evaluated, they observed a reduction in a subset of 8, including key components of the nuclear pore complex scaffold and the transmembrane nucleoporin POM121. Reduction in POM121 appeared to initiate a decrease in the expression of seven additional nucleoporins, ultimately affecting the localization of the Ran GTPase and subsequent cellular toxicity in C9orf72 iPSNs. Thus, the expression of expanded C9orf72 ALS/FTD repeat RNA affects nuclear POM121 expression in the initiation of a pathological cascade affecting nucleoporin levels within neuronal nuclei and ultimately downstream neuronal survival (Coyne et al. 2020). Involved in the organization of the nuclear envelope, implicating EMD, SUN1 and A-type lamina (Gudise et al. 2011), but it also promotes breast cancer metastasis by positively regulating TGFbeta signaling (Kong et al. 2021). Nucleoporin POM121 signals TFEB-mediated autophagy via activation of the SIGMAR1/sigma-1 receptor chaperone by pridopidine (Wang et al. 2022). AI-based structural prediction empowers integrative structural analysis of human nuclear pores (Mosalaganti et al. 2022). With a molecular weight of approximately 120 MDa, the human NPC is one of the largest protein complexes. Its ~1000 proteins are taken in multiple copies from a set of about 30 distinct nucleoporins (NUPs). They can be roughly categorized into two classes. Scaffold NUPs contain folded domains and form a cylindrical scaffold architecture around a central channel. Intrinsically disordered NUPs line the scaffold and extend into the central channel where they interact with cargo complexes. The NPC architecture is highly dynamic. It responds to changes in nuclear envelope tension with conformational breathing that manifests in dilation and constriction movements. AI-based predictions generated an extensive repertoire of structural models of human NUPs and their subcomplexes (Mosalaganti et al. 2022). The 70-MDa atomically resolved model covers >90% of the human NPC scaffold. It captures conformational changes that occur during dilation and constriction. It also reveals the precise anchoring sites for intrinsically disordered NUPs, the identification of which is a prerequisite for a complete and dynamic model of the NPC. This exempli-fies how AI-based structure predictions may accelerate the elucidation of subcellular architecture at atomic resolution. The nucleocytoplasmic transport protein, importin-5, plays a role in the crosstalk between activin and BMP signalling in human testicular cancer cell lines (Radhakrishnan et al. 2023). Viral targeting of importin alpha-mediated nuclear import blocks innate immunity (Vogel et al. 2023). The nuclear pore protein POM121 regulates subcellular localization and transcriptional activity of PPARgamma. (Yu et al. 2024). Stabilization of KPNB1 by deubiquitinase USP7 promotes glioblastoma progression through the YBX1-NLGN3 axis (Li et al. 2024). Retroviral hijacking of host transport pathways are used for viral genome nuclear export (Behrens and Sherer 2023). Biallelic variants in AAAS, encoding ALADIN, cause triple A syndrome (Allgrove syndrome). Triple A syndrome, characterized by alacrima, achalasia, and adrenal insufficiency, often includes progressive demyelinating polyneuropathy and other neurological complaints (Smits et al. 2024).
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Eukaryota | Metazoa, Chordata | NPC of Homo sapiens Nuclear pore complex protein Nup98-Nup96 [Cleaved into: Nuclear pore complex protein Nup98 (98 kDa nucleoporin) (Nucleoporin Nup98) (Nup98); Nuclear pore complex protein Nup96 (96 kDa nucleoporin) (Nucleoporin Nup96) (Nup96)]; 1817aa; P52948 |
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1.I.1.1.4 | Ciliate nucleopore complex, NPC. Regulates protein import and nuclear division (Malone et al. 2008). The NPC contributes to nucleus-selective transport in ciliates (Iwamoto et al. 2009). The transmembrane components, Pom121 and Pom82, localize exclusively to the macro (MAC)- and micro (MIC)-nuclear NPCs, respectively. Functional nuclear dimorphism in ciliates is likely to depend on compositional and structural specificity of the NPCs (Iwamoto et al. 2017). |
Eukaryota | Ciliophora | NPC of Tetrahymena thermophila |
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1.I.1.1.5 | The nuclear envelope consists of the outer and the inner nuclear membrane, the nuclear lamina and the nuclear pore complexes, which regulate nuclear import and export (Batsios et al. 2019). The major constituent of the nuclear lamina of Dictyostelium is the lamin NE81. It can form filaments like B-type lamins, and it interacts with Sun1, as well as with the LEM/HeH-family protein Src1. Sun1 and Src1 are nuclear envelope transmembrane proteins involved in the centrosome-nucleus connection and nuclear envelope stability at the nucleolar regions, respectively. In conjunction with a KASH-domain protein, Sun1 usually forms a so-called LINC complex. Two proteins with functions reminiscent of KASH-domain proteins at the outer nuclear membrane of Dictyostelium are known; interaptin which serves as an actin connector and the kinesin Kif9 which plays a role in the microtubule-centrosome connector, both of which lack the conserved KASH-domain. The link of the centrosome to the nuclear envelope is essential for the insertion of the centrosome into the nuclear envelope and appropriate spindle formation. Centrosome insertion is involved in permeabilization of the mitotic nucleus, which ensures access of tubulin dimers and spindle assembly factors (Batsios et al. 2019). |
Eukaryota | Evosea | Nuclear Membrane Complex of Dictyosteilium discoidium
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1.I.2.1.1 | Recognized or proposed constituents or associated constituents of the plant plasmodesmata. CX32 is a transmembrane protein with 2 TMSs that contains a protein kinase domain (Maule, 2008). Formins 1 (Q9SE97) and 2 (O22824) are believed to regulate the plasmodesmata's permeability by capping, anchoring and stabilizing actin filaments that are localized to it (Diao et al. 2018). Formins are large proteins (~900 to 1,100 aas) with 2 or 3 N-terminal TMSs. |
Eukaryota | Viridiplantae, Streptophyta | Plant plasmodesmata of Arabidopsis thaliana. |
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1.I.3.1.1 | The bacterial (Planctomycetes) Nuclear Pore-like Complex, B-NPC (Sagulenko et al. 2017). Several proteins were found to associate with the pore-containing membranes, and some were found to possess structural domains found in eukaryote nuclear pore complexes (Sagulenko et al. 2017). Six proteins, shown to be associated with the B-NPC structure, are listed under this TC#. They show sequence similarity with members of autotransport families 1 and 2 (TC#s 1.B.12 and 1.B.40) as well as members of a bacterial pore-forming toxin family (e.g., TC# 1.C.75). However these proteins have an unusual amino acid composition with lots of As, Gs, D, and Es, possibly (partially) accounting for the good scores. |
Bacteria | Planctomycetota | B-NPC of Gemmata obscuriglobus |
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1.J.1.1.1 | P98 virion egress pyrimidal structure forming protein of 98 aas and one N-terminal TMS (Quax et al., 2011). |
Viruses | Zilligvirae, Taleaviricota | P98 of Sulfolobus islandicus rod-shaped virus 2 (Q8V9M0) |
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1.J.1.1.2 | Sulfolobus turreted icosahedral virus (STIV) c92 pyrimidal protein of 92 aas and one N-terminal TMS (Snyder et al. 2011). This protein alone is responsible for the formation of the pyramidal lysis structure in the cell membrane and is essential for virus replication. |
Viruses | Bamfordvirae, Preplasmiviricota | c92 protein of Sulfolobus sulfataricus turreted icosahedral virus (Q6Q0L7) |
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1.J.1.1.3 | SRSV P92 pyrimidal protein of 92 aas and 1 N-terminal TMS. |
Viruses | Zilligvirae, Taleaviricota | P92 of Stygiolobus rod-shaped virus (B6EFE0) |
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1.J.1.1.4 | Uncharacterized protein of 92 aas with 1 N-terminal TMS plus a C-terminal region of lesser hydrophobic character that might be a TMS. |
Archaea | Thermoproteota | UP of Sulfolobaceae
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1.J.1.1.5 | Putative pyramid forming protein of 98 aas and 1 N-terminal TMS. |
Viruses | Zilligvirae, Taleaviricota | Pyramid-forming protein of Saccharolobus solfataricus rod-shaped virus 1 |
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1.K.1.1.1 | Baseplate structural protein complex (GP5 is a lysozyme showing limited similarity to ComA of Neisseria species (3.A.11.2.1)) plus Gp18 tail sheath protein of phage T4. Gp5 (575 aas), the baseplate hub subunit, contains (1) an N-terminal GP5_OB domain, (2) a central lysozyme domain, and (3) a C-terminal domain of ~200 aas with repeat units that resemble BigA (1.B.12.5.5; residues 400-600) and ComA (3.A.11.2.1; residues 400-600). Twenty proteins comprise the entire tail complex of T4. See Rossmann et al. 2004 and Leiman et al. 2010) for tabulation of the properties and evidence concerning the functions of these constituents. gp27 and gp29 may comprise the transmembrane channel (Hu et al. 2015). The tail complex of T4 resembles the type VI protein secretion systems (TC# 3.A.23) of enteric bacteria (Shneider et al. 2013). |
Viruses | Heunggongvirae, Uroviricota | Tail complex of E. coli phage T4
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1.K.2.1.1 | PRD1 phage DNA delivery system (Proteins P11, P18 and P32) |
Viruses | Bamfordvirae, Preplasmiviricota | PRD1 DNA delivery system |
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1.K.3.1.1 | The Pilot spike protein H. Forms a hollow tube through which the phage DNA passes from the phage particle to the cytoplasm of the host bacterial cell (Sun et al. 2013). A single molecule of the minor spike H protein can be found on each of the 12 spikes of the microvirus shell. |
Viruses | Sangervirae, Phixviricota | Pilot protein H of phage PhiX174 |
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1.K.3.1.2 | Minor spike protein H of 332 aas. |
Viruses | Sangervirae, Phixviricota | Protein H of Enterobacteria phage phiK (Bacteriophage phi-K) |
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1.K.3.1.3 | Enterobacterial phage NC35 GpH protein of 325 aas and 1 N-terminal TMS |
Viruses | Sangervirae, Phixviricota | GpH of Enterobacterial phage NC35 |
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1.K.4.1.1 | DNA/protein translocase of phage Salmonella phage P22 consisting of gp7, gp20, gp16 and gp26 (Perez et al., 2009). A homologue of gp20 in the phage Sf6 of S. flexneri, gp12, forms a decameric constricted channel though the outer member of the bacterium (Zhao et al. 2016). The other two recognized constituents of the Sf6 phage injectisome are gp11 (like gp7 of phage P22) and gp13 (like gp16 of phage P22). |
Viruses | Heunggongvirae, Uroviricota | DNA/protein translocase of phage P22 |
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1.K.4.1.2 | Injectisome of enterbacteriia phage IME_EC2 with three comoponents. |
Viruses | Heunggongvirae, Uroviricota | Injectisome of enterbacteriia phage IME_EC2 with three comoponents |
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1.K.5.1.1 | The marine podoviurus (phage) P-SSP7 nozzel complex including gp12 (the nozzel) and gp11 (the adaptor). gp12 is 192 aas long, and 6 copies are present in a 6x symmetry. gp11 is 204 aas long and has 12 copies in a 6x symmetry. See the family description for details (Liu et al. 2010). |
Viruses | Heunggongvirae, Uroviricota | gp12, 192 aas, Q58N56 |
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1.K.5.1.2 | Protein FG37_gp075 of Escherichia phage FFH2 |
Viruses | Heunggongvirae, Uroviricota | Protein FG37_gp075 of Escherichia phage FFH2 |
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1.L.1.1.1 | Tumor necrosis factor alpha-induced protein 2 of 654 aas, TNFaip2 or M-Sec (Kimura et al. 2012). |
Eukaryota | Metazoa, Chordata | TNFaip2 of Homo sapiens |
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1.L.1.1.2 | Tumor necrosis factor, alpha-induced protein 2 of 587 aas and 0 TMSs.
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Eukaryota | Metazoa, Chordata | TNF of Pteropus alpcto (Black flying fox) |
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1.L.1.1.3 | TNF alpha induced protein 2 of 794 aas. |
Eukaryota | Metazoa, Chordata | TNFα induced protein of Anas platyrhynchos (malard duck) |
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1.M.1.1.1 | The Spanin1 (Rz; inner membrane, IM)/Spanin2 (Rz1; outer membrane, OM) complex. Spanin1, 153 aas; Spanin2, 60 aas. Together they span the periplasm and mediate fusion of the IM and OM. By doing so, they disrupt the double membrane barrier (Berry et al. 2008; Rajaure et al. 2015; Kongari et al. 2018). |
Viruses | Heunggongvirae, Uroviricota | Rz/Rz1 of E. coli phage lambda |
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1.M.1.1.10 | Uncharacterized protein, SEA_CAMERICO_42, of 125 aas and 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | UP of Gordonia phage Camerico |
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1.M.1.1.11 | Uncharacterized protein of 122 aas and 1 TMS. |
Bacteria | Pseudomonadota | UP of Aminobacter aminovorans |
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1.M.1.1.13 | Putative phage spanin of 126 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | PPS of Mesorhizobium sp. |
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1.M.1.1.2 | Rz/Rz1 spanin complex of Burkholderia phage BcepIL02 |
Viruses | Heunggongvirae, Uroviricota | Rz/Rz1 of Burkholderia phage BcepIL02
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1.M.1.1.3 | Putative Rz (143 aas; W1IXJ3) inner membrane spanin (i-spanin) of a possible Rz/Rz1 spanin complex of lambdoid prophage Rac. No o-spanin was found, but an adjacent gene (UniProt encodes a 62 aa addiction module toxin, HicA which could be either a o-spanin or a toxin which could be exported via the Rz protein. |
Bacteria | Pseudomonadota | Rz protein of Xenorhabdus szentirmaii
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1.M.1.1.4 | Two component spanin consisting of Rz (IM, 145 aas and 1 TMS) and Rz1 (OM, 61 aas and 1 TMS). |
Viruses | Heunggongvirae, Uroviricota | Spanin of Enterobacteria phage P22 (Bacteriophage P22) |
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1.M.1.1.5 | Putative spanin of 164 aas and 1 TMS |
Bacteria | Pseudomonadota | Putative spanin of Arsenophonus nasoniae (son-killer infecting Nasonia vitripennis) |
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1.M.1.1.6 | Putative phage spanin Rz of 128 aas and 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | PPS of Mycobacterial phage Ptience, gene 45. |
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1.M.1.1.7 | Putative phage spanin, Aminay, of 132 aas and 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | PPS of Mycobacterial phage spanin, Aminay. |
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1.M.1.1.8 | Uncharacterized protein of 107 aas and 1 N-terminal TMS. |
Bacteria | Actinomycetota | UP of Prescottella equi (Rhodococcus equi) |
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1.M.1.1.9 | Uncharacterized protein, putative spanin, of 134 aas and 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | UP of Mycobacterium phage Rope |
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1.M.1.2.1 | Rz-like/Rz1-like spanin complex; Rz-like, 148 aas and Rz1-like, 163 aas. |
Viruses | Heunggongvirae, Uroviricota | Rz/Rz1 complex of Klebsiella phage KP32 |
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1.M.1.2.2 | Two component Spanin, eRz/eRz1 of 147 and 74 aas, respectively. |
Viruses | Heunggongvirae, Uroviricota | Spanin of Pseudomonas phage Phi15 |
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1.M.1.2.3 | Spanin pair: i-spanin (gene 18.5; 143 aas; P03803) + o-spanin (gene 18.7; 83 aas; P03788). |
Viruses | Heunggongvirae, Uroviricota | Spanin pair of Phage T7 |
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1.M.1.2.4 | Uncharacterized protein of 162 aas and 1 N-terminal TMS. |
Bacteria | Thermodesulfobacteriota | UP of Desulfovibrio sp. (coral metagenome) |
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1.M.1.2.5 | Uncharacterized protein of 123 aas and 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | UP of E. coli phage rB |
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1.M.1.3.1 | Putative two component spanin (of 109 and 89 aas, each with 1 TMS). |
Viruses | Heunggongvirae, Uroviricota | Spanin of Enterobacteria phage phiKMV (Pseudomonas phage phiKMV) |
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1.M.1.3.10 | Putative spanin of 248 aas and 0 TMSs |
Bacteria | Pseudomonadota | UP of Labrenzia alexandrii |
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1.M.1.3.11 | Two component spannin, LysB (R4JGE0)/LysC (R4JDL9) of 146 and 97 aas, respectively. LysBC can lyse E. coli cells (Khakhum et al. 2016). |
Viruses | Heunggongvirae, Uroviricota | LysB/LysC of Burkholderia phage ST79 |
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1.M.1.3.12 | Uncharacterized protein of 114 aas and 1 TMS. |
Viruses | Bamfordvirae, Nucleocytoviricota | UP of Acanthocystis turfacea Chlorella virus TN603.4.2 |
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1.M.1.3.13 | Putative spanin (phage hypothetical protein of Tenacibaculum maritimum) of 115 aas and possibly 1 N-terminal TMS. |
Bacteria | Bacteroidota | Putative spanin of Tenacibaculum maritimum |
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1.M.1.3.14 | Spanin complex consisting of inner and outer membrane spanin (i- and o-spanin) components of 162 and 129 aas, respectively. |
Viruses | Heunggongvirae, Uroviricota | Spannin of Caulobacter phage phiCbK |
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1.M.1.3.15 | Spanin (inner membrane spanin of 168 aas and outer membrane spanin of 126 aas. |
Viruses | Heunggongvirae, Uroviricota | Spanin of Caulobacter phage CorColossus |
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1.M.1.3.16 | Putative phage spanin of 153 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | PPS of Histophilus somni |
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1.M.1.3.17 | Phage spanin of 148 aas and 1 N-terminal TMS. |
Pseudomonadota | Spanin of Pseudoalteromonas distincta |
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1.M.1.3.18 | Phage spanin Rz of 145 aas and 1 N-terminal TMS, Shewanella frigidmarina strain NCIMB 400, Gene: Sfri_1672 |
Bacteria | Pseudomonadota | Spanin Rz of Shewanella frigidmarina strain NCIMB 400 |
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1.M.1.3.19 | Uncharacterized phage spanin Rz of 114 aas and 1 TMS. |
Viruses | Bamfordvirae, Nucleocytoviricota | Rz ofAcanthocystis turfacea Chlorella virus TN603.4.2
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1.M.1.3.2 | Spanin (i-spanin of 114 aas and o-spanin of 82 aas) |
Viruses | Heunggongvirae, Uroviricota | Spanin of Caulobacter phage Percy |
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1.M.1.3.20 | Uncharacterized protein HOR29, gp46, of 119 aas with 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | UP of Pectpbacterium phage PP2 |
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1.M.1.3.21 | Uncharacterized protein of 119 aas |
Bacteria | Pseudomonadota | UP of Jiella sp. CBK1P-4 |
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1.M.1.3.22 | Uncharacterized DUF6468 domain-containing protein of 116 aa |
Bacteria | Pseudomonadota | UP of Aureimonas sp. AU20 |
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1.M.1.3.23 | Phage spanin Rz of 111 aa |
Bacteria | Pseudomonadota | Rz of Fulvimarina pelagi HTCC2506 |
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1.M.1.3.24 | Putative phage spanin of 94 aas and 1 TMS from a Xylella phage. |
Viruses | Heunggongvirae, Uroviricota | PPS of a Xylella phage |
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1.M.1.3.3 | Uncharacterized putative spanin protein of 136 aas. |
Viruses | Heunggongvirae, Uroviricota | Putative spanin of Burkholderia phage Bp-AMP1 |
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1.M.1.3.34 | Putative lipoprotein of 79 aas with one N-terminal TMS. It may be a bacterial lysin (Liu et al. 2023). |
Bacteria | Campylobacterota | LP of Campylobacter hyointestinalis subsp. hyointestinalis |
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1.M.1.3.4 | Putative inner membrane i-panin of 90 aas and 1 N-terminal TMS, Rz, and putative outer membrane spanin, o-spanin of 107 aas with 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | Spanin of Ralstonia phage RSJ2 |
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1.M.1.3.5 | Putative two component spanin, Rz of 118 aas and Rz1 of 83 aas. |
Viruses | Heunggongvirae, Uroviricota | Rz/Rz1 of Burkholderia phage JG068 |
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1.M.1.3.6 | Spanin Rz/Rz1 pair of 110 and 86 aas, each with 1 N-terminal TMS |
Viruses | Heunggongvirae, Uroviricota | Rz/Rz1 of Caulobacter phage Cd1 |
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1.M.1.3.7 | Rz/Rz1 spanin pair of 142 and 82 aas, respectively. |
Bacteria | Pseudomonadota | Rz/Rz1 of Klebsiella pneumoniae |
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1.M.1.3.8 | Putative spanin complex with two proteins of 109 and 136 aas, both with an N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | Spanin of phage APSE-6 |
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1.M.1.3.9 | Uncharacterized spanin Rz homologue of 224 aas and 1 TMS. |
Bacteria | Bacillota | UP of Butyrivibrio sp. AE3004 |
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1.M.1.4.11 | Phage-like spanin of 166 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | PS of Albitalea terrae |
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1.M.1.4.12 | Uncharacterized protein of 184 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of Vibrio vulnificus |
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1.M.1.4.13 | Rz/RzI spanin protein of 166 aas and 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | Rz/RzI of Escherichia phage IME11 |
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1.M.1.4.14 | Uncharacterized protein, i-spanin 114 of 114 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | i-spanin 114 of Stutzerimonas stutzeri
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1.M.1.4.16 | Uncharacterized protein of 131 aas and 1 TMS. |
Bacteria | Pseudomonadota | UP of Rhizobium leguminosarum |
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1.M.1.4.17 | Uncharacterized protein of 108 aas and 1 N-terminal TMS. |
Bacteria | Proteobacteria | UP of Methyloterrigena soli |
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1.M.1.4.18 | Uncharacterized protein annotated as a P-loop NTPase superfamily protein of 131 aas and 1 TMS. |
Viruses | Heunggongvirae, Uroviricota | UP of Dinoroseobacter phage vB_DshS-R5C |
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1.M.1.4.19 | Uncharacterized protein of 113 aas. |
Viruses | Duplodnaviria | UP of Myoviridae |
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1.M.1.4.2 | Uncharacterized Rz spanin of 180 aas and 1 TMS. |
Bacteria | Pseudomonadota | Rz of Ralstonia solanacearum |
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1.M.1.4.20 | Putative phage spanin of 138 aas and 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | PPS of Pseudomonas phage PAK P5 (Gene: PAK_P500031) |
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1.M.1.4.21 | Uncharacterized protein of 123 aas and 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | UP of Cronobacter phage CR3 |
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1.M.1.4.22 | Uncharacterized protein of 134 aas and 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | UP of Cronobacter phage vB_CsaM_GAP31 |
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1.M.1.4.3 | Lysis system i-spanin subunit Rz of 166 aas |
Bacteria | Pseudomonadota | UP of Microvirgula aerodenitrificans |
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1.M.1.4.4 | Annotated as "lysozyme" of 208 aas and 1 N-terminal TMS. A member of the Pfam Phage_lysis superfamily. However, it appears to be a large spanin and is designated here as an uncharacterized protein (UP) (unpublished observations). |
Bacteria | Pseudomonadota | UP of Pseudomonas fluorescens |
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1.M.1.4.5 | Probable spanin of 165 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | Spanin of Luteibacter sp. |
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1.M.1.4.7 | Phage spanin of 165 aas and 1 N-terminal TMS. |
Viruses | Duplodnaviria | PS of Myoviridae sp. (insect metagenome) |
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1.M.1.4.8 | Uncharacterized protein of 177 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of Sphaerotilus montanus |
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1.M.10.1.1 | Putative phage spanin-10 of 129 aas and 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | PPS of Ralstonia phage RSB3 |
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1.M.11.1.1 | Putative phage spanin of 204 aas and 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | PPS of Mycobacterial phage Swish |
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1.M.11.1.2 | Putative phage spanin of 183 aas and 2 N-terminal TMSs. |
Viruses | Heunggongvirae, Uroviricota | PSS of Mycobacterium phage JacoRen57 |
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1.M.11.1.3 | Uncharacterized putative phage spanin of 183 aas and 2 N-terminal TMSs. |
Bacteria | Actinomycetota | UP of Pseudonocardia sp. (rhizosphere metagenome) |
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1.M.12.1.1 | Putative phage spanin Rz of Clostridium cellulovorans of 165 aas and 1 N-terminal TMS. |
Bacteria | Bacillota | PS Rz of Clostridium cellulovorans |
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1.M.12.1.2 | Uncharacterized protein of 150 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of Citrobacter freundii |
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1.M.12.1.3 | Uncharacterized protein of 139 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of Xanthomonas translucens |
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1.M.12.1.4 | Uncharacterized protein of 155 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of Pantoea agglomerans |
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1.M.12.1.5 | Uncharacterized protein of 160 aas and 2 N-terminal TMSs. |
Bacteria | Bacillota | UP of Priestia megaterium |
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1.M.12.1.6 | Uncharacterized protein of 176 aas and 1 N-terminal TMS. |
Bacteria | Bacteroidota | UP of Saprospiraceae bacterium (activated sludge metagenome) |
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1.M.12.1.7 | Uncharacterized protein of 142 aas and 1 N-terminal TMS. |
Bacteria | Campylobacterota | UP of Campylobacter sp. (pig gut metagenome) |
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1.M.12.1.8 | Uncharacterized protein of 135 aas and 1 N-terminal TMS. |
Bacteria | Bacteroidota | UP of Flavobacterium sp. D33 |
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1.M.12.1.9 | Uncharacterized protein of 161 aas and 1 N-terminal TMS. |
Bacteria | Planctomycetota | UP of Zavarzinella formosa |
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1.M.13.1.1 | Putative phage i-spanin of 109 aas and 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | PPS of Escherichia phage TheodorHerzl |
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1.M.13.1.2 | Putative Salmonella phage spanin Rz of 118 aas and 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | PPS26 of Salmonella phage FSL SP-038 |
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1.M.13.1.3 | Uncharacterized protein of 120 aas with one N-terminal TMS. |
Bacteria | Pseudomonadota | Putative spanin homolog of Enterobacter hormaechei |
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1.M.13.2.1 | Spanin of 163 aas and 1 N-terminal TMS of Salmonella phage vB_SenS_ST1UNAM (Rodea M et al. 2024). |
Viruses | Heunggongvirae, Uroviricota | Spanin of Salmonella phage vB_SenS_ST1UNAM |
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1.M.13.2.2 | DUF2514 family protein of 164 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | DUF2514 family protein of Klebsiella pneumoniae |
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1.M.13.2.3 | DUF2514 Spanin of 168 aas and 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | DUF2514 spanin of Caudoviricetes sp. |
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1.M.13.2.4 | Rz-like spanin of 162 aas and 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | Spanin of Salmonella phage Segz_1 |
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1.M.13.3.2 | Hypothetical protein PUB04_01615 of 109 aas and 1 N-terminal TM |
Bacteria | Bacillota | PUB04_01615 of Clostridia bacterium |
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1.M.13.3.3 | Hypothetical protein MRZ64_04125 of 147 aas and 1 N-terminal TMS. |
Bacteria | Bacillota | MRZ64_04125 of Bacteroides pectinophilus |
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1.M.13.3.4 | Hypothetical protein of 147 aas and 1 N-terminal TM |
Bacteria | Bacillota | HP of Lachnospira eligens |
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1.M.15.1.1 | Putative phage spanin of 135 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | PPS of Shewanella baltica (strain OS195) |
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1.M.15.1.2 | Uncharacterized protein of 165 aas with one N-terminal TMS. |
Bacteria | Pseudomonadota | UP of Pseudomonas cavernicola |
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1.M.15.1.3 | Putative phage spanin of 159 aas and 1 N-terminal TMS. DUF4670 domain-containing protein. |
Bacteria | Pseudomonadota | PPS of Burkholderiaceae bacterium |
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1.M.15.1.4 | Putative phage spanin of Candidatus Saccharibacteria bacterium of 149 aas and 1 N-terminal TMS. |
Bacteria | Candidatus Saccharibacteria | Spanin of Candidatus Saccharibacteria bacterium |
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1.M.16.1.1 | Outer membrane disruptin, Gp28, of 56 aas and 1 central TMS. (see the TC family 1.M.16 description for properties and activities of this small membrane associated protein (Khan et al. 2023). NCBI refers to this protein as a hypothetical OmpW family transmembrane protein, but it does not seem to be related to OmpW proteins which are much larger outer membrane porins. A nearly identical protein to Gp28 of the same length is encoded within Escherichia phage FGT2, but no other homologues were detected using NCBI BLAST.
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Viruses | Heunggongvirae, Uroviricota | Gp28 antimicrobial peptide of Escherichia phage phiKT (φKT) |
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1.M.2.1.1 | Enterobacterial phage T1 U-spanin, gp11, of 133 aas (Summer et al. 2007). It disrupts the host outer membrane and participates in cell lysis during virus exit. The spanin complex usually conducts the final step in host lysis by disrupting the outer membrane after holin and endolysin action have permeabilized the inner membrane and degraded the host peptidoglycans. Host outer membrane disruption is possibly due to local fusion between the inner and outer membrane performed by the spanin (Young 2014; Fernandes and São-José 2018). This spanin has been used for phage-based antimicrobial development (Yamashita et al. 2024). gp11 mediates lysis in the absence of holin and endolysin function when the peptidoglycan density is depleted by starvation for murein precursors. Thus, the peptidoglycan is a negative regulator of gp11 function, supporting a model in which gp11 acts by fusing the inner and outer membranes, a mode of action analogous to but mechanistically distinct from that proposed for two-component spanin systems (Kongari et al. 2018). |
Viruses | Caudovirales | U-spanin of phage T1 (Q6XQ97) |
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1.M.2.1.2 | Uncharacterized spanin of 188 aas and 2 TMSs, N- and C-terminal. |
Viruses | Heunggongvirae, Uroviricota | UP of Pantoea phage LIMEzero |
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1.M.2.1.3 | Uncharacterized spanin of 134 aas and 2 TMSs, N- and C-terminal. |
Viruses | Heunggongvirae, Uroviricota | UP of Escherichia virus KP26 |
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1.M.2.1.4 | Uncharacterized putative spanin of 134 aas and 2 TMSs, N- and C-terminal. |
Viruses | Heunggongvirae, Uroviricota | Spanin of Proteus phage PM16 |
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1.M.2.1.5 | Uncharacterized putative spanin of 132 aas and 2 TMSs, N- and C-terminal. |
Viruses | Heunggongvirae, Uroviricota | UP of Marinomonas phage CB5A |
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1.M.2.2.1 | Uncharacterized putative spanin of 161 aas and 2 or 3 TMSs with one N-terminal and one or two C-terminnal. |
Viruses | Heunggongvirae, Uroviricota | UP of Colwellia phage 9A |
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1.M.2.2.2 | Uncharacterized putative spanin of 141 aas and 2 TMSs, N- and C-terminal. |
Viruses | Heunggongvirae, Uroviricota | UP of Pseudoalteromonas phage PH357 |
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1.M.2.2.3 | Uncharacterized putative spanin of 135 aas and 1 N-terminal TMS. May be incomplete. |
Bacteria | Actinomycetota | UP of Kibdelosporangium sp. MJ126-NF4 |
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1.M.2.3.1 | Uncharacterized putative spanin of 117 aas and 2 TMSs, N- and C-terminal. |
Bacteria | Pseudomonadota | UP of Salinihabitans flavidus |
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1.M.2.3.2 | Uncharacterized putative spanin of 109 aas and 2 TMSs, N- and C-terminal. |
Bacteria | Pseudomonadota | UP of Rhodovulum sulfidophilum |
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1.M.2.3.3 | Uncharacterized putative spanin of 124 aas and 2 TMSs, N- and C-terminal. |
Bacteria | Pseudomonadota | UP of Mameliella alba |
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1.M.2.3.4 | Uncharacterized putative spanin of 112 aas and 2 TMSs, N- and C-terminal. |
Viruses | Heunggongvirae, Uroviricota | UP of Roseobacter virus SIO1 |
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1.M.3.1.1 | Putative phage spainin of 126 aas with an N-terminal TMS. |
Bacteria | Bacillota | PPS of Anaerococcus tetradius |
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1.M.3.1.2 | Uncharacterized protein of 142 aas and 1 N-terminal TMS. |
Viruses | Duplodnaviria | UP of Siphoviridae sp. |
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1.M.3.1.3 | Uncharacterized protein of 133 aas and 1 or 2 N-terminal TMSs. |
Bacteria | Bacillota | UP of Lachnospiraceae bacterium (gut metagenome) |
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1.M.4.1.1 | Spanin of 203 aas and 2 or 3 TMSs, RIO-1_6. |
Viruses | Heunggongvirae, Uroviricota | Spanin of Pseudoalteromonas phage RIO-1 |
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1.M.4.1.2 | One component spanin of 189 aas and 2 (possibly 3) TMSs, N- and C-terminal, with one possible TMS adjacent to the N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | Spanin of Pseudoalteromonas phage HP1 |
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1.M.5.1.1 | Two component putative spanin of 103 and 57 aas, respectively. |
Viruses | Heunggongvirae, Uroviricota | Spanin of Burkholderia phage BcepF1 |
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1.M.5.1.2 | i-spanin/o-spanin of 104 and 57 aas, respectively, each with one N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | Spanin of Burkholderia phage Maja |
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1.M.5.1.3 | Spanin of 116 aas and 1 N-terminal TMS with two additional potential weakly hydrophobic TMSs. |
Viruses | Duplodnaviria | Spanin of Myoviridae sp.
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1.M.5.1.4 | Spanin of 104 aas and 1 N-terminal TMS + 2 weakly hydrophobic putative TMSs. |
Viruses | Heunggongvirae, Uroviricota | Spanin of Burkholderia phage BCSR52 |
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1.M.7.1.1 | Phage Mu spanin, Span1, of 128 aas and 1 N-terminal TMS. See Chamblee et al. 2022 for its identification. It may function with Span1.1. See the family description for more details. It is an inner membrane subunit, and its gene and protein designations are Mup23 and gp23. |
Viruses | Heunggongvirae, Uroviricota | Span1 of phage Mu |
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1.M.7.1.2 | DUF2570 spanin of unknown function of 121 aas and one N-terminal TMS. |
Viruses | Duplodnaviria | Spanin of Siphoviridae sp. |
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1.M.7.1.3 | DUF2570 domain-containing protein of 130 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | DUF2570 domain protein of E. coli |
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1.M.7.1.4 | Uncharacterized protein of 125 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | UP of Morganella morganii |
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1.M.7.1.5 | DUF2570 domain-containing protein of 127 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | DUF2570 protein of Citrobacter portucalensis |
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1.M.7.1.6 | DUF2570 domain-containing protein of 129 aas and 1 N-terminal TMS. |
Bacteria | Pseudomonadota | DUF2570 protein of Raoultella ornithinolytica |
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1.M.8.1.1 | Putative phage spanin of 120 aas with 1 N-terminal TMS. |
Viruses | Heunggongvirae, Uroviricota | PPS of Alteromonas phage vB _AmaP |
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1.M.9.1.1 | Putative phage spanin Rz of Campylobacter jejuni subsp. jejuni (Uni Prot acc# D2MYC2). |
Bacteria | Campylobacterota | Putative phage spanin Rz of Campylobacter jejuni |
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1.M.9.1.2 | Uncharacterized spanin of 152 aas and 1 TMS. |
Bacteria | Campylobacterota | Putative spanin of Campylobacter mucosalis |
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1.M.9.1.3 | Uncharacterized protein of 146 aas and 1 TMS. |
Bacteria | Campylobacterota | UP of Campylobacter avium |
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1.M.9.1.4 | Uncharacterized protein of 150 aas and 1 N-terminal TMS with a moderately hydrophobic peak near the C-terminus. |
Bacteria | Campylobacterota | UP of Sulfurospirillum sp. |
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1.N.1.1.1 | The Osteoclast fusion complex including DC-STAMP (470 aas; 7 TMSs), OC-STAMP (566 aas and 7 TMSs) and Leucocyte surface antigen, CD47 of 323 aas and 5 TMSs (Chiu et al. 2016; Møller et al. 2016; Zhang et al. 2014). CD47 is homologous to the first 5 TMSs of Presenilin-1 of Homo sapiens (1.A.54.1.1). It is therefore a presenilin homologue (unpublished observation). Sulforaphene (SFE) downregulates mRNA expression of DC-STAMP, OC-STAMP, and Atp6v0d2, which encode cell-cell fusion molecules (Takagi et al. 2017). SFE attenuates pre-osteoclast multinucleation via suppression of cell-cell fusion. ITIM on DC-STAMP is a functional motif that regulates osteoclast differentiation through the NFATc1/Ca2+ axis (Chiu et al. 2017). |
Eukaryota | Metazoa, Chordata | SFC of Homo sapiens |
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1.N.2.1.1 | Myomaker (Tmem8c) of 221 aas and 7 TMSs and Myomerger/Mymx/Minion of 84 aas and at least 1 N-terminal TMS, although there may be as many as 3 TMSs. These two proteins were thought to be myoblast-specific proteins that mediate
myoblast fusion, essential for the formation of multi-nucleated
muscle fibers. They actively participate in the membrane fusion reaction (Schejter 2016). Fusion is dependent on the fusogenic peptide, myomixer (Bi et al. 2017). Myomaker is also required for stem cell fusion in skeletal muscle (Goh and Millay 2017). While Myomaker initiates the fusion process by creating the hemifusion intermediate, Myomerger (Myomixer) is the fusogenic peptide that completes the fusion of the two membranes by formation of a continuous bilayer (Leikina et al. 2018). Reviewed by Hernández and Podbilewicz 2017. |
Eukaryota | Metazoa, Chordata | Myomaker/Myomerger of Homo sapiens |
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1.N.2.1.2 | Myomaker homologue of 993 aas |
Eukaryota | Metazoa, Arthropoda | Myomaker homologue of Drosophila melanogaster (Fruit fly) |
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1.N.2.1.3 | Myomaker; Tmem8c of 220 aas and 7 TMSs (Jia et al. 2016). |
Eukaryota | Metazoa, Chordata | Tmem8c of Gallus gallus (Chicken) |
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1.N.2.1.4 | Myomaker (Tmem8c) of 220 aas and 7 TMSs. Essential for myocyte fusion in zebrafish (Landemaine et al. 2014). Myomaker is necessary for fast twitch myocyte fusion in zebrafish embryos (Zhang and Roy 2017). |
Eukaryota | Metazoa, Chordata | Myomaker of Danio rerio (Zebrafish) (Brachydanio rerio) |
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1.N.2.1.5 | Tmem8b of 605 aas and 8 TMSs. |
Eukaryota | Metazoa, Arthropoda | Tmem8b of Daphnia pulex (Water flea) |
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1.N.2.1.6 | Tmem8a of 771 aas and 7 or more TMSs |
Eukaryota | Metazoa, Chordata | Tmem8a of Homo sapiens |
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1.N.2.1.7 | Tmem8b of 472 aas and 7 TMSs. May function as a regulator of the EGFR pathway. Probable tumor suppressor which may function in cell growth, proliferation and adhesion (Peng et al. 2006). |
Eukaryota | Metazoa, Chordata | Tmem8b of Homo sapiens |
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1.N.3.1.1 | Hapless 2, HAP-2 of 705 aas and 2 TMSs, one N-terminal and one near the C-terminus. More TMSs giving hydrophobic peaks of lesser size may be present. Essential for pollen tube guidance, successful gamete attachment and fertilization (von Besser et al. 2006; Mori et al. 2006; Wong et al. 2010). |
Eukaryota | Viridiplantae, Streptophyta | HAP-2 of Arabidopsis thaliana (Mouse-ear cress) |
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1.N.3.1.2 | HAP-2 of 952 aas with 2 or more TMSs (Steele and Dana 2009). |
Eukaryota | Metazoa, Porifera | HAP-2 of Amphimedon queenslandica (Sponge) |
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1.N.3.1.3 | Male gamete fusion factor, HAP-2 of 742 aas and at least 2 TMSs. HAP2 is expressed in all seven mating types of T. thermophila and fertility is only blocked when the gene is deleted from both cells of a mating pair. HAP2 deletion strains of complementary mating types can recognize one another and form pairs, but pair stability is compromised and membrane pore formation at the nuclear exchange junction is blocked (Cole et al. 2014). Cole et al. 2014 proposed a model in which each of the several hundred membrane pores established at the conjugation junction of mating Tetrahymena represents the equivalent of a male/female interface, and that pore formation is driven on both sides of the junction by the presence of HAP2. |
Eukaryota | Ciliophora | HAP-2 of Tetrahymena thermophila |
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1.N.3.1.4 | Uncharacterized protein of 821 aas and 2 TMSs. |
Eukaryota | UP of Vitrella brassicaformis
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1.N.3.1.5 | HAP2-B-like isoform X2 protein of 708 aas and 2 TMSs. |
Eukaryota | Metazoa, Arthropoda | HAP2-B of Parasteatoda tepidariorum (House spider) (Achaearanea tepidariorum) |
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1.N.3.1.6 | Hapless 2, HAP2 or GCS1 of 1139 aas and 1 TMS. HAP2, an Arabidopsis sterility protein, localizes at the fusion site of Chlamydomonas minus gametes and mediates formation of tight prefusion membrane attachments with their respective gamete partners (Fédry et al. 2017). Membrane dye experiments show that HAP2 is essential for membrane merger (Liu et al. 2008). This protein may be essential for gamete fusion in animals, plants, fungi and protists (Ning et al. 2013). X-ray crystallographic studies reveal homology to class II viral membrane fusion proteins. Targeting the segment corresponding to the fusion loop by mutagenesis or by antibodies blocks gamete fusion (Fédry et al. 2017). |
Eukaryota | Viridiplantae, Chlorophyta | HAP2 of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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1.N.3.1.7 | HAP2 of 812 aas and 1-3 TMSs. Functions in gamete fusion as does HAP2 in Chlamydomonas (TC# 1.N.3.6) (Liu et al. 2008; Fédry et al. 2017). |
Eukaryota | Apicomplexa | HAP2 of Plasmodium berghei |
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1.N.4.1.1 | EFF-1A of 658 aas and 2 TMSs, N- and C-terminal. Required for normal cell fusion. The EFF-1A endodomain is required for normal rates of EFF-1-dependent epidermal cell fusions (Shinn-Thomas et al. 2016). |
Eukaryota | Metazoa, Nematoda | EFF1A of Caenorhabditis elegans |
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1.N.4.1.2 | EFF-1B of 596 aas and 2 TMSs, N- and C-terminal (Kontani and Rothman 2005). |
Eukaryota | Metazoa, Nematoda | EFF-1B of Caenorhabditis elegans |
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1.N.4.1.3 | Myoblast syncytium formation protein generated by plasma membrane fusion of 852 aas and 4 - 5 TMSs. The roles of the major signaling pathways in mammalian myoblast fusion have been reviewed (Hindi et al. 2013).
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Eukaryota | Metazoa, Chordata | FFF protein of Branchiostoma floridae (Florida lancelet) (Amphioxus) |
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1.N.4.1.4 | Cell fusion protein, AFF-1 of 589 aas and 2 TMSs, one N-terminial and one C-terminal (Soulavie and Sundaram 2016). Required for cell fusion events during development including the fusion of anchor cells (AC), vulval A and vulval D rings, and late epidermal seam cells (Sapir et al. 2007). In response to environmental stressors, C. elegans enters a diapause state, termed dauer, which is accompanied by remodeling of sensory neuron receptive endings, dependent on AFF-1 (Procko et al. 2011). |
Eukaryota | Metazoa, Nematoda | AFF-1 of Caenorhabditis elegans |
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1.N.4.1.5 | Uncharacterized fusogen protein of 567 aas and 2 TMSs. |
Eukaryota | Metazoa, Nematoda | Putative fusogen of Trichinella spiralis (Trichina worm) |
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1.N.5.1.1 | Atlastin 1, ALT1, of 558 aas and 2 closely packed C-terminal TMSs (McNew et al. 2013). |
Eukaryota | Metazoa, Chordata | Atlastin 1 of Homo sapiens |
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1.N.5.1.2 | Atlastin of 541 aas and 2 TMSs near the C-terminus of the protein. It is a GTPase, tethering membranes through formation of trans-homooligomers and mediating homotypic fusion of endoplasmic reticulum membranes (Orso et al. 2009). It functions in endoplasmic reticulum tubular network biogenesis and may also regulate microtubule polymerization and Golgi biogenesis. It is required for dopaminergic neurons survival and the growth of muscles and synapses at neuromuscular junctions (Lee et al. 2009). |
Eukaryota | Metazoa, Arthropoda | Alastin of Drosophila melanogaster (Fruit fly) |
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1.N.5.1.3 | Atlastin of 968 aas and 1 or 2 TMSs, possibly one N-terminal TMS and one C-terminal TMS. |
Eukaryota | Atlastine of Blastocystis sp. |
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1.N.5.1.4 | Atlastin-1-like isoform X2 of 270 aas and 2 TMSs, one at residue 140 and one at residue 180. |
Eukaryota | Metazoa, Arthropoda | ATL1 of Varroa jacobsoni |
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1.N.5.1.5 | Atlastin homologue of 602 aas and 1 putative N-terminal TMS and 3 C-terminal TMSs. |
Eukaryota | Viridiplantae, Streptophyta | Putative Atlastin of Arabidopsis thaliana |
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1.N.5.1.6 | Sey1 of 776 aas and 2 C-terminal TMSs, possibly with 1 or 2 N-terminal TMS(s). It cooperates with the reticulon proteins RTN1 and RTN2 (see TC family 8.A.102) and the tubule-shaping DP1 family protein YOP1 to generate and maintain the structure of the tubular endoplasmic reticulum network. Has GTPase activity, which is required for its function in ER membrane fusion and reorganization (Hu et al. 2009; Hu and Rapoport 2016). Ergosterol interacts with Sey1p to promote atlastin-mediated endoplasmic reticulum membrane fusion (Lee et al. 2019).
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Eukaryota | Fungi, Ascomycota | Sey1 of Saccharomyces cerevisiae (Baker's yeast) |
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1.N.6.1.1 | The mitochondrial inner/outer membrane fusion complex, Fzo/Mgm1/Ugo1. Only the Ugo1 protein is a member of the MC superfamily, and PCD2 is a functional domain required for mitochondrial fusion. It has a single carrier domain (Coonrod et al. 2007). |
Eukaryota | Fungi, Ascomycota | The Fzo/Mgm1/Ugo1 complex of Saccharomyces cerevisiae |
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1.N.6.1.2 | The mammalian mitochondrial membrane fusion complex, Mitofusin 1/2 (Mfn1)/Mfn2/Optical Atrophy Protein 1 (OPA1) complex (the equivalent of the yeast Ugo1 protein)/dynamin-related protein 1 Drp1 (Chandhok et al. 2018). Mfn1 and Mfn2 are two very similar (60% identity) GTPase dynamin-like proteins in the outer mitochondrial membrane (members of the CDD P-loop[ NTPase Family) while OPA1 is a sequence divergent GTPase in the inner membrane (Chen and Chan, 2010). Mfn2 plays roles in mitochondrial fusion and mitochondrial endoplasmic reticulum interactions (Ranieri et al. 2013; Schneeberger et al. 2013). Mfn2, when defective can give rise to Charcot-Marie-Tooth disease, diabetes, neurodegenerative diseases, obesity and vascular diseases (Chandhok et al. 2018). It may also function in insulin-dependent myogenesis (Pawlikowska et al. 2007). Drp1 (DLP1, DNM1L) mediates membrane fusion and fission through oligomerization into membrane-associated tubular structures that wrap around the scission site to constrict and sever the mitochondrial membrane in a GTP hydrolysis-dependent mechanism (Smirnova et al. 2001; Taguchi et al. 2007). Sequences flanking the TMSs facilitate membrane fusion by mitofusin (Huang et al. 2017). Opa1 is a mitochondrial remodeling protein with a dual role in maintaining mitochondrial morphology and energetics by mediating inner membrane fusion and maintaining the cristae structure. This and the fusion/fission process by dynamins is described by Lee and Yoon 2018. MFN2 deficiency affects calcium homeostasis in lung adenocarcinoma cells via downregulation of UCP4 (Zhang et al. 2023). Inhibition of MFN1 restores tamoxifen-induced apoptosis in resistant cells by disrupting aberrant mitochondrial fusion dynamics (Song et al. 2024). Mfn2 regulates calcium homeostasis and suppresses PASMCs proliferation via interaction with IP3R3 to mitigate pulmonary arterial hypertension (Wang et al. 2025). |
Eukaryota | Metazoa, Chordata | Mfn1/Mfn2/OPA1/Drp1 complex of Homo sapiens |
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1.N.7.1.1 | Huntingtin-interacting protein 1, HIP1, of 1037 aas and one C-terminal TMS. It plays a role in clathrin-mediated endocytosis and trafficking (Waelter et al. 2001, Mishra et al. 2001, Legendre-Guillemin et al. 2002). It is involved in regulating AMPA receptor trafficking in the central nervous system in an NMDA-dependent manner, and it regulates presynaptic nerve terminal activity. |
Eukaryota | Metazoa, Chordata | HIP1 of Homo sapiens |
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1.P.1.1.1 | The SV40 ER membrane penitration complex involving the DnaJ-B12 protein of 375 aas and 1 TMS or the transmembrane J-protein B14 as well as Erlin1 (SPFH1; 346 aas and 1 TMS) and Erlin2 (SPFH2; 339 aas and 1 TMS) (Inoue and Tsai 2017). Kinesin-1 (KIF5B or KNS1) may serve as the motor (Ravindran et al. 2017). See family description for details. |
Eukaryota | Metazoa, Chordata | The SV40 penitration complex |
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1.Q.1.1.1 | Septal pore-associated proteins, SPA1 - 18 (Lai et al. 2012). Many SPA proteins (at least a dozen) are homologous to each other. |
Eukaryota | Fungi, Ascomycota | SPA1 - 18 of Neurospora crassa |
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1.R.1.1.1 | Membrane Contact Site (MCS). Functions include lipid and ion transport between organelles as well as organelle positioning and division (Wu et al. 2018). |
Eukaryota | Metazoa, Chordata | Membrane contact site (MCS) of Homo sapiens |
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1.R.1.1.2 | ATPase family AAA domain-containing protein 1 isoform 1, Msp1 or ATAD1, is a P5A-ATPase of 361 aas and 1 N-terminal TMS. It is a conserved eukaryotic AAA+ ATPase localized to the outer mitochondrial membrane, where it may extract mislocalized tail-anchored proteins (McKenna et al. 2020). Msp1's ATPase activity depends on its hexameric state. Castanzo et al. 2020 showed that Msp1 is a robust bidirectional protein translocase that is able to unfold diverse substrates by processive threading through its central pore. This unfoldase activity is inhibited by Pex3, a membrane protein proposed to regulate Msp1 at the peroxisome surface (Castanzo et al. 2020). This P5A-ATPase belongs to a eukaryotic-specific subfamily of P-type ATPases with previously unknown substrate specificity (McKenna et al. 2020). It interacts directly with mitochondrial tail-anchored proteins (McKenna et al. 2020). Msp1 (ATAD1 in mammals, also referred to as Thorase), can be found in the outer mitochondrial membrane and in peroxysomes as well as the ER (Dederer and Lemberg 2021). Structures of Spf1 (TC# 3.A.3.10.3) and this dismutase reveal how they remove mislocalized TA proteins from the ER and outer mitochondrial membranes, respectively (Sinning and McDowell 2022). |
Eukaryota | Metazoa, Chordata | Msp1 of Homo sapiens |
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1.R.1.1.3 | Outer mitochondrial transmembrane helix translocase, MSP1, of 362 aas and 1 N-terminal TMS. It is required to remove mislocalized tail-anchored transmembrane proteins in mitochondria (Li et al. 2019; Matsumoto et al. 2019). Its structure indicates how this is accomplished (Sinning and McDowell 2022; McDowell et al. 2023). |
Eukaryota | Fungi, Ascomycota | MSP1 of Saccharomyces cerevisiae |
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1.R.1.1.4 | Atad3 of Symbiodinium natans of 870 aas and up to 5 TMSs, about equally spaced throughout the length of the protein. ATPase family AAA domain containing protein 3, commonly known as ATAD3, is a versatile mitochondrial protein that is involved in a large number of pathways. ATAD3 is a transmembrane protein that spans both the inner mitochondrial membrane and outer mitochondrial membrane. It, therefore, functions as a connecting link between the mitochondrial lumen and the endoplasmic reticulum, facilitating their cross-talk. ATAD3 contains an N-terminal domain which is amphipathic in nature and is inserted into the membranous space of the mitochondria, while the C-terminal domain is present towards the lumen of the mitochondria and contains the ATPase domain. ATAD3 is known to be involved in mitochondrial biogenesis, cholesterol transport, hormone synthesis, apoptosis and several other pathways. It has also been implicated to be involved in cancer and many neurological disorders making it an interesting target for extensive studies. Goel and Kumar 2024 provided an updated comprehensive account of the role of ATAD3 in the mitochondria especially in lipid transport, mitochondrial-endoplasmic reticulum interactions, cancer and inhibition of mitophagy. |
Eukaryota | ATAD3 of Symbiodinium natans |
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1.R.1.1.5 | ATAD3 of Homo sapiens of 648 aas and possibly 2 TMS at residue 250 and at the C-terminus of the protein. |
Eukaryota | Metazoa, Chordata | ATAD3 of Homo sapiens |
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1.R.2.1.1 | The BLTP3B protein of 1464 aas and 0 - 2 TMSs. Also called the SHIP164 protein. BLTP3B or SHIP164 is of 1464 aas and 0 - 2 TMSs. It is a tube-forming lipid transport protein which mediates the transfer of lipids between membranes at organelle contact sites and is required for retrograde trafficing of vesicle clusters in the early endocytic pathway to the Golgi complex (Otto et al. 2010). Cellular membranes differ in protein and lipid compositions as well as in the protein-lipid ratio. Progression of membranous organelles along traffic routes requires mechanisms to control bilayer lipid chemistry and their abundance relative to proteins. Structural and functional characterization of VPS13-family proteins has suggested a mechanism through which lipids can be transferred in bulk from one membrane to another at membrane contact sites, and thus independently of vesicular traffic. Hanna et al. 2022 showed that SHIP164 (UHRF1BP1L) shares structural and lipid transfer properties with these proteins and is localized on a subpopulation of vesicle clusters in the early endocytic pathway whose membrane cargo includes the cation-independent mannose- 6-phosphate receptor (MPR). Loss of SHIP164 disrupts retrograde traffic of these organelles to the Golgi complex. These findings raise the possibility that bulk transfer of lipids to endocytic membranes may play a role in their traffic (Hanna et al. 2022). |
Eukaryota | Metazoa, Chordata | BLTP3B of Homo sapiens |
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1.R.2.1.2 | Bridge-like lipid transfer protein family member 3A, BLTP3A, of 1440 aas and 0 - 2 TMSs. |
Eukaryota | Metazoa, Chordata | BLTP3A of Homo sapiens |
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1.R.2.1.3 | Intermembrane lipid transfer protein Vps13A; Vacuolar protein sorting-associated protein 13A of 3373 aas. The Vps13-like protein BLTP2 is pro-survival and regulates phosphatidylethanolamine levels in the plasma membrane to maintain its fluidity and function (Banerjee et al. 2024). |
Eukaryota | Evosea | Vps13A of Dictyostelium discoideum |
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1.R.2.1.4 | Intermembrane lipid transfer protein, VPS13B, of 4022 aas. Mediates the transfer of lipids between membranes at organelle contact sites and binds phosphatidylinositol 3-phosphate. |
Eukaryota | Metazoa, Chordata | VPS13B of Homo sapiens |
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1.R.2.1.6 | The chorcin (VPS13A) protein of 3174 aas and possibly several central TMSs. See family description for details of its function. The N-terminal region shows appreciable sequence similarity with members of the APT family (TC#9.A.15). Erythroid differentiation is dependent on interactions of VPS13A with XK at the plasma membrane of K562 cells (Amos et al. 2023). |
Eukaryota | Metazoa, Chordata | Chorcin of Homo sapiens |
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1.S.1.1.1 | The PduA shell protein of 99 aas which forms a hexameric array with a pore in the array for diffusion of 1,2-propanediol but not propionaldehyde (Park et al. 2017). A serine that protrudes into the pore at the point of construction to form a hydrogen bond with propionaldehyde prevent it's free diffusion. Substrates enter these microcompartments by passing through the central pores in hexameric assemblies of shell proteins. Limiting the escape of toxic metabolic intermediates created inside the microcompartments confers a selective advantage for the host organism. The pore of the PduA hexamer has a lower energy barrier for passage of the propanediol substrate compared to the toxic propionaldehyde generated within the microcompartment (Park et al. 2017). PduA forms a selectively permeable pore tailored for the influx of 1,2-propanediol while restricting the efflux of propionaldehyde, a toxic intermediate of 1,2-propanediol catabolism (Chowdhury et al. 2015). The hexamer-hexamer interactions seen in PduA crystals persist in the cytoplasmic structures and reveal the profound influence of the two key amino acids, Lys-26 and Arg-79, on tiling, not only in the crystal lattice but also in the bacterial cytoplasm (Pang et al. 2014). There are several shell proteins, PduA and PduT being two of them, and their crystal structures have been determined (Crowley et al. 2010). PduA forms a symmetric homohexamer whose central pore appears tailored for facilitating transport of the 1,2-propanediol substrate. PduT is a novel, tandem domain shell protein that assembles as a pseudohexameric homotrimer. Its structure reveals an unexpected site for binding an [Fe-S] cluster at the center of the PduT pore (Crowley et al. 2010). The location of a metal redox cofactor in the pore of a shell protein suggests a novel mechanism for either transferring redox equivalents across the shell or for regenerating luminal [Fe-S] clusters.It is a minor shell protein of the Salmonella enterica microcompartment (BMC) dedicated to 1,2-propanediol (1,2-PD) degradation. The isolated BMC shell component protein ratio for J:A:B':B:K:T:U is approximately 15:10:7:6:1:1:2 (Crowley et al. 2010). PduJ is 89% identical to PduA; PduB is protein 1.S.2.1.2; PduU is protein 1.S.2.3.1 in TCDB. |
Bacteria | Pseudomonadota | PduA of Salmonella typhimurium |
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1.S.1.1.10 | ComK2 shell protein of 184 aas with 4 regions of mild hydrophobicity. It is a BMC-T protein (Faulkner et al. 2020). |
CcmK2 of Salmonella enterica subsp. enterica serovar Newport |
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1.S.1.1.11 | Cut BMC shell protein, CmcB, of 94 aas (Ochoa et al. 2023). This shell protein plays a major role in choline transport across the shell of the choline utilization microcompartment of Escherichia coli 536 (Ochoa et al. 2023). |
CmcB of E. coli |
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1.S.1.1.13 | Shell protein of 213 aas, an internal duplication of single domain proteins such as listed under TC#s 1.S.1.1.1 and 1.S.1.1.2, It shows 62 - 65 % identity with the latter two proteins. |
Bacteria | Myxococcota | Duplicated shell protein of Haliangium ochraceum |
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1.S.1.1.14 | Duplicated BMC domain-containing shell protein of 208 aas. |
Bacteria | Planctomycetota | Shell protein of Planctomycetaceae bacterium |
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1.S.1.1.2 | EutM pore-forming shell protein of 96 aas with most of the protein except the C-terminus showing substantial hydrophobicity. It is in the ethanolamine metabolizing Eut microcompartment (Takenoya et al. 2010). Compartmentalization prevents escape of volatile or toxic intermediates, prevents off-pathway reactions, and creates private cofactor pools. Encapsulation in synthetic microcompartment organelles enhances the function of heterologous pathways. To this end, Slininger Lee et al. 2017 explored how small differences in the shell protein structure result in changes in the diffusion of metabolites through the shell. The ethanolamine utilization (Eut) protein EutM properly incorporates into the 1,2-propanediol utilization (Pdu) microcompartment, altering native metabolite accumulation and the resulting growth on 1,2-propanediol as the sole carbon source. Further, we identified a single pore-lining residue mutation that confers the same phenotype as substitution of the full EutM protein, indicating that small molecule diffusion through the shell is the cause of growth enhancement. The hydropathy index and charge of pore amino acids are important indicators to predict how pore mutations affect growth on 1,2-propanediol, likely by controlling diffusion of one or more metabolites. This study highlights the use of two strategies to engineer microcompartments to control metabolite transport: altering the existing shell protein pore via mutation of the pore-lining residues, and generating chimeras using shell proteins with the desired pores (Slininger Lee et al. 2017). This is a BMC-H protein. |
Bacteria | Pseudomonadota | EutM of E. coli |
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1.S.1.1.3 | Uncharacterized carboxysome shell protein of 103 aas. The carboxysome shell is permeable to protons (Menon et al. 2010). |
Bacteria | Cyanobacteriota | UP of Nostoc sphaeroides |
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1.S.1.1.4 | BMC domain-containing protein of 185 aas. It has an internally duplicated domain of about 80 aas, corresponding to and homologous to the smaller (~90 residue) members of this family. |
Bacteria | Bacillota | BMC protein of Thermovenabulum gondwanense |
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1.S.1.1.5 | BMC domain-containing protein of 96 aas |
Bacteria | Actinomycetota | BMC protein of Amycolatopsis jejuensis |
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1.S.1.1.6 | Carbon dioxide-concentrating mechanism protein, CcmK, of 103 aas. |
Bacteria | Cyanobacteriota | CcmK of Leptolyngbya foveolarum (microbial mat metagenome) |
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1.S.1.1.7 | ComK1 of 111 aas, possibly with one N-terminal TMS. It is one of four Carboxysome shell proteins called ComK1 - 4, all of which are homologous to each other (Kerfeld et al. 2005). The structures of other proteins in the carboxysome have been solved structurally. These include CsoSCA (formerly CsoS3), a bacterial carbonic anhydrase localized in the shell of the carboxysome, where it converts HCO3- to CO2 for use in carbon fixation by ribulose-bisphosphate carboxylase/oxygenase (RuBisCO) (Sawaya et al. 2006). The carboxysome contains a viral capsid-like protein shell (see above) (Yeates et al. 2007) and a RuBisCO chaperone protein, RbcX (Tanaka et al. 2007). Atomic-level models of the bacterial carboxysome shell have been proposed (Tanaka et al. 2008). Molecular simulations have unraveled the molecular principles that mediate selective permeability of carboxysome shell proteins (Faulkner et al. 2020). |
Bacteria | Cyanobacteriota | CcmK1 of Synechocystis sp. PCC6803 |
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1.S.1.1.8 | CcmK3 shell protein of 102 aas. Heterohexamers formed by CcmK3 and CcmK4 increase the complexity of beta carboxysome shells (Sommer et al. 2019). |
Bacteria | Cyanobacteriota | CcmK3 of Synechococcus elongatus PCC7942 |
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1.S.1.1.9 | Carboxysome shell protein, CcmK4, of 113 aas. It is a minor shell protein component of the carboxysome, a polyhedral inclusion where RuBisCO is sequestered. The central pore probably regulates metabolite flux, as might the gaps between assembled homohexamers (Kerfeld et al. 2005). Homohexamers make sheets that probably form the facets of the polyhedral carboxysome (Dryden et al. 2009). This subunit probably makes both homohexamers and heterohexamers with CcmK3 (Sommer et al. 2019). Trettel et al. 2024 have summarized the properties of carboxysomes including the pore-forming shell protein subunits, ComK4, and considered how that can be useful for biotechnological purposes. They have also compared the shell proteins of carboxysomes with those of other metabolic compartments. Their models predict the biophysical properties surrounding the central pore in BMC-H shell subunits, which in turn dictate the efficiency of substrate diffusion (Trettel et al. 2024). |
Bacteria | Cyanobacteriota | CcmK4 of Synechococcus elongatus PCC7942 |
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1.S.10.1.1 | Nanocompartment encapsulin of 262 aas and 2 quite hydrophobic peaks at residues 40 and 155. The nanocompartment contains the dye-decolorizing peroxidase DyP. This nanocompartment is important for the ability of Mtb to resist oxidative stress in low pH environments, including during infection of host cells and upon treatment with a clinically relevant antibiotic (Lien et al. 2021). Shell component of a type 2A encapsulin nanocompartment. It forms nanocompartments about 24 nm in diameter from 60 monomers, and probably encapsulates at least cysteine desulfurase (CyD, Acc # O32975) and allows passage of cysteine into its interior, probably involved in sulfur metabolism. |
Bacteria | Actinomycetota | Encapsulin of Mycobacterium leprae |
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1.S.10.1.2 | Heavy metal-binding domain-containing protein of 411 aas. |
Bacteria | Pseudomonadota | HMBD protein of Legionella longbeachae serogroup 1 |
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1.S.10.1.3 | Heavy metal-binding domain-containing protein of 376 aas and containing an internal duplication, in which the first half (residues 1 - 130) and the second half (residues 131 - 343) are similar in sequence. |
Bacteria | Planctomycetota | HMBD protein of Singulisphaera acidiphila |
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1.S.11.1.1 | Encapsulin shell protein in a type 4 A-domain encapsulin nanocompartment system. Its size is 99 aas. Its cargo may be glyceraldehyde-3-phosphate dehydrogenase (AC P61879). |
Archaea | Euryarchaeota | EncP of Pyrococcus furiosus |
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1.S.11.1.2 | Encapsulin of 97 aas |
Archaea | Euryarchaeota | Esp of Thermococcus kodakarensis |
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1.S.11.1.3 | DUF1884 protein of 95 aas. |
Archaea | Euryarchaeota | DUF1884 protein of Pyrococcus furiosus |
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1.S.2.1.1 | The pore-forming shell protein, EutL, of 219 aas, of the bacterial ethanolamine-utilizing (ethanolamine ammonialyase )microcompartment (BMC) (Takenoya et al. 2010). The crystal structure has been described (Sagermann et al. 2009). It allows E. coli to use thanolamine as the sole source for carbon and nitrogen. The crystal structure of this shell protein at 2.2-Å resolution was determined. It is the largest representative of this BMC's shell proteins. In the crystal, EutL forms a trimer that exhibits a hexagonally shaped tile structure. The tiles arrange into a tightly packed 2D array that resembles the proteinaceous membrane of the intact BMC. In contrast to other BMC shell proteins, which have only 1 pore per tile, EutL exhibits 3 pores per tile, thereby significantly increasing the overall porosity of this protein membrane. Each of the individual pores is lined with negatively charged residues and aromatic residues that are proposed to facilitate passive transport of specific solutes. The characteristic shape of the hexagonal tile, which is also found in the microcompartments of carbon-fixating bacteria, may present an inherent and fundamental building unit that may provide a general explanation for the formation of differently sized microcompartments (Sagermann et al. 2009). Ethanolamine, the substrate of the Eut microcompartment, acts as a negative allosteric regulator of EutL pore opening (Thompson et al. 2015). Specifically, a series of X-ray crystal structures of EutL from Clostridium perfringens, along with equilibrium binding studies, revealed that ethanolamine binds to EutL at a site that exists in the closed-pore conformation and which is incompatible with opening of the large pore for cofactor transport. The allosteric mechanism proposed is consistent with the cofactor requirements of the Eut microcompartment, leading to a new model for EutL function (Thompson et al. 2015). |
Bacteria | Pseudomonadota | EutL of E. coli |
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1.S.2.1.2 | PduB shell protein of 270 aas of a propanediol utilization polyhedral body |
Bacteria | Pseudomonadota | PduB of Salmonella paratyphi C |
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1.S.2.1.3 | Trimeric bacterial microcompartment shell protein of 230 aas. The protein hydropathy plot shows 5 peaks moderate hydrophobicity that may be TMSs. Two bacterial microcompartment shell proteins [EtuA (ethanol utilization shell protein A) and EtuB] are encoded in the genome clustered with the genes for ethanol utilization. The function of the bacterial microcompartment is to facilitate fermentation by sequestering the enzymes, substrates and intermediates. Recent structural studies of bacterial microcompartment proteins have revealed both hexamers and pentamers that assemble to generate the pseudo-icosahedral bacterial microcompartment shell. Some of these shell proteins have pores on their symmetry axes. Heldt et al. 2009 reported the structure of the trimeric bacterial microcompartment protein EtuB, which has a tandem structural repeat within the subunit and pseudo-hexagonal symmetry. The pores in the EtuB trimer are within the subunits rather than between symmetry related subunits. The evolutionary advantage of this is that it releases the pore from the rotational symmetry constraint allowing more precise control of the fluxes of asymmetric molecules, such as ethanol, across the pore. EtuA was modeled suggesting that the two proteins have the potential to interact to generate the casing for a metabolosome (Heldt et al. 2009). |
Bacteria | Firmicute | EutB of Clostridium kluyveri |
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1.S.2.2.1 | Uncharacterized DUF692 domain-containing protein of 286 aas with a moderately hydrophobic profile, and with possibly 4 moderately hydrophobic peaks in the C-terminal half of the protein. It is not known if this is a shell protein, but it appears to be destantly related to some of them (e.g., the protein listed under TC# 1.S.2.1.1). |
Bacteria | Actinomycetota | UP of Nocardia grenadensis |
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1.S.2.3.1 | PduU shell protein of 116 aas. The hydropathy plot indicates two moderately hydrophobic peaks that may not be sufficiently hydrophobic to pass through the membrane. The Pdu microcompartment is a proteinaceous, subcellular structure that serves as an organelle for the metabolism of 1,2-propanediol in Salmonella enterica (Crowley et al. 2008). It encapsulates several related enzymes within a shell composed of a few thousand protein subunits. Structural studies on the carboxysome, a related microcompartment involved in CO2 fixation, have concluded that the major shell proteins from that microcompartment form hexamers that pack into layers comprising the facets of the shell. The crystal structure of PduU was determined. Though PduU is a hexamer like other characterized shell proteins, it has undergone a circular permutation leading to dramatic differences in the hexamer pore. In view of the hypothesis that microcompartment metabolites diffuse across the outer shell through these pores, the unique structure of PduU suggests the possibility of a special functional role (Crowley et al. 2008). |
Bacteria | Pseudomonadota | PduU of Salmonella enterica (typhimurium) |
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1.S.2.3.2 | The BMC-H or CutR: BMC shell protein of 116 aas. Sutter et al. 2019 have engineered a synthetic protein that consists of a tandem duplication of BMC-H connected by a short linker. The synthetic protein forms cyclic trimers that self-assemble to form a smaller (25 nm) icosahedral shell with gaps at the pentamer positions. When coexpressed in vivo with the pentamer fused to an affinity tag, complete icosahedral shells could be purified (Sutter et al. 2019). It is a minor shell protein of the choline degradation-specific bacterial microcompartment (BMC). Proteins such as this one with circularly permuted BMC domains may play a key role in conferring heterogeneity and flexibility in this BMC. |
Bacteria | Firmicutes | CutR of Streptococcus intermedius SK54 |
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1.S.3.1.1 | Carboxysome shell protein CcmP; (Carbon dioxide concentrating mechanism protein) of 213 aas and as many as 4 peaks of moderate hydrophobicity, in a 2 + 2 TMS arrangement, that could be TMSs. The crystal structure is known (see Larsson et al. 2017 and the family description for details). The structure of CcmP, a tandem bacterial microcompartment domain protein from a β-carboxysome, forms a subcompartment within a microcompartment (Cai et al. 2013). Carboxysomes, encoded by 10 genes, can be heterologously produced in E. coli. Expression of carboxysomes in E. coli resulted in the production of icosahedral complexes similar to those from the native host. In vivo, the complexes were capable of both assembling with carboxysomal proteins and fixing CO2. Characterization of purified synthetic carboxysomes indicated that they were well formed in structure, contained the expected molecular components, and were capable of fixing CO2 in vitro. In addition, the postulated pore-forming protein CsoS1D, may modulate function (Bonacci et al. 2012). |
Bacteria | Cyanobacteriota | CcmP of Synechococcus elongatus PCC 7942 |
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1.S.3.1.2 | Microcompartment protein, CcmP, of 212 aas. |
Bacteria | Cyanobacteriota | CcmP of Spirulina subsalsa |
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1.S.3.1.3 | CsoS1D of 213 aas and 4 moderately hydrophobic peaks in a 2 + 2 TMS arrangement. It is a pore-forming protein in a cyanobacterial carboxysome, and it modulates the function of this enclosed protein machinary (Bonacci et al. 2012). |
Bacteria | Cyanobacteriota | CsoS1D of Microcystis aeruginosa |
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1.S.4.1.1 | Grp shell protein, GrpU, of 107 aas with 2 mildly hydrophobic regions centered at residues 40 and 75. See family description for details of this iron-sulfur cluster-containing protein (Thompson et al. 2014). |
Bacteria | Pseudomonadota | GrpU of Pectobacterium parmentieri |
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1.S.5.1.1 | CcmL shell protein of cyanobacterial carboxysomes, The protein is of 99 aas with two very moderately hydrophobic regions, the larger N-terminal region, and the shorter C-terminal region. It probably forms vertices in the carboxysome, a polyhedral inclusion where RuBisCO (ribulose bisphosphate carboxylase, rbcL-rbcS) is sequestered. It has been modeled to induce curvature upon insertion into an otherwise flat hexagonal molecular layer of CcmK subunits (Cameron et al. 2013). |
Bacteria | Cyanobacteriota | CcmL of Synechococcus elongatus (ATCC33912); also called Anacystis nodulans (R2)
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1.S.5.1.2 | EutN (CchB) shell protein of the ethanolamine utilization microcompartiment. It is of 99 aas with a broad region of hydrophobicity throughout the N-terminal regioni, and a shorter but more hydrophobic region at the C-terminus. It has been described by (Kinney et al. 2011). The ethanolamine (EA) catabolic bacterial microcompartment (BMC) probably concentrates low levels of ethanolamine catabolic enzymes, concentrates volatile reaction intermediates, keeps the level of toxic acetaldehyde low, generates enough acetyl-CoA to support cell growth, and maintains a pool of free coenzyme A (CoA) and NAD (Brinsmade et al. 2005; Kofoid et al. 1999). |
Bacteria | Pseudomonadota | EutN of Salmonella enterica (subtype Typhimurium) |
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1.S.6.1.1 | Encapsulin of 259 aas and probably no TMSs, but 4 evenly spaced short regions of moderate hydrophobicity. The protein has been described by Sutter et al. 2008. Williams et al. 2018 redesigned the pore-forming loop region in encapsulin from Thermotoga maritima, and successfully enlarged the pore diameter up to an estimated 11 Å and increased mass transport rates by 7-fold. A 2.87 Å resolution cryo-EM structure has been determined (Xiong et al. 2020). It has the viral capsid protein-HK97-fold. |
Bacteria | Thermotogota | Encapsulin of Thermotoga maritima |
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1.S.6.1.2 | Encapsulin shell protein, Enc or Cfp29, of 265 aas. |
Bacteria | Actinomycetota | Enc of Mycobacterium tuberculosis |
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1.S.6.1.3 | The encapsulin shell protein of 280 aas with four equidistant peaks of moderate hydrophobicity. This encapsulin nanocompartment protein is formed by 60 subunits; monomers form pentamers which assemble to form shells. There are 12 pores where the pentamers meet as well as 3-fold axis channels and dimer channels; none are larger than 3-4 Angstroms in diameter. The N-terminus of the protein is inside the shell, the C-terminus is outside (He et al. 2016). The shell component is for a type 1 encapsulin nanocompartment. It assembles into proteinaceous icosahedral shells 24 nm in diameter in the presence and absence of its ferritin cargo protein. The center of cargo-loaded nanocompartments is loaded with iron. The empty encapsulin nanocompartment sequesters about 2200 Fe ions while the cargo-loaded nanocompartment can maximally sequester about 4150 Fe ions. It does not have detectable ferroxidase activity (He et al. 2016). |
Bacteria | Pseudomonadota | Encapsulin of Rhodospirillum rubrum |
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1.S.7.1.1 | Encapsulin nanocompartment cargo protein EncC of 130 aas. |
Bacteria | Myxococcota | Encapsulin of Myxococcus xanthus |
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1.S.7.1.2 | Encapsulin B, EncB, of 158 aas and 0 TMSs. |
Bacteria | Myxococcota | EncB of Myxococcus xanthus |
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1.S.7.1.3 | Ferritin-like-encapsulin shell fusion protein, EncP1, of 345 aas is a fusion of the shell and cargo protein of a type 1 encapsulin nanocompartment (Akita et al. 2007). The nanocompartment is probably involved in iron storage. Expression in E. coli generates spherical particles about 30 nm in diameter (Namba et al. 2005). The purified N-terminus has ferroxidase activity (He et al. 2019). |
Archaea | Euryarchaeota | Encapsulin of Pyrococcus furiosus |
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1.S.7.1.4 | Encapsulated ferritin-like protein, Fer, of 131 aas and a moderately hydrophilic character throughout its sequence. It may function in iron transport and storage. |
Bacteria | Myxococcota | Fer of Haliangium ochraceum |
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1.S.7.1.5 | Type 1 encapsulin shell protein of 287 aas, EncA. This protein has the viral capsid protein, HK97-fold.
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Bacteria | Myxococcota | EncA of Myxococcus xanthus |
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1.S.8.1.1 | Type 2A encapsulin shell protein SrpI (SynE7) of 306 aas. See fanily description for details (Nichols et al. 2021). |
Bacteria | Cyanobacteriota | SrpI of Synechococcus elongatus PCC 7942 |
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1.S.8.1.2 | Encapsulin of 307 aas, a type 2A encapsulin shell protein, EncP2 It forms encapsulin nanocompartments about 24 nm in diameter from 60 monomers. Probably encapsulates at least cysteine desulfurase (CyD, AC O32975) and allows passage of cysteine into its interior, probably involved in sulfur metabolism (Triccas et al. 1996). |
Bacteria | Actinomycetota | EncP2 of Mycobacterium leprae |
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1.S.8.1.3 | Type 2A encapsulin shell protein of 303 aas. The protein has two halves, the N-terminal domain is uniformly hydrophilic while the C-terminal domain contains 4 short regions of moderate hydrophobicity.
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Bacteria | Pseudomonadota | Encapsulin of Hyphomicrobium nitrativoran |
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1.S.9.1.1 | EncD is a cargo protein of a type 1 encapsulin nanocompartment. It may help nucleate Fe atoms in the interior of the encapsulin nanocompartment. and is present in about 47 copies/encapsulin nanocompartment (McHugh et al. 2014). The encapsulin and a cargo construct (an encB-encC-encD fusion) can be overexpressed in E. coli and in human HEK293T cells. In HEK293T in the presence of 0.5 M ferrous ammonium sulfate (Sigmund et al. 2019). |
Bacteria | Myxococcota | EncD of Myxococcus xanthus |
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1.S.9.1.2 | Uncharacterized protein of 112 aas |
Bacteria | Myxococcota | UP of Thermococcus kodakarensis |
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1.S.9.1.3 | Uncharacterized protein of 90 aas. |
Bacteria | Myxococcota | UP of Pyxidicoccus fallax |
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1.S.9.2.1 | Uncharacterized protein of 309 aas. |
Eukaryota | UP of Aureococcus anophagefferens (Harmful bloom alga) |
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1.V.1.1.1 | Cyanobacterial septa (also called microplasmodesmata) between vegetative cells and between vegetative cells and N2-fixing heterocysts that appear to include at least 3 proteins: SepJ, which is a member of the DMT superfamily (2.A.7.3.81) and seems to transport acidic amino acids and other hydrophilic amino acids, as well as FraC, and FraD which seem to be cyanobacterium-specific (Nürnberg et al. 2015). FraC and FraD each have 4 or 5 and 5 TMSs, respectively, and are encoded in a single operon, fraCDE. The septa have a mean diameter of about 7 - 8 nm with varying numbers of nanopores (holes in the peptidoglycan) (Flores et al. 2018). Each septa has a cap and a cyanophycin plug as well as a cytoplasmic membrane-anchored tube crossing the intercellular space between cells. The AmiC amidase may drill holes in the peptidoglycan druing septal biogenesis to generate the nanopores. The septa can transport a variety of sugars, amino acids, peptides and 5-carboxyflorescein. Proteins that affect nanopore formation include the product of the alr3353 gene (SjcF1; 760 aas; a peptidoglycan binding protein LytM-like factor) which is homologous to B. subtilis proteins in gap junction-like structures (TC# 1.A.34.1.1-3) and the SpoIIA-SpoQ2 complex (TC# 9.B.70.1.1) (Flores et al. 2018). |
Bacteria | Cyanobacteriota | The septum proteins, FraC, FraD and SepJ of Anabaena (Nostoc) sp. strain PCC 7120 |
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1.V.1.1.2 | FraCD/SepJ with FraC of 172 aas with 4 TMSs, FraD of 193 aas with 5 TMSs, and SepJ (DUF6) of 566 aas with 10 C-terminal TMSs and a long N-terminal hydrophilic domain. |
Bacteria | Cyanobacteriota | FraCD/SepJ of Arthrospira platensis (Spirulina platensis) |
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1.V.1.1.3 | FraCD/SepJ; FraC, 194 aas with 4 or 5 TMSs; FraD, 180 aas with 4 TMSs; and SepJ, 431 aas with 10 TMSs. SepJ is a DMT superfamiy member. |
Bacteria | Cyanobacteriota | FraCD/SepJ of Roseofilum reptotaenium |
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1.W.1.1.1 | Samonella phage P22 portal protein 1 of 725 aas and no TMSs. It forms a dodecameric ring structure and plays an important role in ejection of the phage DNA, through the cell envelope, into the host cell cytoplasm (Lokareddy et al. 2017). See family description for more details. |
Viruses | Heunggongvirae, Uroviricota | Portal protein of Salmonella phage P22 |
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1.W.1.1.2 | Phage portal protein of 703 aas. |
Viruses | Heunggongvirae, Uroviricota | PP of EBPR podovirus 1 |
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1.W.1.1.3 | Phage portal protein of 623 aas |
Bacteria | Pseudomonadota | Portal protein of Bartonella alsatica |
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1.W.1.1.4 | Portal protein of 749 aas |
Bacteria | Pseudomonadota | PP of Comamonas testosteroni |
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1.W.1.1.5 | Coil containing protein of 696 aa |
Viruses | Heunggongvirae, Uroviricota | Coil-containing protein of Vibrio phage 1.205.O. |
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1.W.1.1.6 | Putative phage portal protein of 701 aa |
Viruses | PPP of a prokaryotic dsDNA virus |
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1.W.1.1.7 | Uncharacterized protein of 697 aas |
Bacteria | Pseudomonadota | UP of Tatlockia micdadei |
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1.W.1.1.8 | Portal protein p19 of 750 aas. This protein reveals good extensive similarity with other members of the subfamily with TC#s 1.W.1.1, but also with the hydrophilic domain of TC# 1.W.1.2.1 (e-11). The N-terminal hydrophobic domain is lacking in this protein. |
Bacteria | Pseudomonadota | PP of Acinetobacter harbinensis |
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1.W.1.1.9 | Uncharacterized protein of 613 aas. |
Bacteria | Fibrobacterota | UP of Fibrobacter sp. UWP2 |
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1.W.10.1.1 | Head-tail connector (Escherichia phage T7 gene product 8) portal protein of 536 aa |
Viruses | Heunggongvirae, Uroviricota | PPP of Escherichia phage T7 |
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1.W.10.1.2 | Bacteriophage head to tail connecting portal protein |
Bacteria | Pseudomonadota | PPP of Roseomonas stagni |
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1.W.10.1.3 | Phage head-tail adapter portal protein of 553 aas |
Bacteria | Pseudomonadota | PPP of Oxalobacteraceae bacterium |
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1.W.10.1.5 | Uncharacterized protein of 560 aas |
Bacteria | Spirochaetota | UP of Treponema denticola |
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1.W.10.1.6 | Uncharacterized protein of 556 aas |
Bacteria | Pseudomonadota | UP of Aminobacter aminovorans |
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1.W.10.2.1 | Uncharacterized protein of 517 aa |
Bacteria | Fusobacteriota | UP of Fusobacterium varium |
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1.W.10.2.2 | Uncharacterized protein of 505 aas |
Archaea | Candidatus Thermoplasmatota | UP of Thermoplasmata archaeon |
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1.W.10.3.1 | Phage portal protein of 651 aas from a freshwater cyanophage Pf-WMP3, Infecting the cyanobacterium, Phormidium foveolarum (Liu et al. 2008). |
Viruses | Heunggongvirae, Uroviricota | PPP of Phormidium virus WMP3 |
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1.W.10.3.2 | Head-to-tail joining portal protein of 582 aas |
Viruses | Heunggongvirae, Uroviricota | PP of Vibrio phage 1.235.O._10N.261.52.B2 |
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1.W.10.3.3 | Uncharacterized protein of 688 aas |
Bacteria | Actinomycetota | UP of Acidimicrobiaceae bacterium |
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1.W.10.3.4 | Phage portal protein of 702 aas |
Viruses | Heunggongvirae, Uroviricota | PPP of Sinorhizobium phage phiM6 |
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1.W.2.1.1 | Phage T5 portal protein of 403 aas (Huet et al. 2016). It forms the portal vertex of the capsid and plays a role in governing correct capsid geometry. This portal plays critical roles in capsid assembly, genome packaging, head completion protein attachment, and genome ejection. The portal protein multimerizes as a single ring-shaped homododecamer arranged around a central channel (By similarity). It binds to the terminase subunits to form the packaging machine (Huet et al. 2016). |
Viruses | Heunggongvirae, Uroviricota | Portal protein of E. coli bacteriophage T5 |
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1.W.2.1.10 | Phage portal protein of 658 aa |
Bacteria | Deinococcota | Phage portal protein of Deinococcus actinosclerus |
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1.W.2.1.11 | The (potential) pore-forming minor capsid protein of B. subtilis phage SPP1, gp7 of 308 aas and 0 putative TMSs (Vinga et al. 2006). See family description for details. |
Viruses | Heunggongvirae, Uroviricota | Gp7 of Bacillus subtilis phage, SPP1. (Q38442) |
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1.W.2.1.12 | Phage head morphogenesis, SPP1 gp7 family domain protein of 460 aas and 0 TMSs. |
Bacillota | Gp7 of Clostridioides difficile |
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1.W.2.1.13 | Uncharacterized protein of 814 aas |
Bacteria | Actinomycetota | UP of Nocardia cyriacigeorgica |
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1.W.2.1.14 | Minor capsid protein of 475 aa |
Bacteria | Pseudomonadota | Capsid protein of Haemophilus influenzae |
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1.W.2.1.15 | Minor capsid protein of766 aa |
Viruses | Heunggongvirae, Uroviricota | Capsid protein of Gordonia phage Tangent |
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1.W.2.1.16 | Uncharacterized protein of 359 aas and 1 N-terminal TMS |
Bacteria | Bacillota | UP of Macrococcus canis |
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1.W.2.1.17 | Uncharacterized protein of 503 aas |
Bacteria | Bacteroidota | UP of Rudanella sp. |
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1.W.2.1.18 | Uncharacterized protein of 538 aas |
Viruses | Heunggongvirae, Uroviricota | UP of uncultured Mediterranean phage uvMED |
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1.W.2.1.19 | Uncharacterized protein of 1030 aas |
Archaea | UP of Candidatus Pacearchaeota archaeon (marine metagenome) |
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1.W.2.1.2 | Phage portal protein of 426 aas. The third gene upstream from the protease gene encodes the portal protein for phage HK97. The presence of the portal protein is not required for assembly of the capsid protein in this system (Duda et al. 1995). |
Bacteria | Pseudomonadota | PPP of Vibrio parahaemolyticus phage HK97 |
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1.W.2.1.20 | Uncharacterized protein of 341 aas |
Bacteria | Pseudomonadota | UP of Oceaniglobus sp. YLY08 |
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1.W.2.1.21 | Phage head morphogenesis protein of 298 aa |
Bacteria | Pseudomonadota | Morphogenesis protein of E. coli |
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1.W.2.1.3 | Phage portal protein of 416 aa |
Bacteria | Bacillota | PPP of Clostridium botulinum |
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1.W.2.1.4 | Uncharacterized protein of 414 aas |
Bacteria | Armatimonadota | UP of Armatimonadetes bacterium CP1_7O (hot springs metagenome) |
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1.W.2.1.5 | Phage portal protein of 469 aa |
Bacteria | Actinomycetota | PPP of Bifidobacterium longum |
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1.W.2.1.6 | HK97 family phage portal protein of 418 aa |
Bacteria | Fusobacteriota | PPP of Fusobacterium nucleatum |
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1.W.2.1.7 | Phage portal protein of 433 aa |
Bacteria | Chlorobiota | PPP of Chlorobi bacterium OLB5 |
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1.W.2.1.8 | Uncharacterized protein of 455 aas |
Bacteria | Campylobacterota | UP of Sulfuricurvum sp. MLSB (wastewater metagenome) |
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1.W.2.1.9 | Uncharacterized protein sk1p04 of 378 aas |
Viruses | Heunggongvirae, Uroviricota | UP of Lactococcus virus sk1 |
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1.W.3.1.1 | Phage P2 portal protein of 344 aas (Rishovd et al. 1994). |
Viruses | Heunggongvirae, Uroviricota | PPP of Escherichia phage P2 (Bacteriophage P2) |
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1.W.3.1.2 | Putative phage portal protein of 354 aas |
Bacteria | Campylobacterota | PPP of Campylobacter fetus |
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1.W.3.1.3 | Phage portal protein of 406 aas |
Bacteria | Pseudomonadota | PPP of Candidatus Lambdaproteobacteria bacterium (subsurface metagenome) |
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1.W.3.1.4 | Putative phage portal protein of 481 aas. |
Bacteria | Bacillota | PPP of Geobacillus thermodenitrificans |
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1.W.3.1.5 | Phage portal protein of 560 aa |
Viruses | Heunggongvirae, Uroviricota | PPP of Nonlabens phage |
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1.W.3.1.6 | Phage portal protein of 432 aa |
Bacteria | Calditrichota | PPP of Caldithrix abyssi |
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1.W.3.1.7 | Streptomyces phage portal protein of 511 aas |
Viruses | Heunggongvirae, Uroviricota | PPP of Streptomyces phage Jay2Jay |
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1.W.3.1.8 | Uncharacterized protein of 395 aas |
Bacteria | Candidatus Cloacimonadota | UP of Candidatus Cloacimonas sp. SDB (marine sediment metagenome) |
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1.W.3.1.9 | Phage portal protein of 523 aas |
Bacteria | Actinomycetota | PPP of Streptomyces aureus |
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1.W.3.2.1 | Uncharacterized protein of 374 aas |
Archaea | Candidatus Woesearchaeota | UP of Candidatus Woesearchaeota archaeon (marine sediment metagenome) |
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1.W.3.2.2 | Uncharacterized protein of 405 aas |
Archaea | Euryarchaeota | UP of Candidatus Methanoperedens nitroreducens |
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1.W.3.2.3 | Phage portal protein of 648 aa |
Viruses | Heunggongvirae, Uroviricota | PPP of Bacillus phage 0305phi8-36 |
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1.W.3.2.4 | Uncharacterized protein DRN04_13085 of 461 aas |
Archaea | Thermoproteota | UP of Thermoprotei archaeon |
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1.W.3.2.5 | Uncharacterized protein of 528 aas |
Archaea | Candidatus Hydrothermarchaeota | UP of Candidatus Hydrothermarchaeota archaeon (marine sediment metagenome) |
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1.W.3.2.6 | Phage portal protein of 526 aas |
Bacteria | Thermodesulfobacteriota | PPP of Desulfosarcina alkanivorans |
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1.W.4.1.1 | UL6 portal protein of 676 aas for entry of DNA into the viral capsid (Newcomb et al. 2001). |
Viruses | Heunggongvirae, Peploviricota | UL6 portal protein of Human herpesvirus 1 (strain 17) (HHV-1) (Human herpes simplex virus 1) |
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1.W.4.1.2 | Uncharacterized viral protein of 503 aas Human betaherpesvirus 6 (HHV-6) |
Viruses | Heunggongvirae, Peploviricota | UP of Human β-herpesvirus 6 (HHV-6) |
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1.W.4.1.3 | TSC22 domain family protein 2 isoform X3 of 583 aa |
Eukaryota | Metazoa, Chordata | TSC22 protein of Oryzias latipes |
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1.W.4.1.4 | Capsid portal protein of 712 aas |
Viruses | Herpesvirales | PP of Psittacid herpesvirus 5 |
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1.W.4.1.5 | Uncharacterized protein of 441 aas. This protein is annotated as a partial sequence from a bacterium. Several fragmentary proteins from bacteria are present in the NCBI protein database that are homologous with the members of this family. Whether these are errors or valid fragments from the sources indicated by the annotations has not been determined. |
Bacteria | Actinomycetota | UP of Cellulomonas oligotrophica |
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1.W.4.1.6 | ORF43 portal protein of 605 aas. It forms a portal in the viral capsid through which viral DNA is translocated during DNA packaging. It assembles as a dodecamer at a single fivefold axe of the T=16 icosahedric capsid and binds to the molecular motor that translocates the viral DNA, termed terminase, The KSHV icosahedral capsid includes a portal vertex, composed of 12 protein subunits encoded by open reading frame (ORF) 43, which enables packaging and release of the viral genome into the nucleus through the nuclear pore complex (NPC) (Dünn-Kittenplon et al. 2021). ORF43 enables packaging and release of the viral genome into the nucleus through the nuclear pore complex (NPC). Capsid vertex-specific component (CVSC) tegument proteins, which directly mediate docking at the NPCs, are organized on the capsid vertices and are enriched on the portal vertex. The portal vertex of KSHV promotes docking of capsids at nuclear pores (Dünn-Kittenplon et al. 2021). The tegument proteins (e.g., E5LBZ1) directly mediates docking at the NPC. |
Viruses | Heunggongvirae, Peploviricota | ORF43 portal protein of Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus) |
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1.W.4.2.1 | VP4 protein of 642 aas |
Viruses | Orthornavirae, Duplornaviricota | VP4 of african horse sickness virus |
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1.W.5.1.1 | The E. coli phage lambda portal protein (PPP) of 533 aas. See family description for the characteristics of this protein. |
Viruses | Heunggongvirae, Uroviricota | PPP of E. coli phage lambda |
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1.W.5.1.2 | Phage portal protein of 552 aa |
Bacteria | Pseudomonadota | PPP of Pseudomonas fluorescens |
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1.W.5.1.3 | Phage portal protein [ of 528 aas and possibly C-terminal TMSs. |
Bacteria | Pseudomonadota | PPP of Bradyrhizobium sp. RP6 |
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1.W.5.1.4 | Phage portal protein of 497 aa |
Bacteria | Pseudomonadota | PPP of Pseudomethylobacillus aquaticus |
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1.W.5.1.5 | Phage portal protein of 502 aas |
Bacteria | Bacillota | PPP of Clostridium symbiosum |
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1.W.5.1.6 | Phage portal protein of 454 aas |
Bacteria | Pseudomonadota | PPP of Sulfitobacter guttiformis |
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1.W.5.1.7 | Phage portal protein of 473 aas |
Bacteria | Planctomycetota | PPP of Planctomycetes bacterium (freshwater metagenome) |
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1.W.5.1.8 | Phage portal protein of 599 aas |
Archaea | PPP of Candidatus Pacearchaeota archaeon (marine metagenome) |
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1.W.5.1.9 | Phage portal protein of 570 aas. This protein is homologous to protein in TC subclass 1.W.7.8. |
Bacteria | Thermodesulfobacteriota | PPP of Mailhella massiliensis |
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1.W.6.1.1 | The Bacillus phage phi29 (φ29) portal protein of 309 aas. It forms the portal vertex of the capsid (Ibarra et al. 2000; Fu and Prevelige 2009; Grimes et al. 2011). This portal plays roles in head assembly, genome packaging, neck/tail attachment, and genome ejection. The portal protein multimerizes as a single ring-shaped homododecamer arranged around a central channel (Guasch et al. 2002, Grimes et al. 2011). It binds to the 6 packaging RNA molecules (pRNA), forming a double-ring structure which in turn binds to the ATPase gp16 hexamer, forming the active DNA-translocating motor (Xiao et al. 2005, Simpson et al. 2000). This complex is essential for the specificity of packaging from the left DNA end. |
Viruses | Heunggongvirae, Uroviricota | PPP of Bacillus phage phi29 |
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1.W.6.1.2 | Uncharacterized protein of 358 aas |
Bacteria | Candidatus Melainabacteria | UP of Candidatus Melainabacteria bacterium (human gut metagenome) |
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1.W.6.1.3 | Capsid and scaffold protein of 344 aa |
Viruses | Heunggongvirae, Uroviricota | Capsid protein of Enterococcus phage vB_EfaP_Efmus1 |
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1.W.6.2.1 | Uncharacterized protein of 309 aas |
Bacteria | Mycoplasmatota | UP of endosymbiont GvMRE |
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1.W.6.2.2 | Uncharacterized protein of 310 aas |
Bacteria | Mycoplasmatota | UP of endosymbiont GvMRE of Glomus versiforme |
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1.W.6.3.1 | Uncharacterized protein of 334 aas |
Bacteria | Mycoplasmatota | UP of Mycoplasmataceae bacterium CE_OT135 (symbiont metagenome) |
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1.W.6.3.2 | Uncharacterized protein of 306 aas |
Bacteria | Mycoplasmatota | UP of endosymbiont DhMRE of Dentiscutata heterogama |
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1.W.6.3.3 | Uncharacterized protein of 275 aas |
Eukaryota | Fungi, Ascomycota | UP of Terfezia boudieri |
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1.W.6.4.1 | Uncharacterized protein of 700 aas |
Eukaryota | Fungi, Ascomycota | UP of Pseudogymnoascus verrucosus |
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1.W.6.4.2 | Uncharacterized protein of 643 aas |
Eukaryota | Fungi, Basidiomycota | UP of Kalmanozyma brasiliensis |
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1.W.7.1.1 | Bacillus phage SPP1 portal protein of 503 aa |
Viruses | Heunggongvirae, Uroviricota | PPP of Bacillus phage SPP1 |
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1.W.7.1.2 | Phage portal protein of 474 aas |
Bacteria | Bacillota | PPP of Staphylococcus aureus |
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1.W.7.1.3 | Phage portal protein of 515 aas |
Bacteria | Bacillota | PPP of Weissella cibaria |
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1.W.7.1.4 | Page portal protein of 523 aas |
Bacteria | Bacillota | PPP of unclassified Lactonifactor |
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1.W.7.1.5 | Phage portal protein of 441 aa |
Bacteria | Bacillota | PPP of Domibacillus antri |
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1.W.7.2.1 | Phage portal protein of 497 aas |
Bacteria | Bacteroidota | PPP of Sphingobacterium deserti |
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1.W.7.2.2 | Phage portal protein of 456 aas |
Bacteria | Bacteroidota | PPP of Apibacter mensalis |
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1.W.7.2.3 | Portal protein of 479 aas |
Bacteria | Bacteroidetes | PPP of Flavobacterium spartansii |
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1.W.7.2.4 | Phage portal protein of 506 aas |
Bacteria | Bacteroidota | PPP of Odoribacter sp. |
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1.W.7.2.5 | Phage portal protein of 523 aa |
Bacteria | Chloroflexota | PPP of Dehalococcoides mccartyi |
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1.W.7.2.6 | Portal protein of 470 aa |
Bacteria | Pseudomonadota | PP of Komagataeibacter xylinus |
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1.W.7.2.7 | Uncharacterized protein of 535 aas |
Bacteria | Chloroflexota | UP of Chloroflexi bacterium RBG_19FT_COMBO_48_23 (subsurface metagenome) |
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1.W.7.3.1 | Phage portal protein of 473 aas |
Bacteria | Actinomycetota | PPP of Streptomyces sp. |
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1.W.7.3.2 | Phage portal protein of 464 aa |
Bacteria | Actinomycetota | PPP of Cellulomonas iranensis |
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1.W.7.3.3 | Phage portal protein of 480 aa |
Bacteria | Actinomycetota | PPP of Bifidobacterium animalis |
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1.W.7.3.4 | Phage portal protein of 501 aa |
Bacteria | Bacillota | PPP of Sporosarcina koreensis |
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1.W.7.3.5 | Phage portal protein of 445 aa |
Bacteria | Actinomycetota | PPP of Cutibacterium sp. |
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1.W.7.3.6 | Phage portal protein of 465 aa |
Viruses | Heunggongvirae, Uroviricota | PPP of Microbacterium phage Teagan |
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1.W.7.3.7 | Phage portal protein of 486 aas |
Viruses | Heunggongvirae, Uroviricota | PPP of Mycobacterium phage L5 (Mycobacteriophage L5) |
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1.W.7.4.1 | Putative portal protein of 435 aas |
Bacteria | Pseudomonadota | PPP of Sulfitobacter sp. HI0129 |
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1.W.7.4.2 | Uncharacterized protein of 558 aas |
Bacteria | Pseudomonadota | UP of Yangia sp. CCB-MM3 |
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1.W.7.4.3 | Site-specific integrase of 576 aa |
Bacteria | Pseudomonadota | Recombinase of Roseovarius aestuariivivens |
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1.W.7.5.1 | Uncharacterized protein of 460 aas |
Bacteria | Pseudomonadota | UP of Chromobacterium haemolyticum |
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1.W.7.5.2 | Uncharacterized protein of 485 aas |
Bacteria | Calditrichota | UP of Calditrichaeota bacterium (freshwater sediment metagenome) |
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1.W.7.5.3 | Uncharacterized protein of 474 aas |
Archaea | UP of Candidatus Pacearchaeota archaeon (groundwater metagenome) |
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1.W.7.7.1 | Uncharacterized protein of 470 aas |
Bacteria | Bacillota | UP of Acidaminococcus fermentans |
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1.W.7.7.2 | DUF4055 domain-containing protein [ of 465 aa |
Bacteria | Pseudomonadota | DUF4055 protein of Glaesserella parasuis |
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1.W.7.7.3 | DUF4055 domain-containing protein of 492 aa |
Bacteria | Myxococcota | DUF4055 protein of Polyangium spumosum |
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1.W.7.7.4 | Uncharacterized protein of 537 aas |
Bacteria | Planctomycetota | UP of Planctomyces sp. SH-PL62 |
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1.W.7.7.5 | Uncharacterized protein of 503 aas |
Bacteria | Cyanobacteriota | UP of Cyanobium sp. |
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1.W.7.7.6 | DUF4055 domain-containing protein of 479 aa |
Bacteria | Pseudomonadota | DUF4055 protein of Ensifer sojae |
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1.W.7.8.1 | Uncharacterized protein of 584 aas |
Archaea | UP of Candidatus Pacearchaeota archaeon (marine metagenome) |
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1.W.7.8.2 | Uncharacterized protein of 591 aas |
Archaea | UP of Candidatus Pacearchaeota archaeon (marine metagenome) |
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1.W.7.8.3 | DUF1073 domain-containing protein of 560 aa |
Bacteria | Pseudomonadota | DUF1073 protein of Xenorhabdus bovienii |
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1.W.7.8.4 | Phage portal protein of 602 aa |
Bacteria | Bacillota | PPP of Listeria monocytogenes |
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1.W.8.1.1 | The (Enterobacterial phage T4) Portal Protein, gp20, of 524 aa |
Viruses | Heunggongvirae, Uroviricota | gp20 of Enterobacterial phage T4 |
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1.W.8.1.10 | Uncharacterized protein of 647 aas |
Bacteria | Pseudomonadota | UP of Hyphomicrobiaceae bacterium |
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1.W.8.1.2 | Phage portal vertex protein of 731 aa |
Viruses | Heunggongvirae, Uroviricota | PPP of Bacillus phage AR9 |
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1.W.8.1.3 | Vertex protein of head of 534 aa |
Viruses | Heunggongvirae, Uroviricota | Vertex protein of Bacillus phage vB_BceM-HSE3 |
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1.W.8.1.4 | Uncharacterized protein of 582 aas |
Bacteria | Bacteroidota | UP of Bacteroidetes bacterium HGW-Bacteroidetes-1 (groundwater metagenome) |
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1.W.8.1.5 | Similar to portal vertex protein of head of 533 aa |
Viruses | Heunggongvirae, Uroviricota | UP of Rhodothermus phage RM378 |
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1.W.8.1.7 | Uncharacterized bacteriophage T4-like capsid assembly protein (Gp20 of 1011 aas |
Archaea | UP of uncultured archaeon |
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1.W.8.1.8 | Portal vertex protein of 577 aa |
Viruses | Heunggongvirae, Uroviricota | PPP of Tenacibaculum phage PTm1 |
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1.W.8.1.9 | Uncharacterized protein of 471 aas |
Archaea | Euryarchaeota | UP of Thermococci archaeon |
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1.W.9.1.1 | Vortex phage mu portal protein of 512 aas |
Viruses | Heunggongvirae, Uroviricota | PPP of E. coli phage Mu |
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1.W.9.1.10 | Uncharacterized structural protein of 498 aas |
Viruses | Heunggongvirae, Uroviricota | UP of Curvibacter phage P26059A |
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1.W.9.1.11 | Portal protein of 472 aa |
Viruses | Heunggongvirae, Uroviricota | PP of Arthrobacter phage KBurrousTX |
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1.W.9.1.12 | DUF935 protein of 452 aas |
Bacteria | Planctomycetota | DUF935 protein of Planctomycetes bacterium Pla85_3_4 |
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1.W.9.1.13 | Portal protein of 448 aas. The structure is known (PDB entries 4ZJN and 5NGD) |
Viruses | Heunggongvirae, Uroviricota | PPP of Thermus virus P74-26 |
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1.W.9.1.14 | DUF935 family protein of 584 aas. This protein shows significant sequence similarity to members of 1.W.5, 1.W.7 as well as other members of 1.W.9. |
Bacteria | Myxococcota | DUF935 protein of Sandaracinus amylolyticus |
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1.W.9.1.15 | DUF935 family protein of 429 aa |
Bacteria | Campylobacterota | DUF935 family protein of Campylobacter corcagiensis |
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1.W.9.1.16 | DUF935 family protein of 731 aas. This protein shows sequence similarity with TC#s 1.W.9.3.1 and 4.1. |
Bacteria | Atribacterota | DUF935 protein of Candidatus Atribacteria bacterium |
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1.W.9.1.2 | The DUF935 family protein (phage portal protein) of 487 aas |
Viruses | Heunggongvirae, Uroviricota | DUF935 protein of Meiothermus phage MMP7 |
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1.W.9.1.3 | Uncharacterized protein of 401 aas |
Bacteria | Spirochaetota | UP of Spirochaetia bacterium |
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1.W.9.1.4 | DUF935 family protein of 1036 aa |
Bacteria | Bacteroidota | DUF935 putative portal protein of Hymenobacter nivis |
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1.W.9.1.5 | DUF935 family protein of 467 aa |
Bacteria | Campylobacterota | DUF935 protein of Sulfurospirillum cavolei |
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1.W.9.1.6 | DUF935 protein of 509 aas |
Bacteria | Verrucomicrobiota | DUF935 protein of Puniceicoccaceae bacterium |
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1.W.9.1.7 | DUF935 protein of 416 aas |
Bacteria | Spirochaetota | DUF935 protein of Treponema phagedenis |
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1.W.9.1.8 | DUF935 protein of 617 aas |
Bacteria | Campylobacterota | DUF935 protein of Desulfurellales bacterium |
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1.W.9.1.9 | DUF935 famiy protein of 557 aas |
Bacteria | Atribacterota | DUF935 protein of Candidatus Atribacteria bacterium |
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1.W.9.2.1 | Uncharacterized protein of 408 aas |
Bacteria | Chloroflexota | UP of Chloroflexi bacterium |
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1.W.9.2.2 | Uncharacterized protein of 433 aas |
Bacteria | Acidobacteriota | UP of Bryobacterales bacterium, Solibacterales bacterium (sediment metagenome) |
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1.W.9.3.1 | Portal protein of 589 aas |
Viruses | Heunggongvirae, Uroviricota | PP of Gordonia phage RobinSparkles |
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1.W.9.4.1 | Uncharacterized protein of 340 aas |
Bacteria | Candidatus Rokubacteria | UP of Candidatus Rokubacteria bacterium (groundwater metagenome) |
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1.X.1.1.1 | The Intraflagellar transporter (IFT) multiprotein complex. WD repeat-containing protein 35 of 1181 aas and possibly as many as 7 or 8 TMSs. It is a component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs). It is thus involved in ciliogenesis and ciliary protein trafficking (Takahara et al. 2018) (see the family description). Many other proteins play a role as constituents of the IFT complex, and some of these (but not all of them) are listed under this TC# (Lechtreck 2022). |
Eukaryota | Metazoa, Chordata | IFT complex of Homo sapiens |
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1.X.1.1.2 | The sensory ciliary function underlying hearing in the adult fly requires an active maintenance program which involves DmIFT88 and at least two of its signalling transmembrane cargoes, DmGucy2d and Inactive (Werner et al. 2024). |
Eukaryota | Metazoa, Arthropoda | Complex of three proteins of Drosophila melanogaster |
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1.X.1.1.3 | Intraflagellar transport protein complex of several proteins, IFT52, of 426 aas and possibly 1 TMS at about residue 180; IFT57, of 429 aas; IFT43, of 208 aas; IFT46, of 301 aas, and IFT20, of 132 aas (Reddy Palicharla and Mukhopadhyay 2024). See 1.X.1.1.1 for description. |
Eukaryota | Metazoa, Chordata | IFT complex of Mus musculus |
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2.A.1.1.1 | Galactose:H+ symporter, GalP. Also transports glucose, xylose, fucose (6-deoxygalactose), 2-deoxygalactose and 2-deoxyglucose) (Henderson and Giddens 1977; Henderson et al. 1977; Hernández-Montalvo et al., 2001). Relative substrate affinities of wild-type and mutant forms of the E. coli sugar transporter GalP have been determined by solid-state NMR (Patching et al., 2008). GalP may exist as a trimer with each subunit having a sugar transporting channel (Zheng et al. 2010). |
Bacteria | Pseudomonadota | GalP of E. coli (P0AEP1) |
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2.A.1.1.10 | Maltotriose/maltose:H+ symporter, Mal6T or Mal61 (Dietvorst et al. 2005). The orthologue (90% identical) in Saccharomyces pastorianus (Lager yeast) (Saccharomyces cerevisiae x Saccharomyces eubayanus), MTT1 or Mty1 of 615 aas, has higher affinity for maltotriose than maltose (Magalhães et al. 2016). |
Eukaryota | Fungi, Ascomycota | MAL6 of Saccharomyces cerevisiae |
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2.A.1.1.100 | Probable metabolite transport protein YFL040W | Eukaryota | Fungi, Ascomycota | YFL040W of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.101 | Probable metabolite transport protein YDR387C | Eukaryota | Fungi, Ascomycota | YDR387C of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.102 | Plastidic glucose transporter 4 (AtpGlcT) | Eukaryota | Viridiplantae, Streptophyta | At5g16150 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.103 | D-xylose-proton symporter-like 3, chloroplastic | Eukaryota | Viridiplantae, Streptophyta | At5g59250 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.104 | Myo-inositol transporter 2 | Eukaryota | Fungi, Ascomycota | ITR2 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.105 | Hexose transporter HXT11 (Low-affinity glucose transporter LGT3) | Eukaryota | Fungi, Ascomycota | HXT11 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.106 | Probable metabolite transport protein CsbC | Bacteria | Bacillota | CsbC of Bacillus subtilis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.107 | Hexose transporter HXT15 | Eukaryota | Fungi, Ascomycota | HXT15 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.108 | Low-affinity glucose transporter HXT1 of 570 aas and 12 TMSs. Substitutions of equivalent salt bridge-forming residues in Hxt1, Rgt2, and Glut4 are predicted to lock them in an inward-facing conformation but lead to different functional consequences. The salt bridge networks in yeast and human glucose transporters and yeast glucose receptors may play different roles in maintaining their structural and functional integrity (Kim et al. 2023). |
Eukaryota | Fungi, Ascomycota | HXT1 of Saccharomyces cerevisiae |
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2.A.1.1.109 | Hexose transporter HXT14 | Eukaryota | Fungi, Ascomycota | HXT14 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.11 | General α-glucoside:H+ symporter, Gtr3, Mal11,Mal1T, Mtp1 or Agt1 . (Substrates include trehalose, maltotriose, maltose, turanose, isomaltose, α-methyl-glucoside, maltotriose, palatinose, and melezitose) (Smit et al., 2008). Maltotriose is transported with higher affinity than maltose (Magalhães et al. 2016). |
Eukaryota | Fungi, Ascomycota | AGT1 of Saccharomyces cerevisiae |
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2.A.1.1.110 | Hexose transporter HXT13 | Eukaryota | Fungi, Ascomycota | HXT13 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.111 | High-affinity glucose transporter HXT2. Asp340 and Asn331 in part determine the high glucose affinity (Kasahara et al. 2007; Kasahara and Kasahara 2010). |
Eukaryota | Fungi, Ascomycota | HXT2 of Saccharomyces cerevisiae |
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2.A.1.1.112 | High-affinity glucose transporter Ght1 (Hexose transporter 1) | Eukaryota | Fungi, Ascomycota | Ght1 of Schizosaccharomyces pombe | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.113 | Putative metabolite transport protein YyaJ |
Bacteria | Bacillota | YyaJ of Bacillus subtilis |
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2.A.1.1.114 | Putative metabolite transport protein YaaU |
Bacteria | Pseudomonadota | YaaU of Escherichia coli |
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2.A.1.1.115 | Putative metabolite transport protein YdjK |
Bacteria | Pseudomonadota | YdjK of Escherichia coli |
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2.A.1.1.116 | Arabinose/xylose transporter, AraE (Wang et al. 2013). |
Bacteria | Actinomycetota | AraE of Coynebacterium glutamicum |
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2.A.1.1.117 | Glucose transporter Rco-3 or MoST1. MoST1 plays a specific role in conidiation and mycelial melanization which is not shared by other hexose transporter family members in M. oryzae (Saitoh et al. 2013). |
Eukaryota | Fungi, Ascomycota | MoST1 of Magnaporthe oryzae |
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2.A.1.1.118 | MFS porter of 435 aas |
Archaea | Thermoproteota | MFS porter of Sulfolobus solfataricus |
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2.A.1.1.119 | The galacturonic acid (galacturonate) uptake porter, GatA, of 518 aas and 12 TMSs (Sloothaak et al. 2014). |
Eukaryota | Fungi, Ascomycota | GatA of Aspergillus niger |
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2.A.1.1.12 | Glucose uniporter, Glut3 (also transports dehydro-ascorbate; Maulén et al., 2003). Down-regulated in the brains of Alzheimer's disease patients (Liu et al., 2008b). The structure of the human orthologue with D-glucose bound was solved at 1.5 Å resolution in the outward occluded conformation (Deng et al. 2015). Sugars are predominantly coordinated by polar residues in the C-terminal domain. The conformational transition from the outward-open to the outward-occluded states entails a prominent local rearrangement of the extracellular part of TMS 7. Comparison of the outward-facing GLUT3 structures with inward-open GLUT1 provides insight into the alternating access cycle for GLUTs, whereby the C-terminal domain provides the primary substrate-binding site and the N-terminal domain undergoes rigid-body rotation with respect to the C-terminal domain (Deng et al. 2015). Glut3 is involved in several disease states in humans (Lechermeier et al. 2019). Resveratrol and soy isoflavones alone and in combination improve the learning and memory of aging rats. The mechanism may be related to up-regulating the expression of GLUT1 and GLUT3 genes and proteins in the hippocampus (Zhang et al. 2020). |
Eukaryota | Metazoa, Chordata | Gtr3 (Glut3) of Rattus norvegicus (rat) |
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2.A.1.1.120 | Major myo-inositol transporter, IolT1, of 456 aas (Kröger et al. 2010). |
Bacteria | Pseudomonadota | IolT1 of Samonella enterica |
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2.A.1.1.121 | Minor myo-inositol transporter, IolT2, of 478 aas (Kröger et al. 2010). |
Bacteria | Pseudomonadota | IolT2 of Salmonella enterica |
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2.A.1.1.122 | Sorbitol (glucitol):H+ co-transporter, SOT2 (Km for sorbitol of 0.81 mM) of 491 aas and 12 TMSs (Gao et al. 2003). SOT2 of Prunus cerasus is mainly expressed only early in fruit development and not in leaves (Gao et al. 2003). |
Eukaryota | Viridiplantae, Streptophyta | SOT2 of Pyrus pyrifolia (Chinese pear) (Pyrus serotina) |
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2.A.1.1.123 | Sorbitol (D-Glucitol):H+ co-transporter, SOT1 (Km for sorbitol of 0.64 mM) of 509 aas and 12 TMSs (Gao et al. 2003). SOT1 of P. cerasus is expressed throughout fruit development, but especially when growth and sorbitol accumulation rates are highest. In leaves, PcSOT1 expression is highest in young, expanding tissues, but substantially less in mature leaves (Gao et al. 2003). |
Eukaryota | Viridiplantae, Streptophyta | SOT1 of Prunus salicina |
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2.A.1.1.124 | The high affinity sugar:H+ symporter (sugar uptake) porter of 514 aas and 12 TMSs, STP10. It transports glucose, galactose and mannose, and is therefore a hexose transporter (Rottmann et al. 2016). The 2.4 Å structure with glucose bound has been solved, explaining high affinity sugar recognition (Paulsen et al. 2019). The results suggest a proton donor/acceptor pair that links sugar transport to proton translocation. It contains a Lid domain, conserved in all sugar transport proteins, that locks the mobile transmembrane domains through a disulfide bridge, and creates a protected environment which allows efficient coupling of the proton gradient to drive sugar uptake (Paulsen et al. 2019). |
Eukaryota | Viridiplantae, Streptophyta | STP10 of Arabidopsis thaliana |
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2.A.1.1.125 | Glycerol:H+ symporter of 530 aas and 12 TMSs, GT1. It is essnetial for the glycerol repression of the alcohol oxidase 1 (AOX1 gene (Zhan et al. 2016), and plays a role in glycerol and methanol metabolism in Pichia pastoris (Li et al. 2017). . |
Eukaryota | Fungi, Ascomycota | GT1 of Komagataella pastoris (Yeast) (Pichia pastoris) |
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2.A.1.1.126 | Myo inositol uptake porter of 574 aas and 12 TMSs, Fst1. Also takes up the polyketide mycotoxin produced by Fusarium verticillioides during the colonization of maize kernels, Fumonisin B1 (FB1). The activity was demonstrated with the orthologue in Weissella verticillioides (Niu et al. 2016). |
Eukaryota | Fungi, Ascomycota | Fst1 of Weissella confusa |
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2.A.1.1.127 | Hexose:proton symporter of 525 aas and 12 TMSs, Hxt5. Takes up D-glucose, D-fructose, D-xylose, D-mannose, D-galactose with decreasing affinity in this order (Rani et al. 2016). |
Eukaryota | Fungi, Basidiomycota | Hxt5 of Piriformospora indica |
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2.A.1.1.128 | Facilitative (Na+-independent) glucose-specific transporter (Km = 3 mM) of 486 aas and 12 TMSs, HT1; inhibited by cytochalasin B and localized to the midgut (Price et al. 2007). |
Eukaryota | Metazoa, Arthropoda | HT1 of Nilaparvata lugens (Brown planthopper) |
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2.A.1.1.129 | High-capacity facilitative transporter for
trehalose, TRET1, required to induce anhydrobiosis. Anhydrobiotic larvae can
survive almost complete dehydration. Does not transport maltose, sucrose
or lactose. Transports trehalose synthesized in the fat body
and incorporates trehalose into other tissues that require a
carbon source, thereby regulating trehalose levels in the hemolymph (Kikawada et al. 2007; Kanamori et al. 2010). 70% identical to the Drosophila homologue, TC# 2.a.1.1.99. |
Eukaryota | Metazoa, Arthropoda | TRET1 of Polypedilum vanderplanki (Sleeping chironomid) |
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2.A.1.1.13 | Fructose uniporter, GLUT5. The proteins from rat and cow have been crystalized and their structures have been determined in the open outward- and open inward-facing conformations, respectively. On the basis of comparisons of the inward-facing structures of GLUT5 and human GLUT1, a ubiquitous glucose transporter, a single point mutation proved to be enough to switch the substrate-binding preference from fructose to glucose. A comparison of the substrate-free structures of GLUT5 with occluded substrate-bound structures of E. coli XylE suggested that, in addition to a global rocker-switch-like re-orientation of the bundles, local asymmetric rearrangements of carboxy-terminal transmembrane bundle helices, TM7 and TM10, underlie a 'gated-pore' transport mechanism (Nomura et al. 2015). GLUT5 is preferentially used for fructose uptake under (near) anoxic glycolysis to avoid feedback inhibition of phosphofructokinase (Park et al. 2017). Residues involved in fructose recognition have been identified (Ebert et al. 2017). Glucose (Glut-1 and 3) and fructose (Glut-2 and 5) transporter expression and regulation in the hummingbird occur independently of each other (Ali et al. 2020). Complex plastic mechanisms allow adaptation to environmental changes (Huang et al. 2023). C-3 modified 2,5-anhydromannitol (2,5-AM) compounds are inhibitory D-fructose analogues (Rana et al. 2023). Discrimination of GLUTs by fructose isomers enables simultaneous screening of GLUT5 and GLUT2 activities in live cells (Gora et al. 2023). It may play a role in tumorigenesis (Hadzi-Petrushev et al. 2024).
|
Eukaryota | Metazoa, Chordata | SLC2A5 of Homo sapiens |
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2.A.1.1.130 | Glucose transporter 1, GLUT1 or Slc2A1 of 491 aas and 12 TMSs. Expression occurs in the mesodermal region of Xenopus embryos, especially in the dorsal blastopore lip at the gastrula stage. It is an important player during gastrulation cell movement (Suzawa et al. 2007). This system is required for hepatocellular carcinoma proliferation and metastasis (Fang et al. 2021). |
Eukaryota | Metazoa, Chordata | GLUT1 of Xenopus laevis (African clawed frog) |
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2.A.1.1.131 | Myo-inositol-specific uptake transporter, ITR1 of 509 aas and 12 TMSs. The Km for myo-inositol is about 1 mM; glucose and other inositols are apparently not transported (Cushion et al. 2016). |
Eukaryota | Fungi, Ascomycota | ITR1 of Pneumocystis carinii |
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2.A.1.1.132 | Bloom1 of 524 aas and 12 TMSs in a 6 + 6 arrangement. Mutations in the encoding gene give rise to shiny soybean seads with increased amounts of oil (Zhang et al. 2018). This protein is 50% identical to the sorbitol transporter of Prunus salicina (TC# 2.A.1.1.123). |
Eukaryota | Viridiplantae, Streptophyta | Bloom1 of Glycine max (Soybean) (Glycine hispida) (Glycine soja) |
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2.A.1.1.133 | Facilitative glucose transporter, GLUT2 of 503 aas and 12 TMSs. Evidence suggests that the blunt snout bream is able to regulate its ability to metabolize glucose by improving GLUT2, GK, and PK expression levels (Liang et al. 2018). The ortholog in grass carp (Ctenopharyngodon idellus) is exactly the same size and 98% identical throughout its length. It is found in the anterior and mid intestine as well as the liver (Liang et al. 2020). |
Eukaryota | Metazoa, Chordata | GLUT2 of Megalobrama amblycephala (Chinese blunt snout bream) (Brema carp) |
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2.A.1.1.134 | Sugar (mannose, fructose, glucose, galactose xylose) transporter of 521 aas and 12 TMSs, STP2 (Liu et al. 2018). |
Eukaryota | Viridiplantae, Streptophyta | STP2 of Manihot esculenta (Cassava) (Jatropha manihot) |
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2.A.1.1.135 | Galactose-specific uptake porter of 515 aas and 12 TMSs, STP16 (Liu et al. 2018). |
Eukaryota | Viridiplantae, Streptophyta | STP16 of Manihot esculenta (Cassava) (Jatropha manihot) |
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2.A.1.1.136 | Monosaccharide uptake porter of 529 aas and 12 TMSs, STP7. Transports mannose, galactose, glucose and fructose, but not xylose (Liu et al. 2018). |
Eukaryota | Viridiplantae, Streptophyta | STP7 of Manihot esculenta (Cassava) (Jatropha manihot) |
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2.A.1.1.137 | Glycerol:H+ symporter,WaStl1, of 561 aas and 12 TMSs. WaStl1 is a concentrative glycerol-H+ symporter with twice the affinity of S. cerevisiae. It is repressed by glucose and derepressed/induced by glycerol. This yeast, aerobically growing on glycerol, was found to produce ethanol, providing a redox escape to compensate the redox imbalance at the level of cyanide-resistant respiration (CRR) and glycerol 3P shuttle (da Cunha et al. 2019). |
Eukaryota | Fungi, Ascomycota | Glycerol porter of Wickerhamomyces anomalus |
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2.A.1.1.138 | Maltose permease, HPMAL2, of 582 aas and 12 TMSs in a 1 + 5 + 6 TMS arrangement. Expression of both of the adjacent HPMAL1 and HPMAL2 genes is coordinately regulated, repressed by glucose, and induced by maltose (Viigand et al. 2005). |
Eukaryota | Fungi, Ascomycota | MAL2 of Pichia angusta (Yeast) (Hansenula polymorpha) |
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2.A.1.1.139 | Glut3 or Slc2a3a of 541 aas and 12 TMSs. Transcript analysis of zebrafish GLUT3 genes, slc2a3a and slc2a3b, have define overlapping as well as distinct expression domains in the central nervous system (Lechermeier et al. 2019). |
Eukaryota | Metazoa, Chordata | Glut3 of Danio rerio |
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2.A.1.1.14 | Hexose:H+ symporter of 534 aas and 12 TMSs. Substrate accumulation can be up to 1500-fold; one proton is symporter per hexose taken up. Helices I, V, VII and XI interact with the sugar during translocation and line the transport path through the membrane (Tanner 2000). |
Eukaryota | Viridiplantae, Chlorophyta | Hup1 of Chlorella kessleri |
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2.A.1.1.140 | Cellodextrin transporter, CtA or CDT-1, of 535 aas and 12 TMSs. It transports cellobiose, cellotriose, cellotetraose and cellopeptaose, and its synthesis is induced by degradation products of cellulose (Lin et al., Feb. 2020, Identification and Characterization of a Cellodextrin Transporter in Aspergillus niger). It is 37% identical to the N crassa protein of the same specificity (TC# 2.A.1.1.82). |
Eukaryota | Fungi, Ascomycota | CtA of Aspergillus niger |
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2.A.1.1.141 | Lactose permease of 533 aas and 12 TMSs; 45% identical to 2.A.1.1.140 (Havukainen et al. 2020). |
Eukaryota | Fungi, Ascomycota | Lactose permease of Aspergillus nidulans |
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2.A.1.1.142 | MFS-type cellodextrin transporter, CdtG, of 538 aas and 12 TMSs (Havukainen et al. 2020). |
Eukaryota | Fungi, Ascomycota | CdtG of Penicillium sp. 2HH |
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2.A.1.1.145 | Plant MFS porter of 521 aas and 12 TMSs. This system affects nutrient minerals concentrations in wheat grains and showed a pleiotropic effect on Ca2+, K+, Mg2+, Mn2+, and Sulfur (Alomari et al. 2021). In view of its association with sugar uptake porters, we suggest that it is a sugar transporter, and sugar uptake increases the energy of the grains so as to stimulate elemental ion uptake. |
Eukaryota | Viridiplantae, Streptophyta | MFS porter of Triticum aestivum (bread wheat) |
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2.A.1.1.146 | MFS-type sugar/inositol transporter of 510 aas and 12 TMSs. An orthologous system has been shown to be a highly specific L-arabinose transporter from Trichoderma reesei (Havukainen et al. 2021). Considering the high affinity for L-arabinose and low inhibition by D-glucose or D-xylose, Trire2_104072 could serve as a good candidate for improving the existing pentose-utilizing yeast strains (Havukainen et al. 2021). |
Eukaryota | Fungi, Ascomycota | L-Arabinose transporter of Penicillium sp. |
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2.A.1.1.147 | MFS glucose transporter, Mfs1, of 550 aas and 12 TMSs. It is required for sugar transport, oxidative stress resistance, and pathogenicity of Colletotrichum gloeosporioides in Hevea brasiliensis (Liu et al. 2021). C. gloeosporioides is the causal agent of anthracnose in various plant species. |
Eukaryota | Fungi, Ascomycota | Mfs1 of Colletotrichum gloeosporioides |
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2.A.1.1.148 | Glucose transporter 1, GLUT1, of 500 aas and 12 TMSs. EgGLUT1 Is crucial for the viability of Echinococcus granulosus sensu stricto metacestode and may be a new therapeutic target (Amahong et al. 2021). |
Eukaryota | Metazoa, Platyhelminthes | GLUT1 of Echinococcus granulosus |
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2.A.1.1.149 | High affinity hexose transporter, HxtA of 531 aas and 12 TMSs. HxtA is induced in vegetative hyphae upon starvation and in ascogenous hyphae during cleistothecium formation (Wei et al. 2004). |
Eukaryota | Fungi, Ascomycota | HxtA of Emericella nidulans (Aspergillus nidulans) |
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2.A.1.1.15 | Putative sugar transporter | Archaea | Thermoproteota | Porter of Sulfolobus solfataricus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.150 | Hexose transporter-like protein, GCR1, of 541 aas and 12 TMSs. Substrates include glucose, mannose and fructose. It functions in catabolite repression (as does Snf3p in S. cerevisiae (TC# 2.A.1.1.18)) of peroxisome biogenesis and of peroxisomal enzymes (Stasyk et al. 2004). |
Eukaryota | Fungi, Ascomycota | GCR1 of Ogataea polymorpha (Hansenula polymorpha) |
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2.A.1.1.151 | Facilitated trehalose transporter, Tret1-like, of 485 aas and 12 TMSs in a 6 + 6 TMS arrangement. Trehalose is the main blood sugar in insects and plays an important role in energy metabolism and stress resistance. Plutella xylostella (L.) is an agricultural pest worldwide. Tret1-like was cloned, knoched out and studied (Zhou et al. 2022). It was found that expression of the gene encoding PxTret1-like was affected by ambient temperature. A knockout mutation of PxTret1-like was generated, and the trehalose content and trehalase activity of the mutant increased at different developmental stages. The trehalose content increased in the fat body of the fourth-instar and decreased in the hemolymph. There was no significant change in glucose in the fat body and hemolymph. Mutant deletion strains of P. xylostella showed a significantly reduced survival rate, fecundity and ability to withstand extreme temperatures. Thus, PxTret1-like could affect the development, reproduction and temperature adaptability of P. xylostella by regulating the trehalose content in the fat body and hemolymph (Zhou et al. 2022). |
Eukaryota | Metazoa, Arthropoda | Tret1-like transporter of Plutella xylostella |
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2.A.1.1.152 | INT7 of 504 aas and 12 TMSs in a 6 + 6 TMS pattern. There are nine INT homologues in Populus trichocarpa, all presumed to transport inositor, and they are involved in stress responses (Zhang et al. 2023).
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Eukaryota | Viridiplantae, Streptophyta | INT7 of Populus alba x Populus glandulosa |
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2.A.1.1.154 | Solute carrier family 2, facilitated glucose transporter member 8 of 509 aas and 12 TMSs. Symbiotic cnidarians such as corals and anemones form highly productive and biodiverse coral reef ecosystems in nutrient-poor ocean environments, a phenomenon known as Darwin's paradox (Cui et al. 2023). Using the sea anemone Aiptasia, we show that during symbiosis, the increased availability of glucose and the presence of the algae jointly induce the coordinated up-regulation and relocalization of glucose and ammonium transporters. These molecular responses are critical to support symbiont functioning and organism-wide nitrogen assimilation through glutamine synthetase/glutamate synthase-mediated amino acid biosynthesis (Cui et al. 2023). |
Eukaryota | Metazoa, Cnidaria | Glucose transporter of Exaiptasia diaphana |
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2.A.1.1.155 | Sugar transporter ERD6-like 4 of 496 aas and 12 TMSs. Vacuolar sugar transporter EARLY RESPONSE TO DEHYDRATION 6-LIKE4 affects fructose signaling and plant growth (Khan et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | ERD6-like 4 of Triticum aestivum |
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2.A.1.1.157 | Putative sugar uptake transporter of 456 aas and 18 TMSs in a 6 + 6 + 6 TMS arrangement. This protein has an N-terminal 6 TMSs that are not related to the MFS transporters, but the last 12 TMSs are homologous to members of MFS family 2.A.1.1. The N-terminal 6 TMSs are not related to sequences of the MFS but are homologous to members of the |
Bacteria | Bacteroidota | MFS transporter of Alistipes sp. HGB5
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2.A.1.1.158 | Plastid glucose transporter 2, pGlcT2, of 493 aas and 12 TMSs. pGlcT2-GFP localized to the chloroplast envelope and is mainly produced in seedlings and in the rosette centers of mature Arabidopsis plants. Therefore, pGlcT2 acts as a glucose importer that can limit cytosolic glucose availability in developing pGlcT2-overexpressing seedlings (Valifard et al. 2023). Possibly pGlcT2 contributes to a release of glucose derived from starch mobilization late in the light phase. |
Eukaryota | Viridiplantae, Streptophyta | pGlcT2 of Arabidopsis thaliana |
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2.A.1.1.159 | Solute carrier family 2, facilitated glucose transporter member 1a, Glut1 of 488 aas and 12 TMSs. Bisphenol S inhibits Glucose Transporter 1, leading to ATP excitotoxicity in the Zebrafish brain (Wang et al. 2024). |
Eukaryota | Metazoa, Chordata | GLUT1 of Danio rerio |
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2.A.1.1.16 | Low-affinity hexose (glucose, fructose, mannose, 2-deoxyglucose) uniporter. The evolution of hexose transporters in kinetoplastid protozoans has been studied (Pereira and Silber 2012). |
Eukaryota | Euglenozoa | Gtr2 (D2) of Leishmania donovani |
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2.A.1.1.160 | L-Arabinose high specificity and affinity uptake transporter of 514 aas and 12 TMSs in a 6 + 6 TMS arrangement. The system has low affinity for D-xylose and almost no affinity for D-glucose. It has use for bioengineering purposes (Havukainen et al. 2021). Due to its high affinity for L-arabinose and low inhibition by D-glucose or D-xylose, Trire2_104072 (AraE) could serve as a good candidate for improving existing pentose-utilizing yeast strains. |
Eukaryota | Fungi, Ascomycota | AraE of Tricoderma reesei |
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2.A.1.1.17 | Glucose transporter of 884 aas and 12 TMSs with a 100 aa hydrophilic N-terminus and a 340 aas hydrophilic C-terminus. |
Eukaryota | Fungi, Ascomycota | Th2A of Trypanosoma brucei |
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2.A.1.1.18 | Glucose/mannose/fructose transporter and high affinity sensor, Snf3p, (regulates glucose transport via other systems). Residues involved in ligand preference are similar to those involved in transport (Dietvorst et al. 2010). Snf3p in Candida glabrata is essential for growth in low glucose media but not high glucose media, and plays a role in the induction of severall hexose transporters (Ng et al. 2015). |
Eukaryota | Euglenozoa | Snf3p of Saccharomyces cerevisiae |
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2.A.1.1.19 | Glucose transporter and low affinity sensor, Rgt2p (regulates glucose transport in conjunction with Snf3p). Rgt2 generates an intracellular signal in response to glucose that leads to inhibition of the Rgt1 transcriptional repressor and consequently to derepression of HXT genes encoding glucose transporters. They have unusually long C-terminal tails that bind to Mth1 and Std1, paralogous proteins that regulate the function of the Rgt1 transcription factor. Scharff-Poulsen et al. 2018 showed that the C-terminal tail of Rgt2 is not responsible for its inability to transport glucose. RGT2 mutations that cause constitutive signal generation alter evolutionarily-conserved amino acids in the transmembrane spanning regions involved in maintaining an outward-facing conformation or the substrate binding site. These mutations may cause Rgt2 to adopt inward-facing or occluded conformations that generate the glucose signal. The cytoplasmic C-terminal domains of the yeast cell surface receptors Rgt2 and Snf3 play multiple roles in glucose sensing and signaling (Kim et al. 2024). |
Eukaryota | Fungi, Ascomycota | Rgt2p of Saccharomyces cerevisiae |
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2.A.1.1.2 | Arabinose (xylose; galactose):H+ symporter, AraE (low affinity high capacity) (Khlebnikov et al. 2001). |
Bacteria | Pseudomonadota | AraE of E. coli (P0AE24) |
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2.A.1.1.20 | Myoinositol:H+ symporter, MIT | Eukaryota | Euglenozoa | MIT of Leishmania donovani; most similar to ITRI of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.21 | Hexose:H+ symporter, Ght2 (Glucose > Fructose) | Eukaryota | Fungi, Ascomycota | Ght2 of Schizosaccharomyces pombe | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.22 | Hexose:H+ symporter, Ght6 (Fructose > Glucose) | Eukaryota | Fungi, Ascomycota | Ght6 of Schizosaccharomyces pombe | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.23 | Gluconate:H+ symporter, Ght3 | Eukaryota | Fungi, Ascomycota | Ght3 of Schizosaccharomyces pombe | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.24 | Hexose (Glucose and Fructose) transporter, PfHT1 of 504 aas and 12 TMSs. This is the only hexose transporter, and it is found in the plasma membrane. It is an antimalarial drug target (Meier et al. 2018; Wunderlich 2022). |
Eukaryota | Apicomplexa | PfHT1 of Plasmodium falciparum |
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2.A.1.1.25 | Myoinositol:H+ symporter, HMIT (also transport other inositols including scyllo-, muco- and chiro-, but not allo-inositol) (Aouameur et al., 2007). Expressed in the Golgi of the hippocampus and cortex. May also transport inositoltriphosphate (Di Daniel et al., 2009). Interacts directly with γ-secretase (9.B.47.1.1) to regulate its activity and the production of Abeta production, important in Alzheimer's disease (Teranishi et al. 2015). |
Eukaryota | Metazoa, Chordata | SLC2A13 of Homo sapiens |
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2.A.1.1.26 | Major myoinositol:H+ symporter, IolT, of 473 aas and 12 TMSs in a 6 + 6 TMS pattern (Yoshida et al. 2002). |
Bacteria | Bacillota | IolT (YdjK) of Bacillus subtilis |
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2.A.1.1.27 | Minor, low affinity myoinositol:H+ symporter, IolF, of 438 aas and 12 TMSs (Yoshida et al. 2002). |
Bacteria | Bacillota | IolF of Bacillus subtilis |
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2.A.1.1.28 | The erythrocyte/brain hexose facilitator, glucose transporter-1, Gtr1. SLC2a1 or Glut1. Transports D-glucose, dehydroascorbate, arsenite and the flavonone, quercetin, via one pathway and water via a distinct channel. Sugar transport has been suggested to function via a sliding mechanism involving several sugar binding sites (Cunningham et al., 2006). Glut1 is the receptor for human T-cell leukemia virus (HTLV)) (Manel et al., 2003). The orientation of the 12 TMSs and the conformation of the exofacial glucose binding site of GLUT1 have been proposed (Mueckler and Makepeace 2004). It is regulated by stomatin (TC# 8.A.21) to take up dehydroascorbate (Montel-Hagen et al., 2008). Mutations cause Glut1 deficiency syndrome, a human encephalopathy that results from decreased glucose flux through the blood brain barrier (Pascual et al., 2008). Mueckler and Makepeace (2009) have presented a model of the exofacial substrate-binding site and helical folding of Glut1. Glut1, 2, 4 and 9 are functional both in the plasma membrane and the endoplasmic reticulum (Takanaga and Frommer, 2010). Glut1 is down-regulated in the brains of Alzheimer's disease patients (Liu et al., 2008b). Metabolic stress rapidly stimulates blood-brain barrier endothelial cell sugar transport by acute up-regulation of plasma membrane GLUT1 levels, possibly involving an AMP-activated kinase activity (Cura and Carruthers, 2010). Serves as a receptor for neuropilin-1 (923aas; 2 TMSs; O14786) and heparan sulfate proteoglycans (HSPGs) (Hoshino, 2012). Glut1 has a nucleotide binding site, and nucleotide binding affects transport activity (Yao and Bajjalieh 2009). The protein serves as a receptor for dermatin and β-adducin which help link the spectrin-actin junctional complex to the erythrocyte plasma membrane (Khan et al. 2008). May play a role in paroxysmal dyskinesias (Erro et al. 2017). GLUT1 mediates infection of CD4+ lymphocytes by human T cell leukemia virus type 1 (Jin et al. 2006). Mutations in disordered regions can cause disease by introducing dileucine motifs, For example, mutations that are causative of GLUT1 deficiency syndrome are of this type, and the mutated protein mislocalizes to intracellular compartments (Meyer et al. 2018). Glucose transits along a transmembrane pathway through significant rotational motions while maintaining hydrogen bonds with the protein (Galochkina et al. 2019). It is phosphoryated by protein kinase C-B (TC# 8.A.104.1.4) (Lee et al. 2015). GLUT1-mediated exchange of fluorosugars has been studied (Shishmarev et al. 2018). Resveratrol and soy isoflavones alone and in combination improve the learning and memory of aging rats. The mechanism may be related to up-regulating the expression of GLUT1 and GLUT3 genes in the hippocampus (Zhang et al. 2020). The pore diameters of the transmembrane glucose transporters of all Class I GLUT proteins are constricted upon depletion of unsaturated fatty acids in the membranes (Weijers 2020). Diclofenac inhibits tumor cell glycolysis and growth by decreasing GLUT1 expression (Yang et al. 2021). Almost the entire populations of Glut1 and three other transmembrane proteins are immobilized by either the incorporation within large multiprotein complexes or entrapment within the protein network of the cortical spectrin cytoskeleton (Kodippili et al. 2020). This system is required for hepatocellular carcinoma proliferation and metastasis (Fang et al. 2021). The main triggers FoR activation of transport are located within the solvent accessible linker regions in the extramembranous zones (Gonzalez-Resines et al. 2021). DHHC9-mediated GLUT1 S-palmitoylation is requuired for plasma membrane localization and promotes glioblastoma glycolysis and tumorigenesis (Zhang et al. 2021). An ancient family of arrestin-fold proteins, termed alpha-arrestins, have conserved roles in regulating nutrient transporter trafficking and cellular metabolism as adaptor proteins. One alpha-arrestin, TXNIP (thioredoxin-interacting protein), is known to regulate myocardial glucose uptake, but the in vivo role of the related alpha-arrestin, ARRDC4 (arrestin domain-containing protein 4), was unknown. Interactions of ARRDC4 with GLUT1 prove to mediate metabolic stress in the ischemic heart (Nakayama et al. 2022). Mercury (Hg2+) decreased membrane deformability, impairing RBC capacity to deal with the shear forces in the circulation, increasing membrane fragmentation, and affecting transport (Notariale et al. 2022). GLUT-1 and GLUT-3 play important roles in the development of some types of malignant tumors, including glioblastoma, and expression of both is regulated by miRNAs (Beylerli et al. 2022). Glucose uptake inhibitors via Glut1 are potential anticancer agents (Hung et al. 2022). GLUT1 deficiency syndrome (GLUT1DS1) is a rare genetic metabolic disease, characterized by infantile-onset epileptic encephalopathy, global developmental delay, progressive microcephaly, and movement disorders (e.g., spasticity and dystonia) (Mauri et al. 2022). It is caused by heterozygous mutations in the SLC2A1 gene, which encodes the GLUT1 protein, a glucose transporter across the blood-brain barrier (BBB). Most commonly, these variants (~2 dozen) arise de novo, resulting in sporadic cases, although several familial cases with AD inheritance pattern have been described (Mauri et al. 2022). Fluoride exposure affects the expression of glucose transporters (GLUT1 and 3) and ATP synthesis (Chen et al. 2023). GLUT1 is necessary for the flexor digitorum brevis (FDB) to survive hypoxia, but overexpression of GLUT1 was insufficient to rescue other skeletal muscles from hypoxic damage (Amorese et al. 2023). The role of GLUT inhibitors, micro-RNAs, and long non-coding RNAs that aid in inhibiting glucose uptake by cancer cells have been discussed as potential theraputics (Chamarthy and Mekala 2023). GLUT1 overexpression in tumor cells is a potential target for drug therapy (Zhao et al. 2023). HSP90B1-mediated plasma membrane localization of GLUT1 promotes radioresistance of glioblastomas (Li et al. 2023). The core genes (Fgf2, Pdgfra, Ptpn11, Slc2a1) are highly expressed in sevoflurane anesthesia brain tissue samples. The 4 core genes (Fgf2, Pdgfra, Ptpn11, and Slc2a1) are associated with neurodegenerative diseases, brain injuries, memory disorders, cognitive disorders, neurotoxicity, drug-induced abnormalities, neurological disorders, developmental disorders, and intellectual disabilities. Fgf2 and Ptpn11 are highly expressed in brain tissue after sevoflurane anesthesia, the higher the expression level of Fgf2 and Ptpn11, the worse the prognosis (Zhang and Xu 2023). Target separation and potential anticancer activity of withanolide-based glucose transporter protein 1 inhibitors from Physalis angulata var. villosa have been evaluated (Zhang et al. 2023). PIGT is a subunit of the glycosylphosphatidylinositol transamidase which is involved in tumorigenesis and invasiveness. PIGT promotes cell growth, glycolysis, and metastasis in bladder cancer by modulating GLUT1 glycosylation and membrane trafficking (Tan et al. 2024). PDGF-stimulated glucose uptake via Glut1 has been reported to be dependent on receptor/transporter endocytosis (Tsutsumi et al. 2024). Glucose transporter-1 deficiency syndrome gives rise to extreme phenotypic variability in a five-generation family carrying a novel SLC2A1 variant (Giugno et al. 2024). A 4-furanylvinylquinoline derivative is a new scaffold for the design of oxidative stress initiator and a glucose transporter inhibitor via GLUT1 (Kuczak et al. 2024). SLC2A1 is a prognostic factor in hepatocellular carcinoma (HCC) (Xu et al. 2025). Several GLUT isoforms, especially GLUT1 and GLUT3 in humans, are overexpressed in many tumors, and inhibitors have been identified (Kawatani and Osada 2025). |
Eukaryota | Metazoa, Chordata | SLC2A1 of Homo sapiens |
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2.A.1.1.29 | Glucosamine/glucose/fructose uniporter, Glut-2, Glut2 or ATG9A; it may also transport dehydroascorbate (Mardones et al., 2011; Maulén et al., 2003), and cotransports water against an osmotic gradient (Naftalin, 2008). Mutations may give rise to the rare autosomal recessive Fanconi-Bickel syndrome (Batool et al. 2019). It mediates intestinal transport of quercetrin (Li et al. 2020) and can transport the drug gastrodin, a seditive with a strcture of a phenolic glucoside (Huang et al. 2023). It also functions in autophagy. The cryoEM structure of the human ATG9A isoform at 2.9-Å resolution has been solved (Guardia et al. 2020). The structure reveals a fold with a homotrimeric domain-swapped architecture, multiple membrane spans, and a network of branched cavities, consistent with ATG9A being a membrane transporter. Mutational analyses support a role for the cavities in the functions of ATG9A. Structure-guided molecular simulations predict that ATG9A causes membrane bending, explaining the localization of this protein to small vesicles and highly curved edges of growing autophagosomes (Guardia et al. 2020). Both GLUT2 and GLUT3 have been expressed in yeast and exhibit most of the characteristics of the proteins expressed in humans (Schmidl et al. 2020). Autophagy is a highly conserved pathway that the cell uses to maintain homeostasis, degrade damaged organelles, combat invading pathogens, and survive pathological conditions. A set of proteins, called ATG proteins, comprise the core autophagy machinery and work together in a defined hierarchy. ATG9A vesicles are at the heart of autophagy, as they control the rapid de novo synthesis of an organelle called the phagophore. ATG9A is present in different membrane compartments (van Vliet et al. 2023). Metformin increases the uptake of glucose into the gut from the circulation in high-fat diet-fed male mice, which is enhanced by a reduction in whole-body Slc2a2 expression (Morrice et al. 2023). Increased expression of Glucose Transporter 2 (GLUT2) is observed on the peripheral blood insulin-producing cells (PB-IPC) in type 1 diabetic patients after receiving stem cell educator therapy (Zhao et al. 2024).
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Eukaryota | Metazoa, Chordata | SLC2A2 of Homo sapiens |
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2.A.1.1.3 | Xylose (xylopyranose):H+ symporter of 491 aas and 12 TMSs (Wambo et al. 2017). Also transports and binds D-glucose and 6-bromo-6-deoxy-D-glucose. The 3-d structure is known in three conformers, outward occluded, inward occluded and inward open (Sun et al. 2012: Quistgaard et al. 2013). Most of the sugar-binding residues are conserved with the human Glut-1, 2, 3 and 4 homologues. The coalescence of intramolecular tunnels and cavities has been postulated to account for facilitated diffusion of sugars (Cunningham and Naftalin 2014). Protonation of a conserved aspartate triggers a conformational transition from the outward-facing to the inward-facing state. This transition only occurs in the presence of substrate xylose, while the inhibitor glucose locks the transporter in the outward-facing state (Jia et al. 2020). |
Bacteria | Pseudomonadota | XylE of E. coli (P0AGF4) |
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2.A.1.1.30 | Low affinity, constitutive, glucose (hexose; xylose) uniporter, Hxt4 (LGT1; Rag1) (also transports arsenic trioxide [As(OH)3] as do Hxtl, 3, 5, 7 and 9) (Liu et al., 2004). The Kluyveromyces lactis ortholog is 73% identical and is similarly regulated (Rolland et al. 2006). Key residues for efficient glucose transport by the hexose transporter CgHxt4 in the high sugar fermentation yeast Candida glycerinogenes.have been identified (Qiao et al. 2021). |
Eukaryota | Fungi, Ascomycota | Hxt4 of Saccharomyces cerevisiae |
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2.A.1.1.31 | High affinity, glucose-repressible, glucose (hexose) uniporter (Hxt6/Hxt7). Asn331 and hydrophobic residue side chains in TMS5 determine substrate affinity (Kasahara et al., 2011; Kasahara and Kasahara 2010). Also transports xylose (Wang et al. 2013). |
Eukaryota | Fungi, Ascomycota | Hxt6/Hxt7 of Saccharomyces cerevisiae |
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2.A.1.1.32 | Glucose/fructose:H+ symporter, GlcP (Zhang et al., 1989) | Bacteria | Cyanobacteriota | GlcP of Synechocystis sp. (P15729) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.33 | Fructose:H+ symporter, Frt1 (Diezemann and Boles, 2003) | Eukaryota | Fungi, Ascomycota | Frt1 of Kluyveromyces lactis (CAC79614) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.34 | The broad specificity sugar/sugar alcohol (myo-inositol, glycerol, ribose, sorbitol, mannitol, xylitol, erythritol, etc) H+ symporter, AtPLT5 (transports a wide range of hexoses, pentoses, tetroses, sugar alcohols and a sugar acid, but not disaccharides) (Reinders et al., 2005) (expressed in roots, leaves and floral organs) (Klepek et al., 2004) | Eukaryota | Viridiplantae, Streptophyta | AtPLT5 of Arabidopsis thaliana (Q8VZ80) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.35 | The major glucose (or 2-deoxyglucose) uptake transporter, GlcP (van Wezel et al., 2005) | Bacteria | Actinomycetota | GlcP of Streptomyces coelicolor (Q7BEC4) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.36 | The low affinity, glucose-inducible glucose transporter, MstE (Forment et al., 2006) |
Eukaryota | Fungi, Ascomycota | MstE of Aspergillus nidulans (Q400D8) |
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2.A.1.1.37 | The glucose/fructose facilitator, Glut7 (SLC2A7) (a single mutation, I314V, results in loss of fructose transport but retention of glucose transport (Manolescu et al., 2005) | Eukaryota | Metazoa, Chordata | SLC2A7 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.38 | The glycerol:H+ symporter, Stl1p (Ferreira et al., 2005) | Eukaryota | Fungi, Ascomycota | Stl1p of Saccharomyces cerevisiae (NP_010825) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.39 | The high affinity glucose transporter, Hgt1 (Baruffini et al., 2006) | Eukaryota | Fungi, Ascomycota | Hgt1 of Kluyveromyces lactis (P49374) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.4 | Glucose uniporter of 473 aas and 12 TMSs. Several GLUT isoforms, especially GLUT1 and GLUT3 in humans, are overexpressed in many tumors, and inhibitors have been identified (Kawatani and Osada 2025). |
Bacteria | Pseudomonadota | Glf of Zymomonas mobilis |
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2.A.1.1.40 | The xylose facilitator, Xylhp (Nobre et al., 1999) | Eukaryota | Fungi, Ascomycota | Xylhp of Debaryomyces hansenii (AAR06925) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.41 | The D-xylose:H+ symporter, XylT (Km=220 μM; inhibited competitively by 6-deoxyglucose (Ki=220 μM), but not by other sugars tested) (Chaillou et al., 1998) | Bacteria | Bacillota | XylT of Lactobacillus brevis (O52733) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.42 | The D-glucose:H+ symporter, GlcP (glucose uptake is inhibited by 2-deoxyglucose, mannose and galactose) (Parche et al., 2006) | Bacteria | Actinomycetota | GlcP of Bifidobacterium longum (AAN25419) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.43 | The monosaccharide (MST) (glucose > mannose > galactose > fructose):H+ symporter, MST1 (Schussler et al., 2006). |
Eukaryota | Fungi, Mucoromycota | MST1 of Geosiphon pyriformis (A0ZXK6) |
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2.A.1.1.44 | The hexose (glucose and fructose but not galactose) transporter (Glut11; SLC2A11) (Scheepers et al., 2005) | Eukaryota | Metazoa, Chordata | SLC2A11 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.45 | Vacuolar (tonoplast) glucose transporter1, Vgt1 (important for seed germination and flowering) (Aluri and Büttner, 2007) |
Eukaryota | Viridiplantae, Streptophyta | Vgt1 of Arabidopsis thaliana (Q8L6Z8) |
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2.A.1.1.46 | The blastocyst/testis glucose transporter, Glut8 (Doege et al., 2000) (insulin stimulated in blastocysts) (Carayannopoulos et al., 2000). |
Eukaryota | Metazoa, Chordata | Glut8 of Mus musculus (Q9JIF3) |
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2.A.1.1.47 | The embryonic liver, kidney, and other tissue uric acid (urate) transporter, Glut9 (SLC2A9) (Wright et al. 2010). Mutations in this transporter cause severe renal hyperuricemia. It transports hexoses as well as urate, the latter by an electrogenic uniport mechanism. It's transcription is regulated by a hepatocyte nuclear factor, HNF4α (Prestin et al. 2014). |
Eukaryota | Metazoa, Chordata | Glut9 of Mus musculus (Q5ERC7) |
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2.A.1.1.48 | The pentose/hexose transporter (sugar transport protein 2), STP2. (Expressed during pollen maturation and early stages of gametophyte development) (Truernit et al., 1999) | Eukaryota | Viridiplantae, Streptophyta | STP2 of Arabidopsis thaliana (Q9LNV3) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.49 | The sink-specific, stress-regulated monosaccharide uptake porter, STP4. (Induced upon wounding or infection with bacteria or fungi; expressed in roots and flowers) (Truernit et al., 1996) | Eukaryota | Viridiplantae, Streptophyta | STP4 of Arabidopsis thaliana (Q39228) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.5 | Hexose uniporter | Eukaryota | Fungi, Ascomycota | HxtO of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.50 | The glucose/fructose:H+ symporter, STP13 (sugar transport protein 13). Expressed in vascular tissues and induced during programmed cell death (Norholm et al., 2006). Used to combat bacterial infection by competing with them for sugars by phosphorylation of STP13 by the BAK1 receptor kinase (Yamada et al. 2016). |
Eukaryota | Viridiplantae, Streptophyta | STP13 of Arabidopsis thaliana (Q94AZ2) |
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2.A.1.1.51 | Glucose/xylose: H+ symporter, Gsx1 (Leandro et al., 2006) | Eukaryota | Fungi, Ascomycota | Gsx1 of Candida intermedia (Q2MEV7) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.52 | The glucose transport protein, GTP1 (Skelly et al., 1994) | Eukaryota | Metazoa, Platyhelminthes | GTP1 of Schistosoma mansoni (Q26579) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.53 | Myo-Inositol uptake porter, IolT1 (Km=0.2mM) (Krings et al., 2006). Can also transport D-glucose (Ikeda et al. 2011). |
Bacteria | Actinomycetota | IolT1 of Corynebacterium glutamicum (Q8NTX0) |
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2.A.1.1.54 | Myo-Inositol (Km=0.45mM) uptake porter, IolT2 (Krings et al., 2006). Can not transport D-glucose (Ikeda et al. 2011). |
Bacteria | Actinomycetota | IolT2 of Corynebacterium glutamicum (Q8NL90) |
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2.A.1.1.55 | L-arabinose:proton symporter, AraE (Sa-Nogueira and Ramos, 1997). Also transports xylose, galactose and α-1,5 arabinobiose (Ferreira and Sá-Nogueira, 2010). |
Bacteria | Bacillota | AraE of Bacillus subtilis (P96710) |
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2.A.1.1.56 | High affinity monosaccharide (KM ≈ 20 µM):H+ symporter, Stp6 (takes up glucose, 3-O-methylglucose, mannose, fructose, galactose and to a lesser extent, xylose and ribulose. (Scholz-Starke et al., 2003) | Eukaryota | Viridiplantae, Streptophyta | Stp6 of Arabidopsis thaliana (Q9SFG0) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.57 | High affinity (15 μM) glucose (monosaccharides including xylose):H+ symporter, MstA (Jørgensen et al., 2007). |
Eukaryota | Fungi, Ascomycota | MstA of Aspergillus niger |
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2.A.1.1.58 | Low affinity glucose:H+ symporter, MstC (Jørgensen et al., 2007). |
Eukaryota | Fungi, Ascomycota | MstC of Aspergillus niger |
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2.A.1.1.59 | The glucose transporter, GLUT10, was originally believed to be responsible for Type 2 diabetes. It is now believed to be responsible for arterial tortuosity, a rare autosomal recessive connective tissue disease (Callewaert et al., 2007). GLUT10 transports glucose and 2-deoxy glucose (Km=0.3 mM), and is inhibited by galactose and phloretin (Coucke et al., 2006). | Eukaryota | Metazoa, Chordata | SLC2A10 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.6 | Galactose, glucose uniporter, Gal2. Also transports xylose (Wang et al. 2013). This transporter has been engineered by mutation (N376F) to transport xylose without being inhibited by glucose or transporting other hexoses (Farwick et al. 2014). The 3-d structure is known (Wang et al. 2015). |
Eukaryota | Fungi, Ascomycota | Gal2 of Saccharomyces cerevisiae |
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2.A.1.1.60 | The major hexose transporter, Htr1 (mediates the active uptake of hexoses by sugar:H+ symport. Can transport glucose, 3-O-methylglucose, fructose, xylose, mannose, galactose, fucose, 2-deoxyglucose and arabinose. Confers sensitivity to galactose in seedlings. Km=20 uM for glucose) (Stadler et al., 2003; Boorer et al., 1994) | Eukaryota | Viridiplantae, Streptophyta | Htr1 of Arabidopsis thaliana (P23586) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.61 | High affinity monosaccharide (Km = 25 µM) transporter (takes up glucose, galactose, mannose, xylose and 3-O-methylglucose, but not fructose and ribose), STP11 (expressed in pollen tubes) (Schneidereit et al., 2005). This protein is also called Sugar Transport Protein (STP). Expression profiles of homologues in cabbage have been studied (Zhang et al. 2019). |
Eukaryota | Viridiplantae, Streptophyta | STP11 of Arabidopsis thaliana (Q9FMX3) |
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2.A.1.1.62 | High affinity (0.24mM) plasma membrane myoinositol-specific H+ symporter, INT4 (Schneider et al., 2006) | Eukaryota | Viridiplantae, Streptophyta | INT4 of Arabidopsis thaliana (O23492) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.63 | Low affinity inositol (myoinsoitol (Km = 1 mM), scylloinositol, d-chiroinositol and mucoinositol):H+ symporter (expressed in the anther tapetum, the vasculature, and the leaf mesophyll (Schneider et al., 2007) | Eukaryota | Viridiplantae, Streptophyta | INT2 of Arabidopsis thaliana (Q9C757) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.64 | The hexose sensor, Hxs1 (believed to be non-transporting) (Stasyk et al., 2008) | Eukaryota | Fungi | Hxs1 of Hansenula polymorpha (B1PM37) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.65 | Glucose permease GlcP (Pimentel-Schmitt et al., 2008) (most similar to 2.A.1.1.32) | Bacteria | Actinomycetota | GlcP of Mycobacterium smegmatis (A0QZX3) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.66 | The tonoplast H+:Inositol symporter 1, Int1 (mediates efflux from the tonoplast to the cytoplasm (Schneider et al., 2008) (most similar to 2.A.1.1.63 and 2.A.1.1.62). |
Eukaryota | Viridiplantae, Streptophyta | Int1 of Arabidopsis thaliana (Q8VZR6) |
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2.A.1.1.67 | Glucose/xylose facilitator-1, GXF1 (functions by sugar uniport; low affinity (Leandro et al., 2008) | Eukaryota | Fungi, Ascomycota | GXF1 of Candida intermedia (Q2MDH1) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.68 | The Glucose Transporter/Sensor Rgt2 |
Eukaryota | Fungi, Ascomycota | Rgt2 Pichia stipitis (A3M0N3) |
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2.A.1.1.69 | Sugar & polyol transporter 1 (SPT1): broad specificity; takes up glucose (Schilling and Oesterhelt, 2007). Loss of the first 3 TMSs of the 12 TMSs does not prevent sugar uptake or sugar recognition but lowers substrate affinity & transport rate, and abolished H+ symport (Schilling and Oesterhelt, 2007). | Eukaryota | Rhodophyta | SPT1 of Galdieria sulphuraria (A1Z264) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.7 | Quinate:H+ symporter | Eukaryota | Fungi, Ascomycota | Qay of Neurospora crassa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.70 | MFS Permease |
Eukaryota | Fungi, Ascomycota | MFS Permease of Phaeosphaeria nodurum |
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2.A.1.1.71 | Hexose (glucose) transporter, GT4 (D2) (almost identical to 2.A.1.1.16). The L. infantum ortholog (A4I8N6) is 95% identical to this protein and is the dominant protein in the plasma membrane of this organims (Oliveira et al. 2020). |
Eukaryota | Euglenozoa | Hexose transporter, GT4 of Leishmania mexicana (B1PLM1) |
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2.A.1.1.72 | The kidney basolateral urate efflux transporter (SLC2A9, URATv1 or GLUT9) (orthologue of 2.A.1.1.47) (Anzai et al., 2008). Human SLC2A9a and SLC2A9b isoforms mediate electrogenic transport of urate with different characteristics in the presence of hexoses (Witkowska et al., 2012). It transports hexoses, glucose and fructose, but not galactose, at a rate 50-fold slower than urate the latter by a uniport mechanism, thus catalyzing uptake as well as efflux. The ITM2B protein Q9Y287; 266 aas and 1 TMS) inhibits urate uptake and stimulates efflux (Mandal and Mount 2019). GLUT9's transcription is regulated by a hepatocyte nuclear factor, HNF4α (Prestin et al. 2014). Residues involved in urate transport have been identified (Long et al. 2017). Pathogenic variants of SLC22A12 (URAT1) and SLC2A9 (GLUT9) can give rise to renal hypouricemia (Perdomo-Ramirez et al. 2023). The structural basis for the transport and substrate selection have been described (He et al. 2024). Cryo-EM structures of human URAT1(R477S), its complex with urate, and its closely related homolog OAT4 have been determined. URAT1(R477S) and OAT4 exhibit major facilitator superfamily (MFS) folds with outward- and inward-open conformations, respectively. Structural comparison reveals a 30° rotation between the N-terminal and C-terminal domains, supporting an alternating access mechanism. A conserved arginine (OAT4-Arg473/URAT1-Arg477) is found to be essential for chloride-mediated inhibition (He et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC2A9 of Homo sapiens |
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2.A.1.1.73 | Glycerol uptake permease (Glycerol:H+ symporter) Stl1. (Involved in salt stress relief) (Kayingo et al. 2009) (similar to Stl1 of S. cerevisiae (2.A.1.1.38)) | Eukaryota | Fungi, Ascomycota | Stl1 of Candida albicans (Q5A8J5) |
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2.A.1.1.74 | The putative L-rhamnose porter, RhaY |
Bacteria | Bacillota | RhaY of Listeria monocytogenes (Q926Q9) |
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2.A.1.1.75 | The fructose/xylose:H+ symporter, PMT1 (polyol monosaccharide transporter-1). Also transports other substrates at lower rates. PMT2 is largely of the same sequence and function. Both are present in pollen and young xylem cells (Klepek et al., 2005). A similar ortholog has been identifed in pollen grains of Petunia hybrida (Garrido et al. 2006). |
Eukaryota | Viridiplantae, Streptophyta | PMT1 of Arabidopsis thaliana (Q9XIH7) |
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2.A.1.1.76 | Glucose transporter, GT1. GT1, 2, and 3 are homologues. GT2 and GT3 transport ribose as well as glucose at different rates. GT3 transports ribose with 6-fold lower efficiency due to two threonines in GT3 that are alanines in GT2. They are in two loops between TMSs 3, 4, and 7, 8 (Naula et al., 2010). GT1 is expressed in the flagellar membrane and may be both a glucose transporter and sensor, allowing the parasites to enter the stationary phase when they deplete glucose although in the absence of the sensor, they lose viability (Rodriguez-Contreras et al. 2015). |
Eukaryota | Euglenozoa | GT1 of Leishmania mexicana (Q9F315) |
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2.A.1.1.77 | The D-glucose/D-ribose transporter, LmGT2 (Most similar to 1.A.1.1.18) (Naula et al., 2010). |
Eukaryota | Euglenozoa | LmGT2 of Leishmania mexicana (O61059) |
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2.A.1.1.78 | The glucose transporter, LmGT3 (homologous to LmGT2 (1.A.1.1.75)). Two threonine residues located in the hydrophilic loops connecting TMSs 3 & 4 and 7 & 8 of GT3 prevent transport of D-ribose. Changing these two residues to alanine (as in GT2) allows transport of ribose. Thus, loops 3-4 and 7-8 partially determine substrate specificity (Naula et al., 2010). |
Eukaryota | Euglenozoa | LmGT3 of Leishmania mexicana (O61060) |
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2.A.1.1.79 | Polyol (xylitol):H+ symporter, PLT4 (Kalliampakou et al., 2011)
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Eukaryota | Viridiplantae, Streptophyta | PLT4 of Lotus japonicus (Q1XF07) |
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2.A.1.1.8 | Myoinositol:H+ symporter
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Eukaryota | Fungi, Ascomycota | ITR1 of Saccharomyces cerevisiae |
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2.A.1.1.80 |
Insulin-responsive facilitative glucose transporter in skeletal and cardiac muscle, adipose, and other tissues, Glut4 (GTR4; SLC2A4; 509aas). Defects in Glut4 cause noninsulin-dependent diabetes mellitus (NIDDM). Hyperinsulinemia leads to uncoupled insulin regulation of the GLUT4 glucose transporter and the FoxO1 transcription factor (Gonzalez et al., 2011). The first luminal loop confers insulin responsiveness to GLUT4 (Kim and Kandror, 2012). Exercise increases Glut4 synthesis in a process involving several protein kinases, the Glut4 enhancer factor (GEF; SLC2A4 regulator; Q9NR83), and the myocyte enhancing factor 2 (MEF2; NP_001139257). (McGee and Hargreaves 2006; Wright 2007; Zorzano et al. 2005). monoclonal antibodies against the GLUT4 inward-open and outward-open states have been isoated (Tucker et al. 2018). It is phosphoryated by protein kinase C-β, PRKCB or PKCB (Lee et al. 2015). Insulin-induced GLUT4 transport is observed in the heart and brain in addition to the skeletal muscle and adipocytes, and hormones other than insulin can enhance GLUT4 transport (Wang et al. 2020). Prolonged preoperative fasting induces postoperative insulin resistance by ER-stress mediated Glut4 down-regulation in skeletal muscle (Lin et al. 2021). GLUT4 is the primary glucose transporter in adipose and skeletal muscle tissues, and its cellular trafficking is regulated by insulin signaling. Failed or reduced plasma membrane localization of GLUT4 is associated with diabetes. The cryo-EM structures of human GLUT4 bound to a small molecule inhibitor cytochalasin B (CCB) at resolutions of 3.3 Å which exhibits an inward-open conformation. The cryo-EM structure reveals an extracellular glycosylation site and an intracellular helix that is invisible in the crystal structure of GLUT1 (Yuan et al. 2022). Tectorigenin targets PKACα to promote GLUT4 expression in skeletal muscle and improve insulin resistance in vitro and in vivo (Yao et al. 2023). Key molecular players in insulin resistance (IR) are the insulin receptor and glucose transporter 4, and certain natural products, such as lipids, phenols, terpenes, antibiotics and alkaloids have beneficial effects on IR which are named "membrane-active immunomodulators" (MAIMs) (Izbicka and Streeper 2023). An example is the medium chain fatty acid ester diethyl azelate (DEA), which increases the fluidity of plasma membranes with subsequent downstream effects on cellular signaling and improves the symptoms of IR. The intracellular helical bundle of human glucose transporter GLUT4 is important for complex formation with ASP (Huang et al. 2023). Diabetes-induced electrophysiological alterations on neurosomes in ganglia of the peripheral nervous system have been reported (Leal-Cardoso et al. 2023). Regulated dynamic subcellular GLUT4 localization has been revealed by proximal proteome mapping in human muscle cells (Ray et al. 2023). In goats, this system is closely associate with lipid metabolism (Zhang et al. 2024). New compounds lowered the systolic blood pressure (from 149 to 120 mmHg), but only LQM312 and LQM319 improved the metabolic state of hypoxic cardiomyocytes mediated by GLUT1 and GLUT4 (Hernández-Serda et al. 2024). In silico studies suggested that Captopril and LQM312 mimic the interaction with the AMPK γ-subunit. Therefore, these compounds could activate AMPK, promoting the GLUT4 trafficking signaling pathway (Hernández-Serda et al. 2024). Indian lychee honey ameliorates hepatic glucose uptake by regulating the ChREBP/Glut4 axis under insulin-resistant conditions (Ghosh et al. 2025). |
Eukaryota | Metazoa, Chordata | SLC2A4 of Homo sapiens |
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2.A.1.1.81 | The glucose uptake porter, GluP (Araki et al., 2011). |
Bacteria | Actinomycetota | GluP of Rhodococcus jostii (Q0SE66) |
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2.A.1.1.82 | The cellobiose/cellotriose/cellotetraose/latose/cellodextrin transporter, Cdt-1 of 579 aas and 12 TMSs. It is a proton symporter with a Km of about 4 μM (Galazka et al., 2010). |
Eukaryota | Fungi, Ascomycota | Cdt-1 of Neurospora crassa (Q7SCU1) |
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2.A.1.1.83 | The cellobiose/cellotriose/cellodextrin/lactose transporter, Cdt-2, of 525 aas and 12 TMSs. It functions by facilitated diffusion but with low efficiency and high affinity (Km = 3 μM). Mutations can increase its activity substantially (Lian et al. 2014). It appears to be capable of catalyzing efflux of 2'-fucosyllactose (2'FL), the most abundant oligosaccharide in human breast milk, following genetic engineering (Hollands et al. 2019). It may also take up lactose (Tamayo et al. 2024). |
Eukaryota | Fungi, Ascomycota | Cdt2 of Neurospora crassa (Q7SD12) |
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2.A.1.1.84 | The heteromeric TMT1/TMT2 glucose/sucrose:H+ antiporter. Catalyzes glucose/sucrose antiport into vacuoles (Schulz et al., 2011). |
Eukaryota | Viridiplantae, Streptophyta | The TMT1/2 sugar:H+ anti-porter of Arabidopsis thaliana. TMT1 (Q96290). TMT2 (Q8LPQ8). |
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2.A.1.1.85 | Zebrafish Slc2A10 (Glut10) facilitative glucose transporter. |
Eukaryota | Metazoa, Chordata | Zebrafish Glut10 of Danio rerio (A8KB28) |
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2.A.1.1.86 | The sea bream facilitative glucose transporter 1 (GLUT1) (Balmaceda-Aguilera et al., 2012). |
Eukaryota | Metazoa, Chordata | Glut1 of Sparus aurata (H9BPB6) |
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2.A.1.1.87 | solute carrier family 2, member 12, Glut12 of 617 aas and 12 TMSs. In contrast to most mammalian members of this family, this protein has been reported to be a glucose:proton symporter (Wilson-O'Brien et al. 2010). |
Eukaryota | Metazoa, Chordata | SLC2A12 of Homo sapiens |
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2.A.1.1.88 | solute carrier family 2 (facilitated glucose transporter), member 6 | Eukaryota | Metazoa, Chordata | SLC2A6 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.89 | Solute carrier family 2, facilitated glucose transporter member 8 (Glucose transporter type 8) (GLUT-8) (Glucose transporter type X1) | Eukaryota | Metazoa, Chordata | SLC2A8 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.9 | Lactose, galactose:H+ symporter | Eukaryota | Fungi, Ascomycota | LacP of Kluyveromyces lactis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.90 | Solute carrier family 2, facilitated glucose transporter member 14 (Glucose transporter type 14) (GLUT-14) | Eukaryota | Metazoa, Chordata | SLC2A14 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.91 | Solute carrier family 2, facilitated glucose transporter member 3 (Glucose transporter type 3, brain) (GLUT-3 or GLUT3). It mediates the facilitative uptake of glucose, 2-deoxyglucose, galactose, mannose, xylose and fucose, and probably dehydroascorbate, but not fructose (Seatter et al. 1998, Deng et al. 2015). GLUT3, a key neuronal transporter, exhibits multiple intermediate states (Sun and Zheng 2019). SLC2A3 may play a role in the progression of colorectal cancer (CRC) by regulating the epithelial-mesenchymal transition (EMT) classical pathway as well as PD-L1 mediated immune responses (Gao et al. 2021). GLUT3 is consistently upregulated in actively proliferating human oral squamous cell carcinoma cells (Paolini et al. 2022). GLUT-1 and GLUT-3 play roles in the development of some types of malignant tumors including glioblastoma, and expression of both is regulated by miRNAs (Beylerli et al. 2022). The overexpression of GLUT3 or GLUT1 may be monitored alone or in combination (GLUT1/GLUT3 ratio) as a biomarker for preeclampsia onset, phenotype, and progression (Agbani et al. 2023). Several GLUT isoforms, especially GLUT1 and GLUT3 in humans, are overexpressed in many tumors, and inhibitors have been identified (Kawatani and Osada 2025). |
Eukaryota | Metazoa, Chordata | SLC2A3 of Homo sapiens |
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2.A.1.1.92 | Inner membrane metabolite transport protein YdjE |
Bacteria | Pseudomonadota | YdjE of E. coli |
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2.A.1.1.93 | Vacuolar protein sorting-associated protein 73 | Eukaryota | Fungi, Ascomycota | VPS73 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.94 | Putative metabolite transport protein YDL199C | Eukaryota | Fungi, Ascomycota | YDL199C of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.95 | Inner membrane metabolite transport protein YgcS |
Bacteria | Pseudomonadota |
YgcS of E. coli |
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2.A.1.1.96 | Probable metabolite transport protein YBR241C | Eukaryota | Fungi, Ascomycota | YBR241C of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.97 | Sugar transporter ERD6 (Early-responsive to dehydration protein 6) (Sugar transporter-like protein 1) | Eukaryota | Viridiplantae, Streptophyta | ERD6 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.1.98 | Sugar transporter ERD6-like 6, ERD6L6, of 487 aas and 12 TMSs. It is 92% identical to ERD6L4 (488 aas and 12 TMSs) of A. thaliana, and ERD6-like 4 is candidate gene for foliar water-soluble carbohydrate accumulation in Trifolium repens (Pearson et al. 2022). Vacuolar sugar transporter EARLY RESPONSE TO DEHYDRATION 6-LIKE4 affects fructose signaling and plant growth (Khan et al. 2023). Regulation of intracellular sugar homeostasis is maintained by regulation of activities of sugar import and export proteins residing at the tonoplast. ERDL4 protein resides in the vacuolar membrane in Arabidopsis thaliana. Gene expression and subcellular fractionation studies indicated that ERDL4 participates in fructose allocation across the tonoplast, and modification of cytosolic fructose levels influences plant organ development and stress tolerance (Khan et al. 2023). . |
Eukaryota | Viridiplantae, Streptophyta | At1g75220 of Arabidopsis thaliana |
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2.A.1.1.99 | Facilitated trehalose transporter Tret1-1 (DmTret1-1); transports trehalose with a Km of 11 mM (Kanamori et al. 2010). Tret1 orthologs of other insects examined have differing Km values (Apis mellifera, 9 mM; Anopheles gambiae, 46 mM, and Bombyx mori, 72 mM). |
Eukaryota | Metazoa, Arthropoda | Tret1-1 of Drosophila melanogaster |
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2.A.1.10.1 | Nucleoside porter, NupG. Guanosine, inosine, cytidine and thymidine but not uridine, adenosine and xanthosine are transported (Patching et al. 2005). ADP-glucose is also a substrate of this system (Almagro et al. 2018). |
Bacteria | Pseudomonadota | NupG of E. coli (P0AFF4) |
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2.A.1.10.2 | Xanthosine porter, XapB. Xanthosine, inosine, adenosine, cytidine and thymidine but not guanosine and uridine are transported (Seeger et al. 1995). The Km for Xanthosine is 136 μM (Nørholm and Dandanell 2001). The transporter is encoded within an operon with xanthosine phosphorylase which is inactive in S. enterica but can be mutated to the active form (Hansen et al. 2006). |
Bacteria | Pseudomonadota | XapB of E. coli |
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2.A.1.10.3 |
Putative low affinity ribonucleoside transporter, YegT, of 425 aas and 12 TMSs. |
Bacteria | Pseudomonadota | YegT of Escherichia coli |
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2.A.1.11.1 | The oxalate:formate antiporter. Residues and TMSs involved in the translocation pathway and substrate binding have been identified (Fu and Maloney 1998; Fu et al. 2001; Ye and Maloney 2002; Wang et al. 2006). Beuming and Weinstein 2005 developed a method to predict the structures of membrane proteins consisting of (1) identifying TMSs from sequence; (2) assigning buried and lipid-exposed faces of the TMSs; and (3) assembling the TMSs into a bundle, based on geometric restraints obtained from EM data. The OxlT structure was modeled (Beuming and Weinstein 2005). |
Bacteria | Pseudomonadota | OxlT of Oxalobacter formigenes |
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2.A.1.11.10 | MFS carrier of 577 aas and 12 TMSs |
Eukaryota | Evosea | MFS protein of Entamoeba histolytica |
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2.A.1.11.11 | PfMFSDT (PF3D7_0210300) is a drug exporter (Maurya et al. 2024). It confers resistance to antifungal agents, ketoconazole and itraconazole. The nanomolar inhibitory effects of the drugs on the intra-erythrocytic growth of Plasmodium falciparum highlight their antimalarial properties. An assay to identify inhibitors of multiple validated and potential antimalarial drug targets has been developed (Lindblom et al. 2024). |
Eukaryota | Apicomplexa | PfMFSDT of Plasmodium falciparum |
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2.A.1.11.2 | Putative MFS transporter of 399 aas; 12 TMSs. |
Bacteria | Pseudomonadota | MFS porter of Pseudomonas aeruginosa (Q9I458) |
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2.A.1.11.3 | Inner membrane protein BtsT or YhjX (probably a pyruvate:proton symporter that can also function as an exporter) (Vilhena et al. 2017). Regulated by Crp as well as the LytS-like histidine sensor kinase, BtsS or YehU, and the corresponding LytTR-like response regulator, BtsR or YehT (Kristoficova et al. 2017). Possibly induced by peptides as cells enter the stationary growth phase because they release extracellular pyruvate, the true inducer (Kristoficova et al. 2017). Forms a complex with the BtsT (CsiA; YjiY) transporter (TC# 2.A.114.1.9) and two sensor kinase/response regulator pairs, BtsS/BtsR (YehU/YehT) and YdpA/YdpB, both of which respond to extracellular pyruvate, but with differing affinities (Behr et al. 2014). The carbon storage regulator A (CsrA) is involved in posttranscriptional regulation of both BtsT (YjiY) and YjiX, a 67 aa soluble protein of unknown function (Behr et al. 2014). The two proteins, YhjX (TC# 2.A.1.11.3) and YjiY (TC# 2.A.114.1.9) may function together as an oligomer, and confusingly, have both been given the designation: BtsT (see UniProt entries). |
Bacteria | Pseudomonadota | BtsT or YhjX of Escherichia coli |
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2.A.1.11.4 | Uncharacterized membrane protein YJL163C | Eukaryota | Fungi, Ascomycota | YJL163C of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.11.5 |
MFS-type transporter YcxA (ORF5) of 408 aas and 12 TMSs. Capable of exporting the peptide antibiotic, surfactin, synthsized by a non-ribosome mechanism in B. subtilis (Li et al. 2015). |
Bacteria | Bacillota | YcxA of Bacillus subtilis |
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2.A.1.11.6 | Uncharacterized MFS-type transporter YbfB |
Bacteria | Bacillota | YbfB of Bacillus subtilis |
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2.A.1.11.7 | Uncharacterized protein of 512 aas and 12 TMSs. |
Eukaryota | Rhodophyta | UP of Chondrus crispus |
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2.A.1.11.8 | Uncharacterized protein of 404 aas |
Bacteria | Pseudomonadota | UP of Pseudomonas aeruginosa |
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2.A.1.11.9 | Uncharacterized MFS porter of 508 aas and 12 TMSs. |
Eukaryota | Evosea | UP of Entamoeba histolytica |
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2.A.1.12.1 | The sialic acid porter, NanT, of 496 aas and 14 TMSs. N-acetylneuraminic acid (Neu5Ac) serves as a sole source of carbon and nitrogen for E. coli. It is a mucus-derived carbon source in the mammalian gut. NanT can also take up and allow efficient growth on the related sialic acids, N-glycolylneuraminic acid (Neu5Gc) and 3-keto-3-deoxy-d-glycero-d-galactonononic acid (KDN) (Hopkins et al. 2013). In animals, N-glycolylneuraminic acid is transported by exo- and endo-cytosis (He et al. 2023). |
Bacteria | Pseudomonadota | NanT of E. coli |
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2.A.1.12.2 | The lactate/pyruvate:H+ symporter of 616 aas and 12 TMSs. Residues in the substrate translocation pathway have been reported (Soares-Silva et al., 2011). This systems and its orthologs in fungi have been reviewed (Guo et al. 2018). |
Eukaryota | Fungi, Ascomycota | Jen1 (YKL217w) of Saccharomyces cerevisiae |
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2.A.1.12.3 | Jen2 of 513 aas and 12 TMSs. It is a dicarboxylic acid (succinate, malate, fumarate) uptake porter, and is subject to catabolite repression by glucose. It is induced during infection, being upregulated following the phagocytosis of C. albicans cells by neutrophils and macrophages. It may be important during early stages of virulence (Vieira et al. 2010). In the acid-tolerant yeast, Pichia kudriavzevii, it transports the above mentioned dicarboxylates as well as α-ketoglutarate (sometimes) and citrate, and possibly lactate (Xi et al. 2021). |
Eukaryota | Fungi, Ascomycota | Jen2 of Candida albicans |
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2.A.1.12.4 | Jen1 of 541 aas and 12 TMSs. Zt is a monocarboxylate (lactate) uptake porter that is upregulated following the phagocytosis of Candida albicans cells by neutrophils and macrophages. It may be important for virulence (Soares-Silva et al. 2013; Vieira et al. 2010). It may be the only lactate uptake porter and is subject to glucose catabolite repression. However, growth on lactate affects biofilm formation, morphology and susceptibility to fluconazole, and both Jen1 and Jen2 may play a role in these processes. Thus, the adaptation of Candida cells to the carbon source present in the host niches affects their pathogenicity (Alves et al. 2017; Alves et al. 2020). |
Eukaryota | Fungi, Ascomycota | Jen1 of C. albicans |
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2.A.1.13.1 | The low affinity proton-linked monocarboxylate (lactate, pyruvate, mevalonate, branched chain oxo acids, β-hydroxybutyrate, γ-hydroxybutyrate, butyrate, acetoacetate, acetate and formate, succinate) uptake/efflux porter (Moschen et al. 2012; Reddy et al. 2020). pH-gated succinate secretion regulates muscle remodeling in response to exercise (Reddy et al. 2020). The structural basis of MCT1 inhibition by anti-cancer drugs has been considered (Wang et al. 2020). MCT1 also transports anti-tumor alkylating agents, 3-bromopyruvate and dichloroacetate (Cooper et al. 1989; Su et al. 2016; Bailey et al. 2019) as well as artemisinin (Girardi et al. 2020). Activity is stimulated by direct interaction with carbonic anhydrase isoform II (Becker et al., 2005). This transporter interacts physically with the chaperone protein Basigin (CD147; TC #8.A.23.1.1) which is required both for targetting to the plasma membrane and for activity. Mct-2 uses a different chaperone protein, GP70. Mct-1 also transports the methionine hydroxy analogue 2-hydroxy (4-methylthio) butanate (Martin-Venegas et al., 2007; Becker and Deitmer, 2008). MCT1, 3 and 4 require the ancillary protein, basigin (P35613; 8.A.23.1.1) for plasma membrane localization (Ovens et al., 2010). It partially localizes to the peroxysomal membrane (Visser et al. 2007). MCT1 is regulated by CD147 proteins, and this association is important for lactate export and cell proliferation in certain cancer cells (Walters et al. 2013). It is upregulated in some cancers and maintains the metabolic phenotype of these cancer cells by mediating lactate efflux together with a proton, promoting pH homeostasis (Baltazar et al. 2014). MCT-1 functions as a positive regulator of osteoblast differentiation via suppression of p53 (Sasa et al. 2018). It plays a role in aggressive breast cancer subtypes (Li et al. 2018) as well as other cancers (Park et al. 2018). The SLC16A1 gene is a potential marker to predict race performance in Arabian horses (Ropka-Molik et al. 2019). MCT1 is a negative regulator and MCT2 and a positive regulator of osteoclast differentiation, while MCT2 is required for bone resorption by osteoclasts (Imai et al. 2019). MCTs 1 and 4 are present in increased amounts in solid tumors, and inhibitors as potential therapeutics have been reviewed (Puri and Juvale 2020). Interleukin-1beta induces monocarboxylate transporter-1 in an oxygen tension-dependent manner (Tanaka et al. 2022). Substrate protonation is a pivotal step in the mechanisms of several MCT-unrelated weak acid translocating proteins, but utilization of the proton binding and transfer capabilities of the transporter-bound substrate is probably a universal theme for weak acid anion/H+ cotransport (Geistlinger et al. 2023). This transporter is over expressed in breast cancer (Arponen et al. 2023). Fasting upregulates MCT1 at the rat blood-brain barrier through PPAR δ activation (Chasseigneaux et al. 2024). The anticancer effect of androgen deprivation therapy can be enhanced by an MCT1 inhibitor in prostate cancer cells (Kim et al. 2024). Sulforaphane (SFN) inhibits non-small cell lung cancer (NSCLC) growth and metastasis by reducing lactate production by regulating the expressions of monocarboxylate transporter 1 (MCT1) and MCT4 that transport lactate across cell membrane (Shi et al. 2024). The N-terminal signature motif on MCT1 is critical for CD147-mediated trafficking (see TC#s 3.A.3.2.1 and 8.A.23.1.1as well as 2.A.1.13.1) (Seka et al. 2024). A cluster of non-steroidal anti-inflammatory drugs (NSAIDs) are inhibitors of lactate transport via MCT1 (Wegner et al. 2024). The structures and functions of MCTs, their participation in cancer, and developed inhibitors have been reviewed (Koltai and Fliegel 2024). |
Eukaryota | Metazoa, Chordata | MCT1 (SLC16A1) of Homo sapiens |
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2.A.1.13.10 |
MCT8 (SLC16a2) homodimeric monocarboxylate thyroid hormone transporter 8 of 613 or 539 aas and 12 TMSs (Visser et al. 2009; Arjona et al., 2011). It is the X-linked mental retardation Allan-Herndon-Dudley syndrome (AHDS) (a severe psychomotor retardation syndrome) protein (Schweizer and Köhrle 2012; Boccone et al. 2010; Johannes et al. 2016). Lack of MCT8 function produces serious neurological disturbances, most likely due to impaired transport of thyroid hormones across brain barriers during development, resulting in severe brain hypothyroidism (Grijota-Martínez et al. 2020). Arg residues important for function have been identified (Groeneweg et al. 2013). Thyroid hormone (TH) transporters in the brain and across the blood brain barrier have been reviewed (Wirth et al. 2014; Bernal et al. 2015). The product facilitates both TH uptake and efflux across the cell membrane. The disease goes together with low serum T4 and high T3 levels. The mechanisms underlying MCT8-deficient brain development in various animal models including humans has been reviewed (Vancamp and Darras 2017). Together with OATP1C1 (TC# 2.A.60.1.15), MCT8 controls skeletal muscle regeneration (Mayerl et al. 2018). Deafness and loss of cochlear hair cells occurs in the absence of thyroid hormone transporters, Slc16a2 (Mct8) and Slc16a10 (Mct10) (Sharlin et al. 2018). Stable levels of MCT8 protein in endothelial cells of the blood-brain barrier, choroid plexus epithelial cells and tanycytes during postnatal development has been demonstrated (Wilpert et al. 2020). Oligomerization involves noncovalent interactions between the N-terminal halves of MCT8 proteins (Groeneweg et al. 2020). Genetic variants in MCT8, cause intellectual and motor disability and abnormal serum thyroid function tests, known as MCT8 deficiency (van Geest et al. 2020). Shaji 2021 identified natural inhibitors against MCT8. Emodin exhibited the best binding energy of -8.6 kcal/mol followed by helenaquinol, cercosporamide and resveratrol. Emodin and helenaquinol exhibit high binding energy. Cercosporamide and resveratrol exhibited higher binding energy than triac and desipramine and showed the binding energy similar to silychristin. Thus, these compounds could be promising candidates for further evaluation for AHDS prevention. MCT8 deficiency induces severe X-linked psychomotor retardation (Iwayama et al. 2021). It is common and severe in homozygous males (one X chromosome) but mild in heterozygous females (XX) (Dumitrescu et al. 2004). Thyroid normone transporters MCT8 and OATP1C1 are expressed in pyramidal neurons and interneurons in the adult motor cortex of human and macaque brains (Wang et al. 2023). Thyroid hormone transporters MCT8 and OATP1C1 are expressed in projection neurons and interneurons of basal ganglia and motor thalamus in adult human brains (Wang et al. 2023). MCT8 plays a vital role in maintaining brain thyroid hormone homeostasis. This transporter is expressed at the brain barriers, as the blood-brain barrier (BBB), and in neural cells, being the sole known thyroid hormone-specific transporter to date. Inactivating mutations in the MCT8 gene cause the Allan-Herndon-Dudley Syndrome (AHDS) or MCT8 deficiency, a rare X-linked disease characterized by delayed neurodevelopment and severe psychomotor disorders as well as BBB leakage (Guillén-Yunta et al. 2023). A novel SLC16A2 gene mutation produced a rare case of delayed myelination with dysthyroidism, v Allan-Herndon-Dudley syndrome (Mahesan et al. 2023). MCT8 inhibitors include methylmercury, bisphenol-AF and bisphenol-Z as well as previously known MCT8 inhibitors (Wagenaars et al. 2024). Monocarboxylate transporter 8 (MCT8) mediates the cellular delivery of thyroid hormones, L-thyroxine (T4) and 3,5,3'-triiodo-L-thyronine (T3). In humans, the MCT8 protein is encoded by the SLC16A2 gene, and mutations in the transporter cause a genetic neurological disorder known as Allan-Herndon-Dudley Syndrome (AHDS). MCT8 deficiency leads to impaired transport of thyroid hormones in the brain (Giri et al. 2024). MCT8 deficiency is a rare and devastating disorder characterized by central hypothyroidism and peripheral thyrotoxicosis (Çelik et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC16A2 of Homo sapiens |
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2.A.1.13.11 | Solute carrier family 16, member 5 (monocarboxylic acid transporter 6) of 505 aas and 12 TMSs. Found on the luminal side of small intestinal epithelial cells (Kohyama et al. 2013). MCT6 mediates uptake of nateglinide, an oral hypoglycemic agent. The K(t) for nateglinide is 46 μM. Thus, MCT6 may play a role in the intestinal absorption of nateglinide, although other transporters are also likely to be involved (Kohyama et al. 2013). 5-carboxyfluorescein is also a substrate of this system, and uptake is stimulated by Cl- (Higuchi 2024). |
Eukaryota | Metazoa, Chordata | SLC16A5 of Homo sapiens |
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2.A.1.13.12 | Solute carrier family 16, member 14 (monocarboxylic acid transporter 14), ATBo or MCT14. Transports carnitine with low affinity (~ 1 mM) (Ingoglia et al. 2015). Its tissue localization in the mouse has been determined (Roshanbin et al. 2016).
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Eukaryota | Metazoa, Chordata | SLC16A14 of Homo sapiens |
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2.A.1.13.13 | solute carrier family 16, member 11 (monocarboxylic acid transporter 11) | Eukaryota | Metazoa, Chordata | SLC16A11 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.13.14 | Solute carrier family 16, member 12, SLC16A12, or monocarboxylic acid transporter 12; MCT12. Facilitative monocarboxylate transporter that mediates creatine transport across the plasma membrane (Abplanalp et al. 2013; Takahashi et al. 2020). It is the cataract and glucosuria associated monocarboxylate transporter. |
Eukaryota | Metazoa, Chordata | SLC16A12 of Homo sapiens |
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2.A.1.13.15 | Monocarboxylate transporter 7 (MCT 7; mTORC1) (Monocarboxylate transporter 6) (MCT 6) (Solute carrier family 16 member 6) of 523 aas and 12 TMSs in a 6 + 6 TMS arrangement. SLC16a6, mTORC1, and autophagy regulate ketone body excretion in intestinal cells (Uebanso et al. 2023). Taurine is a substrate of this system (Higuchi 2024). |
Eukaryota | Metazoa, Chordata | SLC16A6 of Homo sapiens |
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2.A.1.13.16 | Monocarboxylate transporter 9 (MCT 9) (Solute carrier family 16 member 9) | Eukaryota | Metazoa, Chordata | SLC16A9 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.13.17 | Monocarboxylate transporter 13 (MCT 13) (Solute carrier family SLC16 member 13). Cephradine is a substrate of this system (Higuchi 2024), and uptake is stimulated by K+. |
Eukaryota | Metazoa, Chordata | SLC16A13 of Homo sapiens |
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2.A.1.13.18 | Probable transporter MCH2 | Eukaryota | Fungi, Ascomycota | MCH2 of Saccharomyces cerevisiae S288c | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.13.19 | Probable transporter MCH4 | Eukaryota | Fungi, Ascomycota | MCH4 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.13.2 | The low affinity aromatic amino acid (Tyr, Trp, Phe) transporter, TAT1 (T-type amino acid transporter), MCT10, Slc16a10. Also transports N-methyl amino acids and thyroid hormones. Essential for aromatic amino acid homeostasis in various tissues of mice (Mariotta et al. 2012). MCT10 is 58% identical to MCT8. Both transporters mediate T3 transport, but while MCT8 also transports rT3 and T4, these compounds are not efficiently transported by MCT10. A few amino acyl residue substitutions in the human orthologue broadens the substrate specificity of this porter (Johannes et al. 2016). The Six1 trahscription factor promotes a skeletal muscle thyroid hormone response through regulation of the MCT10 transporter (Girgis et al. 2021). |
Eukaryota | Metazoa, Chordata | Tat1 of Rattus norvegicus |
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2.A.1.13.20 | Putative permease of 468 aas |
Eukaryota | Rhodophyta | Putative permease of Galdieria sulphuraria |
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2.A.1.13.21 | MFS porter of 392 aas |
Bacteria | Pseudomonadota | MSF porter of Pseudomonas stutzeri |
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2.A.1.13.22 | SLC16 Family protein of 771 aas and 12 TMSs, GEM-1. GEM-1 acts in parallel to the GON-2 channel (TC# 1.A.4.5.10) to promote cation uptake within the developing gonad (Kemp et al. 2009). |
Eukaryota | Metazoa, Nematoda | Gem1 of Caenorhabditis elegans |
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2.A.1.13.23 | Chicken MCT8 of 509 aas and 12 TMSs. Transports pro-thyroid hormone, T4, with high affiinity, and T3 as well (Nele Bourgeois et al. 2016). |
Eukaryota | Metazoa, Chordata | MCT8 of Gallus gallus (Chicken) |
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2.A.1.13.24 | MCT10 (SLC16A10) of 400 aas and 11 TMSs. Transports thyroid hormones, especially T3 (Nele Bourgeois et al. 2016). |
Eukaryota | Metazoa, Chordata | MTC10 of Gallus gallus (chicken) |
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2.A.1.13.25 | Thyroid hormones (TH) transporter, MCT8 of 526 aas and 12 TMSs (Zada et al. 2017). The mechanisms underlying MCT8-deficient brain development in various animal models including zebra fish and humans has been reviewed (Vancamp and Darras 2017). |
Eukaryota | Metazoa, Chordata | TH transporter of Danio rerio (Zebrafish) (Brachydanio rerio) |
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2.A.1.13.26 | Thyroid hormones (TH) transporter, MCT10 of 505 aas and 12 TMSs. |
Eukaryota | Metazoa, Chordata | MCT10 of Danio rerio (Zebrafish) (Brachydanio rerio) |
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2.A.1.13.27 | MfsG of 447 aas and 12 TMSs. Exports fungicides such as glucosinolates and isothiocyanates. Exposure to glucosinolate-breakdown products induces expression of mfsG. MfsG functions in fungitoxic compound efflux (Vela-Corcía et al. 2019). |
Eukaryota | Fungi, Ascomycota | MfsG of Botryotinia fuckeliana (Noble rot fungus) (Botrytis cinerea) |
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2.A.1.13.28 | Uncharacterized protein of 652 aas and 12 TMSs |
Eukaryota | Metazoa, Arthropoda | UP of Trachymyrmex zeteki |
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2.A.1.13.3 | The thyroid hormone transporter, MCT8 (transports L- and D-isomers of thyroxine (T4), 3,3',5-triiodothyronine (T3), 3,3'5'-triiodothyronine (rT3) and 3,3'-diiodothyronine [Km values = 2-5 μM; Leu, Phe, Trp and Tyr were not transported]) (Friesema et al., 2003). Loss of function mutations in MCT8 leads to Allan-Herndon-Dudley syndrome, severe X-linked psychomotor retardation and elevated serum T3 levels (Jansen et al., 2008). Essential molecular determinants for thyroid hormone transport and their structural implications are presented by Kinne et al. (2010). Induced by retinoic acid (Kogai et al., 2010). Mediates energy-independent bidirectional transport. MCT8 is specific for L-iodothyronines and requires at least one iodine atom per aromatic ring. Thyronamines, decarboxylated metabolites of iodothyronines, triiodothyroacetic acid and tetraiodothyroacetic acid, TH derivatives lacking both chiral center and amino group, are not substrates (Kinne et al., 2010). A deficiency causes altered thyroid morphology and a persistent high triiodothyronine/thyroxine ratio after thyroidectomy (Wirth et al., 2011). Primary and secondary thyroid hormone transporters have been reviewed (Kinne et al., 2011). A differential effect of a shortage of thyroid hormone was observed compared with a knockout of thyroid hormone transporters Mct8 and Mct10 on murine macrophage polarization (Hoen et al. 2024). |
Eukaryota | Metazoa, Chordata | MCT8 of Mus musculus (O70324) |
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2.A.1.13.4 | The high affinity (17 μM) facilitated diffusion, riboflavin-regulated riboflavin uptake system, Mch5 (Reihl and Stolz, 2005) |
Eukaryota | Fungi, Ascomycota | Mch5 of Saccharomyces cerevisiae (NP_014951) |
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2.A.1.13.5 | Low affinity monocarboxylate transporter-2 (MCT2). Transports γ-hydroxybutyrate (Wang and Morris, 2007). MCT2 requires the ancillary protein, embigin (Q6PCB8; 8.A.23.1.2) for plasma membrane localization (Ovens et al., 2010). It is present in neurons but not astrocytes where the low affinity MCT1 and MCT4 predominate (Hertz and Dienel 2013). Partially localizes to the peroxysomal membrane (Visser et al. 2007). MCT1 is a negative regulator and MCT2 a positive regulator of osteoclast differentiation, while MCT2 is required for bone resorption by osteoclasts (Imai et al. 2019). Atorvastatin exerts more selective inhibitory effects on hMCT2 than on hMCT1 and hMCT4 (Yamaguchi et al. 2023). MCT2 is a neuronal, but not glial, ketone transporter, and it is a potential counteracting factor by facilitating neurons' energy uptake independently of insulin (Antal et al. 2025). |
Eukaryota | Metazoa, Chordata | MCT2 (SLC16A7) of Homo sapiens |
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2.A.1.13.6 |
Plasma membrane proton-linked monocarboxylate transporter, MCT4 or MCT-4 (SLC16A3). It catalyzes the rapid low affinity plasma membrane transport of many monocarboxylates such as lactate, pyruvate, branched-chain oxo acids derived from leucine, valine and isoleucine, and the ketone bodies acetoacetate, beta-hydroxybutyrate and acetate. It is the main transporter that catalyzes lactate efflux from glycolyzing cells (Halestrap 2013; Papakonstantinou et al. 2021). Residues binding high affinity inhibitors have been identified (Nancolas et al. 2015). It forms a complex with binding partner, CD147/BSG, which regulates the transport activity (Fisel et al. 2015). It plays a role in aggressive breast cancer subtypes (Li et al. 2018) as well as other cancers (Park et al. 2018). MCT4 may be a therapeutic target for colorectal cancer (Kim et al. 2018). MCTs 1 and 4 are present in increased amounts in solid tumors, and inhibitors are potential therapeutics (Puri and Juvale 2020). Anagliptin promotes apoptosis in mouse colon carcinoma cells via MCT-4/lactate-mediated intracellular acidosis (Li et al. 2022). Dietary folate deficiency promotes lactate metabolic disorders that sensitize lung cancer metastasis through mTOR-signaling-mediated targets (Chen et al. 2023). Shikonin reduced MCT4 expression and activation, resulting in inhibition of aerobic glycolysis in cancer-associated fibroblasts (CAFs) and overcoming CAF-induced gemcitabine resistance in pancreatic cancer (PC). Shikonin is a promising chemosensitizing phytochemical agent when used in combination with gemcitabine for PC treatment. The results suggest that disrupting the metabolic coupling between cancer cells and stromal cells might provide an attractive strategy for improving gemcitabine efficacy (Hu et al. 2024). Sulforaphane (SFN) inhibits non-small cell lung cancer (NSCLC) growth and metastasis by reducing lactate production by regulating the expressions of monocarboxylate transporter 1 (MCT1) and MCT4 that transport lactate across cell membrane (Shi et al. 2024). |
Eukaryota | Metazoa, Chordata | MCT4 (SLC16A3) of Homo sapiens |
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2.A.1.13.7 | Monocarboxylate transporter-5 (MCT5 or SLC16A4; sometimes referred to as MCT4). Lactate transport via the MCT5 is non enzymatically stimulated by carbonic anhydrase II (Becker et al., 2010). MCTs require an ancillary 1TMS glycoprotein, either Embigin (Q6PCB8; TC# 8.A.23.1.2) or basigin (P35613; TC# 8.A.23.1.1) for plasma membrane localization (Ovens et al., 2010). Upregulated in some cancers and maintains the metabolic phenotype of these cancer cells by mediating lactate efflux together with a proton, promoting pH homeostasis (Baltazar et al. 2014). Also transports the chemotheraputic agent, 3-bromopyruvate (Baltazar et al. 2014). Embigin (EMB) is a prognostic biomarker for glioblastoma multiforme (GBM) and EMB drives GBM progression. Ganxintriol A is a promising therapeutic candidate for GBM treatment (Cheng et al. 2025). |
Eukaryota | Metazoa, Chordata | SLC16A4 of Homo sapiens |
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2.A.1.13.8 | Monocarboxylate transporter, MCT10. Transports thyroid horomones as well as aromatic amino acids (Visser et al., 2010). Primary and secondary thyroid hormone transporters have been reviewed (Kinne et al., 2011). Deafness and loss of cochlear hair cells occurs in the absence of thyroid hormone transporters, Slc16a2 (Mct8) and Slc16a10 (Mct10) (Sharlin et al. 2018). Tissue-specific functions of thyroid hormone transporters in mice, including MCT8, MCT10 and Oatp1c1 have been reviewed (Salveridou et al. 2020). |
Eukaryota | Metazoa, Chordata | SLC16A10 of Homo sapiens |
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2.A.1.13.9 | Short chain monocarboxylate (lactate) transporter 3, MCT3. MCT1, 3 and 4 require the ancillary protein, basigin (P35613; 8.A.23.1.1) for plasma membrane localization (Ovens et al., 2010). |
Eukaryota | Metazoa, Chordata | SLC16A8 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.14.1 | Glucarate porter, GudT, of 455 aas and 12 TMSs. Hydrogen-stimulated carbon acquisition in Salmonella enterica serovar Typhimuriumhas been described (Lamichhane-Khadka et al. 2011). Additionally, a link between gut community metabolism and pathogenesis: molecular hydrogen-stimulated glucarate catabolism aids Salmonella virulence (Lamichhane-Khadka et al. 2013). |
Bacteria | Bacillota | GudT of Bacillus subtilis |
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2.A.1.14.10 | Lysosomal sialate transporter (Salla disease and infantile sialate storage disease protein, Sialin, of 419 aas and 12 TMSs (Morin et al., 2004)). Also transports glucuronic acid and aspartate. Structure-function studies have identify crucial residues and substrate-induced conformational changes (Courville et al., 2010). Also called SLC17A5. The substrate binding pocket has been identified based on modeling studies (Pietrancosta et al., 2012). NAAG (N-acetylaspartylglutamate) an abundant neuropeptide in the vertebrate nervous system that is released from synaptic terminals in a calcium-dependent manner and acts as an agonist at the type II metabotropic glutamate receptor mGluR3, is transported into synaptic vesicles before it is secreted. Lodder-Gadaczek et al. 2013 demonstrate that vesicular uptake of NAAG and the related peptide NAAG2 (N-acetylaspartylglutamylglutamate) is mediated by sialin (SLC17A5). Sialin is probably the only vesicular transporter for NAAG and NAAG2, because transport of both peptides was not detectable in vesicles isolated from sialin-deficient mice. Sialin also transports nitrate in the plasma membrane of salivary glands (Qin et al. 2012). Sialin interacts with nitrate and participates in the regulation of NO production and cell biological functions for body homeostasis (Wang and Qin 2022). Sialin mediates the flux of sialic acid from lysosomes to the cytoplasm (Li et al. 2022). Altered sialin mRNA expression in the main tissues of male type 2 diabetes rats has been documented (Yousefzadeh et al. 2023). Base editing corrects the common Salla disease SLC17A5 c.115C>T variant (Harb et al. 2023). |
Eukaryota | Metazoa, Chordata | SLC17A5 of Homo sapiens |
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2.A.1.14.11 | Plasma membrane, high affinity nicotinate permease, Tna1 | Eukaryota | Fungi, Ascomycota | Tna1 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.14.12 | Plasma membrane, high affinity biotin:H+ symporter, Vht1 | Eukaryota | Fungi, Ascomycota | Vht1 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.14.13 | Broad specificity brain synaptic vesicle anion:Na+ symporter (transports glutamate, phosphate, chloride, etc.)(BNPI, EAT-4, VGLUT1) Chloride and ketone bodies regulate VGLUT activities (Omote et al., 2011). Reduction in presynaptic glutamate release by lupeol in rats prevents glutamate excitotoxicity (Lu et al. 2025). |
Eukaryota | Metazoa, Chordata | BNPI of Rattus norvegicus |
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2.A.1.14.14 |
Probable D-galactarate (glucarate?):H+ symporter, GarP or YhaU. May also function as a glucarate:glycerate antiporter (Moraes and Reithmeier 2012) and a glucose transporter. This sequence is incomplete. |
Bacteria | Pseudomonadota | GarP (YhaU) of E. coli |
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2.A.1.14.15 | Apical membrane renal proximal tubular voltage-driven but Na+-independent organic anion transporter, OATv1 (transports p-aminohippurate; probably transports organic anions but not cations and not inorganic phosphate. It may catalyze excretion of various drugs, xenobiotics, and their metabolites) (Jutabha et al., 2003) |
Eukaryota | Metazoa, Chordata | OATv1 of Sus scrofa (Q7YQJ7) |
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2.A.1.14.16 | The broad specificity brain synaptic vesicle anion transporter, VGLUT-2 (transports glutamate in a Δψ-dependent fashion requiring Cl-, but phosphate by a Na+-dependent mechanism via a different pathway/mechanism (Juge et al., 2006). VGLUT1-3 concentrate glutamate into synaptic vesicles before its exocytotic release. Two distinct roles for Cl- in both allosteric activation and permeation have been proposed (Chang et al. 2018). The 3-D structure has been solved at 3.8 Å resolution revealing mechanisms of substrate recognition and allosteric activation by low pH and Cl-. It shows how the activities of VGLUTs are coordinated by changes in proton and chloride concentration during the synaptic vesicle cycle (Li et al. 2020). |
Eukaryota | Metazoa, Chordata | VGLUT2 of Rattus norvegicus (Q9JI12) |
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2.A.1.14.17 | Pantothenate:H+ symporter, Liz1 (mutants cause abnormal mitosis due to a defect in ribonucleotide reductase) (Stolz et al., 2004) | Eukaryota | Fungi, Ascomycota | Liz1 of Schizosaccharomyces pombe (O43000) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.14.18 | Pantothenate:H+ symporter, Fen2 | Eukaryota | Fungi, Ascomycota | Fen2 of Saccharomyces cerevisiae (P25621) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.14.19 | Plasma membrane, high affinity vitamin H transporter 1 (H+:biotin symporter), Vht1 (Stolz, 2003) | Eukaryota | Fungi, Ascomycota | Vht1 of Schizosaccharomyces pombe (O13880) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.14.2 | Hexuronate (glucuronate; galacturonate) porter, ExuT (Nemoz et al. 1976). It also transports D-glucose (Kim et al. 2020). |
Bacteria | Pseudomonadota | ExuT of E. coli (P0AA78) |
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2.A.1.14.20 | Endoplasmic reticular cysteine transporter, Yct1 (Kaur and Bachhawat, 2007) |
Eukaryota | Fungi, Ascomycota | Yct1 of Saccharomyces cerevisiae (Q12235) |
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2.A.1.14.21 | The vesicular purine nucleotide (ADP, ATP, GTP) transporter, VNUT or SLC17A9. It is found in synaptic vesicles and chromafin granules (Sawada et al., 2008)) and is associated with disseminated superficial actinic porokeratosis (DSAP), a rare autosomal dominant genodermatosis (Cui et al. 2014). It plays a key role in purinergic signaling through its ability to transport nucleotides using the pmf. It catalyzes Cl--dependent transport activity involving essential arginines in the transmembrane region. Ketoacids inhibit these transporters through modulation of Cl- activation, but Cl- and the arginine residues are not important for ATP binding (Iwai et al. 2019). High expression of SLC17A9 correlates with a poor prognosis for colorectal cancer (Yang et al. 2019). |
Eukaryota | Metazoa, Chordata | SLC17A9 of Homo sapiens |
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2.A.1.14.22 | The chloroplast thylakoid Na+:phosphate symporter, ANTR1 (512aas) (Pavón et al., 2008). Residues essential for function have been identified (Ruiz-Pavón et al., 2010). |
Eukaryota | Viridiplantae, Streptophyta | ANTR1 of Arabidopsis thaliana (O82390) |
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2.A.1.14.23 | Vesicular glutamate transporter #3 (VGLUT3) [Its absence in mice causes sensorineural deafness and seizures]. 70% identical to VGLUT2 (TC# 2.A.1.14.16) (Gras et al., 2002). VGLUT1-3 concentrate glutamate into synaptic vesicles before its exocytotic release and contribute to the regulation of serotonergic transmission and anxiety (Amilhon et al., 2010). It may catalyze uptake of the neurotransmitter coupled with H+ export and K+ uptake (Farsi et al. 2016). |
Eukaryota | Metazoa, Chordata | VGLUT3 of Mus musculus (Q8BFU8) |
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2.A.1.14.24 | Intestinal mucosal sodium/phosphate symporter, SLC17A4. Maintains phosphate homeostasis; mediates intestinal absorption, bone deposition and resorption and renal excretion. |
Eukaryota | Metazoa, Chordata | SLC17A4 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.14.25 | The putative D-mannuronate porter, AlgT (Rodionov et al., 2010). |
Bacteria | Pseudomonadota | AlgT of Shewanella frigidimarina (Q07YH1) |
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2.A.1.14.26 | The plasma membrane Lethal (2)01810 glutamate uptake porter (Km=0.07μM) (Inhibited by aspartate) (Shim et al., 2011) |
Eukaryota | Metazoa, Arthropoda | L(2)01810 of Drosophila melanogaster (F2YPN7) |
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2.A.1.14.27 | Voltage-driven Na+:phosphate cotransporter; solute carrier family 17, member 1. Orthologous to 2.A.1.14.6. Transports other anions including urate; functions in urate cell elimination at the renal apical membrane (Prestin et al. 2014). |
Eukaryota | Metazoa, Chordata | SLC17A1 of Homo sapiens |
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2.A.1.14.28 | Solute carrier family 17 (sodium phosphate), member 3. Catalyzes voltage-driven Na+:phosphate cotransport, but also functions in cell elimination of urate at renal tubular cell apical membranes (Prestin et al. 2014). |
Eukaryota | Metazoa, Chordata | SLC17A3 of Homo sapiens |
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2.A.1.14.29 | Sodium-dependent phosphate transport protein 3 (Na(+)/PI cotransporter 3) (Sodium/phosphate cotransporter 3) (Solute carrier family 17 member 2) | Eukaryota | Metazoa, Chordata | SLC17A2 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.14.3 | Putative tartrate porter, TtuB or TUB3, of 449 aas and 12 TMSs. |
Bacteria | Pseudomonadota | TtuB of Agrobacterium vitis |
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2.A.1.14.30 | Vesicular glutamate transporter 1, VGluT1 or PNP1 of 560 aas and 12 TMSs. Brain-specific Na+-dependent inorganic phosphate cotransporter; Solute carrier family 17 member 7). Several proteins must be retrieved to the synaptic vesicle before it can export neurotransmitters, and cargo retrieval is a collective cargo-driven process, dependent on VGluT1 (Pan et al. 2015). The amino-terminal and carboxyl-terminal regions of VGLUT2 in membranes face the cytoplasm (Jung et al. 2006). It is involved in nervous system diseases (Du et al. 2020). VGLUT1 and VGLUT2, selectively label and define functionally distinct neuronal subpopulations at each relay level of the neural hierarchies comprising spinal and trigeminal sensory systems (Zhang et al. 2018). An overview of the physiologic sites for VGLUT regulation that can modulate glutamate release in an over-active synapse or in a disease state has been presented (Pietrancosta et al. 2020). |
Eukaryota | Metazoa, Chordata | SLC17A7 of Homo sapiens |
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2.A.1.14.31 | Vesicular glutamate transporter 2 (VGluT2) (Differentiation-associated BNPI) (Differentiation-associated Na+-dependent inorganic phosphate cotransporter) (Solute carrier family 17 member 6, SLC17A6). It has 582 aas with 12 probable TMSs. It is expressed in different nerve fibre populations that selectively contact pulmonary neuroepithelial bodies (Brouns et al. 2004). |
Eukaryota | Metazoa, Chordata | SLC17A6 of Homo sapiens |
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2.A.1.14.32 | Vesicular glutamate transporter 3 (VGluT3) (Solute carrier family 17 member 8). Loss in mice produces circadian-dependent hyperdopaminergia and amiliorates motor disfunction and dopa-mediated dyskinesias in a model of Parkinson's Disease (Divito et al. 2015). VGLUT3 is expressed selectively in the inner hair cells (IHCs) and transports the neurotransmitter glutamate into synaptic vesicles. Mutation of the SLC17A8 gene is associated with DFNA25 (deafness, autosomal dominant 25), a non-syndromic hearing loss (ADNSHL) in humans (Ryu et al. 2016). Glut3 contributes to stress response and related psychopathologies (Horváth et al. 2018). An adeno-associated virus carrying the Slc17a8 gene restored vesicular Glut3 in the inner hair cells of the cochlea, thereby rescuing loss in mice that lacked Glut3 (Mathiesen et al. 2023). | Eukaryota | Metazoa, Chordata | SLC17A8 (VGluT3) of Homo sapiens |
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2.A.1.14.33 |
L-galactonate transporter, YjjL or DgoT of 460 aas and 12 TMSs. The D-galactonate transporter DgoT has been solved at atomic resolution (Dmitrieva et al. 2024). Protonation of D46 and E133 precedes galactonate binding, and substrate binding induces closure of the extracellular gate, with the conserved R47 coupling substrate binding to transmembrane helix movement. After isomerization to an inward-facing conformation, deprotonation of E133 and subsequent proton transfer from D46 to E133 opens the intracellular gate and permits galactonate dissociation either in its unprotonated form or after proton transfer from E133. After release of the second proton, apo DgoT returns to the outward-facing conformation (Dmitrieva et al. 2024). |
Bacteria | Pseudomonadota | YjjL or DgoT of Escherichia coli |
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2.A.1.14.34 | Putative inorganic phosphate cotransporter | Eukaryota | Metazoa, Arthropoda | Picot of Drosophila melanogaster | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.14.35 | Inner membrane transport protein RhmT | Bacteria | Pseudomonadota | RhmT of Escherichia coli |
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2.A.1.14.36 | Thiamine pathway transporter THI73 | Eukaryota | Fungi, Ascomycota | THI73 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.14.37 | Probable transporter SEO1 | Eukaryota | Fungi, Ascomycota | SEO1 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.14.38 | Transporter YIL166c (Hellborg et al. 2008) of 542 aas and 12 TMSs. May transport inorganic sulfur-containing compounds such as sulfate, sulfite, thiosulfate and sulfonates. |
Eukaryota | Fungi, Ascomycota | YIL166c of Saccharomyces cerevisiae |
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2.A.1.14.39 | Uncharacterized transporter YybO | Bacteria | Bacillota | YybO of Bacillus subtilis |
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2.A.1.14.4 | Dipeptide (e.g., Gly-Leu), allantoate, ureidosuccinate, allantoin porter (Cai et al., 2007). | Eukaryota | Fungi, Ascomycota | Dal5 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.14.40 |
Glucarate transporter, GudP. Encoded in an operon with GudD, a glucarate dehydratase (Moraes and Reithmeier 2012). |
Bacteria | Pseudomonadota | GudP of E. coli |
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2.A.1.14.41 | The Aldohexuronate (glucuronate, galacturonate) uptake porter (Valmeekam et al. 2001). |
Bacteria | Pseudomonadota | ExuT of Erwinia chrysanthemi This sequence is incomplete. |
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2.A.1.14.42 | Vesicular glutamate transporter, EAT-4/VGLUT of 576 aas (Serrano-Saiz et al. 2013). EAT-4 is responsible for loading glutamate into synaptic vesicles, and thus in defining the glutamatergic phenotype of a neuron (Serrano-Saiz et al. 2013). |
Eukaryota | Metazoa, Nematoda | EAT-4 of Caenorhabditis elegans |
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2.A.1.14.43 | Uncharacterized but putative sulfonate (and other inorganic sulfur-containing compounds) uptake transporter of 537 aas and 12 TMSs. |
Eukaryota | Fungi, Ascomycota | UP of Ashbya gossypii (Yeast) (Eremothecium gossypii) |
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2.A.1.14.44 | Vesicular Glutamate transporter, VGlut of 632 aas and 10 TMSs with the N- and C-termini in the cytoplasm (Fei et al. 2007). |
Eukaryota | Metazoa, Arthropoda | VGlut of Drosophila melanogaster |
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2.A.1.14.45 | AtPHT4;4, or ANTR2 of 541 aas and 12 TMSs, an ascorbate transporter in the chloroplast envelope membrane. It may be required for tolerance to strong light stress (Miyaji et al. 2015). |
Eukaryota | Viridiplantae, Streptophyta | ANTR2 of Arabidopsis thaliana |
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2.A.1.14.46 | Vesicular glutamate transporter, VGLU-2, of 573 aas and 12 TMSs. In addition to being present in nerve cells, it may play a role in collagen trafficking in the skin. The C. elegans SLC17A6/7/8 family members probaly have diverse functions within and outside the nervous system (Serrano-Saiz et al. 2019). |
Eukaryota | Metazoa, Nematoda | VGLU-2 of Homo sapiens |
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2.A.1.14.47 | MFS2 of 1379 aas and 12 TMSs in a 6 + 6 TMS arrangement at the C-terminal end of the protein (residues 800 - 1379). The N-terminal 800 residues are strongly hydrophilic (Wunderlich 2022). |
Eukaryota | Apicomplexa | MFS2 of Plasmodium falciparum |
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2.A.1.14.48 | MFS general substrate transporter of 451 aas and 12 TMSs, MFS-3-6. It facilitates the export of lactate from the cell under acidic conditions (Tian et al. 2022). |
Bacteria | Bacillota | MFS-3-6 of Weizmannia coagulans (strain 2-6) (Bacillus coagulans) |
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2.A.1.14.49 | Uncharacterized MFS carrier of 453 aas and probably 12 TMSs in a 6 + 6 TMS arrangement. The encoding gene is responsive to the presence of Ivermectin (Dube et al. 2023). |
Eukaryota | Metazoa, Nematoda | UP of Caenorhabditis elegans |
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2.A.1.14.5 | Phthalate porter, Pht1 of 451 aas and 11 or 12 TMSs. |
Bacteria | Pseudomonadota | Pht1 of Pseudomonas putida |
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2.A.1.14.50 | MFS carrier, a putative drug exporter of 450 aas and 12 TMSs in a 6 + 6 TMS arrangement. It exports polymyxin B, CCCP and verapamil (Gao et al. 2023). |
Bacteria | Pseudomonadota | Polymyxin exporter of Pandoraea pnomenusa |
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2.A.1.14.51 | Vacuoloar glutamate transporter 1, VGLUT1 of 483 aas and 12 TMSs in a 6 + 6 TMS arrangement. Regulatory mechanisms of the six glutamate transporters (3 excitatory and 3 vesicular) in the response of the pacific oyster upon high-temperature stress have been studied (Zhang et al. 2024). |
Eukaryota | Metazoa, Mollusca | VGLUT1 of the pacific oyster (Crassostrea gigas) |
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2.A.1.14.6 | Na:Pi symporter, NPT1 or SLC17A1. (Renal chloride-dependent polyspecific anion exporter; transports organic acids such as p-aminohippurate, ureate, and acetylsalicylate (asprin)). Catalyzes ureate excretion. A mutant form shows increased risk of gout in humans. |
Eukaryota | Metazoa, Chordata | Npt1 of Mus musculus |
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2.A.1.14.7 | Galactonate transporter | Bacteria | Pseudomonadota | DgoT (YidT) of E. coli (P0AA76) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.14.8 | Phthalate porter | Bacteria | Pseudomonadota | OphD of Burkholderia cepacia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.14.9 | Putative p-hydroxyphenylacetate porter | Bacteria | Pseudomonadota | HpaX of Salmonella dublin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.15.1 | 4-Hydroxybenzoate/protocatechuate porter (Nichols and Harwood 1997). |
Bacteria | Pseudomonadota | PcaK of Pseudomonas putida |
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2.A.1.15.10 | The gentisate (2,5-dihydroxybenzoate) uptake porter, GenK (does not take up either benzoate or 3-hydoxybenzoate). |
Bacteria | Actinomycetota | GenK of Corynebacterium glutamicum (Q8NLB7) |
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2.A.1.15.11 | The Vanillate porter, VanK |
Bacteria | Actinomycetota | VanK of Corynebacterium glutamicum (Q6M372) |
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2.A.1.15.12 | Inner membrane transport protein YdiM. Catalyzes export of medium chain alcohols such as isoprenol (Wang et al. 2015). |
Bacteria | Pseudomonadota | YdiM of Escherichia coli |
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2.A.1.15.13 | Inner membrane transport protein, YdiN (similar to 2.A.1.15.12). Induced under carbon limitation but not phosphate limitation (Johansson and Lidén 2006). |
Bacteria | Pseudomonadota | YdiN of Escherichia coli |
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2.A.1.15.14 | Probable uptake transporter for 2,4-dichlorophenoxyacetic acid (2,4-D), CadK (Kitagawa et al. 2002). |
Bacteria | Pseudomonadota | CadK of Bradyrhizobium sp. HW13 |
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2.A.1.15.15 | Unncharacterized permease of 436 aas and 12 TMSs. |
Bacteria | Spirochaetota | UP of Treponema brennaborense |
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2.A.1.15.16 | Aromatic/benzoate uptake transporter of 442 aas and 12 TMSs, BenK (Choudhary et al. 2017). |
Bacteria | Pseudomonadota | BenK of Pseudomonas putida |
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2.A.1.15.2 | MhpT. A specific 3-(3-hydroxyphenyl)propionate (3HPP) transporter; vital for E. coli K-12 W3110 to grow on this substrate. Transports 3HPP but not benzoate, 3-hydroxybenzoate or gentisate (Xu et al. 2013). May also export arabinose but not xylose (Koita and Rao 2012). |
Bacteria | Pseudomonadota | MhpT of E. coli |
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2.A.1.15.3 | 2,4-Dichlorophenoxyacetate porter (Hawkins and Harwood 2002). |
Bacteria | Pseudomonadota | TfdK of Ralstonia eutropha |
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2.A.1.15.4 | cis,cis-muconate porter, MucK (Williams and Shaw 1997). |
Bacteria | Pseudomonadota | MucK of Acinetobacter sp. ADP1 |
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2.A.1.15.5 | Benzoate porter, BenK | Bacteria | Pseudomonadota | BenK of Acinetobacter sp. ADPP1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.15.6 | Vanillate porter, VanK |
Bacteria | Pseudomonadota | VanK of Acinetobacter sp. ADP1 |
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2.A.1.15.7 | Aromatic compound (benzoate) uptake transporter of 450 aas (Clark et al. 2002). |
Bacteria | Pseudomonadota | BenK of Acinetobacter baylyi |
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2.A.1.15.8 | Probable 1-hydroxy-2-naphthoate transporter, orf1 (Iwabuchi and Harayama, 1997). | Bacteria | Actinomycetota | Orf1 of Nocardioides sp. (O24723) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.15.9 | Probable 4-methylmuconolactone transporter, MmlH (Erb et al., 1998) | Bacteria | Pseudomonadota | MmlH of Ralstonia eutropha (O51798) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.16.1 | Siderophore-iron (ferrioxamine):H+ symporter, Sit1 (Arn3) (in vesicles) |
Eukaryota | Fungi, Ascomycota | Sit1 (YEL065w) of Saccharomyces cerevisiae |
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2.A.1.16.2 | The ferric enterobactin:H+ symporter, Enb1 | Eukaryota | Fungi, Ascomycota | Enb1 (YOL158c) of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.16.3 | The ferric triacetylfusarinine C:H+ symporter, Taf1 | Eukaryota | Fungi, Ascomycota | Taf1 (YHL047c) of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.16.4 | The ferrichrome:H+ symporter, Arn1p (Moore et al., 2003) | Eukaryota | Fungi, Ascomycota | Arn1 of Saccharomyces cerevisiae (NP_011823) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.16.5 | Siderophore iron transporter 2 | Eukaryota | Fungi, Ascomycota | str2 of Schizosaccharomyces pombe | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.16.6 | Eukaryota | Fungi, Ascomycota | Str1 of Schizosaccharomyces pombe |
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2.A.1.16.7 |
Ferri-siderophore transporter, MirB. Transports hydroxamate siderophores such as triacetylfusarinine C (TAFC) (Raymond-Bouchard et al. 2012). |
Eukaryota | Fungi, Ascomycota | MirB of Emericella nidulans |
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2.A.1.16.8 | Fusarum iron-related protein, Fir1 of 585 aas and 14 TMSs. Probably an iron-siderophre transporter (López-Errasquín et al. 2006). |
Eukaryota | Fungi, Ascomycota | Fir1 if Gibberella moniliformis (Maize ear and stalk rot fungus) (Fusarium verticillioides) |
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2.A.1.16.9 | Siderophore iron transporter 3, Str3 of 630 aas and 14 TMSs in a 6 + 7 + 1 TMS arrangement. It transports siderophore iron and so plays a role in iron homeostasis (Pelletier et al. 2003). It also transports heme, and the peroxiredoxin, Tpx1 (Q74887; 192 aas and 0 - 2 possible TMSs), is a binding partner of Str3 (Normant et al. 2020). Under microaerobic conditions, cells deficient in heme biosynthesis and lacking the heme receptor Shu1 exhibit poor hemin-dependent growth in the absence of Tpx1, a cytoplasmic heme binding protein. Tpx1 exhibits an equilibrium constant value of 0.26 muM for hemin. The association of Tpx1 with hemin protects hemin from degradation by H2O2, and the peroxidase activity of hemin is lowered when it is bound to Tpx1 (Normant et al. 2020).
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Eukaryota | Fungi, Ascomycota | Str3 of Schizosaccharomyces pombe (Fission yeast) |
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2.A.1.17.1 | Cyanate transport system, CynT. Encoded with cyanate aminohydrolase, CynS, and carbonic anhydrase, CynX (Anderson et al. 1990; Moraes and Reithmeier 2012). |
Bacteria | Pseudomonadota | CynX of E. coli |
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2.A.1.17.2 | Glucose transporter, OEOE_0819. Does not transport fructose (Kim et al., 2011) |
Bacteria | Bacillota | OEOE_0819 of Oenococcus onei (Q04FN1) |
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2.A.1.17.3 | Inner membrane transport protein, NimT or YeaN of 393 aas and 12 TMSs. It exports 2-nitroimidazole from the cytoplasm, confering resistance to this anitbiotic, and transcription of this gene as well as NimO, within the same operon, is regulated by the repressor, NimR (YeaM) (Ogasawara et al. 2015). |
Bacteria | Pseudomonadota | NimT or YeaN of Escherichia coli |
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2.A.1.17.4 | MFS porter of 390 aas and 12 TMSs |
Bacteria | Campylobacterota | MFS porter of Campylobacter peloridis |
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2.A.1.18.1 | D-Arabinitol:H+ symporter of 425 aas and 12 TMSs, DalT (Heuel et al. 1997; Heuel et al. 1998). |
Bacteria | Pseudomonadota | DalT of Klebsiella pneumoniae |
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2.A.1.18.2 | Ribitol:H+ symporter of 427 aas and 12 TMSs, RbtT (Heuel et al. 1997; Heuel et al. 1998). |
Bacteria | Pseudomonadota | RbtT of Klebsiella pneumoniae |
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2.A.1.18.3 | Alpha-ketoglutarate permease of 435 aas and 12 TMSs (Gomez and Cutting 1997). |
Bacteria | Bacillota | CsbX of Bacillus subtilis |
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2.A.1.19.1 | The basolateral multivalent, potential-sensitive, organic cation (tetramethyl-ammonium; N'-methylnicotinamide; cationic drugs, xenobiotics, vitamins, neuro-transmitters, etc.) transporter (uni-porter)-1, Oct1. Cysteyl residues essential for transport and substrate binding have been identified (Sturm et al. 2007). Subtype-specific affinity of rat organic cation transporters rOCT1 and rOCT2 for corticosterone depends on three amino acids within the substrate binding region (Gorboulev et al. 2005). Differences in metformin and thiamine uptake between human and mouse Oct1 transporters have been demonstrated (Meyer et al. 2020). Methods for the quantification of organic cation transporters' mediated metformin uptake and its inhibition in cells have been developed (Bajraktari-Sylejmani et al. 2024). |
Eukaryota | Metazoa, Chordata | Oct1 of Rattus norvegicus (Q63089) |
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2.A.1.19.10 | The apical proximal tubular kidney/placenta organic anion transporter 4, Oat4 (Slc22a11) (transports estrone sulfate (Km = 1 µM), dehydroepiandrosterone sulfate (Km = 60µM), many anionic drugs, diuretics, bile salts, urate and ochratoxin A). Catalyzes Na+-independent efflux, possibly using glutamate as a counter anion in an exchange reaction, especially in the placenta (Lofthouse et al. 2015). Functions in renal urate reabsorption (Prestin et al. 2014). Chlorine decreases the expression of the gene encoding this transporter (Suman et al. 2023). hOAT4 is mainly expressed in the kidney and placenta, and is essential for the disposition of numerous drugs, toxins, and endogenous substances. It is regulated by insulin-like growth factor and portein kinase B (Yu et al. 2023). FRα and multiple transporters such as PCFT, RFC, OAT4, and OATPs are likely involved in the uptake of methotraxate (MTX), whereas MDR1 and BCRP are implicated in the efflux of MTX from choriocarcinoma cells (Bai et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC22A11 (Oat4) of Homo sapiens |
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2.A.1.19.11 | The apical proximal tubular renal urate:anion exchanger, URAT1 (Slc22a12). Catalyzes Na+-independent anion efflux (secretion) and reabsorption (Eraly et al., 2003a,b; Anzai and Endou, 2011; Prestin et al. 2014) Regulated by the PDZK1 protein; Anzai et al., 2004). Also transports orotate, a precursor of pyrimidine biosynthesis (Miura et al., 2011). Mutations in URAT1 cause hereditary renal hypouricemia/gaut. Residues involved in urea and inhibitor binding have been identified (Tan et al. 2016). Mutations can cause renal hypouricemia (RHUC), a heterogeneous genetic disorder that is characterized by decreased serum uric acid concentrations and increased fractional excretion of uric acid (Zhou et al. 2018; Kaynar et al. 2022). Mutation in transmembrane domain 8 of the human urate transporter 1 (residue K393) disrupts uric acid recognition and transport (Lan et al. 2022). Pathogenic variants of SLC22A12 (URAT1) and SLC2A9 (GLUT9) can give rise to renal hypouricemia (Perdomo-Ramirez et al. 2023). Biphenyl carboxylic acid derivatives are potent URAT1 inhibitors (Hou et al. 2023). |
Eukaryota | Metazoa, Chordata | URAT1/SLC22A12 of Homo sapiens |
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2.A.1.19.12 | The high affinity L-carnitine transporter, CT2, present in the luminal membranes of epididymal epithelia and Sertoli cells of the testis (Enomoto et al., 2002b). It also catalyzes uptake of the anticancer polyamine analogue, bleomycin-A5 (Aouida et al. 2010). Carnitine transport and metabolism have been reviewed (Nałęcz and Nałęcz 2017). SLC22A16 (CG6126) transports ergothioneine (Zhang et al. 2021). |
Eukaryota | Metazoa, Chordata | SLC22A16 of Homo sapiens |
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2.A.1.19.13 | The organic cation transporter, Oct1 (transports L-carnitine; expressed in vascular tissues of various organs and at sites of lateral root formation) (Lelandais-Briere et al, 2007). It also transports spermine and other polyamines and is induced by them (Sagor et al. 2016). It protects against the polyamine, cadaverine, which affects root length (Strohm et al. 2015). |
Eukaryota | Viridiplantae, Streptophyta | Oct1 of Arabidopsis thaliana (Q9CAT6) |
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2.A.1.19.14 |
Brush border glycosylated urate (Km= 1.2 mM) tranporter, RST. Orthologous to the human URAT1. Inhibited by 50 μM benzbromarone, 1 mM probenecid and 10 mM lactate which may also be transported and trans-stimulate urate uptake. May be orthologous to 2.A.1.19.11 as well (Hosoyamada et al., 2004). Involved in urate absorption across the apical membrane, but probably not the primary route (Eraly et al. 2008; Prestin et al. 2014). |
Eukaryota | Metazoa, Chordata | RST/Slc22a12 of Mus musculus |
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2.A.1.19.15 | The liver multispecific organic anion transporter, NLT or OAT2. Transports salicylate, KM=90µM, acetylsalicylate, prostaglandin E2, dicarboxylate, p-aminohippurate, etc. (Sekine et al., 1998) | Eukaryota | Metazoa, Chordata | NLT of Rattus norvegicus (Q63314) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.19.16 | The organic anion transporter, Oat6 or SLC22a20 of 556 aas and 12 TMSs. Binding and transport rates for 40 anionic substrates have been studied and compared with those for Oat1 (TC# 1.A.1.19.4) (Kaler et al., 2007). Oat6 transports many antiviral agents (Truong et al., 2008). It can bind odorants and is present in the mouse olfactory mucosa; it has been proposed to be an odorant receptor and/or odorant transporter (Wu et al. 2015). Mouse OAT6 is expressed predominantly in olfactory mucosa but not in kidney or brain (Monte et al. 2004). |
Eukaryota | Metazoa, Chordata | Oat6 of Mus musculus (Q80UJ1) |
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2.A.1.19.17 | Kidney organic cation transporter-like 3 ORCTL-3 (OAT10; SLC22A13; Like-3) (Bahn et al., 2008) (transports nicotinate, p-aminohippurate and urate; KM=20-40 mμM) via exchange for lactate). Activated by tumorigeneic mutations in this antitumor gene to promote apoptosis (AbuAli and Grimm 2014). Functions in urate reabsorption (Prestin et al. 2014). Substrate binding and lipid-mediated allostery in the human organic anion transporter 1 have been examined at the atomic-scale (Janaszkiewicz et al. 2023). |
Eukaryota | Metazoa, Chordata | SLC22A13 of Homo sapiens |
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2.A.1.19.18 | Oranic anion transporter, Oat7 (exchanges sulfate conjugates (steroids) and other anions for butyrate) (Shin et al., 2007). SLC22A9 and SLC29A2 are transporters mediating cellular uptake of 3,5,3'-Triiodothyroacetic acid (TRIAC), a T3-receptor agonist pharmacologically used in patients to mitigate T3 resistance. SLC22A9 encodes the organic anion transporter 7 (OAT7), a sodium-independent organic anion transporter expressed in the plasma membrane in brain, pituitary, liver, and other organs. Competition with the SLC22A9/OAT7 substrate estrone-3-sulfate reduced 125I-TRIAC uptake. SLC29A2 encodes the equilibrative nucleoside transporter 2 (ENT2), which is ubiquitously expressed, including the pituitary and brain. Coincubation with the SLC29A2/ENT2 inhibitor nitrobenzyl-6-thioinosine reduced 125I-TRIAC uptake. Moreover, ABCD1, an ATP-dependent peroxisomal pump, was identified as a 125I-TRIAC exporter in transfected MDCK1 cells (Becker et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC22A9 of Homo sapiens |
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2.A.1.19.19 | The rat kidney basolateral potential-driven symport carrier, Oct2 (transports tetraethylammonium and many other organic cations) (Sweet and Pritchard 1999). A cysteyl residue critical for substrate binding and transport has been identified (Sturm et al. 2007). Subtype-specific affinity of rat organic cation transporters rOCT1 and rOCT2 for corticosterone depends on three amino acids within the substrate binding region (Gorboulev et al. 2005). |
Eukaryota | Metazoa, Chordata | Oct2 of Rattus norvegicus (Q9R0W2) |
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2.A.1.19.2 | The ergothionine/carnitine/hydroxyurea/organic zwitterion transporter, OCTN1 or SVOP (SLC22A4). It is upregulated in polycythemia vera hematopoietic stem and progenitor cells (Tan and Meier-Abt 2021). It is associated with rheumatoid arthritis (Barton et al., 2005). Acetylcholine is a physiological substrate, and its transport could be involved in nonneuronal cholinergic functions (Pochini et al. 2013). OCTN1 and OCTN2 are associated with several pathologies, such as inflammatory bowel disease, primary carnitine deficiency, diabetes, neurological disorders, and cancer. It transports TEA, and transoirts acetylcholine better than acetylcarnitine (Pochini et al. 2015). Molecular perturbations across several metabolite classes precede autism. The cyclic dipeptide cyclo-leucine-proline and the carnitine-related 5-aminovaleric acid betaine (5-AVAB) were associated with an increased probability for autism, independently of known prenatal and genetic risk factors. Analysis of genetic and dietary data in adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy and with variants near SLC22A4 and SLC22A5 coding for transmembrane carnitine transporter proteins involved in controlling intracellular carnitine levels (Ottosson et al. 2024). OCTN1 (SLC22A4) and OCTN2 (SLC22A5) play specific roles in inflammation. The link between these proteins and inflammation may be based on their link to some chronic inflammatory diseases such as asthma, Crohn's disease, and rheumatoid arthritis. These two transporters can mediate the transport of several compounds including carnitine, carnitine derivatives, acetylcholine, ergothioneine, and gut microbiota by-products, which have been specifically associated with inflammation for their anti- or proinflammatory action. Therefore, the absorption and distribution of these molecules rely on the presence of OCTN1 and OCTN2, whose expression is modulated by inflammatory cytokines and transcription factors typically activated by inflammation (Pochini et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC22A4 (OCTN1) of Homo sapiens (O14546) |
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2.A.1.19.20 | Prostaglandin (PGE2, PGE2α, and PGD(2)) -specific organic anion transporter. Exhibits Na+ -independent and saturable transport. Shows narrow substrate selectivity and high affinity (Shiraya et al., 2010). |
Eukaryota | Metazoa, Chordata | Slc22a22 (OAT-PG) of Mus musculus (Q8R0S9) |
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2.A.1.19.21 | solute carrier family 22, member 24 | Eukaryota | Metazoa, Chordata | SLC22A24 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.19.22 | solute carrier family 22, member 14, Slc22a14, is crucial for sperm motility and male fertility in mice. It is expressed specifically in male germ cells, and mice lacking the Slc22a14 gene show severe male infertility as well as sperm morphological changes (Maruyama et al. 2016). |
Eukaryota | Metazoa, Chordata | SLC22A14 of Homo sapiens |
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2.A.1.19.23 | solute carrier family 22, member 31 | Eukaryota | Metazoa, Chordata | SLC22A31 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.19.24 | Solute carrier family 22 member 3 (Extraneuronal monoamine transporter) (EMT) (Organic cation transporter 3) of 556 aas and 12 TMSs. Induction of astrocytic Slc22a3 (EMT) regulates sensory processing through histone serotonylation (Sardar et al. 2023). |
Eukaryota | Metazoa, Chordata | SLC22A3 of Homo sapiens |
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2.A.1.19.25 | Solute carrier family 22 member 7 (liver transporter) (Organic anion transporter 2) (hOAT2), transports cyclic nucleotodes and the anti-viral drug, acyclovir (Dahlin et al. 2013). Expressed mostly in liver, but also in kidney, brain and red blood cells (Sager et al. 2018). slc22 transporter homologs in flies, worms, and humans clarify the phylogeny of organic anion (OATs) and cation (OCTs) transporters (Eraly et al. 2004). |
Eukaryota | Metazoa, Chordata | SLC22A7 of Homo sapiens |
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2.A.1.19.26 | SLC22 OAT ortholog, Multispecific anion transporter, oat-1 (George et al. 1999) |
Eukaryota | Metazoa, Nematoda | oat-1 of Caenorhabditis elegans |
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2.A.1.19.27 | Solute carrier family 22 member 10 (Organic anion transporter 5) | Eukaryota | Metazoa, Chordata | SLC22A10 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.19.28 | Solute carrier family 22 member 23. The rat orthologue may be inactive (Bennett et al. 2011). Human SLC22A23 is expressed in many tissues including brain (brain organic cation transporter (BOCT2) (Bennett et al. 2011). |
Eukaryota | Metazoa, Chordata | SLC22A23 of Homo sapiens |
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2.A.1.19.29 | Solute carrier family 22 member 1 (Organic cation transporter 1) (hOCT1). May be a primary polyamine uptake porter (Abdulhussein and Wallace 2013). Amino acids in TMS1 confer major functional differences between human and mouse orthologs of the polyspecific membrane transporter, OCT1. Reduced function alleles of OCT1 associate significantly with high LDL cholesterol levels (Yee et al. 2023). Structures provided atomic-level insight into the dynamic metformin transfer process via hOCT1 and the mechanism by which spironolactone inhibits it. A 'YER' motif critical for the conformational flexibility of hOCT1 and likely other SLC22 family transporters has been identified (Zhang et al. 2024). This system is inhibited by various canabis products (Anderson et al. 2022). |
Eukaryota | Metazoa, Chordata | SLC22A1 of Homo sapiens |
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2.A.1.19.3 |
The polyspecific organic cation (L- and D-carnitine, butyryl-L-carnitine, acetyl carnitine, γ-butyro-betaine, glycinebetaine, β-lactam antibiotics with a quaternary nitrogen such as cephaloridine, and others):Na+ symporter, OCTN2 (SLC22A5). Carnitine is transporter with high affinity (2 - 20 μM0 (Ingoglia et al. 2015). Associated with Crohn''s disease (Barton et al., 2005) as well as primary carnitine deficiency. The protein is glycosylated on extracytoplasmic asparagines, and these residues are in a region important for function and turnover (Filippo et al. 2011). OCTN2 maintains the carnitine homeostasis, resulting from intestinal absorption, distribution to tissues, and renal excretion/reabsorption (Pochini et al. 2013). OCTN1 and OCTN2 are associated with several pathologies, such as inflammatory bowel disease, primary carnitine deficiency, diabetes, neurological disorders, and cancer. OCTN2 is activated in a process dependent on Caveolin1 (Q03135) which interacts directly with OCTN2 and by protein kinase C which does not phosphorylate OCTN2 directly (Czeredys et al. 2013). Cholesterol stimulates the cellular uptake of L-carnitine by the carnitine/organic cation transporter novel 2 (OCTN2) (Zhang et al. 2020). A dataset of OCTN2 variant functions and localization has been created, revealing important disease-causing mechanisms (Koleske et al. 2022). Primary carnitine deficiency (PCD) is caused by pathogenic variants of the SLC22A5 gene, which encodes a high affinity carnitine transporter. Carnitine is essential for the transport of acyl-CoA, produced from fatty acids, into the mitochondria where they are oxidised to produce energy (Khries et al. 2023). OctN2 transports doxorubicin (Yi et al. 2023). A novel pathogenic variant in the carnitine transporter gene, SLC22A5, is associated with metabolic carnitine deficiency and cardiomyopathy features (Jolfayi et al. 2024). Molecular perturbations across several metabolite classes precede autism. The cyclic dipeptide cyclo-leucine-proline and the carnitine-related 5-aminovaleric acid betaine (5-AVAB) were associated with an increased probability for autism, independently of known prenatal and genetic risk factors. Analysis of genetic and dietary data in adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy and with variants near SLC22A4 and SLC22A5 coding for transmembrane carnitine transporter proteins involved in controlling intracellular carnitine levels (Ottosson et al. 2024). OCTN1 (SLC22A4) and OCTN2 (SLC22A5) play specific roles in inflammation. The link between these proteins and inflammation may be based on their link to some chronic inflammatory diseases such as asthma, Crohn's disease, and rheumatoid arthritis. These two transporters can mediate the transport of several compounds including carnitine, carnitine derivatives, acetylcholine, ergothioneine, and gut microbiota by-products, which have been specifically associated with inflammation for their anti- or proinflammatory action. Therefore, the absorption and distribution of these molecules rely on the presence of OCTN1 and OCTN2, whose expression is modulated by inflammatory cytokines and transcription factors typically activated by inflammation (Pochini et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC22A5 (OCTN2) of Homo sapiens |
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2.A.1.19.30 | Solute carrier family 22 member 2 (Organic cation transporter 2) (hOCT2). Oct2 is a low affinity high efficiency choline transporter, enriched in synaptic vesicles of cholinergic neurons (Nakata et al. 2013). May also transport peptides and peptide derivatives (Volková et al. 2015). It also transports L-carnitine (Adeva-Andany et al. 2017). OCT2 is a multispecific transporter with cholesterol-dependent allosteric features. The role of cholesterol recognition/interaction amino acid consensus sequences (CRAC and CARC) in the allosteric binding to 1-methyl-4-phenylpyridinium (MPP+) has been reported (Sutter et al. 2021). Comparisons of the inhibitory potential of elacridar and imazalil on metformin uptake with that on MPP uptake revealed substrate-dependent differences in hOCT2 and mOct2 for both inhibitors (Kuehne et al. 2022). This system is inhibited by various canabis products (Anderson et al. 2022). |
Eukaryota | Metazoa, Chordata | SLC22A2 or Oct2 of Homo sapiens |
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2.A.1.19.31 | Solute carrier family 22 member 6 (Organic anion transporter 1) (hOAT1) (PAH transporter) (hPAHT) (Renal organic anion transporter 1) (hROAT1), Probably orthologous to 2.A.1.19.4. Functions in anti-oxidant transport, and in urate uptake from the circulation across the basolateral membrane of tubular cells (Prestin et al. 2014). It transports methotrexate (anticancer), acyclovir (antiviral), and adefovir (antiviral) (Nigam 2015). This system is inhibited by various canabis products (Anderson et al. 2022). |
Eukaryota | Metazoa, Chordata | SLC22A6 of Homo sapiens |
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2.A.1.19.32 | Solute carrier family 22 member 15 (Fly-like putative transporter 1) (Flipt 1). This system is required for hepatocellular carcinoma proliferation and metastasis (Fang et al. 2021). SLC22A15 (FLIPT1) prefers zwitterionic compounds over cations and anions. Eight zwitterions transported include ergothioneine, carnitine, carnosine, gabapentin, as well as four cations including MPP+ , thiamine and cimetidine. Carnosine was a specific substrate of SLC22A15 among the transporters in the SLC22A family. SLC22A15 transport was sodium-dependent and exhibited higher Km values for ergothioneine, carnitine, and carnosine compared to previously identified transporters for these ligands (Yee et al. 2020). Many carnitine derivatives (i.e., (R)-3-hydrixybutryl carnitine, hexanoyl carnitine and glutaryl carnitine amoung others) are also transported. In mice, SLC22a15 transports carnitine derivatives, a range of anti-oxidants, signalling molecules, hormones, neurotransmitters, nutrients and lipid metabolites (P Zhang & S Nigam, personal communication). |
Eukaryota | Metazoa, Chordata | SLC22A15 of Homo sapiens |
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2.A.1.19.33 | Solute carrier family 22 member 25 (Organic anion transporter UST6). Expressed exclusively in liver in both embryo and adult (Eraly et al. 2004). It may take up a nucleobase-containing compound (Meixner et al. 2020). |
Eukaryota | Metazoa, Chordata | SLC22A25 of Homo sapiens |
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2.A.1.19.34 | Multispecific drug transporter, solute carrier family 22 member 8 (Organic anion transporter 3) (hOAT3). Both OAT1 and OAT3 of humans are inhibited by caffeic acid (Ki ~ 17 μM) (Uwai et al. 2011; Wu et al. 2013). It is the principal uptake system for steviol glucuronide (SVG), the major metabolite derived from steviol, the aglycone of stevioside and rebaudioside A (Wang et al. 2015). Also functions in urate uptake from the circulation across the basolateral membrane of renal tubular cells (Prestin et al. 2014). Inhibition of the proteasome, but not the lysosome, upregulates organic anion transporter 3 (Fan et al. 2022). See also 2.A.1.19.9. |
Eukaryota | Metazoa, Chordata | SLC22A8 of Homo sapiens |
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2.A.1.19.35 | Solute carrier family 22 member 20 (Organic anion transporter 6; OAT6) of 555 aas and 12 probable TMSs. This protein is an apparent anionic odorant transporter in the olfactory epithelium of mice (Monte et al. 2004; Kaler et al. 2006). |
Eukaryota | Metazoa, Chordata | SLC22A20 of Homo sapiens |
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2.A.1.19.36 |
Organic cation transporter-like protein, OrcT, of 548 aas and 12 TMSs (Taylor et al. 1997). |
Eukaryota | Metazoa, Arthropoda | OrcT of Drosophila melanogaster |
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2.A.1.19.37 | Organic cation transporter 1 (CeOCT1) of 568 aas and 12 TMSs. It transports tetraethylammonium ions and has broad substrate specificity (Wu et al. 1999). |
Eukaryota | Metazoa, Nematoda | Oct-1 of Caenorhabditis elegans |
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2.A.1.19.38 | Uncharacterized MFS-type transporter PB1E7.08c | Eukaryota | Fungi, Ascomycota | SPAPB1E7.08c of Schizosaccharomyces pombe | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.19.39 | Organic cation/carnitine transporter 6 (AtOCT6) | Eukaryota | Viridiplantae, Streptophyta | OCT6 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.19.4 | The polyspecific organic anion, cation and neutral molecule transporter, Oat1 (Slc22a6) (transports neutral compounds such as cardiac glycosides [i.e., ouabain] and steroids [i.e., aldosterone; cortisol; dexamethasone]; cationic compounds such as N-propylajmalinium, and anionic compounds such as p-aminohippurate, dicarboxylates, cyclic nucleotides, prostaglandins, urate, β-lactam antibiotics, nonsteroidal anti-inflammatory drugs, diuretics, bile salts and steroid conjugates [i.e., estrone-3-sulfate and estradiol-17-glucuronide]) transporter (H+ symporter or uniporter) Probably catalyzes organic anion (uptake):dicarboxylate (efflux) antiport in the basolateral membrane of kidney proximal tubules) (Eraly et al., 2003a,b). A 3-dimensional model of OAT1 has led to the identification of residues involved in differential transport of substrates such as p-aminohippurate and cidofovir (Perry et al., 2006). Oat1 transports many antiviral agents (Truong et al., 2008). The human orthologue (Q4U2R8; 563aas) has been shown to be a multispecific organic anion transporter on the basolateral membrane of the proximal tubule in human kidney (Hosoyamada et al. 1999). A substrate binding hinge domain is required for transport-related structural changes (Egenberger et al., 2012). Transports environmental toxins and clinically important drugs including anti-HIV therapeutics, anti-tumor drugs, antibiotics, anti-hypertensives, and anti-inflammatories (Duan et al., 2011). hOAT1 has two GXXXG motifs in TMSs 2 and 5 which play critical roles in stability (Duan et al., 2011). Both OAT1 and OAT3 of humans are inhibited by caffeic acid (Ki ~ 17 μM) (Uwai et al. 2011). |
Eukaryota | Metazoa, Chordata | Oat1 of Rattus norvegicus (O35956) |
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2.A.1.19.40 |
Organic anion transporter, Oat9. A splice variant with 443 aas and 8 TMSs (Oa9S) was reported to transport L-carnitine (3 μM), cimetidine (16 μM) and salicylic acid (175 μM), but the full length protein of 551 aas and 12 TMSs (Oat9L) was reported to be inactive (Tsuchida et al. 2010). |
Eukaryota | Metazoa, Chordata | Oat9 of Mus musculus |
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2.A.1.19.41 | Organocation transporter, OCTN3. Identified only in mouse; mediates carnitine transport (Pochini et al. 2013). 81% identical to 2.A.1.19.3. Also called SLC22a21 and SLC22a9. |
Eukaryota | Metazoa, Chordata | OctN3 of Mus musculus |
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2.A.1.19.42 | Slc22 homologue of 580 aas. |
Eukaryota | Viridiplantae, Chlorophyta | Slc19 homologue of Ostreococcus tauri |
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2.A.1.19.43 | Organocation transporter, Oct4 of 526 aas and 12 TMSs. It is induced under drought conditioins. |
Eukaryota | Viridiplantae, Streptophyta | Oct4 of Arabidopsis thaliana (Mouse-ear cress) |
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2.A.1.19.44 | Uncharacterized protein of 556 aas |
Eukaryota | Viridiplantae, Chlorophyta | UP of Chlorella variabilis (Green alga) |
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2.A.1.19.45 | MFS transporter of 569 aas |
Eukaryota | Ciliophora | MFS transporter of Tetrahymena thermophila |
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2.A.1.19.46 | MFS transporter of 593 aas |
Eukaryota | Ciliophora | MFS porter of Oxytricha trifallax |
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2.A.1.19.47 | MFS porter of 691 aas |
Eukaryota | Viridiplantae, Chlorophyta | MFS porter of Volvox carteri (Green alga) |
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2.A.1.19.48 | Fungal MFS homologue of 520 aas |
Eukaryota | Fungi, Ascomycota | UP of Aspergillus terreus |
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2.A.1.19.49 | Putative glucose transporter 1 (Gluct1) of 569 aas and 12 TMSs. Constitutively synthesized in many tissues. Serves as the receptor of white spot syndrom virus (WSSV) (Huang et al. 2012). |
Eukaryota | Metazoa, Arthropoda | Gluct1 of Litopenaeus vannamei (Whiteleg shrimp) (Penaeus vannamei) |
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2.A.1.19.5 | The putative apical polyspecific organic cation transporter (cation:H+ or cation:cation antiporter), Oct2 (substrates include monoamine neurotransmitters such as dopamine, noradrenaline, adrenaline and 5-hydroxytryptamine) (Oct2 exhibits some properties of an ion channel with an inner diameter of ~4 Å. Selectivity: Cs+ > Rb+ > K+ > Na+ %u2248 Li+ (Schmitt and Koepsell, 2005)) Chloride dependent, but a single mutation (R466K) abolishes this dependency (Rizwan et al., 2007). Also transports ochratoxin (Rizwan et al., 2007) and cisplatin and oxaliplatin (Yonezama et al., 2006). |
Eukaryota | Metazoa, Chordata | Oct2 of Sus scrofa (O02713) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.19.50 | Uncharacterized solute carrier family 22 member 15-like of 543 aas and 12 TMSs (Posavi et al. 2020). |
Eukaryota | Metazoa, Arthropoda | UP of Eurytemora affinis |
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2.A.1.19.6 | The polyspecific potential-sensitive organic cation uptake transporter, Oct3 (transport substrates include the neurotoxin 1-methyl-4-phenylpyridinium and monoamine neurotransmitters such as dopamine). Mediates paraquat (herbicide) neurotoxicity (Rappold et al., 2011). SLC22 transporters involved in drug elimination and organ distribution are polyspecific. The cryo-EM structure of SLC22A3 (OCT3) is available (Meyer-Tönnies and Tzvetkov 2023). OCT3 and MATE2 genetic polymorphisms can give rise to poor responses to metformin in type 2 diabetes mellitus (Naem et al. 2024). |
Eukaryota | Metazoa, Chordata | Oct3 of Rattus norvegicus (O88446) |
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2.A.1.19.7 | The polyspecific organic anion (and cation) (anions: p-aminohippurate, ochratoxin A, estrone sulfate, anionic drugs, anionic neurotransmitter metabolites; cation: cimetidine) transporter, Oat3 (slc22a8) (catalyzes organic anion (uptake): dicarboxylate (efflux) antiport in the basolateral membrane of the renal proximal tubule) (Eraly et al., 2003a,b); transports many antiviral agents (Truong et al., 2008). | Eukaryota | Metazoa, Chordata | Oat3 of Rattus norvegicus (Q9R1U7) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.19.8 |
The human organic cation transporter, SLC22A17. The rat orthologue may be inactive (Bennett et al. 2011). It is also the cell surface receptor for Lipocalin-2 (LCN2) that plays a key role in iron homeostasis and transport. It is able to bind iron-LCN2, followed by internalization and release of iron, thereby increasing intracellular iron concentration and leading to inhibition of apoptosis (Cabedo Martinez et al. 2016). It also binds iron-free LCN2, followed by internalization and its association with an intracellular siderophore, leading to iron chelation and iron transfer to the extracellular medium, thereby reducing intracellular iron concentrations and resulting in apoptosis. The SLC22A17/lipocalin-2 receptor plays a role in renal endocytosis of proteins involved in metalloproteins, particularly on iron- and cadmium-binding proteins (Thévenod et al. 2023). Other renal functions of SLC22A17 include its contribution to osmotic stress adaptation, protection against urinary tract infection, and renal carcinogenesis. |
Eukaryota | Metazoa, Chordata | SLC22A17 of Homo sapiens |
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2.A.1.19.9 | The osteosclerosis protein, Roct (organic anion transporter 3, Oat3) (Slc22a8) (catalyzes organic anion (uptake):di-carboxylate (efflux) antiport in the basolateral membrane of the renal proximal tubule) (Eraly et al., 2003a,b); transports glutathione and many antiviral agents (Truong et al., 2008). It is a multispecific drug transporter, critical for the renal handling of common drugs (e.g, antibiotics, antivirals, diuretics) and toxins. Probably handles hydroxylated and glucouronidated metabolites, consistent with the "remote sensing and signaling hypothesis" (Wu et al. 2013). It may also handle dietary flavonoids and antioxidants. |
Eukaryota | Metazoa, Chordata | Roct (Oat3) of Mus musculus (O88909) |
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2.A.1.2.1 | Pyridoxine, pyridoxal, pyridoxamine, amiloride:H+ cotransporter (Km (pyridoxine) = 22 μM) (Stolz et al., 2005). Also takes up thiamine (Vogl et al., 2008). |
Eukaryota | Fungi, Ascomycota | Bsu1 (Car1) of Schizosaccharomyces pombe (P33532) |
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2.A.1.2.10 | Quinolone (and other drug):H+ antiporter, NorA. Many synthetic inhibitors have been identified (Bhaskar et al. 2016). 1,8-Naphthyridines sulfonamides are NorA efflux pump inhibitors (Oliveira-Tintino et al. 2021). |
Bacteria | Bacillota | NorA of Staphylococcus aureus (P0A0J7) |
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2.A.1.2.100 | Bcr/CflA family drug resistance efflux transporter of 389 aas and 12 TMSs. Multidrug-resistance in S. aureus is inhibited by the endocannabinoid, anandamide (Sionov et al. 2022). Butyrolactone I enhances the efficacy of gentamycin in methicillin-resistant S. aureus (Jiang et al. 2024). |
Bacteria | Bacillota | MDR exporter of Staphylococcus aureus |
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2.A.1.2.101 | Bmr-like protein SblA of 395 aas and 12 TMSs. |
Bacteria | Bacillota | SblA of Staphylococcus aureus |
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2.A.1.2.102 | TetA class C (TetA(C)) of 396 aas and 12 TMSs. The TetA(C) of the transposon, Tn10, not only exports tetracycline by a proton antiport mechanism, it also increases susceptibility to cadmium, fusaric acid, bleomycin and several classes of cationic aminoglycoside antibiotics (Griffith et al. 1995). For this reason, it has been used to generate dual counter selection procedures (Li et al. 2013). It is not certain that this is due to import of these compounds as this increased susceptibility could be due to a secondary effect. |
Bacteria | Pseudomonadota | TetA(C) of E. coli |
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2.A.1.2.103 | Tetracycline:H+ class D, (TetA(D)) antiporter of 286 aas and 12 TMSs. |
Bacteria | Pseudomonadota | TetA(D) of E. coli |
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2.A.1.2.104 | MFS carrier of 490 aas and 12 TMSs, MfsD14a or Hiat1 (Hippocampus abundant transcript 1 protein) is a member of the SLC18 family. It is 76% identical to 2.A.1.2.30. Mutant mice (Mus musculus, strain 129S6Sv/Ev) were generated with the Mfsd14a gene disrupted with a LacZ reporter gene. Mutant mice are viable and healthy, but males are sterile due to a 100-fold reduction in the number of spermatozoa in the vas deferens. Male mice have adequate levels of testosterone and show normal copulatory behaviour. The few spermatozoa that are formed show rounded head defects similar to those found in humans with globozoospermia. Spermatogenesis proceeds normally up to the round spermatid stage, but the subsequent structural changes associated with spermiogenesis are severely disrupted with failure of acrosome formation, sperm head condensation and mitochondrial localization to the mid-piece of the sperm. Mfsd14a expression occurs in Sertoli cells, suggesting that MFSD14A may transport a solute from the bloodstream that is required for spermiogenesis (Doran et al. 2016). MFSD14A and MFSD14B are intracellular neuronal membrane-bound proteins, expressed in the Golgi and ER, and their levels of expression are affected by both starvation and a high fat diet to varying degrees in the mouse brain (Lekholm et al. 2017). It is associated with milk production in buffalo and sheep breeds, as well as growth of chickens and goats, and drastically affect s sperm morphogenesis (Luo et al. 2023). The functional InDel polymorphism (rs1089950828) reflects growth traits in domestic sheep populations (Luo et al. 2023). |
Eukaryota | Metazoa, Chordata | MfsD14a of Homo sapiens |
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2.A.1.2.105 | MFSD9 of 474 aas and 12 TMSs. In the mouse, this protein and MFS4a localize to neurons in the brain; their mRNA expression levels are affected by diet (Perland et al. 2017). This protein is in the SLC18 family (Gyimesi and Hediger 2022). |
Eukaryota | Metazoa, Chordata | MFSD9 of Homo sapiens |
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2.A.1.2.106 | Uncharacterized MFS-type transporter YvmA |
Bacteria | Bacillota | yvmA of Bacillus subtilis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.107 | MFS porter of 399 aas and 12 TMSs, HepP, involved in the uptake of glycoside(s), with a specific physiological role in production of heterocyst exopolysaccharide, HEP (López-Igual et al. 2012). |
Bacteria | Cyanobacteriota | HepP of Anabaena or Nostoc sp. (strain PCC 7120) |
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2.A.1.2.108 | Putative spermine uptake porter of 552 aas and 12 TMSs, SPBC409.08. Spermine and the spermine-precursor, spermidine, are implicated in ageing as they are involved in autophagy-dependent lifespan extension (Ellis et al. 2018). |
Eukaryota | Fungi, Ascomycota | SPBC409.08 of Schizosaccharomyces pombe |
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2.A.1.2.109 | MFS porter of 414 aas and 12 TMSs. It has been suggested that it could be a citrate efflux porter (Braakman et al. 2017). |
Bacteria | Cyanobacteriota | MFS porter of Prochlorococcus marinus |
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2.A.1.2.11 | Monoamine transporter; drug (doxorubicin, ethidium bromide-6-G):H+ antiporter | Eukaryota | Metazoa, Chordata | VMAT1 of Rattus norvegicus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.110 | Florfenicol-chloramphenicol resistance drug exporter, FloR of 404 aas and 12 TMSs (Braibant et al. 2005). This system in V. cholerae (98.8% identical) exports chlorampenicol (Saha et al. 2024). |
Bacteria | Pseudomonadota | FloR of Salmonella enterica subsp. enterica serovar Typhimurium str. DT104 |
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2.A.1.2.111 | Zinc-induced facilitator-like protein 1, ZIFL1 or Tpo1p of 478 aas and 12 TMSs. It confers resistance to the herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D) and is transcriptionally activated in response to this herbicide. Tpo1p is required to reduce the intracellular concentration of 2,4-D (Cabrito et al. 2009). K+ may be its physiological substrate, and it may play a dual role in polar auxin transport and drought stress tolerance (Remy et al. 2013). It is also involved in auxin efflux and acts as a positive regulator of shootward transport at the root apex. Possibly, it may mediate proton efflux from the vacuolar compartment (Remy et al. 2013). |
Eukaryota | Viridiplantae, Streptophyta | Tpo1 of Arabidopsis thaliana |
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2.A.1.2.112 | Uncharacterized protein of 904 aas with 16 TMSs in a 6 + 6 + 3 + 1 TMS arrangement, where the last 300 aas comprise the non-MFS integral membrane domain with at least 4, and maybe as many as 6 TMSs. May possibly play a role in lipid transport. |
Eukaryota | Fungi, Ascomycota | UP of Aspergillus ruber |
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2.A.1.2.113 | Uncharacterized MFS transporter of 539 aas and 11 TMSs. It is probably similar in sequence to MfsT, described as a penicillin G (isopenicillin N) precursor in Monascus ruber (Ramzan et al. 2019). |
Eukaryota | Fungi, Ascomycota | MFS porter of Aspergillus clavatus |
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2.A.1.2.114 | MFS1 of 728 aas and 12 TMSs. The MFS1 transporter contributes to Penicilliun digitatum fungicide resistance and fungal virulence during citrus fruit infection (de Ramón-Carbonell et al. 2019). |
Eukaryota | Fungi, Ascomycota | MFS1 of Penicillium digitatum |
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2.A.1.2.115 | Multidrug resistance MDR exporter of 583 aas and 12 TMSs. It is involved in resistance to the antifungal drugs miconazole, tioconazole, clotrimazole and ketoconazole as well as to quinidine (Costa et al. 2013; Costa et al. 2016). It also plays a role in biofilm formation. Compared to the wild type, the C. glabrata ∆qdr2 mutant showed lower adhesion activity and higher fluconazole susceptibility when assessed as a biofilm. The mutant also showed decreased metabolic activity during biofilm formation and grew more slowly under neutral-basic pH conditions. The qdr2 deletion in C. glabrata resulted in an impaired ability to maintain pH homeostasis, which led in turn to a reduction of cell growth and of adherence to an artificial matrix (Widiasih Widiyanto et al. 2019). Mitochondrion-targeted antifungal drugs have been reviewed (Qin et al. 2023). |
Eukaryota | Fungi, Ascomycota | MDR pump of Candida glabrata (Yeast) (Torulopsis glabrata) |
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2.A.1.2.116 | MDR efflux pump, Bcr/CflA, of 411 aas and 12 TMSs. Confer's chloramphenicol resistance (Yang et al. 2019). |
Bacteria | Myxococcota | Brc of Myxococcus xanthus |
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2.A.1.2.117 | Uncharacterized protein of 510 aas and 12 TMSs. |
Eukaryota | Bacillariophyta | UP of Fistulifera solaris |
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2.A.1.2.118 | Na+ (K+ or Li+)/H+ antiporter and multidrug:Na+ anitporter, MdrP of 424 aas and 12 TMSs. It exports ethidium and norfloxacin in exchange for Na+ taken up (Abdel-Motaal et al. 2018). D223 acts as a key determinant in the Na+ translocation coupled to norfloxacin efflux (R. Zhang, Abdel-Motaal et al, 2020). |
Bacteria | Bacillota | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.119 | AaMFS1 is an efflux pump for the transmembrane transport of tenuazonic acid (TeA) (Sun et al. 2022). See 4.C.1.1.19 for relevant information about the TeA synthetase that makes TeA before exporting it (Sun et al. 2022). The genes encoding these two proteins are adjacent to each other. |
Eukaryota | Fungi, Ascomycota | MFS1 of Alternaria alternata |
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2.A.1.2.12 | Chromaffin granule monoamine (and drug) transporter, VAT1. It is involved in the transport of biogenic monoamines such as serotonin from the cytoplasm into the secretory vesicles of neuroendocrine and endocrine cells (Essand et al. 2005). It is strongly inhibited by reserpine, and to a lesser extent by ketanserin and fenfluramine, but not by tetrabenazine (Erickson et al. 1996). Fine-tuning novel monoamine reuptake inhibitor selectivities has been acieved through manipulation of inhibitor stereochemistry (chirality) (Kalaba et al. 2023). |
Eukaryota | Metazoa, Chordata | SLC18A1 of Homo sapiens |
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2.A.1.2.120 | Major Familitator, MFS6 of 550 aas and 12 TMSs in a 6 + 6 TMS arrangement with a central ~ 200 aa hydrophilic domain. The substrate is not known (Wichers et al. 2022). |
Eukaryota | Apicomplexa | MFS6 of Plasmodium malariae |
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2.A.1.2.121 | MFS permease of 550 aas and 12 TMSs in a 6 + 6 TMS arrangement with a large central hydrophilic domain betweem residues 200 and 370. |
Eukaryota | Apicomplexa | MFS permease of Plasmodium ovale (malaria parasite P. ovale) |
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2.A.1.2.122 | MfsC (Smlt0549), a probable diamide exporter of 379 aas and 12 TMSs in a 6 + 6 TMS arrangement. It is encoded within the mfsBC operon controlled by the DitR TetR-like transcript factor which binds diamide to displace the repressing factor from the DNA. MfsB (BeFL18) may be a sugar uptake porter (Boonyakanog et al. 2022). |
Bacteria | Pseudomonadota | MfsC of Stenotrophomonas maltophilia |
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2.A.1.2.123 | Fluconazole resistance protein 1, Flu1 of 610 aas and 12 TMSs. It mediates resistance to structurally and functionally unrelated compounds including cycloheximide but also azoles such as fuconazole, ketoconazole and itraconazole (Calabrese et al. 2000). It mediates efflux of histatin 5, a salivary human antimicrobial peptide, and is responsible for reduction of its toxicity in C.albicans (Li et al. 2013, Hampe et al. 2017). Mutations in the Erg251 ergosterol biosynthetic enzyme can also give rise to azole resistance (Zhou et al. 2024). Batzelladine D, a marine natural product, reverses the fluconazole resistance phenotype mediated by transmembrane transporters in Candida albicans. It also interferes with biofilm formation (Domingos et al. 2024). |
Eukaryota | Fungi, Ascomycota | Flu1 of Candida albicans |
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2.A.1.2.124 | Putative MDR pump, MDT; MFS1, of 442 aas and 12 TMSs (Wunderlich 2022). |
Eukaryota | Apicomplexa | MDR pump of Plasmodium falciparum |
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2.A.1.2.125 | MFS drug-resistance efflux pump of 401 aas and 12 TMSs. This system exports tetracycline and doxycycline and is induced by several drugs in addition to these compounds (Li et al. 2023). |
Bacteria | Bacillota | SAUSA300_09310 of Staphylococcus aureus |
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2.A.1.2.126 | MFS permease of 405 aas and 12 TMSs, KpsrMFS (He et al. 2024). This efflux pump is a proton-driven transporter that can reduce the intracellular tetracycline concentration. In normal conditions, the expression of kpsrmfs was at a low level, while artificial overexpression of it led to increased endogenous reactive oxygen species (ROS) production. By comparing the functions of adjacent genes of kpsrmfs, another four genes that can confer similar phenotypes, indicating a special regulon that regulates cell growth.. |
Bacteria | Pseudomonadota | KpsrMFS of Klebsiella pneumoniae |
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2.A.1.2.127 | SLC18A2 or Vesicular monoamine transporter 2, VMAT2, of 562 aas with 13 TMSs in a 2 + 5 + 1 + 5 TMS arrangement. Mutations affect motility (Sveinsdóttir et al. 2022). |
Eukaryota | Metazoa, Chordata | SLC18A2 of Danio rerio (Zebrafish) (Brachydanio rerio) |
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2.A.1.2.128 | MDR1 of Candida auris of 549 aas and 12 TMSs in a 6 + 6 TMS arrangement. It is 61% idential to TC# 2.A.1.2.6 and is inhibited by isavuconozole. Alterations in membrane lipid composition and modulation of this drug efflux transporter are critical processes contributing to isavuconozole (and other drug) susceptibilities (Balla et al. 2024). |
Eukaryota | Fungi, Ascomycota | MDR1 of Candida auris |
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2.A.1.2.13 | Vesicular acetylcholine:H+ antiporter, UNC-17/VAChT. Mutants grow slowly and are uncoordinated, but the defects can be corrected by mutation of two interacting monotopic protein, synaptobrevin-1/SNB-1 (109 aas and 1 C-terminal TMS; Sandoval et al. 2006) and SUP-1 (103 aas and 1 C-terminal TMS (Mathews et al. 2012). |
Eukaryota | Metazoa, Nematoda | Unc17 of Caenorhabditis elegans |
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2.A.1.2.14 | Putative arabinose efflux porter, AraJ. |
Bacteria | Pseudomonadota | AraJ of E. coli |
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2.A.1.2.15 | Arabinose (but not xylose) and isopropyl β-D-thio-galactopyranoside:H+ antiporter, YdeA (Koita and Rao 2012). Overexpression of the gene for YdeA allows export of Lacto-N-triose (LNT II) and lacto-N-tetraose (LNT), human milk oligosaccharides (Sugita and Koketsu 2022). |
Bacteria | Pseudomonadota | YdeA of E. coli |
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2.A.1.2.16 | Polyamines (spermine, spermidine, putrescine); paraquat; methylglyoxal bis(guanylhydrazone):H+ antiporter (in the plasma membrane) (activated by phosphorylation) (Uemura et al., 2005) |
Eukaryota | Fungi, Ascomycota | TPO1 (YLL028w) of Saccharomyces cerevisiae |
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2.A.1.2.17 | Fluconazole:H+ antiporter | Eukaryota | Fungi, Ascomycota | Flr1 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.18 | Lactose and melibiose (>>IPTG) efflux pump, SotB | Bacteria | Pseudomonadota | SotB of Erwinia chrysanthemi | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.19 |
The multidrug (chloramphenicol, tetracycline, norfloxacin, doxorubicin, trimethoprim, acriflavin, ethidium bromide, tetraphenylphosphonium, TPP, benzalkonium, ciprofloxacin, thiamphenicol, IPTG) resistance exporter, MdfA (catalyzes both electrogenic and electroneutral transport) (Adler and Bibi, 2004). Can function as a Na+ (K+)/H+ antiporter (Lewinson and Bibi 2001; Higgins, 2007). Is known to provide resistance to a wide variety of dissimilar toxic compounds, including neutral, cationic and zwitterionic substances. Crystals that diffracted to 3.4 Å resolution and belonged to the hexagonal space group P6122 have been obtained (Nagarathinam et al. 2017). For review of MdfA see Lewinson et al., 2006. The conformational switch accompanying transport is induced by the promiscuous binding of substrates and/or inhibitors to the binding pocket (Fluman et al., 2009). MdfA normally extrudes monovalent cationic drugs in exchange for a single proton, but it transports divalent cationic drugs poorly. It can be mutated to antiport a divalent cationic drug for 2 protons (Tirosh et al., 2012). Transporters acting across the inner and outer membranes have synergistic effects with each other, but transporters acting across the same membrane are usually additive but can be synergistic under special circumstances, owing to a bifurcation controlled by the barrier constant (Saha et al. 2020). Promiscuity in the geometry of electrostatic interactions between MdfA and cationic substrates has been demonstrated (Adler and Bibi 2005). With respect to ethidium bromide, the inner membrane transporter MdfA is synergistic to the TolC-dependent efflux across the outer membrane (Saha et al. 2020). The conformational behavior of MdfA in response to substrate binding has been studied (Bahrenberg et al. 2021). Overexpression of the gene for MdfA allows export of Lacto-N-triose (LNT II) and lacto-N-tetraose (LNT), human milk oligosaccharides (Sugita and Koketsu 2022). It may also export ectoine and hydroxyectoine (Czech et al. 2022). |
Bacteria | Pseudomonadota | MdfA of E. coli (P0AEY8) |
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2.A.1.2.2 | Cycloheximide:H+ antiporter | Eukaryota | Fungi, Ascomycota | CyhR of Candida maltosa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.20 | Broad specificity MDR efflux pump, MdtG (YceE) (under SoxSR control) (Fàbrega et al., 2010). Confer resistance to fosfomycin, fluoroquinolone and many other drugs (Nishino and Yamaguchi 2001). It may also export ectoine and hydroxyectoine (Czech et al. 2022). |
Bacteria | Pseudomonadota | MdtG of E. coli |
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2.A.1.2.21 | The norfloxacin/enoxacin resistance protein, MdtH or YceL (Nishino and Yamaguchi 2001). |
Bacteria | Pseudomonadota | MdtH or YceL of E. coli (P69367) |
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2.A.1.2.22 | The multidrug resistance protein, YidY (Nishino and Yamaguchi 2001). |
Bacteria | Pseudomonadota | YidY of E. coli |
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2.A.1.2.23 | The fructose-specific facilitator (uniporter), Ffz1 (Pina et al., 2004) | Eukaryota | Fungi, Ascomycota | Ffz1 of Zygosaccharomyces bailii (CAD56485) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.24 | The multidrug resistance efflux pump, CgMDR (exports fluoroquinolones and chloramphenicol) (Vardy et al., 2005) | Bacteria | Actinomycetota | CgMDR of Corynebacterium glutamicum (NP_600365) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.25 | The purine base/nucleoside (nucleosides: inosine, adenosine and guanosine; bases: hypoxanthine, adenine, guanine, 2-fluoroadenine) efflux pump, YdhL (PbuE) (Johansen et al., 2003; Nygaard and Saxild, 2005; Zakataeva et al., 2007; Sheremet et al. 2011). |
Bacteria | Bacillota | PbuE of Bacillus subtilis (O05504) |
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2.A.1.2.26 | The purine ribonucleoside (inosine, adenosine, guanosine, 6-mercaptopurine ribonucleoside) efflux pump (H+ antiporter), NepI (YicM) (Gronskiy et al., 2005; Sheremet et al. 2011) |
Bacteria | Pseudomonadota | NepI of E. coli (P0ADL1) |
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2.A.1.2.27 | The alcaligin siderophore exporter, AlcS (Brickman and Armstrong, 2005) | Bacteria | Pseudomonadota | AlcS of Bordetella pertussis (CAE42734) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.28 | The vesicular acetylcholine transporter, VAChT (pumps acetylcholine into synaptic vesicles). The acetyl choline and vesamicol binding sites have been identified (Ojeda et al. 2004) and are near the luminal end of the transport pathway (Khare et al. 2010). The SLC18 family has been reviewed (Lawal and Krantz 2018). VAChT in the brain is an important presynaptic cholinergic biomarker (Hu et al. 2023). |
Eukaryota | Metazoa, Chordata | SLC18A3 of Homo sapiens |
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2.A.1.2.29 | The vesicular monoamine transporter, VMAT2 (pumps dopamine, norepinephrine, serotonin and histamine into synaptic vesicles) (Cliburn et al. 2016). VMAT2 physically and functionally interacts with the enzymes responsible for dopamine synthesis (Cartier et al., 2010). Molecular hinge points mediating alternating access have been identified (Yaffe et al. 2013). The substituted amphetamine, 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy), is a widely used drug of abuse that induces non-exocytotic release of serotonin, dopamine, and norepinephrine through their cognate transporters as well as blocking the reuptake of neurotransmitter by the same transporters (Sealover et al. 2016). The slc18a2 gene is expressed at high levels in neuroepithelial cells (Pan et al. 2022). Synaptic vesicle proteins are selectively delivered to axons in mammalian neurons (Watson et al. 2023). VMAT2 may play a role in Parkinson's disease (Zhou et al. 2023). Dopaminergic cell protection and alleviation of neuropsychiatric disease symptoms are aleviated by VMAT2 expression (Lee et al. 2023). Deutetrabenazine and valbenazine are VMAT2 inhibitors for tardive dyskinesia (Golsorkhi et al. 2024). Drug inhibition and substrate transport mechanisms of human VMAT2 have been characterized (Wei et al. 2025). Depression affects about 5% of the population, and there are two groups of antidepressants that are the first-line treatment for depressive disorder: selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. A method for prediction of inhibitors has been developed (Łapińska et al. 2025). |
Eukaryota | Metazoa, Chordata | VMAT2 (SLC18A2) of Homo sapiens |
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2.A.1.2.3 | Chloramphenicol:H+ antiporter, CmlA; Cmr; MdfA. Multidrug exporter that also catalyzes efflux of arabinose (but not xylose) and isopropyl β-thiogalactoside (Koita and Rao 2012). |
Bacteria | Pseudomonadota | CmlA of Pseudomonas aeruginosa |
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2.A.1.2.30 | The hippocampus abundant transcript-like 1 protein, HIATL1 or MFSD14B, of 506 aas and 12 TMSs (putative drug exporter) is a SLC18 family member. There is a correlation between a risk for colorectal cancer, alcohol consumption and variants in the 9q22.32/HIATL1 gene (Gong et al. 2016). MFSD14A (HIAT1) and MFSD14B (HIATL1) are in the mouse central nervous system throughout the adult brain (Lekholm et al. 2017). Expression of SLC22A18 regulates oxaliplatin resistance (Kim et al. 2022), and in cases of oxaliplatin resistance due to low SLC22A18 expression, resistance can be overcome by treatment with an ERK inhibitor (Kim et al. 2022). Two ammonia transporters, HIAT1alpha and HIAT1beta, in the American Horseshoe Crab, Limulus polyphemus, have been identified and characterized (Sachs et al. 2022). This gene is associated with milk production in buffalo and sheep breeds, as well as growth of chickens and goats, and drastically affect sperm formation (Luo et al. 2023). The functional InDel polymorphism (rs1089950828) reflects growth traits in domestic sheep populations (Luo et al. 2023). |
Eukaryota | Metazoa, Chordata | HIATL1 of Homo sapiens (NP_115947) |
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2.A.1.2.31 | The multidrug transporter, QDR2, required for resistance to quinidine, barban, cisplatin, and bleomycin; may play a role in potassium uptake. |
Eukaryota | Fungi, Ascomycota | QDR2 of Saccharomyces cerevisiae (P40474) |
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2.A.1.2.32 | The chloramphenicol resistance protein, ChlR | Bacteria | Actinomycetota | ChlR of Streptomyces lividans (P31141) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.33 | The Hol1 MFS transporter (Mutation allows the uptake of histidinol and other cations (Wright et al., 1996). The N-terminal 200 residues show 22% identity with 2.A.1.2.1 and 2.A.1.2.16). | Eukaryota | Fungi, Ascomycota | Hol1 of Saccharomyces cerevisiae (P53389) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.34 | The MDR efflux pump, PmrA (exports fluoroquinolone and other compounds) and other components including the antimicrobial peptide, colistin (Martinez-Garriga et al. 2007; Pamp et al., 2008). o-Cymen-5-ol nanoemulsion reverses colistin resistance in multidrug-resistant Klebsiella pneumoniae infections, and probably in other bacteria (Sheng et al. 2024). |
Bacteria | Bacillota | PmrA of Streptococcus pneumoniae (P0A4K4) |
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2.A.1.2.35 | The caffeine resistance protein 5 (Caf5) (Benko et al., 2004) |
Eukaryota | Fungi, Ascomycota | Caf5 of Schizosaccharomyces pombe (O94528) |
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2.A.1.2.36 | The multidrug resistance protein Aqr1 (YNL065w) (exports short chain monocarboxylates but not more hydrophobic acids such as octonate and quinidine. Also exports ketoconazole and crystal violet (Tenreiro et al., 2002)). | Eukaryota | Fungi, Ascomycota | Aqr1 of Saccharomyces cerevisiae (P53943) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.37 | The legiobactin (siderophore) exporter (most similar to 2.A.1.2.9; 23% identity) (Allard et al., 2006) | Bacteria | Pseudomonadota | IbtB of Legionella pneumophila LbtA (Q45RG2) LbtB (Q5WX21) |
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2.A.1.2.38 | Tetracycline-specific exporter, TetA39 (most like 2.A.1.2.4) (Thompson et al., 2007). | Bacteria | Pseudomonadota | TetA39 of Acinetobacter spp. (Q56RY7) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.39 | Tetracycline-specific exporter, TetA41 (most like 2.A.1.2.4) (Thompson et al., 2007). | Bacteria | Pseudomonadota | TetA41 of Serratia marcescens (Q5JAK9) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.4 | Tetracycline:H+ antiporter | Bacteria | Pseudomonadota | TetA of E. coli | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.40 | The dityrosine exporter, Dtr1 (required for formation of the outer layer of the cell wall (Morishita and Engebrecht, 2008)). | Eukaryota | Fungi, Ascomycota | Dtr1 of Saccharomyces cerevisiae (P38125) |
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2.A.1.2.41 | The tetracycline resistance determinant, TetA42 from a deep terrestrial subsurface bacterium (Brown et al., 2008). | Bacteria | Actinomycetota | TetA42 of Micrococcus sp. SMCC G8878 (B2YGG2) |
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2.A.1.2.42 | The multidrug efflux pump, EmrD-3 (exports ethidium, linezolid, tetraphenylphosphonium chloride, rifampin, erythromycin, minocycline, trimethoprim, chloramphenicol, and rhodamine) (Smith et al., 2009). |
Bacteria | Pseudomonadota | EmrD-3 of Vibrio cholerae (Q9KMQ3) |
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2.A.1.2.43 | The multidrug efflux pump, Qdr3 (exports polyamines, quinidine, barban, cisplatin and bleomycin). The two halves of the protein each have an N-terminal. 150 residue hydrophilic region found in many fungi followed by a 200 residue, 6 TMS, transmembrane region. This suggests that an intragenic duplication event gave rise to 12 TMS proteins independently of most other MFS carriers, but this has not been demonstrated, possibly because of extensive sequence divergence of the second half. |
Eukaryota | Fungi, Ascomycota | Qdr3 of Saccharomyces cerevisiae (P38227) |
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2.A.1.2.44 | Diglucosyl-diacylglycerol exporter or flippase, LtaA (lipoteichoic acid protein A) (Gründling and Schneewind, 2007). |
Bacteria | Bacillota | LtaA of Staphylococcus aureus (Q2FZP8) |
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2.A.1.2.45 | The fructose-specific uniporter, Ffz1 (69% identical to Ffz2 |
Eukaryota | Fungi, Ascomycota | Ffz1 of Zygosaccharomyces rouxii (C5E4Z7) |
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2.A.1.2.46 | The fructose/glucose uniporter, Ffz2 (64% identical to 2.A.1.2.23). Both sugars are transported with similar affinities and efficiencies (Leandro et al., 2011). |
Eukaryota | Fungi, Ascomycota | Ffz2 of Zygosaccharomyces rouxii (C5DX43) |
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2.A.1.2.47 | The multidrug resistance efflux pump, HsMDR (YfmO2). Exports drugs such as fluoroquinolones and chloramphenicol (Vardy et al., 2005). |
Archaea | Euryarchaeota | HsMDR of Halobacterium salinarum |
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2.A.1.2.48 | tetracycline exporter |
Eukaryota | Fungi, Ascomycota | tetR exporter of Aspergillus niger (A2QTF4) |
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2.A.1.2.49 | Putative tetracycline resistance protein |
Archaea | Thermoproteota | Putative tet resistance pump of Pyrobaculum aerophilum (Q8ZUX8) |
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2.A.1.2.5 | Multidrug (14- and 15-membered macrolides, lincosamides, streptogramins, tetracyclines, daunomycin, ethidium bromide, etc.):H+ antiporter, LmrP. Two proton translocation pathways have been proposed (Bapna et al., 2007), but Schaedler and van Veen, 2010 have provided evidence that a flexible cation binding site in LmrP is associated with variable proton coupling. Basic residues R260 and K357 affect the conformational dynamics of LmrP (Wang and van Veen, 2012). Basic residues, R260 and K357 control the conformational dynamics of the protein (Wang and van Veen 2012). Also specifically catalyzes Ca2+:3H+ antiport with an affinity of 7 μM (Zhang et al. 2012). Two carboxylates (Asp-235 and Glu-327) are critical for Ca2+ binding. Protonation drives major conformational switches (Masureel et al. 2013). The system exhibits plasticity in proton interactions, which is a consequence of the flexibility in the location of key residues that are responsible for proton/multidrug antiport (Nair et al. 2016).
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Bacteria | Bacillota | LmrP of Lactococcus lactis |
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2.A.1.2.50 | MFS porter |
Eukaryota | Evosea | MFS porter of Dictyostelium purpureum (F0ZU09) |
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2.A.1.2.51 | Chloramphenicol resistance pump, CraA (43% identical to MdfA of E. coli) (Roca et al., 2009). It is a broad specificity transporter exporting chloramphenicol, thiamphenicol, florfenicol, ethidium, dequalinium, chlorhexidine, benzalkonium, mitomycin C and TPP+. Glu-38 is essential for activity (Foong et al. 2019). |
Bacteria | Pseudomonadota | CraA of Acinetobacter baumannii (A3M9E9) |
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2.A.1.2.52 | Puromycin resistance MDR protein, MdtM (Soo et al., 2011). Also catalyzes bile salt:H+ antiport, and binds cholate and deoxycholate to the protein with micromolar affinity. Functions as an MDR pump (Nishino and Yamaguchi 2001). Acts synergistically with AcrAB-TolC (Paul et al. 2014). The ortholog has been characterized in Salmonella enterica serovar Typhi, and specific residues have been shown to be important for transport and stability (Shaheen et al. 2021). |
Bacteria | Pseudomonadota | MdtM of E. coli (P39386) |
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2.A.1.2.53 | MDR pump, SLC22A18 in lung cancer cells (Lei et al., 2012). It has 424 aas and 12 TMSs. Allelic loss in the absence of mutations in the polyspecific transporter gene BWR1A on 11p15.5 in hepatoblastoma has been shown (Albrecht et al. 2004). |
Eukaryota | Metazoa, Chordata | SLC22A18 of Homo sapiens |
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2.A.1.2.54 | LigA-like protein |
Bacteria | Actinomycetota | LigA-like protein of Streptomyces coelicolor (Q9KYE9) |
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2.A.1.2.55 | Peptide exporter (Ala-Gln and Ala-branched chain amino and dipeptides) (Hayashi et al., 2010). May also export arabinose (but not xylose) and function as an MDR pump (Koita and Rao 2012). |
Bacteria | Pseudomonadota | YdeE of E. coli (P31126) |
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2.A.1.2.56 | NCL7 or MFSD8. Neuronal ceroid lipofuscinosis, NCL, a neuro-degenerative genetic disease, is caused by mutations in at least 8 different human genes, one of which, CLN7 (MFSD8), is associated with late infantile NCL. CLN7 is localized to lysosomes (Sharifi et al., 2010). Loss of this putative lysosomal transporter in the brain leads to lysosomal dysfunction, impaired constitutive autophagy and neurodegeneration late in the disease (Brandenstein et al. 2015). An in-frame deletion in the MFSD8 gene gave rise to neuronal ceroid lipofuscinosis type 7 (Hosseini Bereshneh and Garshasbi 2018). In D. discoideum, it interacts with cathepsin D (CtsD), as well as human orthologs of CLN3 (Cln3) and CLN5 (Cln5) (Huber et al. 2020). In humans the defect can also affect cardiac conducting cells and cardiomyocytes as well as basophilic degeneration of myocardium. (Iannaccone Farkašová et al. 2019). Moreover, loss of Mfsd8 alters the secretome during Dictyostelium aggregation (Huber et al. 2023). |
Eukaryota | Metazoa, Chordata | NCL7 of Homo sapiens (Q8NHS3) |
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2.A.1.2.57 | MFS-type polyamine transporter SLC18B1 or VPAT (Solute carrier family 18 member B1) of 456 aas and 12 TMSs. Polyamines synthesized in neurons and astrocytes are stored in secretory vesicles and released upon depolarization. Vesicular storage is mediated in an ATP-dependent, reserpine-sensitive process. SLC18B1 is the fourth member of the SLC18 transporter family, which includes vesicular monoamine transporters and a vesicular acetylcholine transporter. Proteoliposomes containing purified human SLC18B1 protein actively transport spermine and spermidine in exchange of H+. The SLC18B1 protein is predominantly expressed in the hippocampus and is associated with vesicles in astrocytes. SLC18B1 gene knockdown decreased both the amount of the SLC18B1 protein and the spermine/spermidine contents of astrocytes (Hiasa et al. 2014). Slc18b1 knock out mice have reduced polyamine content in the brain These mice have impaired short and long term memory in novel object recognition, radial arm maze and self-administration paradigms (Fredriksson et al. 2019). Moreover, Slc18b1 KO mice have altered expression of genes involved in Long Term Potentiation, plasticity, calcium signalling and synaptic functions, and expression of components of GABA and glutamate signalling are alterred. These mutants show partial resistance to diazepam, manifested as lowered reduction in locomotion after diazepam treatment. Possibly, removal of Slc18b1 leads to reduction of polyamine contents in neurons, resulting in reduced GABA signalling due to a long-term reduction in glutamatergic signalling (Fredriksson et al. 2019). Polyamine release and vesicular polyamine transporter, SLC18B1; VPAT,. expression in megakaryoblastic cells and plateletshas been documented (Uehara et al. 2024). |
Eukaryota | Metazoa, Chordata | C6orf192 of Homo sapiens |
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2.A.1.2.58 | Protein ZINC INDUCED FACILITATOR 1 | Eukaryota | Viridiplantae, Streptophyta | ZIF1 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.59 | Uncharacterized MFS-type transporter C330.07c; YJ87 |
Eukaryota | Fungi, Ascomycota | YJ87 of Schizosaccharomyces pombe |
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2.A.1.2.6 | (Benomyl, cycloheximide, methotrexate, fluconazole, etc.):H+ antiporter, CaMDR1 (Basso et al., 2010; Cannon et al., 1998). MDR1 catalyzes efflux of commonly used azoles. The central cytoplasmic loop is critical for MDR function, but does not impart substrate specificity (Mandal et al., 2012). The structural basis for polyspecificity of MDR MFS transporters, based on studies with Mdr1, is the extended capacity brought by residues located at the periphery of a binding core to accomodate compounds differing in size and type (Redhu et al. 2018). Each domain in the protein is arranged in a pseudo-symmetric fold of two tandems of 3-TMSs that alternatly expose the drug-binding site towards the inside or the outside of the yeast to promote drug binding and release. Sharma et al. 2022 provided information on these motifs by having screened a library of 64 drug transport-deficient mutants and their corresponding suppressors spontaneously addressing the deficiency. They found that five strains recovered the drug-resistance capacity by expressing CaMdr1 with a secondary mutation. The pairs of debilitating/rescuing residues are distributed either in the same TMS or 3-TMS repeat, at the hinge of 3-TMS repeat tandems, and between the N- and C-domains. Most of these mutants belong to different signature motifs, highlighting a mechanistic role and interplay thought to be conserved among MFS proteins. Results point to the specific role of TMS 11 in the interplay between the N- and C-domains in the inward- to outward-open conformational transition (Sharma et al. 2022). |
Eukaryota | Fungi, Ascomycota | CaMDR1 of Candida albicans |
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2.A.1.2.60 | YajR of 454 aas and 12 TMSs. The 3-D structure in the outward-facing conformation is available at 3.15Å resolution, and the cytoplasmic C-terminal YAM domain has been solved to 1.07Å resolution. This 65 aa YAM domain is thought to control the conformational states of the protein (Jiang et al. 2013; Jiang et al. 2014). |
Bacteria | Pseudomonadota | YajR of E. coli |
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2.A.1.2.61 | SPX domain-containing membrane protein At1g63010, called Vacuolar Phosphate Transporter 1 (VPT1), It transports phosphate > sulphate > nitrate > chloride and malate. The vpt1 mutant plants were stunted and consistently retained less Pi than wild type plants, especially when grown in medium containing high levels of Pi. In seedlings, VPT1 was expressed primarily in younger tissues under normal conditions, but was strongly induced by high-Pi conditions in older tissues, suggesting that VPT1 functions in Pi storage in young tissues and in detoxification of high Pi in older tissues. As a result, disruption of VPT1 rendered plants hypersensitive to both low-Pi and high-Pi conditions, reducing the adaptability of plants to changing Pi availability (Liu et al. 2015). |
Eukaryota | Viridiplantae, Streptophyta | VPT1 or At1g63010 of Arabidopsis thaliana |
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2.A.1.2.62 |
Putative MDR pump, YdhC or PunC. It has been reporte to export arabinose but not xylose (Koita and Rao 2012). However, it also takes up adenosine, adenine, deoxyadenosine, and other purine nucleosides and nucleobases such as inosine and guanosine as sole nitrogen sources. It also takes up various sulfonamides such as sulfathiazole, sulfadiazine and sulfamethoxazole. Expression of the punC gene is reglulated by the positive transcription factor, PunR (YdhB) (Rodionova et al. 2021). |
Bacteria | Pseudomonadota | PunC (YdhC) of Escherichia coli |
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2.A.1.2.63 | Probable drug/proton antiporter YHK8 | Eukaryota | Fungi, Ascomycota | YHK8 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.64 | Polyamine exporter 4 (Igarashi and Kashiwagi 2010). |
Eukaryota | Fungi, Ascomycota | TPO4 of Saccharomyces cerevisiae |
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2.A.1.2.65 | Inner membrane transport protein YdhP |
Bacteria | Pseudomonadota | YdhP of Escherichia coli |
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2.A.1.2.66 | Polyamine exporter 3 (Igarashi and Kashiwagi 2010). |
Eukaryota | Fungi, Ascomycota | TPO3 of Saccharomyces cerevisiae |
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2.A.1.2.67 | Polyamine exporter 2 (Igarashi and Kashiwagi 2010). |
Eukaryota | Fungi, Ascomycota | TPO2 of Saccharomyces cerevisiae |
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2.A.1.2.68 | Tetracycline resistance protein, class B (TetA(B)) (Metal-tetracycline/H+ antiporter). Mutants defective in either transport or tetracycline binding have been isolated (Wright and Tate 2015). Several amino acid substitutions (i.e., D190C, E192C and S201C) alter the specificity of the porter so that it prefers deoxycycline (3x) and minochcline (6x) over tetracycline (Sapunaric and Levy 2005). |
Bacteria | Pseudomonadota | TetA of Escherichia coli |
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2.A.1.2.69 | Uncharacterized MFS-type transporter YttB |
Bacteria | Bacillota | YttB of Bacillus subtilis |
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2.A.1.2.7 | Bicyclomycin, sulfathiazole, tetracycline, fosfomycin, acriflavin, etc.):H+ antiporter (Nishino and Yamaguchi 2001). Also exports L-cysteine (Yamada et al., 2006). |
Bacteria | Pseudomonadota | Bcr of E. coli |
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2.A.1.2.70 | Multidrug resistance protein 1 (Multidrug-efflux transporter 1) | Bacteria | Bacillota | Bmr of Bacillus subtilis |
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2.A.1.2.71 | Uncharacterized MFS-type transporter Rv2456c/MT2531 | Bacteria | Actinomycetota | Rv2456c of Mycobacterium tuberculosis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.72 | Major facilitator superfamily domain-containing protein 9 | Eukaryota | Metazoa, Chordata | Mfsd9 of Mus musculus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.2.73 | Major facilitator superfamily domain-containing protein 10, MFSD10, a member of the SLC18 family. It is a tetracycline exporter-like protein. This protein is found in the inner nuclear membrane (Cheng et al. 2019) and is a disease protein in humans (Bagchi et al. 2020). Its gene shows increased expression with increased energy consumption (Bagchi et al. 2020). It may confers cellular resistance to apoptosis induced by the non-steroidal anti-inflammatory drugs, indomethacin and diclofenac. A microdeletion proximal to the mfsD10 gene is associated with mild Wolf-Hirschhorn syndrome (Hannes et al. 2012).
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Eukaryota | Metazoa, Chordata | MfsD10 of Mus musculus |
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2.A.1.2.74 | Multidrug resistance protein MdtL | Bacteria | Pseudomonadota | MdtL of Shewanella sp. |
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2.A.1.2.75 | Tetracycline resistance protein, class E (TetA(E)) | Bacteria | Pseudomonadota | TetA of Escherichia coli |
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2.A.1.2.76 | Major facilitator copper transporter 1, Mfc1. Takes up copper in meiotic sporulating cells; present in the forespore membrane. Induced under copper limitation. Required for normal forespore development and spore copper-dependent amine oxidase activity (Beaudoin et al. 2011). |
Eukaryota | Fungi, Ascomycota | Mfc1 of Schizosaccharomyces pombe |
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2.A.1.2.77 |
CefT confers phenylacetate resistance (Fernández-Aguado et al. 2012). It has been reported to be a hydrophilic beta-lactam transporter that is involved in the secretion of hydrophilic beta-lactams containing an α-aminoadipic acid side chain (isopenicillin N, penicillin N and deacetylcephalosporin C) (Cesareo et al. 2007; Ullán et al. 2002). |
Eukaryota | Fungi, Ascomycota | CefT of Acremonium chrysogenum |
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2.A.1.2.78 |
The PaaT (PenT) exporter. PaaT is involved in penicillin production, possibly through the translocation of side-chain precursors (phenylacetate and phenoxyacetate) from the cytosol to the peroxisomal lumen across the peroxisomal membrane of P. chrysogenum. It has a Pex19 (peroxisome biogenesis factor 19) binding sequence (residues 258 - 269) accounting for its peroxysomal location (Fernández-Aguado et al. 2012; Yang et al. 2012). |
Eukaryota | Fungi, Ascomycota | PaaT of Penicillum chysogenum (notatum) |
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2.A.1.2.79 | The host-nonselective polyketide perylenequinone toxin, cercosporin, exporter, Ctb4 (Choquer et al. 2007). |
Eukaryota | Fungi, Ascomycota | Ctb4 of Cercospora nicotianae |
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2.A.1.2.8 | (Spermidine; fluoroquinolones, acriflavin, chloramphenicol, ethidium bromide, etc.):H+ antiporter (Woolridge et al. 1997). |
Bacteria | Bacillota | Blt of Bacillus subtilis |
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2.A.1.2.80 | Putative permease of 458 aas |
Eukaryota | Rhodophyta | Putative permease of Galdieria sulphuraria |
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2.A.1.2.81 | Uncharacterized MFS permease; encoded by a gene adjacent to one encoding a peroxiredoxin (an electron donor and antioxidant; Hanschmann et al. 2013). |
Bacteria | Deinococcota | UP of Deinococcus peraridilitoris |
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2.A.1.2.82 | Uncharacterized MFS permease of 402 aas and 12 TMSs |
Bacteria | Spirochaetota | UP of Leptospira interrogans |
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2.A.1.2.83 | MmrA MFS protein. Homologous to drug exporter. RppA and MmrA are involved in amino acid uptake and efflux of antimicrobial agents including streptomycin, ethidium bromide and norfloxacin (Kimura et al. 2004). |
Bacteria | Myxococcota | MXAN_5906 of Myxococcus xanthus. |
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2.A.1.2.84 | Probable siderophore-specific exporter of 407 aas and 12 TMSs, MxcK. |
Bacteria | Myxococcota | MxcK of Stigmatella aurantiaca |
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2.A.1.2.85 | Peroxysomal phenylacetate/phenoxyacetate transporter, PaaT (CefT) of 564 aas (Fernández-Aguado et al. 2013). |
Eukaryota | Fungi, Ascomycota | PaaT of Penicillium chrysogenum (Penicillium notatum) |
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2.A.1.2.86 | Peroxisomal isopenicillin N importer, PenM (Evers et al. 2004; Fernández-Aguado et al. 2014). |
Eukaryota | Fungi, Ascomycota | PenM of Penicillium chrysogenum (Penicillium notatum) |
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2.A.1.2.87 | Purine efflux porter of 392 aas, CepA. Exports purine analogues, 6-mercaptopurine and 6-mercaptoguanine, but not to 2-aminopurine and purine nucleoside analogues. May show increased resistance to the antibiotics nalidixic acid and ampicillin (Sim et al. 2014). |
Bacteria | Actinomycetota | CepA of Corynebacterium glutamicum |
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2.A.1.2.88 | MFS porter of 442 aas |
Archaea | Euryarchaeota | MFS porter of Pyrococcus furiosus |
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2.A.1.2.89 | MFS porter of 454 aas |
Bacteria | Actinomycetota | MFS porter of Streptomyces coelicolor |
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2.A.1.2.9 | (Hydrophobic uncoupler e.g., CCCP, benzalkonium, SDS and other drugs):H+ antiporter, EmrD (Nishino and Yamaguchi 2001). The 3-d structure (3.5 Å resolution) has been determined (Yin et al., 2006). conformational dynamics studies have revealed details of the transport pathway and some motions of EmrD at an atomic level (Baker et al. 2012). Probably exports arabinose but not xylose (Koita and Rao 2012). |
Bacteria | Pseudomonadota | EmrD of E. coli |
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2.A.1.2.90 | UMF4F of 405 aas and 12 TMSs |
Bacteria | Bacillota | UMF4F of Aectobacterium woodii |
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2.A.1.2.91 | MFS permease of 554 aas and 12 TMSs |
Eukaryota | Fungi, Ascomycota | Putative MFS carrier of Metarhizium robertsii (Metarhizium anisopliae) |
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2.A.1.2.92 | The CefM protein of 482 aas and 12 TMSs. Probably involved in the translocation of penicillin N from the lumen of peroxisomes (or peroxisome-like microbodies) to the cytosol, where it is converted into cephalosporin C (Teijeira et al. 2009). A null mutant accumulates penicillin N, is unable to synthesize deacetoxy- and deacetyl-cephalosporin C as well as cephalosporin C, and shows impaired differentiation into arthrospores (Teijeira et al. 2009). |
Eukaryota | Fungi, Ascomycota | CefM of Acremonium chrysogenum (Cephalosporium acremonium) |
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2.A.1.2.93 | Uncharacterized MFS permease of 433 aas and 12 TMSs |
Bacteria | Bacillota | UP of Lactobacillus buchneri |
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2.A.1.2.94 | Uncharacterized MFS permease of 445 aas and 12 TMSs |
Bacteria | Actinomycetota | UP of Microbacterium maritypicum |
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2.A.1.2.95 | Blt of 422 aas and 12 TMSs. Exports antibiotics such as fluoroquinolones and chloramphenicol (Vardy et al. 2005) |
Bacteria | Actinomycetota | Blt of Mycobacterium smegmatis |
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2.A.1.2.96 | ZIF2 (Zinc-Induced Facilitator 2) of 484 aas and 12 TMSs localises primarily at the tonoplast of root cortical cells and is a functional transporter able to mediate Zn efflux from the cytoplasm (Remy et al. 2014). Activity is controlled by alternative RNA splicing. |
Eukaryota | Viridiplantae, Streptophyta | ZIF2 of Arabidopsis thaliana |
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2.A.1.2.97 | Bcr/CflA family drug exporter, MSMEG_2991 of 428 aas and 12 TMSs. A pmf-dependent multidrug efflux pump that expels diverse groups of antibiotics including ciprofloxacin. May also be involved in biofilm enhancement (Bansal et al. 2016). |
Bacteria | Actinomycetota | Bcr-like exporter of Mycobacterium smegmatis |
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2.A.1.2.98 | Uncharacterized MFS transporter of 427 aas and 12 TMSs. |
Archaea | Thermoproteota | UP of Aeropyrum camini |
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2.A.1.2.99 | Putative siderophore exporter, SbnD of 418 aas and 12 TMSs (Marklevitz and Harris 2016). |
Bacteria | Bacillota | SbnD of Staphylococcus aureus |
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2.A.1.20.1 | Sugar efflux transporter A, SetA. Exports lactose, glucose, aromatic glucosides and galactosides, cellobiose, maltose, α-methylglucoside and isopropyl β-thiogalactosides (IPTG); amino-glycosides, streptomycin and kanamycin are weakly expelled (Liu et al. 1999). Regulated by SgrR (a transcriptional regulator of sgrS) and SgrS (a small RNA that represses trascription of setA). These two regulatory genes are upstream of the setA gene. Uses a pmf-dependent mechanism of energization. Induced in response to glucose-phosphate stress which occurs when a sugar phosphates accumulate in the cytoplam (Sun and Vanderpool 2011). Overexpression of the gene for SetA allows export of Lacto-N-triose (LNT II) and lacto-N-tetraose (LNT), human milk oligosaccharides (Sugita and Koketsu 2022). |
Bacteria | Pseudomonadota | SetA (YabM) of E. coli |
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2.A.1.20.2 | Sugar efflux system, SetB, for lactose and glucose, but not IPTG or galactose (Liu et al. 1999). Overexpression of the gene for SetB allows export of Lacto-N-triose (LNT II) and lacto-N-tetraose (LNT), human milk oligosaccharides (Sugita and Koketsu 2022). |
Bacteria | Pseudomonadota | SetB (YeiO) of E. coli |
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2.A.1.20.3 | Arabinose (but not xylose) exporter, SetC (Koita and Rao 2012). |
Bacteria | Pseudomonadota | SetC (YicK) of E. coli |
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2.A.1.20.4 | Efflux system for arabinose and IPTG (>>lactose), SotA | Bacteria | Pseudomonadota | SotA of Erwinia chrysanthemi | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.21.1 | The macrolide (erythromycin; oleandomycin; azithromycin; telithromycin) efflux pump, MefA, of 405 aas and 12 TMSs (Cantón et al. 2005; Bley et al. 2011). Iannelli et al. 2018 suggested that MefA can function with an ATPase, MsrD (TC# 3.A.1.121.6), and therefore function as an ABC drug exporter. However, the data presented seem inconsistent with this suggestion. The two genes encoding these two proteins are adjacent to each other, suggesting that they may function together (Iannelli et al. 2018). Predicted transmembrane proteins with homology to MefA do not complement a mefA deletion in the MefA-MsrD macrolide efflux system in Streptococcus pneumoniae (Fox et al. 2021). Note: MsrD is an ATPase of the ABC superfamily, so it can not be certain that MefA and MsrD function together. Coupling of an MFS carrier with an ABC-type energizer is very rare, maybe non-existent. |
Bacteria | Bacillota | MefA of Streptococcus pyogenes |
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2.A.1.21.10 | MFS porter |
Archaea | Thermoproteota | MFS porter of Sulfolobus islandicus (D2PCQ8) |
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2.A.1.21.11 | MFS porter |
Bacteria | Actinomycetota | MFS porter of Stackebrandtia nassauensis (D3Q871) |
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2.A.1.21.12 | Multidrug-efflux transporter, Rv1258c/MT1297, of 419 aas and 12 TMSs. Both Rv1634 and Rv1258c are believed to play major roles in drug resistance by altering the protein pump that is required to remove the active drugs from the bacterial cell (Panja et al. 2019). Thymol exhibits inhibitory activity against Mycobacterium smegmatis and shows promising interaction with a combination of isoniazid (INH) and rifampicin (RIF) of TB regimens. It specifically inhibites Rv1258 and Rv0194 (Shankar Das et al. 2024). |
Bacteria | Actinomycetota | Rv1258c of Mycobacterium tuberculosis |
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2.A.1.21.13 | Uncharacterized MFS-type transporter yjbB | Bacteria | Bacillota | YjbB of Bacillus subtilis |
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2.A.1.21.14 | Uncharacterized MFS-type transporter Mb0038c | Bacteria | Actinomycetota | Mb0038c of Mycobacterium bovis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.21.15 | MFS Homologue |
Bacteria | Actinomycetota | MFS homologue of Streptomyces coelicolor (Q9X9Y0) |
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2.A.1.21.16 | MFS Homologue |
Bacteria | Actinomycetota | MFS homologue of Streptomyces coelicolor (Q9X8T4) |
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2.A.1.21.17 | Uncharacterized MFS-type transporter YxaM |
Bacteria | Bacillota | YxaM of Bacillus subtilis |
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2.A.1.21.18 | Uncharacterized protein |
Bacteria | Actinomycetota | Uncharacterized protein of Streptomyces coelicolor |
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2.A.1.21.19 |
Uncharacterized Major Facilitator |
Bacteria | Actinomycetota | UMF of Streptomyces coelicolor |
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2.A.1.21.2 | The multidrug (erythromycin, tetracycline, puromycin, bleomycin) resistance protein, Cmr |
Bacteria | Actinomycetota | Cmr of Corynebacterium glutamicum |
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2.A.1.21.20 |
Unidentified Major Facilitator |
Bacteria | Pseudomonadota | UMF of Pseudomonas syringae |
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2.A.1.21.21 |
Unidentified major facilitator |
Bacteria | Actinomycetota | UMF of Saccharomonospora marina |
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2.A.1.21.22 | Macrolide efflux pump, MefE (Mef; MefA) of 405 aas. Induced by erythromycin and the antimicrobial peptide, LL-37 (Zähner et al. 2010). May act in conjunction with Mel (Q93QE4), an ABC-type ATPase that is encoded in the same operon with the mefA gene (Ambrose et al. 2005). |
Bacteria | Bacillota | MefE of Streptococcus pneumoniae |
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2.A.1.21.23 | Uncharacterized MFS permease of 433 aas and 12 TMSs |
Bacteria | Deinococcota | UP of Deinococcus geothermalis |
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2.A.1.21.24 | MFS_1 protein of 476 aas and 12 TMSs. |
Bacteria | Actinomycetota | MFS_1 of Bifidobacterium longum |
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2.A.1.21.25 | MFS permease of 415 aas and 12 TMSs in a 4 + 2 + 2 + 2 +2 TMS arrangement. Tian et al. 2022 identified an MFS protein that is beneficial to L-lactic acid production by Bacillus coagulans at low pH. Adhesion forces to surfaces play an important role, next to other established driving forces, in staphylococcal channel gating. This provides an interesting extension of our understanding of transmembrane antibiotic uptake and solute efflux in infectious staphylococcal biofilms in which bacteria experience adhesive forces from a wide variety of surfaces, like those of other bacteria, tissue cells, or implanted biomaterials (Carniello et al. 2020). |
Bacteria | Bacillati, Bacillota | MFS protein of Bacillus coagulans 2-6 (Heyndrickxia coagulans 2-6) |
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2.A.1.21.3 | The tetracycline resistance determinant, TetV | Bacteria | Actinomycetota | TetV of Mycobacterium smegmatis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.21.4 | Multidrug resistance efflux pump, Tap | Bacteria | Actinomycetota | Tap of Mycobacterium fortuitum | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.21.5 | The putative bacilysin exporter, BacE | Bacteria | Bacillota | BacE of Bacillus subtilis (P39642) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.21.6 | The tetracycline resistance efflux pump, TetA(P) (Bannam et al., 2004) (21% identity (e-07) with 2.A.1.21.5 and 22% identity (2xe-7) with 2.A.1.2.10). It may be the link between DHA1 and DHA3. | Bacteria | Bacillota | TetA (P) of Clostridium perfringens (Q46305) |
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2.A.1.21.7 | The Staphyloferrin A (siderophore) exporter, NWMN-2081 (Beasley et al. 2009). Independently suggested to be a macrolide exporter (Marklevitz and Harris 2016). |
Bacteria | Bacillota | NWMN-2081 of Staphylococcus aureus (A6QJ21) |
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2.A.1.21.8 | The putative macrolide exporter, TIGR00900 (most similar to 2.A.1.21.1). |
Bacteria | Bacillota | TIGR00900 of Bacillus clausii (Q5WAS7) |
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2.A.1.21.9 | MFS carrier of unknown function |
Archaea | Candidatus Thermoplasmatota | MFS carrier of Thermoplasma acidophilum (Q9HLP1) |
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2.A.1.22.1 | Synaptic vesicle glycoprotein neurotransmitter (e.g., dopamine) transporter, SV2A or SLC22B1. This protein localizes to neurotransmitter-containing vesicles and has a nucleotide binding site (Yao and Bajjalieh 2009). The SV2 family is comprised of three paralogues: SV2A, SV2B, and SV2C. They are present in secretory vesicles, including synaptic vesicles, and are critical to neurotransmission. Structural and functional studies suggest that SV2 proteins may play several roles to promote proper vesicular function. Among these roles are their potential to stabilize the transmitter content of vesicles, to maintain and orient the releasable pool of vesicles, and to regulate vesicular calcium sensitivity to ensure efficient, coordinated release of the transmitter (Stout et al. 2019). SV2A plays a role in neuronal excitability and as such is the specific target for the antiepileptic drug levetiracetam as well as seletracetam and brivaracetam. SV2 proteins also act as the target by which potent neurotoxins, particularly botulinum, gain access to neurons and exert their toxicity. Both SV2B and SV2C are increasingly implicated in diseases such as Alzheimer's disease and Parkinson's disease. Despite decades of intensive research, their exact functions were elusive in 2019 (Stout et al. 2019), but the systems may transport galactose.The human (Q70J3) and rat orthologs are 99% identical. The structure, function, and disease relevance of GP2 (SV2) transporters have been reviewed (Stout et al. 2019). More than one percent of people have epilepsy worldwide. Levetiracetam (LEV) is a successful new-generation antiepileptic drug (AED), and its derivative, brivaracetam (BRV), shows improved efficacy. Synaptic vesicle glycoprotein 2a (SV2A), a membrane transporter in the synaptic vesicles (SVs), has been identified as a target of LEV and BRV. SV2A also serves as a receptor for botulinum neurotoxin (BoNT) (Yamagata et al. 2024). The structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A have been ellucidated (Yamagata et al. 2024). |
Eukaryota | Metazoa, Chordata | SV2 of Rattus norvegicus |
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2.A.1.22.2 | Synaptic vesicle glycoprotein 2B of 556 aas |
Eukaryota | Metazoa, Arthropoda | Glycoprotein 2B of Tribolium castaneum |
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2.A.1.22.3 | AgaP of 537 aas |
Eukaryota | Metazoa, Arthropoda | AgaP of Anopheles gambiae |
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2.A.1.22.4 | Uncharacterized protein of 537 aas |
Eukaryota | Metazoa, Arthropoda | UP of Acyrthosiphon pisum |
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2.A.1.22.5 | Uncharacterized protein of 561 aas |
Eukaryota | Metazoa, Placozoa | UP of Trichoplax adhaerens (Trichoplax reptans) |
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2.A.1.22.6 | Synaptic vesicle 2C, SV2C or SLC22B3, of 727 aas and 11 TMSs. Botulinum neurotoxins (BoNTs) inhibit neurotransmitter release by selectively cleaving core components of the vesicular fusion machinery. The synaptic vesicle proteins Synaptotagmin-I and -II act as receptors for BoNT/B and BoNT/G. Mahrhold et al. 2006 showed that BoNT/A also interacts with a synaptic vesicle protein, the synaptic vesicle glycoprotein 2C (SV2C), but not with the homologous proteins SV2A and SV2B. Binding of BoNT/A occurs at the membrane juxtaposed region preceding transmembrane domain 8. A peptide comprising the intravesicular domain between transmembrane domains 7 and 8 specifically reduces the neurotoxicity of BoNT/A at phrenic nerve preparations, demonstrating the physiological relevance of this interaction (Mahrhold et al. 2006). The interactions of SV2C with BoNT have been reviewed (Li et al. 2020). SV2C is implicated in diseases such as Alzheimer's disease and Parkinson's disease (Stout et al. 2019). It seems to play roles in vesicle trafficking, exocytosis and neurotransmission (Hu et al. 2017). |
Eukaryota | Metazoa, Chordata | SV2C of Homo sapiens |
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2.A.1.22.7 | Synaptic vesicle glycoprotein 2B, SV2B or SLC22B2, of 683 aas and 12 TMSs in a 6 + 1 + 5 TMS arrangement. SV2B, ephrin B1 and the receptors of angiotensin II are expressed in the podocyte, and their expressions were altered in anti-nephrin antibody-induced nephropathy. These proteins may be involved in the development of proteinuria (Kawachi et al. 2009). SV2B and SV2C may be involved in the pathogenesis of epilepsy as well as other neurodegenerative diseases (Löscher et al. 2016) such as Alzheimer's disease and Parkinson's disease (Stout et al. 2019). Defective lysosomal acidification may provide a prognostic marker and therapeutic target for neurodegenerative diseases (Lo and Zeng 2023). |
Eukaryota | Metazoa, Chordata | SV2B of Homo sapiens |
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2.A.1.23.1 | Conjugated bile salt:H+ symporter, CbsT1 of 452 aas and 12 TMSs. Its gene is in an operon with those for CbsT2 and CbsH, a conjugated bile salt hydrolase, and such operons are common amoung the lactobacilli including Lactobacillus acidophilus (Elkins et al. 2001). |
Bacteria | Bacillota | CbsT1 of Lactobacillus johnsonii 100-100 |
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2.A.1.23.2 | Taurocholate:cholate antiporter, CbsT2 of 451 aas and 12 TMSs (Elkins and Savage 2003). |
Bacteria | Bacillota | CbsT2 of Lactobacillus johnsonii 100-100 (AAC34380) |
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2.A.1.24.1 | 58.8 KDa protein, YCL038c | Eukaryota | Fungi, Ascomycota | YCL038c of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.24.2 | Vacuolar amino acid (Arg, Lys, His) transporter, Atg22 (Autophagy-related protein-22) (Sugimoto et al. 2011). |
Eukaryota | Fungi, Ascomycota | Atg22 of Schizosaccharomyces pombe (Q09812) |
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2.A.1.24.3 | MFS permease |
Bacteria | Chloroflexota | MFS permease of Chloroflexus aurantiacus (A9WGR7) |
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2.A.1.24.4 | MFS permease |
Bacteria | Myxococcota | MFS permease of Myxococcus xanthus (Q1CWQ3) |
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2.A.1.24.5 | MFS permease |
Bacteria | Actinomycetota | MFS permease of Micrococcus luteus (Micrococcus lysodeikticus) |
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2.A.1.24.6 | MFS porter of 474 aas |
Bacteria | Pseudomonadota | MFS porter of Hyphomonas neptunium |
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2.A.1.24.7 | Uncharacterized MFS carrier protein of 524 aas. |
Eukaryota | Evosea | UP of Entamoeba histolytica |
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2.A.1.25.1 | The endoplasmic reticular/Golgi acetyl-CoA:CoA antiporter 1, ACATN/ACATN1 (SLC33A1). Allows acetylation of sialic acid residues in gangliosides and lysine residues in membrane proteins. It is associated with neurodegenerative disorders such as sporadic amyotrophic laterial sclerosis (ALS) and Spastic Paraplegia 42, and it is essential for motor neuron viability (Hirabayashi et al. 2013). Abnormal concentrations of acetylated amino acids in cerebrospinal fluid are observed in acetyl-CoA transporter deficiency (Šikić et al. 2022). |
Eukaryota | Metazoa, Chordata | SLC33A1 of Homo sapiens |
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2.A.1.25.2 | Cell wall degradation product (peptides and glycopeptides including N-acetylglucosaminyl β-1,4-anhydro-N-acetyl-muramyl-tri or tetra-peptide) as well as penicillin derivative uptake porter, AmpG (Cheng and Park 2002). The AmpG permease is also required for AmpC beta-lactamase induction (Chahboune et al. 2005; Park and Uehara 2008). AmpG mediates a dynamic relationship between serine beta-lactamase induction and biofilm-formation (Mallik et al. 2018). |
Bacteria | Pseudomonadota | AmpG of E. coli (P0AE16) |
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2.A.1.25.3 | The AmpG peptidoglycan degradation product uptake porter is part of the peptidoglycan recycling pathway (Garcia and Dillard, 2008). It also plays a role in peptidoglycan remodeling, recycling, and toxic fragment release as well as pathogenesis (Schaub and Dillard 2019). |
Bacteria | Pseudomonadota | AmpG of Neisseria gonorrhoeae (Q5F6G0) |
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2.A.1.25.4 | Putative peptide/acetyl-CoA transporter of 560 aas and 12 TMSs. |
Eukaryota | Fungi, Ascomycota | Uncharacterized protein of Saccharomyces cerevisiae (Baker's yeast) |
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2.A.1.25.5 |
Transporter of meuropeptides, N-acetylglucosamine anhydrous N-acetylmuramyl peptides, AmpG (Kong et al. 2010). Necessary for induction of ampC, β-lactamase, and ampicillin resistance (Zhang et al. 2010). Amino acyl residues essential for proper mRNA production and for catalytic activity have been identified (Li et al. 2016). |
Bacteria | Pseudomonadota | AmpG of Pseudomonas aeruginosa |
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2.A.1.25.6 | Uptake transporter, AmpG, of 433 aas and 12 TMSs, specific for muropeptides, fragments of the peptidoglycan cell walls of bacteria (Ruscitto et al. 2017). |
Bacteria | Bacteroidota | AmpG of Tannerella forsythia |
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2.A.1.25.7 | Putative acetyl-CoA:CoA antiporter, ACT or AT1, of 590 aas and 12 or 13 TMSs in a 6 or 7 + 6 TMS arrangement (Wunderlich 2022). |
Eukaryota | Apicomplexa | ACT lf Plasmodium falciparum |
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2.A.1.26.1 | 41.4 KDa Protein, YcaD. It may export ectoine and hydroxyectoine (Czech et al. 2022). |
Bacteria | Pseudomonadota | YcaD of E. coli |
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2.A.1.26.2 | MFS porter, YfkF; possible drug exporter |
Bacteria | Bacillota | YfkF of Bacillus subtilis (O34929) |
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2.A.1.26.3 | Multidrug resistance efflux porter, BC3310 of 396 aas and 12 TMSs. Exports ethidium bromide, sodium dodecyl sulfate and silver nitrate. D105 in TMS4 is essential for activity (Kroeger et al. 2015). |
Bacteria | Bacillota | BC3310 of Bacillus cereus |
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2.A.1.27.1 | The phenylpropionate porter, HcaT (YfhS) (Díaz et al. 1998). |
Bacteria | Pseudomonadota | HcaT (YfhS) of E. coli |
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2.A.1.27.2 | MFS permease of 406 aas and 12 TMSs. |
Bacteria | Pseudomonadota | MFS porter of Methylobacterium nodulans |
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2.A.1.27.3 | Putative metabolite transporter of 393 aas and 12 TMSs. |
Bacteria | Campylobacterota | Porter of Sulfurimonas denitrificans (Thiomicrospira denitrificans |
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2.A.1.28.1 | Cell surface receptor (C-receptor) for anemia-inducing feline leukemia virus subgroup C (FLCVR, Slc49A1 or Mfsd7d) of 555 aas and 12 TMSs. It may function in choline transport (Kenny et al. 2023) or haem export in haemopoietic cells (Latunde-Dada et al., 2006; Khan and Quigley, 2011) and may cause Diamond-Blackfan anemia when defective (Keel et al., 2008). Mutations of FLVCR1 in posterior column ataxia and retinitis pigmentosa result in the loss of heme export activity (Yanatori et al., 2012). Heme accumulation causes toxicity (Khan and Quigley 2018). FLVCR1 is co-induced upon iron insufficiency in the placenta with the LDL receptor-related protein 1 (LRP1) heme receptor, and these two proteins may be important for neonatal iron status (Cao et al. 2014). FLVCR1 is required for erythroid and αβ-, CD4 and CD8 T- cell development (Philip et al. 2015). A splice-site variant of FLVCR1 produces retinitis pigmentosa without posterior column ataxia (Yusuf et al. 2018). Protocols suitable for purification of FLVCR1a, antibody generation and structural characterization of the transporter have been reported (Chiabrando et al. 2020). FLVCR1-related disease is a rare cause of retinitis pigmentosa and hereditary sensory autonomic neuropathy (Grudzinska Pechhacker et al. 2020). More recently, integrative genetic analyses identified FLVCR1 as a plasma-membrane choline transporter in mammals (Kenny et al. 2023). Heme allocation in eukaryotic cells relies on mitochondrial heme export through FLVCR1b to cytosolic GAPDH (Jayaram et al. 2024). |
Eukaryota | Metazoa, Chordata | C-receptor of Homo sapiens |
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2.A.1.28.2 | The MFS-Domain7 protein of 516 aas and 12 TMSs. The MFS-D7 mRNA is expressed in many human tissues, especially in lungs and testis, but its transport substrate is not known (Khan and Quigley 2018). |
Eukaryota | Metazoa, Chordata | MFSD7 of Mus musculus |
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2.A.1.28.3 | Unknown major facilitator of 407 aas and 12 TMSs. |
Bacteria | Actinomycetota | UMF of Coriobacterium glomerans (F2NBU7) |
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2.A.1.28.4 | The Fowler syndrome-associated protein, feline leukemia virus subgroup C receptor-related protein 2, FLVCR2, or SLC49A2, is probably a heme importer (Duffy et al., 2010). Mutations of SLC49A2 are observed in Fowler syndrome, a rare proliferative vascular disorder of the brain (Khan and Quigley 2018). |
Eukaryota | Metazoa, Chordata | FLVCR2 of Homo sapiens (Q9UPI3) |
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2.A.1.28.5 | MFS porter of 401 aas and 12 TMSs. |
Bacteria | Spirochaetota | MFS porter of Leptospira biflexa (B0SL69) |
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2.A.1.28.6 | Electrogenic DIRC2 (Disrupted in renal carcinoma 2) or SLC49A4. It is glycosylated and proteolytically processed (Savalas et al., 2011)) and is targeted to lysosomes via an N-terminal dileueine motif. It is implicated in hereditary renal carcinomas (Khan and Quigley 2018). DIRC2 is an electrogenic lysosomal metabolite transporter which is subjected to and presumably modulated by limited proteolytic processing (Savalas et al. 2011). |
Eukaryota | Metazoa, Chordata | DIRC2 of Homo sapiens (Q96SL1) |
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2.A.1.28.7 | Feline leukemia virus subgroup C receptor-related protein 1, FLVCR1, of 560 aas and 12 TMSs. Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum (Calame et al. 2025). Foveal hypoplasia, optic nerve decussation, and anterior segment dysgenesis (FHONDA) is a rare recessively inherited syndrome first described in 2013. FHONDA is associated with biallelic disease-causing variants in the SLC38A8 gene, which has a strong expression in the photoreceptor layer. To date, 60 different disease-causing variants in the SLC38A8 gene have been described (Teixeira et al. 2025). |
Eukaryota | Metazoa, Chordata | FLVCR1 of Felis catus |
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2.A.1.28.8 | MFSD7, FLVCR2 or SLC49A3 of 560 aas and 12 TMSs. It is the feline leukemia virus subgroup C receptor-2 (FLVCR2), a member of the SLC49 family of four paralogous genes in humans (Khan and Quigley 2018). It is a cell surface heme transporter, essential for erythropoiesis and systemic iron homeostasis. Mutations of SLC49A2, encoding FLVCR1, are noted in patients with Fowler syndrome (Khan and Quigley 2018). FLVCR2 is 30% identical to FLVCR1 (TC# 2.A.1.28.1). |
Eukaryota | Metazoa, Chordata | FLCR2 of Homo sapiens |
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2.A.1.29.1 | Archaeal open reading frame | Archaea | Euryarchaeota | Orf of Archaeoglobus fulgidus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.29.2 | Archaeal open reading frame | Archaea | Thermoproteota | Orf of Aeropyrum pernix | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.29.3 | Bacterial unknown major facilitator |
Bacteria | Actinomycetota | UMF3 member of Frankia sp. Eul1c (E3J3E7) |
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2.A.1.3.1 | The main boron exporter in yeast, Atr1 (Kaya et al. 2009) (Aminotriazole, 4-nitroquinoline-N-oxide, etc.):H+ antiporter. Also exports L-cysteine (Yamada et al., 2006). |
Eukaryota | Fungi, Ascomycota | Atr1 of Saccharomyces cerevisiae |
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2.A.1.3.10 | Methylenomycin:H+ antiporter | Bacteria | Bacillota | MmrB of Bacillus subtilis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.11 | Puromycin:H+ antiporter | Bacteria | Actinomycetota | Pur8 of Streptomyces lipmanii | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.12 | Tetracenomycin:H+ antiporter | Bacteria | Actinomycetota | TcmA of Streptomyces glaucescens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.13 | Unconjugated bile acid uptake transporter | Bacteria | Bacillota | BaiG of Eubacterium sp. strain VPI 12708 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.14 | Methylviologen (paraquat):H+ antiporter, SmvA (also exports ethidium bromide, acriflavin, malachite green, pyronine B and benzyl viologen) (Villagra et al. 2008). |
Bacteria | Pseudomonadota | SmvA of Salmonella typhimurium |
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2.A.1.3.15 | Rifamycin:H+ antiporter | Bacteria | Actinomycetota | RifP of Amycolatopsis mediterranei | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.16 | The Me2+·tetracycline:2H+ antiporter |
Bacteria | Bacillota | TetA(L) of Bacillus subtilis |
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2.A.1.3.17 | The trimethoprim-sensitivity protein, YebQ (increases sensitivity to trimethoprim) | Bacteria | Pseudomonadota | YebQ of E. coli | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.18 | Efflux pump for plant-bacterial signaling molecules, phytoalexins, flavonoids and salicylate as well as drugs, RmrB |
Bacteria | Pseudomonadota | RmrB of Rhizobium etli |
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2.A.1.3.19 | Paraquat efflux pump, PqrB (Cho et al., 2003) |
Bacteria | Actinomycetota | PqrB of Streptomyces coelicolor (AAG45950) |
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2.A.1.3.2 | Exporter of CCCP, nalidixic acid, rhodamine 6G, methylviologen, deoxycholate, growth inhibitory steroid hormones (estradiol and progesterone) (Elkins and Mullis, 2006) SDS, organomercurials, etc. (Nishino and Yamaguchi 2001). |
Bacteria | Pseudomonadota | EmrB of E. coli (P0AEJ0) |
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2.A.1.3.20 | Long chain fatty acid efflux pump, FarB (Lee et al., 2003) (exports antimicrobial long chain fatty acids; functions with MFP auxillary protein, FarA (TC# 8.A.1.1.2)) (Lee et al., 2006) | Bacteria | Pseudomonadota | FarB of Neisseria gonorrhoeae (AAD54074) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.21 | Siderophore, achromobactin efflux pump, YhcA (Franza et al., 2005) | Bacteria | Pseudomonadota | YhcA of Erwinia (Pectobacterium) chrysanthemi (AAL14569) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.22 | The Tet38 tetracycline-resistance protein of 450 aas and 14 TMSs of S. aureus (Truong-Bolduc et al., 2005). Tet38 has distinct functions, including drug efflux and host cell attachment and internalization mediated by interaction with host cell CD36. Truong-Bolduc et al. 2021 identified key amino acids involved in different functions. Cysteine substitutions of arginine 106, situated at the junction of TMS 4 and external loop L2, and glycine 151 of motif C on TMS 5, resulted in 8- to 16-fold reductions in Tet38-mediated resistance to tetracycline, with minimal effect on A549 host cell internalization. In contrast, two three-amino-acid deletions, F411P412G413, in external loop L7, situated between TMSs 13 and 14, and D38D39L40, in external loop L1, situated between TMS 1 and 2, led to decreased tetracycline resistance, but only the former affected S. aureus internalization and impaired binding to CD36 (Truong-Bolduc et al. 2021). |
Bacteria | Bacillota | Tet38 of Staphylococcus aureus (AAV80464) |
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2.A.1.3.23 | The NorB multidrug resistance pump (exports hydrophilic quinolones, ethidium bromide, cetrimide, sparfloxacin, moxifloxacin and tetracycline) (Truong-Bolduc et al., 2005) | Bacteria | Bacillota | NorB of Staphylococcus aureus (BAB42529) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.24 | The VceAB multidrug (hydrophobic compounds including deoxycholate (DOC), antibiotics, such as chloramphenicol and nalidixic acid, and the proton motive force uncoupler, cyanide carbonyl m-chlorophenylhydrazone (CCCP)) resistance pump (functions with outer membrane VceC (TC#1.B.17.3.6) or OprM (2.A.6.2.21), an OMF family member; The C-terminal domain of the Pseudomonas aeruginosa OprM and the alpha-helical hairpin domain of Vibrio cholerae VceA play important roles in recognition/specificity/recruitment in the assembly of a functional, VceAB-OprM chimeric efflux pump (Bai et al., 2010). |
Bacteria | Pseudomonadota | VceAB of Vibrio cholerae |
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2.A.1.3.25 | Actinorhodin (blue pigmented antibiiotic) transporter, ActII-2 |
Bacteria | Actinomycetota | ActII-2, Actinorhodin transporter of Streptomyces coelicolor (P46105). |
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2.A.1.3.26 | Novobiocin/deoxycholate exporting MDR efflux pump, MdtD or YegB (Baranova and Nikaido, 2002). Also exports arabinose but not xylose (Koita and Rao 2012). Regulated by the transcription factor, BaeR (Nagakubo et al. 2002). |
Bacteria | Pseudomonadota | YegB of E. coli (P36554) |
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2.A.1.3.27 | The vacuolar basic amino acid (Arg, Lys, His) transporter, Vba3 (Shimazu et al., 2005) |
Eukaryota | Fungi, Ascomycota | Vba3 of Saccharomyces cerevisiae (P25594) |
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2.A.1.3.28 | MDR multidrug efflux pump, EbrE (involved in colony growth, dependent on Ca2+, Mg2+, Na+ and K+) (Lee et al., 2007) | Bacteria | Actinomycetota | EbrE of Streptomyces lividans (Q939A4) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.29 | The metal:tetracycline/oxytetracycline resistance efflux pump, TctB (563 aas) | Bacteria | Actinomycetota | TctB of Streptomyces rimosus (O69070) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.3 | (Acriflavin, ethidium bromide, fluoroquinolones, etc.):H+ antiporter (Li et al. 2004; Rodrigues et al. 2011). |
Bacteria | Actinomycetota | LfrA of Mycobacterium smegmatis |
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2.A.1.3.30 | Lincomycin resistance protein; Lincomycin:H+ antiporter, LmrB | Bacteria | Bacillota | LmrB of Bacillus subtilis (O35018) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.31 | The hydrophilic fluoroquinolones efflux pump, QepA (Perichon et al., 2008). Exports hydrophilic quinolones, norfloxacin, and ciprofloxacin. |
Bacteria | Pseudomonadota | QepA of E. coli (A5H8A5) |
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2.A.1.3.32 | Landomycin A efflux pump, LanJ (Otash et al., 2008) | Bacteria | Actinomycetota | LanJ of Streptomyces cyanogenus (Q9ZGB6) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.33 | Multidrug (including novobiocin, streptomycin, and actinomycin D) resistance porter, MdtP (YusP) | Bacteria | Bacillota | MdtP of Bacillus subtilis (O32182) |
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2.A.1.3.34 | The P55 (MFS55) triglyceride (TAG)/drug efflux pump (Rv141Oc) (extrudes drugs including rifampicin and clifazimine, first- and second-line anti-tuberculosis drugs.) CCCP and valinomycin inhibited drug resistance (Ramón-García et al., 2009). P55 also exports malachite green, ethidium bromide, isoniazid and ethambutol (Bianco et al. 2011). It functions together with the outer membrane lipoprotein porin, LprG (P9WK45; TC# 9.B.138.1.1), also called P27 and Lpp-27 (Bianco et al. 2011; Farrow and Rubin 2008). MFS55 is required together with LprG for normal colony morphology and sliding motility, possibly due to alterred cell wall composition (Farrow and Rubin 2008). MFS transporter Rv1410 and the periplasmic lipoprotein, LprG, transport triacylglycerides (TAGs) that seal the mycomembrane. Remm et al. 2023 reported a 2.7 Å structure of a mycobacterial Rv1410 homologue, which adopts an outward-facing conformation and exhibits unusual transmembrane helix 11 and 12 extensions that protrude ~20 Å into the periplasm. A small, very hydrophobic cavity suitable for lipid transport is constricted by a functionally important ion-lock likely involved in proton coupling. Combining mutational analyses and MD simulations, the authors proposed that TAGs are extracted from the core of the inner membrane into the central cavity via lateral clefts present in the inward-facing conformation. The functional role of the periplasmic helix extensions is to channel the extracted TAG into the lipid binding pocket of LprG (Remm et al. 2023). |
Bacteria | Actinomycetota | P55 drug efflux pump of Mycobacterium tuberculosis (P71678) |
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2.A.1.3.36 | EmrKY-TolC MDR efflux pump (Nishino and Yamaguchi 2001). (also exports cysteine (Yamada et al., 2006)) (similar to 2.A.1.3.2) |
Bacteria | Pseudomonadota | EmrKY-TolC of E. coli |
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2.A.1.3.37 | The uridine/deoxyuridine/5-fluorouridine uptake transporter, UriP (llmg_0856) (480aas; 14TMSs) (Martinussen et al., 2010) |
Bacteria | Bacillota | UriP of Lactococcus lactis (A2RJJ9) |
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2.A.1.3.38 | MFS porter of unknown function |
Bacteria | Actinomycetota | MFS porter of Streptomyces viridochromogenes (D9X7X8) |
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2.A.1.3.39 | The antimicrobial efflux pump, LmrS. Exports linezolid and tetraphenylphosphonium chloride (TPCL) > sodium dodecyl sulfate (SDS), trimethoprim, and chloramphenicol. (most similar to LmrB (2.A.1.3.30)) (Floyd et al., 2010). |
Bacteria | Bacillota | LmrS of Staphylococcus aureus (Q5HE38) |
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2.A.1.3.4 | (Mono- and divalent organocation):H+ antiporter. Transmembrane helix 12 of QacA lines the bivalent cationic drug binding pocket (Hassan et al., 2007). Two sites, D34 and D411 are involved in substrate recognition, while E407 facilitates substrate efflux as a protonation site and plays a role as a substrate recognition site for the transport of dequalinium, a divalent quaternary ammonium compound (Majumder et al. 2019). TMS 12 and its external flanking loop are required for the structural and functional integrity of QacA, and they contain amino acids directly involved in their interactions with substrates (Dashtbani-Roozbehani et al. 2023). Cryo-EM structures of QacA from S. aureus revealed a novel extracellular loop with an allosteric role (Majumder et al. 2023). |
Bacteria | Bacillota | QacA of Staphylococcus aureus (P0A0J9) |
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2.A.1.3.40 | The phenazine resistance pump. It also exports D-alanyl-griseoluteic acid; possibly in conjunction with a chaperone protein, EhpR. The crystal structure of EhpR is known (Yu et al., 2011). Note: Phenazines are toxic redox active secondary metabolites that many bacteria secrete. It may be involved in the export of griseoluteic acid, an intermediate in the biosynthesis of the broad-spectrum phenazine antibiotic, D-alanylgriseoluteic acid (Dagher et al. 2021). |
Bacteria | Pseudomonadota | EhpJ of Panloea (Enterobacter) agglomerans (O32600) |
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2.A.1.3.43 |
MFS efflux pump, AmvA (AedF). Mediates drug, dye, detergent, antibiotic and disinfectant resistance (Rajamohan et al., 2010; Hassan et al. 2011). 98.6% identical to AdeF (2.A.1.3.46). |
Bacteria | Pseudomonadota | AmvA of Acinetobacter baumannii (C4PAW9) |
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2.A.1.3.44 | MDR pump, AdeF (AmvA) exports ethidium, DAPI, and chlorhexidine (Hassan et al. 2011). 98.6% identical to AmvA (2.A.1.3.45). |
Bacteria | Pseudomonadota | AdeF of Acinetobacter baumannii (A3M6E0) |
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2.A.1.3.46 | The phenicol (florfenicol/chloramphenicol) exporter, FexB (Liu et al., 2012) |
Bacteria | Bacillota | FexB of Enterococcus faecium (G9FS16) |
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2.A.1.3.47 | The trichothecene efflux pump, TRI12 (Alexander et al., 1999; Wuchiyama et al., 2000). Trichothecenes are plant growth promoters and bio-control agents (See also Fang et al. (2012)). TRI12 secretes toxic trichothecene compounds like T-2 toxin, nivalenol and deoxynivalenol. |
Eukaryota | Fungi, Ascomycota | TRI12 of Fusarium sporotrichioides (Q9C1B3) |
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2.A.1.3.48 | Multidrug-efflux transporter Rv1634/MT1670 of 471 aas and 14 TMSs. Both Rv1634 and Rv1258c are believed to play a major role in drug resistance by altering the protein pump that is required to remove the active drug compounds from the bacterial cell (Panja et al. 2019). Ciprofloxacin and norfloxacin are substrates, to which M. tuberculosis strains have become resistant. The expulsion of the drugs to the outside the bacterial cell occurs through the alternating-access mechanism of N and C-terminal domains (Singh and Akhter 2021). |
Bacteria | Actinomycetota | Rv1634 of Mycobacterium tuberculosis |
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2.A.1.3.49 | Multidrug resistance protein Stp (Spectinomycin tetracycline efflux pump) |
Bacteria | Actinomycetota | Stp of Myconbacterium tuberculosis |
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2.A.1.3.5 | (Pristinamycin I and II, rifamycin, etc.):H+ antiporter | Bacteria | Actinomycetota | Ptr of Streptomyces pristinaespiralis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.50 | Multidrug resistance protein 3 (Multidrug-efflux transporter 3) or Brm3, of 512 aas and 14 TMSs. Resistance to puromycin, tosofloxacin, norfloxacin, acriflavin, ethidium, and tetraphenyl phosphonium, but not ofloxacin, nalidixic acid or carbonyl cyanide m-chlorophenylhydrazone (Ohki and Murata 1997). A spontaneous B. subtilis mutant isolated in the presence of a high concentration of puromycin acquired a multidrug-resistant phenotype due to high level expression of the bmr3 gene (Ohki and Tateno 2004), and selection for improved synthesis of menaquinone-7 also caused increased expression (Cui et al. 2020). |
Bacteria | Bacillota | Bmr3 of Bacillus subtilis |
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2.A.1.3.51 | Probable transport protein HsrA (High-copy suppressor of RspA) | Bacteria | Pseudomonadota | HsrA of Escherichia coli |
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2.A.1.3.52 | Drug resistance protein YOR378W. Does not export boron (Bozdag et al. 2011). |
Eukaryota | Fungi, Ascomycota | YOR378W of Saccharomyces cerevisiae |
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2.A.1.3.53 | Azole resistance protein 1 | Eukaryota | Fungi, Ascomycota | AZR1 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.54 | Protein SGE1 (10-N-nonyl acridine orange resistance protein) (Crystal violet resistance protein) | Eukaryota | Fungi, Ascomycota | SGE1 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.55 | Uncharacterized MFS-type transporter YubD |
Bacteria | Bacillota | YubD of Bacillus subtilis |
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2.A.1.3.56 | Putative MFS drug exporter of 461 aas and 14 TMSs. |
Bacteria | Bacillota | Porter of Paenibacillus polymyxa |
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2.A.1.3.57 | Uncharacterized MFS-type transporter YwoD |
Bacteria | Bacillota | YwoD of Bacillus subtilis |
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2.A.1.3.58 | Uncharacterized MFS-type transporter YfiU |
Bacteria | Bacillota | YfiU of Bacillus subtilis |
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2.A.1.3.59 | MDR efflux pump, NorC (Truong-Bolduc et al. 2006). Proposed to be a quinolone resistance exporter, NorB (Marklevitz and Harris 2016). The 3-d x-ray structure at 3.6 Å resolution has been solved in an outward open configuration (Kumar et al. 2021). The structure shows that NorC specifically interacts with an organic cation, tetraphenylphosphonium. Multidrug-resistance in S. aureus is inhibited by the endocannabinoid, anandamide (Sionov et al. 2022). |
Bacteria | Bacillota | NorC (NorB) of Staphylococcus aureus |
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2.A.1.3.6 | Me2+·tetracycline:2H+ or 2K+ antiporter (the optimal Me2+ = Co2+) (Also transports Na+ or K+out in exchange for 2H+.) |
Bacteria | Bacillota | TetK of Staphylococcus aureus (P02983) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.60 |
MDR efflux pump, SdrM. Exports norfloxacin, acriflavin and ethidium bromide (Yamada et al. 2006). Multidrug-resistance in S. aureus is inhibited by the endocannabinoid, anandamide (Sionov et al. 2022). |
Bacteria | Bacillota | SdrM of Staphylococcus aureus |
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2.A.1.3.61 | MDR efflux pump, MdeA. Exports quaternary ammonium compounds and antibiotics (Huang et al. 2004). Also exports hoechst 33342, doxorubicin, daunorubicin, tetraphenyl phosphonium, ethidium bromide and rhodamine 6G (Yamada et al. 2006). Multidrug-resistance in S. aureus is inhibited by the endocannabinoid, anandamide (Sionov et al. 2022). |
Bacteria | Bacillota | MdeA of Staphylococcus aureus |
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2.A.1.3.62 | MDR efflux pump, AedC (Hassan et al. 2011). Shown to export chloramphenicol and tetracycline. |
Bacteria | Pseudomonadota | AedC of Acinetobacter baumannii |
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2.A.1.3.63 | Iron homeostasis protein, AedD; may function in siderophore export (Hassan et al. 2011). |
Bacteria | Pseudomonadota | AedD of Acinetobacter baumannii |
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2.A.1.3.64 | Uptake permease for cholate (steroid) metabolites, CamM of 513 aas and 14 TMSs. Uptake of 3,7(R),12(S)-trihydroxy-9-oxo-9,10-seco-23,24-bisnorchola-1,3,5(10)-trien-22-oate was observed (Swain et al. 2012). |
Bacteria | Actinomycetota | CamM of Rhodococcus jostii |
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2.A.1.3.65 | ThMFS1 of 563 aas and 14 TMSs. Catalyzes export of fungicides causing tolerance. It exports trichodermin, but it is not the only exporter of this secondary metabolite (Liu et al. 2012). Trichothecenes are the sesquiterpenes secreted by Trichoderma spp. residing in the rhizosphere. These compounds have been reported to act as plant growth promoters and bio-control agents (Chaudhary et al. 2016). |
Eukaryota | Fungi, Ascomycota | MFS1 of Trichoderma harzianum (Hypocrea lixii) |
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2.A.1.3.66 | MFS permease of 413 aas and 12 TMSs. Encoded within the SoxR regulon; possibly a drug exporter (Naseer et al. 2014). |
Bacteria | Pseudomonadota | MFS permease of Pseudomonas aeruginosa |
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2.A.1.3.67 | MFS porter of 462 aas and 14 TMSs |
Bacteria | Deinococcota | MFS porter of Deinococcus radiodurans |
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2.A.1.3.68 | The PfMFS transporter (551 aas; 14 putative TMSs) is involved in the acid resistance and intracellular pH homeostasis of Penicillium funiculosum (Xu et al. 2014). This protein (AIJ02309) was not in UniProt when enterred into TCDB, and its closest orthologue, PmMFS of Penicillium marneffei, is therefore presented here. These two proteins are 82% identical. |
Eukaryota | Fungi, Ascomycota | PfMFS of Talaromyces (Penicillium) funiculosum |
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2.A.1.3.69 | Drug resistance pump, YMR279c of 540 aas. When overexpressed, confers boron resistance, but is not induced by boron (Bozdag et al. 2011). |
Eukaryota | Fungi, Ascomycota | YMR279c of Saccharomyces cerevisiae (Baker's yeast) |
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2.A.1.3.7 | Actinorhodin:H+ antiporter, ActVa or ActA (Tahlan et al., 2007) | Bacteria | Actinomycetota | ActVa of Streptomyces coelicolor | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.70 | Probable exporter of aromatic compounds of 559 aas and 16 putative TMSs in an apparent 4 + 4 + 4 + 4 arrangement. May function in aromatic compoound detoxification. Regulated by a MarR-like transcriptional regulator that is encoded in the same operon. A ten-fold induction occurs in response to aromatic aldehydes such as benzaldehyde (Fiorentino et al. 2007). The same MarR protein controls transcription of a gene encoding an NADH-dependent alcohol dehydrogenase (Sso2536). |
Archaea | Thermoproteota | Sso1351 of Sulfolobus solfataricus |
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2.A.1.3.71 | Putative multidrug-resistance exporter of 553 aas and 14 putative TMSs, KNQ1. It is a drug efflux permease for several toxic compounds that in multiple copies confer increased dithiothreitol resistance. KNQ1 does not export dithiothreitol or function in recombinant protein secretion. KNQ1 gene amplification or deletion resulted in enhanced transcription of iron transport genes, suggesting, a role in iron homeostasis on which dithiothreitol tolerance may depend (Marchi et al. 2007). |
Eukaryota | Fungi, Ascomycota | KNQ1 of Kluyveromyces lactis (Yeast) (Candida sphaerica) |
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2.A.1.3.72 | Riboflavin transporter of 456 aas and 14 TMSs, RibZ (Gutiérrez-Preciado et al. 2015). |
Bacteria | Bacillota | RibZ of Peptoclostridium difficile (Clostridium difficile) |
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2.A.1.3.73 | Multidrug resistance Mfs1 protein of 583 aas and 14 TMSs. Exports natural mycotoxins and a variety of fungicides in Mycosphaerella graminicola (Roohparvar et al. 2007). Etridiazole (EDZ) is a thiadiazole-containing fungicide commonly used to control Pythium and Phytophthora spp. Studies have shown that EDZ is teratogenic. A zebrafish (Danio rerio; ZF) model has been used to explore the molecular pathways associated with EDZ toxicity, and itwas concluded that there are several (Vasamsetti et al. 2023). |
Eukaryota | Fungi, Ascomycota | MDR exporter, Mfs1 of Zymoseptoria tritici (Speckled leaf blotch fungus) (Septoria tritici) |
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2.A.1.3.74 | Polyamine/cationinc amino acid exporter, CmgA. Exports L-lysine, L-arginine, L-citrulline, the diamine/polyamine, putrescine, cadaverine, and possibly spermdine and spermine (Nguyen et al. 2015 ;Lubitz et al. 2016). |
Bacteria | Actinomycetota | CmgA of Corynebacterium glutamicum |
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2.A.1.3.75 | Erythromycin/macrolide export system of 499 aas and 14 TMSs, ErmB (Zhou et al. 2014). |
Bacteria | Bacillota | ErmB of Streptococcus pyogenes |
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2.A.1.3.76 | MFS transporter of 530 aas and 14 TMSs, SgvT1. Exports griseoviridin and viridogrisein (etamycin) (Xie et al. 2017). |
Bacteria | Actinomycetota | SgvT1 of Streptomyces griseoviridis |
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2.A.1.3.77 | Drug resistance efflux porter, SgvT3 of 464 aas and 14 TMSs. (Xie et al. 2017). |
Bacteria | Actinomycetota | SgvT3 of Streptomyces griseoviridis |
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2.A.1.3.78 | Drug resistance pump, EfpA of 530 aas and 14 TMSs. May function with IniABC (see TC# 9.B.282), shown to influence resistance to several drugs (Colangeli et al. 2007). CryoEM structures of the essential drug efflux pump EfpA from Mycobacterium tuberculosis reveal the mechanisms of substrate transport and small-molecule inhibition (Wang et al. 2024). It exists in an outward-open conformation, either bound to three endogenous lipids or the inhibitor BRD-8000.3. Three lipids inside EfpA span from the inner leaflet to the outer leaflet of the membrane. BRD-8000.3 occupies one lipid site at the level of inner membrane leaflet, competitively inhibiting lipid binding. EfpA resembles the related lysophospholipid transporter MFSD2A (TC# 2.A.2.3.8) in both overall structure and lipid binding sites and may function as a lipid flippase (Wang et al. 2024). |
Bacteria | Actinomycetota | EfpA of Mycobacterium tuberculosis |
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2.A.1.3.79 | Multidrug resistance MFS exporter, MFS54 of 538 aas and 14 TMSs. A fungal mutant lacking AaMFS54 produced fewer conidia and showed increased sensitivity to many potent oxidants (potassium superoxide and singlet-oxygen generating compounds) as well as xenobiotics (2,3,5-triiodobenzoic acid and 2-chloro-5-hydroxypyridine), and fungicides (clotrimazole, fludioxonil, vinclozolin, and iprodione) (Lin et al. 2018). Virulence assays on citrus leaves inoculated by spraying with spores revealed that AaMFS54 mutant induced less severe lesions than wild-type. |
Eukaryota | Fungi, Ascomycota | MFS54 of Alternaria alternata |
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2.A.1.3.8 | Cephamycin:H+ antiporter | Bacteria | Actinomycetota | CmcT of Nocardia lactamdurans | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.3.80 | Uncharacterized EmrB/QacA-like durg resistance transporter of 540 aas and 14 TMSs. The gene encoding this protein is adjacent to a 3 component putative ABC drug exporter of TC# 3.A.1.122.32. |
Bacteria | Actinomycetota | U-MFS porter of Cellulomonas flavigena |
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2.A.1.3.81 | multidrug (tetracycline, kanamycin, rhodamin 6G, ampicillin, acriflavine, ethidium bromide, and tetraphenylphosphonium chloride) resistance exporter, MdeA, of 453 aas and 14 TMSs (Kim et al. 2013). |
Bacteria | Bacillota | MdeA of Streptococcus mutans |
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2.A.1.3.82 | Multidrug resistance transporter protein of 519 aas and 14 TMSs. It exports 2-thiocyanatopyridine derivatives (Nunvar et al. 2019). |
Bacteria | Pseudomonadota | MDR pump of Burkholderia cenocepacia (Burkholderia cepacia) |
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2.A.1.3.83 | AflT efflux pump of 514 aas and 14 TMSs (Yu et al. 2004). Its gene is part of the gene cluster that mediates the biosynthesis of aflatoxins (Yu et al. 2004). |
Eukaryota | Fungi, Ascomycota | AflT of Aspergillus parasiticus |
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2.A.1.3.84 | Trichothecene efflux pump, Tri12, of 590 aas and 14 TMSs (Lee et al. 2002). It may function as a phospholipid flippase, and five flippases (FgDnfA, B, C1, C2 and D have been identified (Yun et al. 2020). FgDnfA is critical for normal vegetative growth while the other flippases are dispensable. FgDnfA and FgDnfD are crucial for fungal pathogenesis, and a remarkable reduction in deoxynivalenol (DON) production was observed in DeltaFgDNFA and DeltaFgDNFD strains. Deletion of the FgDNFB gene increased DON production to about 30 fold. FgDnfA and FgDnfD play positive roles in the regulation of trichothecene (TRI) gene (TRI1, TRI4, TRI5, TRI6, TRI12, and TRI101) expression and toxisome reorganization, while FgDnfB acts as a negative regulator of DON synthesis. FgDnfB and FgDnfD have redundant functions in the regulation of phosphatidylcholine transport, and double deletion of FgDNFB and FgDnfD showed defects in fungal development, DON synthesis, and virulence. Thus, the distinct and specific functions of flippase family members in F. graminearum have been determined, and FgDnfA, FgDnfD, and FgDnfB have specific spatiotemporal roles during toxisome biogenesis (Yun et al. 2020). This protein is 76% identical to the protein with TC# 2.A.1.3.47, and they probably catalyze the same reaction(s). |
Eukaryota | Fungi, Ascomycota | Tri12 of Gibberella zeae (Wheat head blight fungus) (Fusarium graminearum) |
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2.A.1.3.85 | Acinetobacter baumannii ATCC17978 MDR pump (A1S_0188) of the DHA2 family in the MFS (Hassan et al. 2011). It is of 463 aas with 14 TMSs. There are 6 DHA2 members in A. baumannii. One of these, called AadT, exports a variety of drugs (Naidu et al. 2023). |
Bacteria | Pseudomonadota | MDR pump AedA of Acinetobacter baumannii |
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2.A.1.3.86 | Antimony, SbIII and SbV, resistance MFS efflux protein of xxx aas and 14 TMSs in a 6 + 2 + 6 TMS arrangement with both 6 TMS domains having a 2 + 2 + 2 TMS arrangement (Yang et al. 2024). AntB is encoded on the chromosome of the arsenite-oxidizing bacterium Ensifer adhaerens E-60 that confers resistance to Sb(III) and Sb(V). The antB gene is adjacent to a gene encoding a LysR family transcriptional regulator termed LysRars, which is an As(III)/Sb(III)-responsive transcriptional repressor that is predicted to control expression of antB. Similar antB and lysRars genes are found in related arsenic-resistant bacteria, especially strains of Ensifer adhaerens, and the lysRars gene adjacent to antB encodes a member of a divergent subgroup of putative LysR-type regulators. Closely related AntB and LysRars orthologs contain three conserved cysteine residues, which are Cys17, Cys99, and Cys350 in AntB and Cys81, Cys289 and Cys294 in LysRars, respectively. Expression of antB is induced by As(III), Sb(III), Sb(V) and Rox(III) (4-hydroxy-3-nitrophenyl arsenite). Heterologous expression of antB in E. coli AW3110 (Δars) conferred resistance to Sb(III) and Sb(V) and reduced the intracellular concentration of Sb(III) (Yang et al. 2024). |
Bacteria | Pseudomonadota | AntB of Ensifer adhaerens |
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2.A.1.3.9 | Lincomycin:H+ antiporter | Bacteria | Actinomycetota | LmrA of Streptomyces lincolnensis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.30.1 | Putative abietane uptake permease (in a gene cluster for degradation of abietane diterpenoids), DitE, of 547 aas and 12 TMSs (Martin and Mohn 2000). Abietane diterpenoids are defense compounds synthesized by trees that are abundant in natural environments and occur as significant pollutants from pulp and paper production (Smith et al. 2007). |
Bacteria | Pseudomonadota | DitE of Pseudomonas abietaniphila BKME-9 |
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2.A.1.30.2 | Uncharacterized MFS transporter of 410 aas and 12 TMSs. |
Bacteria | Actinomycetota | MFS porter of Actinomadura macra |
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2.A.1.30.3 | Enterobactin exporter, EntS (gene, tetv1) of 549 aas and 12 TMSs. |
Bacteria | Pseudomonadota | EntS of Stenotrophomonas maltophilia |
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2.A.1.31.1 | The Ni2+ efflux pump, NreB (Ni2+ inductible) | Bacteria | Pseudomonadota | NreB of Achromobacter xylosoxidans plasmid pTOM | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.31.2 | The Ni2+ resistance protein, NrsD | Bacteria | Cyanobacteriota | NrsD of Synechocystis PCC6803 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.31.3 | The unknown porter, YfiS |
Bacteria | Bacillota | YfiS of Bacillus subtilis (O31561) |
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2.A.1.31.4 | Kurstakin/surfactin exporter of 417 aas (in B. subtilis) (Li et al. 2015). This protein is an orthologue of the B. subtilis protein (Li et al. 2015). | Bacteria | Bacillota | KrsE of Bacillus cereus |
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2.A.1.31.5 | Uncharacterized MFS porter of 455 aas |
Eukaryota | Viridiplantae, Chlorophyta | UP of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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2.A.1.31.6 | Uncharacterized MFS porter (residiues 1 - 450) with hydrophilic C-terminal protein kinase domain. The protein is of 858 aas. |
Eukaryota | Viridiplantae, Chlorophyta | UP of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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2.A.1.31.7 | Putative bacilysin exporter, BacE, of 484 aas and10 - 11 TM |
Archaea | Candidatus Heimdallarchaeota | BacE of Candidatus Heimdallarchaeota archaeon AB_125 |
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2.A.1.31.8 | Nickel resistance membrane nickel efflux protein NirA of 432 aas and 12 TMSs. This protein is 99.7% identical to a trunkated homolog from Klebsiella oxytoca (Park et al. 2008). |
Bacteria | Pseudomonadota | NirA of Enterobacter cloacae |
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2.A.1.32.1 | Putative aromatic compound/drug exporter. Enhances expression of the sigma X gene that functions to modify the cell envelope (Turner and Helmann, 2000). yitG is reported to be a mutator gene that inhibits transition base substitutions (Sasaki and Kurusu, 2004). |
Bacteria | Bacillota | YitG of Bacillus subtilis |
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2.A.1.32.2 | Bacillibactin exporter, YmfE (199aas; 6TMSs) (Miethke et al., 2008) (resembles the 2nd half of YitG of B. subtilis (2.A.1.32.1). The sequence provided under acc# O31763 is only a fragment of the full length gene. | Bacteria | Bacillota | YmfE of Bacillus subtilis (O31763) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.32.3 |
Putative copper/multidrug efflux protein, YfmO. The yfmPO operon is autoregulated by the MerR homologue, YfmP (a repressor). The copZA operon encodes CopA, a copper ATPase (TC# 3.A.3.5.18) which is induced by a copper dependent mechanism. Since a yfmP null mutant had poor copZA induction but elevated levels of the YfmO efflux pump, YfmO could catalyze copper efflux and be responsible for reduced copZA induction. Consistent with this model, a yfmP yfmO double mutant showed normal induction by copper (Gaballa et al. 2003). |
Bacteria | Bacillota | YfmO of Bacillus subtilis |
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2.A.1.33.1 | MFS homologue, YqgE. It is cotranscribed with ftsI, encoding the peptidoglycan transpeptidase that crosslinks peptidoglycan strands, releasing free D-alanine. Possibly YqgE is a D-alanine uptake porter. Its expression causes a decrease in the amount of sigma W synthesis, the sigma factor for genes involved in detoxification and antimicrobial synthesis (Turner and Helmann 2000). |
Bacteria | Bacillota | YqgE of Bacillus subtilis (P54487) |
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2.A.1.33.2 | YqgE homologue |
Bacteria | Bacteroidota | YqgE homologue of Bacteroides ovatus (A7LYG9) |
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2.A.1.33.3 | YqgE homologue (encoded near an α-glucuronidase; GH31 family; divergently transcribed). Therefore could be an uptake system for glucouronides. |
Archaea | Thermoproteota | YqgE homologue of Sulfolobus tokodaii (Q96XI6) |
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2.A.1.33.4 | Uncharacterized protein of 385 aas and 12 TMSs. |
Bacteria | Candidatus Beckwithbacteria | UP of Candidatus Beckwithbacteria bacterium |
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2.A.1.34.1 | Sensor kinase (N-terminal 400 residues)/MFS fusion protein. The N-terminal domain resembles the sensor kinase of 414 aas of Anaeromyxobacter sp. KJ (ACG71775). The C-terminal MFS domain most resembles those of TC family 2.A.1.2 (DHA1). |
Bacteria | Pseudomonadota | Fusion protein of Bordetella pertussis (Q7VWI9) |
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2.A.1.34.2 | MFS carrier with N-terminal hydrophilic domain with 3 putative TMSs of about 2880 aas. The protein is of 676 aas with 15 TMSs. |
Bacteria | Pseudomonadota | MFS permease fusion protein of Fodinicurvata fenggangensis |
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2.A.1.34.3 | MFS carrier of 526 aas and an N-terminal hydrophilic domain with 1 TMS. |
Bacteria | Pseudomonadota | MFS carrier fusion protein of Herbaspirillum huttiense |
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2.A.1.35.1 | The fosmidomycin resistance (Fsr) protein (confers fosmidomycin, trimethoprim and carbonylcyanide m-chlorophenylhydrazone (CCCP) resistance) (Fujisaki et al. 1996). |
Bacteria | Pseudomonadota | Fsr of E. coli |
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2.A.1.35.2 | The cationic microbial peptide resistance (RosA) protein | Bacteria | Pseudomonadota | RosA of Yersinia enterocolitica | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.35.3 | MFS transporter of 388 aas and 12 TMSs |
Bacteria | Bacillota | MFS porter of Sulfobacillus acidophilus |
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2.A.1.36.1 | The acriflavin-sensitivity protein, YnfM (increases sensitivity to acriflavin specifically). Also exports arabinose but not xylose (Koita and Rao 2012). |
Bacteria | Pseudomonadota | YnfM of E. coli |
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2.A.1.36.2 | Hypothetical MFS carrier of 411 aas and 12 TMSs. |
Bacteria | Pseudomonadota | MFS carrier of Serratia proteamaculans (A8GHT9) |
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2.A.1.36.3 | Putative uncharacterized transporter YgaY |
Bacteria | Pseudomonadota | YgaY of Escherichia coli |
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2.A.1.36.4 | MdrA. Putative MDR transporter that may export cationic and hydrophobic compounds, Sco4007. Regulated by a TetR-like repressor that binds drugs (Hayashi et al. 2013). |
Bacteria | Actinomycetota | MdrA (Sco4007) of Streptomyces coelicolor |
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2.A.1.36.5 | MFS carrier of 389 aas |
Bacteria | Pseudomonadota | MFS carrier of Rhizobium loti |
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2.A.1.36.6 | Succinate/dicarboxylate transporter, YnfM, of 416 aas and 12 TMSs. It exports succinate under both aerobic and anaerobic conditions (Fukui et al. 2019). |
Bacteria | Actinomycetota | YnfM of Corynebacterium glutamicum |
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2.A.1.37.1 | Unknown Major Facilitator-4 family member, UMF4A, of 396 aas and 12 TMSs. |
Bacteria | Spirochaetota | UMF4A of Brachyspira pilosicoli |
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2.A.1.37.2 | UMF4 family member of 399 aas and 12 TMSs, UMF4B. |
Bacteria | Spirochaetota | UMF4B of Brachyspira murdochii |
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2.A.1.37.3 | UMF4C of 407 aas and 12 TMSs. |
Archaea | Candidatus Thermoplasmatota | UMF4C of Ferroplasma sp. |
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2.A.1.37.4 | UMF4D of 399 aas and 12 TMSs |
Bacteria | Spirochaetota | UMF4D of Sphaerochaeta pleomorpha |
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2.A.1.37.5 | UMF4E of 373 aas and 12 TMSs |
Archaea | Thermoproteota | UMF4E of Caldisphaera lagunensis |
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2.A.1.38.1 | The enterobactin (siderophore) exporter, EntS or YbdA (Bleuel et al., 2005). May also export arabinose but not xylose (Koita and Rao 2012). |
Bacteria | Pseudomonadota | EntS (YbdA) of E. coli |
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2.A.1.38.2 | The putative siderophore exporter (DUF 894; Pfam 05977), VabS | Bacteria | Pseudomonadota | VabS of Listonella anguillarum (Q0E7C5) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.38.3 | Enterobactin exporter, EntS (Crouch et al., 2008) (probably orthologous to 2.A.1.38.1). | Bacteria | Pseudomonadota | EntS of Salmonella typhimurium (Q8ZR35) |
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2.A.1.38.4 | Uncharacterized MFS protein of 429 aas and 12 TMSs. |
Bacteria | Bacillota | UP of Lactobacillus rhamnosus |
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2.A.1.39.1 | The vibrioferrin (siderophore) exporter, PrsC (Tanabe et al., 2003; Tanabe et al., 2006) |
Bacteria | Pseudomonadota | PrsC of Vibrio parahaemolyticus (BAC16546) |
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2.A.1.39.2 | MFS permease of 398 aas and 12 TMSs. |
Bacteria | Pseudomonadota | MFS permease of Xanthomonas campestris |
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2.A.1.39.3 | Putative efflux pump of 383 aas and 12 TMSs. |
Bacteria | Actinomycetota | Efflux pump of Kitasatospora setae (Streptomyces setae) |
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2.A.1.4.1 | Sugar-P:Pi antiporter (transports many sugar-phosphates - both 1- and 6-P esters) | Bacteria | Pseudomonadota | UhpT of E. coli (P0AGC0) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.4.10 | 2-phosphonoacetate/2-phosponopropionate uptake porter of 428 aas, PhnB. The PhnA protein is a hydrolase, and PhnC is a positive transcriptional regulator. Induction occurs with either of the two substrates (Kulakova et al. 2001). |
Bacteria | Pseudomonadota | PhnB of Pseudomonas fluorescens |
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2.A.1.4.11 | Glycerol-3-phosphate:inorganic phosphate antiporter, GlpT (Frohlich and Audia 2013). |
Bacteria | Pseudomonadota | GlpT of Rickettsia prowazekii |
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2.A.1.4.2 | P-glycerate:Pi antiporter, Pgt. Takes up phosphoenolpyruvate, 2-phosphoglycerate, and 3-phosphoglycerate as sole sources of carbon and energy for rapid growth (Saier et al. 1975). Not present in E. coli K12, but is present in many intracellular pathogenic strains of E. coli (Tang and Saier, unpublished observations). |
Bacteria | Pseudomonadota | PgtP of Salmonella typhimurium |
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2.A.1.4.3 | Glycerol-P:Pi antiporter (may function by a 'rocker switch' mechanism; Law et al., 2007). The 3-d structure is known (3.3Å resolution) (Huang et al., 2003; Lemieux et al., 2005; Lemieux, 2007). |
Bacteria | Pseudomonadota | GlpT of E. coli |
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2.A.1.4.4 | Hexose-P:Pi antiporter regulatory protein; senses external glucose-6-P and transports it with high affinity and low efficiency | Bacteria | Pseudomonadota | UhpC of E. coli | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.4.5 | Microsomal (ER/Golgi) glucose-6-P:Pi antiporter (glycogen storage disease (GSD1b and 1c); Gierke''s disease protein) (SLC37A2 in mice, associated with white adipose tissue obesity and expressed at high levels in macrophage) (4 isoforms present in humans (Chen et al., 2008)). SLC37A1 and A2 can not substitute for A4. 91 mutations have been observed in human patients (Chou and Mansfield 2014). Inhibited by cholorogenic acid although SLC37A1 and A2 are not. SLC37A3 had not been characterized by 2014 (Chou and Mansfield 2014). |
Eukaryota | Metazoa, Chordata | SLC37A4 of Homo sapiens |
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2.A.1.4.6 | Glucose-6-P:Pi antiporter, Hpt (may also transport other organophosphates including C3 organophosphates). | Bacteria | Chlamydiota | Hpt of Chlamydia pneumoniae (spQ9Z7N9 & gi9979188) & pirA72050 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.4.7 | Putative glycerol-3-phosphate (G-3-P) transporter, G3PP (most similar to TC# 2.A.1.4.6, 22% identity). Has been shown to catalyze glucose 6-P:Pi antiport across the endoplasmic reticular membrane(Pan et al. 2011). |
Eukaryota | Metazoa, Chordata | SLC37A1 of Homo sapiens |
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2.A.1.4.8 | solute carrier family 37 (putative glycerol-3-phosphate transporter), member 2. Has been shown to catalyze glucose 6-P:Pi antiport across the endoplasmic reticular membrane (Pan et al. 2011). N-glycosylation is critical for the function of bovine PepT2 (Wang et al. 2020). |
Eukaryota | Metazoa, Chordata | SLC37A2 of Homo sapiens |
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2.A.1.4.9 | solute carrier family 37 (glycerol-3-phosphate transporter), member 3 | Eukaryota | Metazoa, Chordata | SLC37A3 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.40.1 | Major facilitator superfamily domain-containing protein 5, MfsD5 or SLC61A1) of 481 aas and 13 TMSs in a 7 + 6 TMS arrangement. |
Eukaryota | Metazoa, Chordata | MfsD5 of Danio rerio |
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2.A.1.40.2 | Major facilitator superfamily domain-containing protein 5, MFSD5 or SLC61A1, of 450 aas and 13 TMSs in a 5 + 2 + 6 TMS arrangement. It mediates high-affinity (550 nM Km) intracellular uptake of the rare oligo-element molybdenum. It is probably a molybdate (the oxianion molybdate)/anion uptake porter (Tejada-Jiménez et al. 2011). In mammals, it is expressed in the brain and may play a role in energy homeostasis (Perland et al. 2016).
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Eukaryota | Metazoa, Chordata | Molybdate uptake porter of Homo sapiens |
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2.A.1.40.3 | Major facilitator superfamily domain-containing protein 5 | Eukaryota | Metazoa, Chordata | mfsd5 of Xenopus tropicalis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.41.1 | Putative pigment transporter (Young and Beatty, 1998) | Bacteria | Pseudomonadota | LhaA of Rhodobacter capsulatus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.41.2 | Putative pigment transporter (Young and Beatty, 1998) | Bacteria | Pseudomonadota | PucC of Rhodobacter capsulatus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.41.3 | Putative bacteriochlorophyll synthase | Bacteria | Pseudomonadota | Bch2 of Rhodobacter capsulatus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.42.1 | The lysophospholipid (LPL) transporter, LplT (Harvat et al., 2005). Substrates include lyso-PE, lyso-cardiolipin, diacylcardiolipin, fully-deacylated cardiolipin and lyso-phosphatidylglycerol, but not lysophosphatidylcholine, lysophosphatidic acid or phosphatidic acid (Lin et al. 2016). Reacylation by acyltransferase/acyl-acyl carrier protein synthetase then occurs on the inner leaflet of the membrane.Thus, a fatty acid chain is not required for LplT transport. A "sideways sliding" mechanism was proposed to explain how a conserved membrane-embedded α-helical interface excludes diacylphospholipids from the LplT binding site to facilitate efficient flipping of lysophospho-lipids across the cell membrane (Lin et al. 2016). Thus, a fatty acid chain is not required for LplT transport. Fruther, LplT cannot transport lysophosphatidic acid, and its substrate binding was not inhibited by either orthophosphate or glycerol 3-phosphate, indicating that either a glycerol or ethanolamine headgroup is the chemical determinant for substrate recognition. Diacyl forms of PE, phosphatidylglycerol, or the tetra-acylated form of cardiolipin could not serve as competitive inhibitors .A "sideways sliding" mechanism was proposed to explain how a conserved membrane-embedded α-helical interface can exclude diacylphospholipids from the LplT binding site. A dual substrate-accessing mechanism, in which LplT recruits LPLs to its substrate-binding site via two routes, either from its extracellular entry site, or through a membrane-embedded groove between transmembrane helices, and it then moves them towards the inner membrane leaflet (Lin et al. 2018). |
Bacteria | Pseudomonadota | LplT of E. coli (NP_417312) |
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2.A.1.42.2 | The lysophospholipid transporter-2-acyl glycerophosphoethanolamine acyl transferase/acyl ACP synthetase (LplT-Pls-ACS) fusion protein (Harvat et al., 2005). |
Bacteria | Pseudomonadota | The fused LplT-PlsC-ACS of Bradyrhizobium japonicum (BAC47589) |
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2.A.1.43.1 | The putative magnetosomal permease, MamH (Schubbe et al., 2003) | Bacteria | Pseudomonadota | MamH of Magnetospirillum gryphiswaldense (Q6NE63) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.43.2 |
The magnetosome permease fused to a C-terminal YedZ-like domain, MamZ (von Rozycki et al., 2004). This protein has 649 aas and 18 TMSs with a C-terminal YedZ domain and is therefore in the YedZ superfamily as well as the MFS. The two MFS proteins in the magnetosome membrane, MamZ and MamH (44% identical to MamZ), appear to overlap in function as deletion of their two genes have additive effects (Raschdorf et al. 2013). Magnetosome biogenesis has been reviewed (). |
Bacteria | Pseudomonadota | PMP of Magnetospirillum magneticum (Q2W8K5) |
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2.A.1.44.1 | The L-amino acid transporter-3, LAT3 (transports neutral amino acids such as L-leucine, L-isoleucine, L-valine, and L-phenylalanine by a Na+-independent, electroneutral, facilitated diffusion process; it also transports amino acid alcohols and thyroid hormones such as 3,3'-T2) (Prostate cancer up-regulated gene product) (Krause and Hinz 2019). |
Eukaryota | Metazoa, Chordata | SLC43A1 of Homo sapiens |
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2.A.1.44.2 | L-amino acid transporter-4 (LAT4) has the same specificity and is 57% identity to LAT3. Na+, Cl- and pH independent; not trans-stimulated; it has been reported to have two kinetic components, a low affinity component sensitive to NEM, and a high affinity component insensitive to NEM. It is found in the basolateral membrane of epithelial cells in the distal tubule and collecting duct of the kidney and the crypt cells in the intestine (Bodoy et al., 2005). It can transport throid hormones such as 3,3'-T2 (Krause and Hinz 2019). |
Eukaryota | Metazoa, Chordata | SLC43A2 of Homo sapiens |
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2.A.1.44.3 | solute carrier family 43, member 3, SLC43A3, of 491 aas and 12 TMSs. It is a key facilitator of tumour cell proliferation and migration (Wu et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC43A3 of Homo sapiens |
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2.A.1.44.4 | Similar to MFS transporter Fmp4; of 614 aas and 12 TMSs in a 6 + 6 TMS arrangement where the two 6 TMS units are separated by a large hydrophilic domain. |
Eukaryota | Fungi, Ascomycota | MFS porter of Leptosphaeria maculans |
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2.A.1.45.1 | The 2,4-diacetylphloroglucinol resistance/general stress porter, PhlE (Abbas et al., 2004) | Bacteria | Pseudomonadota | PhlE of Pseudomonas fluorescens (CAD65845) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.45.2 | Probable metabolite transporter of 440 aas and 12 TMSs. |
Bacteria | Pseudomonadota | Porter of Pseudomonas syringae |
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2.A.1.45.3 | Putative aromatic acid uptake porter of 450 aas and 12 TMSs. |
Bacteria | Pseudomonadota | Porter of Erwinia billingiae |
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2.A.1.46.1 | Probable MDR efflux transporter of 396 aas and 12 TMSs. The closest homolologues are MDR pumps in subfamilies 2.A.1.2 and 2.A.1.3. |
Bacteria | Pseudomonadota | Probable MDR transporter of Bordetella pertussis (Q7W0Q7) |
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2.A.1.46.10 | Probable staphylopine exporter, CntE. Staphylopine is a broad spectrum metalophore similar to plant nicotianamine that binds several divalent ions (nickel, cobalt, zinc, copper and iron) (Ghssein et al. 2016). The uptake system for metal bound staphylpine is TC# 3.A.1.5.43). CntE is downstream of the genes coding for the uptake system, CntABCDF (Ghssein et al. 2016). |
Bacillota | CntE of Staphylococcus aureus |
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2.A.1.46.11 | Uncharacterized MFS porter of 403 aas and 12 TMSs. |
Bacteria | Candidatus Wolfebacteria | UP of Candidatus Wolfebacteria bacterium |
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2.A.1.46.12 | Uncharacterized MFS permease of 406 aas and 12 TMSs. |
Bacteria | Candidatus Saccharibacteria | UP of Candidatus Saccharibacteria bacterium |
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2.A.1.46.13 | Membrane protein of unknown function of 406 aas and 12 TMSs |
Bacteria | Candidatus Saccharibacteria | Membrane protein of unknown function of Canditatus Saccharibacteria bacterium |
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2.A.1.46.2 | Putative MDR efflux transporter of 390 aas and 12 TMSs. The closest homolologues are MDR pumps in subfamilies 2.A.1.2 and 2.A.1.3. |
Bacteria | Actinomycetota | Putative transporter of Tropheryma whipplei (Q83N16) |
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2.A.1.46.3 | Putative drug resistance UMF5 family member |
Eukaryota | Euglenozoa | Putative MDR pump of Leishmania infantum |
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2.A.1.46.4 | UMF15 family member |
Archaea | Euryarchaeota | UMF5 homologue of Methanosphaerula palustris (B8GFY3) |
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2.A.1.46.5 | Putative quinolone resistance protein |
Bacteria | Bacillota | MFS porter of Bacillus cereus (C2UR80) |
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2.A.1.46.6 | UPF0226 protein YfcJ. Catalyzes export of arabinose but not xylose (Koita and Rao 2012). |
Bacteria | Pseudomonadota | YfcJ of E. coli |
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2.A.1.46.7 | UPF0226 protein, YhhS. Exports arabinose but not xylose (Koita and Rao 2012). Also may export the herbicide, glyphosate (Staub et al. 2012). |
Bacteria | Pseudomonadota | YhhS of E. coli |
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2.A.1.46.8 | MFS carrier of 366 aa |
Archaea | Thermoproteota | MFS carrier of Sulfolobus solfataricus |
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2.A.1.46.9 | Uncharacterized MFS porter of 430 aas |
Archaea | Euryarchaeota | MFS porter of Halosimplex carlsbadense |
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2.A.1.47.1 | Putative transporter | Bacteria | Bacillota | Putative transporter of Lactobacillus plantarum (NP_784357) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.47.2 | UMF6 family member |
Bacteria | Bacillota | MFS carrier of Streptococcus suis (A4VY05) |
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2.A.1.47.3 | Possible antibiotic peptide exporter (encoded in an operon together with lantibiotic biosynthesis enzymes) |
Bacteria | Bacillota | UMF6 family member of Streptococcus pneumoniae (B2IRN2) |
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2.A.1.47.4 | MFS permease of 408 aas |
Bacteria | Bacillota | MFS permease of Streptococcus pneumoniae |
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2.A.1.48.1 | The vacuolar basic amino acid (histidine, lysine and arginine) transporter, Vba1 (catalyzes uptake into the vacuoles (equivalent to efflux from the cytoplasm)) (most similar to family 2.A.1.3; DHA2; 13-14 putative TMSs) (Shimazu et al., 2005) | Eukaryota | Fungi, Ascomycota | Vba1 of Saccharomyces cerevisiae (NP_013806) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.48.2 | The vacuolar basic amino acid (Arg, Lys, His) transporter, Vba2 (Shimazu et al., 2005) | Eukaryota | Fungi, Ascomycota | Vba2 of Saccharomyces cerevisiae (P38358) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.48.3 | Vacuolar G0 arrest protein, Fnx1; involved in amino acid (e.g., his, lys, ile, asn, etc) uptake into the vacuole (Chardwiriyapreecha et al., 2008). | Eukaryota | Fungi, Ascomycota | Fnx1 of Schizosaccharomyces pombe (Q09752) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.48.4 | Vacuolar amino acid uptake system, Fnx2 (Chardiwiriyapreecha et al., 2008) | Eukaryota | Fungi, Ascomycota | Fnx2 of Schizosaccharomyces pombe (O59726) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.48.5 | Originally considered to be vacuolar basic amino acid transporter 4, but it my not act on amino acids, but exports drugs such as azoles. May also play a role in vacuolar morphology (Kawano-Kawada et al. 2015). |
Eukaryota | Fungi, Ascomycota | VBA4 of Saccharomyces cerevisiae S288c |
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2.A.1.49.1 | The spinster protein, spin1 or spns1 gene product (involved in synaptic growth regulation; interacts with Bcl-2/Bcl-xL, affecting programmed cell death) (Nakano et al., 2001; Sanyal and Ramaswami, 2002; Yanagisawa et al., 2003). Probably transports sphingosine-1-phosphate (Fukuhara et al. 2012), but polymorphisms in spns1 are associated with alterred triglyceride levels (Västermark et al. 2012). |
Eukaryota | Metazoa, Arthropoda | Spinster of Drosophila melanogaster (AAG43825) |
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2.A.1.49.10 | MFS multidrug exporter of 429 aas and 12 TMSs. Exports capreomycin and ethidium bromide, and deletion mutants grow faster than wild type cells (Zhang et al. 2015). |
Bacteria | Actinomycetota | MDR pump of Mycobacterium smegmatis |
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2.A.1.49.11 | Uncharacterized protein of 656 aas and 12 TMSs |
Eukaryota | Viridiplantae, Chlorophyta | UP of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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2.A.1.49.12 | Spinster 3, SPNS3 (SLC63A3), of 512 aas and 12 TMSs. The evolutionary conservation, predicted structure and neuronal expression have been characterized (Perland et al. 2017). It probably exports sphigosine-1- phosphate. |
Eukaryota | Metazoa, Chordata | SPNS3 of Homo sapiens |
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2.A.1.49.13 | MFS porter, MFR1, of 853 aas and 12 TMSs in an apparent 6 + 2 + 4 TMS arrangement. |
Eukaryota | Apicomplexa | MFR1 of Plasmodium falciparum |
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2.A.1.49.2 |
The spinster homologue, Spin1 or Spns1 (SLC63A1) of 528 aas and 12 TMSs. It interacts with Bc1-2/Bc1-XL to induce a caspase-independent autophagic cell death (Yanagisawa et al., 2003). It is a spingosine-1-phosphate (S1P) (or sphingolipid) exporter (Nijnik et al. 2012). S1P is important for lymphocyte trafficking, immune responses, vascular and embryonic development, cancer, and bone homeostasis (Zhu et al. 2018). S1P is produced intracellularly and then secreted into the circulation to engage in the above physiological or pathological processes by regulating the proliferation, differentiation and survival of target cells. SPNS2 acts as a mediator of intracellular S1P release. The SPNS1-dependent lysosomal lipid transport pathway enables cell survival under choline limitation (Scharenberg et al. 2023). The orphan lysosomal transmembrane protein SPNS1 is critical for cell survival under choline limitation. SPNS1 loss leads to intralysosomal accumulation of lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE). SPNS1 is a proton gradient-dependent transporter of LPC species from the lysosome for their re-esterification into phosphatidylcholine in the cytosol (Scharenberg et al. 2023). Beenken et al. 2024 have reported that Spns1 is an iron transporter essential for megalin-dependent endocytosis. Proximal tubule endocytosis is essential to produce protein free urine as well as to regulate system-wide metabolic pathways, such as the activation of Vitamin D. Beenken et al. 2024 have shown that the proximal tubule expresses an endolysosomal membrane protein, protein spinster homolog1 (Spns1), which engenders a novel iron conductance that is indispensable during embryonic development. Conditional knockout of Spns1 with a novel Cre-LoxP construct specific to megalin-expressing cells led to the arrest of megalin receptor-mediated endocytosis as well as dextran pinocytosis in proximal tubules. The endocytic defect was accompanied by changes in megalin phosphorylation as well as enlargement of lysosomes confirming previous findings in Drosophila and Zebrafish. The endocytic defect was also accompanied by iron overload in proximal tubules. Iron levels regulated the Spns1 phenotypes, because feeding an iron deficient diet or mating Spns1 knockout with divalent metal transporter1 (DMT1) knockout rescued the phenotypes. Conversely, iron loading wild type mice reproduced the endocytic defect, These data demonstrate a reversible, negative feedback for apical endocytosis, and raise the possibility that regulation of endocytosis, pinocytosis, megalin activation, and organellar size and function is nutrient-responsive (Beenken et al. 2024). |
Eukaryota | Metazoa, Chordata | Spin1 of Homo sapiens (Q9H2V7) |
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2.A.1.49.3 |
Probable sphingosine-1-phosphate (or sphingolipid) transporter, spinster homologue 3 (by similarity). |
Eukaryota | Viridiplantae, Streptophyta | Spinster homologue 3 of Arabidopsis thaliana (F4IKF6) |
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2.A.1.49.4 |
Protein Spinster homologue 2 (Spns2 or protein two of hearts). Exports sphingosine-1-P (S1P) and the immunomodulating agent, FTY720 (Hisano et al. 2011; Nijnik et al. 2012). S1P is a secreted lipid mediator that functions in vascular development. In the yolk syncytial layer, Spns2 functions in S1P secretion, thereby regulating myocardial precursor migration (Kawahara et al. 2009). |
Eukaryota | Metazoa, Chordata | Spns2 of Danio rerio |
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2.A.1.49.5 |
Probable sphingosine-1-phosphate or sphingolipid transporter, Spinster homologue 1 (by similarity). |
Eukaryota | Viridiplantae, Streptophyta | At5g65687 of Arabidopsis thaliana |
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2.A.1.49.6 |
Sphingosine-1-phosphate/dehydrosphingosine-1-P transport protein, Spinster 2, SPNS2 of 549 aas and 12 TMSs. It is involved in immune development and lymphocyte trafficing (Nijnik et al. 2012; Fukuhara et al. 2012). The functions and the mechanisms of SPNS2 in the pathogenesis of cancer have been reviewed (Fang et al. 2020). |
Eukaryota | Metazoa, Chordata | SPNS2 of Homo sapiens |
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2.A.1.49.7 |
Bacterial Spinster homologue; possible sphingosine-1-phosphate transporter (by similarity only). |
Bacteria | Myxococcota | Spinster homologue of Myxococcus xanthus |
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2.A.1.49.8 |
Bacterial spinster homologue. Possible sphingosine-1-phosphate transporter (by similarity only). |
Bacteria | Acidobacteriota | Spinster homologue of Terriglobus saanensis |
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2.A.1.49.9 | The cis, cis muconate transporter of 508 aas. |
Eukaryota | Metazoa, Arthropoda | MucK of Bombyx mori (Silk moth) |
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2.A.1.5.1 | β- and α-galactopyranoside:H+ symporter, LacY. Transports lactose, melibiose, thio-β-methyl galactopyranoside (TMG), isopropyl-β-thiogalactoside (IPTG), 4-nitrophenyl-beta-D-galactopyranoside, 4-nitrophenyl-alpha-D-galactopyranoside and galactopyranosyl-1-glycerol. Single point mutations allow transport of sucrose and maltose (King and Wilson 1990). Crystal structures and modeling reveal the cytoplasmic open state and the periplasmic open state (PDB ID: 1PV7). A structure with a bound lactose homolog, beta-D-galactopyranosyl-1-thio-beta-D-galactopyranoside, revealed the sugar-binding site in a cavity, and residues that play major roles in substrate recognition and proton translocation were identified (Abramson et al., 2003; Pendse et al., 2010). The membrane lipid composition determines the topology of LacY (Dowhan and Bogdanov, 2011). Smirnova et al. (2011) have provided evidence that the opening of the periplasmic cavity in LacY is the limiting step for sugar binding. Evidence for an alternating sites mechanism of transport has been summarized (Smirnova et al., 2011). Eames and Kortemme (2012) have shown that when considering expression of the lac operon, LacY function (H+ co-transport) and not protein production is the primary origin of cost fitness. Homology threading of several MFS porters based on the LacY 3-d structure has been reported (Kasho et al., 2006). The alternating-access mechanism has been suggested to arise from inverted topological repeats (Radestock and Forrest, 2011; Madej et al. 2012), but this proposal has been contested (Västermark and Saier 2014; Västermark et al. 2014). Mechanistic features of LacY have been summarized (Kaback 2015). Insertion into the membrane depends on YidC (TC# 2.A.9.3.1) and may occur in a stepwise, stochastic manner employing multiple coexisting pathways to complete the folding process (Serdiuk et al. 2017). The glucose Enzyme IIA (Crr) protein binds LacY to allosterically inhibit its activity, promoting inducer exclusion (Hoischen et al. 1996; Hariharan et al. 2015). Protonated LacY binds D-galactopyranosides specifically, inducing an occluded state that can open to either side of the membrane (Kumar et al. 2014). LacY can form amyloid-like fibrils under destabilizing conditions (Stroobants et al. 2017). Multiple conformations of LacY have been solved (Kumar et al. 2018). Direct interactions between LacY and its lipid environment uniquely contribute to its membrane protein organization and function (Vitrac et al. 2020). The lactose permease purified from E. coli exhibiting varied phospholipid compositions has the same topology and function as in its membrane of origin (Vitrac et al. 2019). |
Bacteria | Pseudomonadota | LacY of E. coli |
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2.A.1.5.2 | Raffinose:H+ symporter, RafB, can be mutated to transport maltose (Van Camp et al., 2007). |
Bacteria | Pseudomonadota | RafB of E. coli |
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2.A.1.5.3 | Sucrose:H+ symporter, CscB, also transports maltose (Peng et al. 2009). CscB recognizes not just sucrose but also fructose and lactulose, but glucopyranosides are not transported and do not inhibit sucrose transport (Sugihara et al. 2011). Direct interactions between LacY and its lipid environment uniquely contribute to its membrane protein organization and function (Vitrac et al. 2020). |
Bacteria | Pseudomonadota | CscB of E. coli |
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2.A.1.5.4 | Melibiose:H+ symporter, MelY (Shinnick et al., 2003). Transports melibiose and lactose, but not TMG, which does however bind to the transporter (Tavoulari and Frillingos, 2008) |
Bacteria | Pseudomonadota | MelY of Enterobacter cloacae |
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2.A.1.5.6 | MFS transporter specific for fructooligosaccharides, FosT, of 412 aas and 12 TMSs (Schouler et al. 2009). |
Bacteria | Pseudomonadota | FosT of E. coli |
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2.A.1.50.1 | The apical intestinal and choroid plexus proton-coupled, high affinity folate transporter, the hereditary folate malabsorption (HFM) protein, PCFT/HCP1 (Shin et al. 2010). Also reported to mediate heme-iron uptake from the gut lumen with duodenal epithelial cells (Shayeghi et al., 2005; Latunde-Dada et al., 2006; Subramanian et al., 2008, Shin et al., 2012b), but it shows a higher affinity for folate than heme) (Qiu et al., 2006). Responsible for folate uptake by choroid plexus epithelial cells (Wollack et al., 2007) and placenta (Yasuda et al., 2008). The rat orthologue (Q5EBA8) catalyzes H+-dependent folate uptake in the intestine (Inoue et al., 2008; Zhao and Goldman, 2007; Qiu et al., 2006; Shin et al., 2012). Evidence for a 12 TMS topology with a renetrant loop between TMSs 2 and 3 has been presented (Zhao et al., 2010; Qiu et al., 2006; Zhao et al., 2011; Wilson et al. 2014). Downregulated in Chronic Kidney Disease (CKD) in heart, liver, and brain, causing malabsorption (Bukhari et al., 2011). An IGXXG motif in TMS5 is important for folate binding and a GXXXG motif is involved in dimerization (Zhao et al., 2012). It is inhibited by bicarbonate, bisulfite, nitrite and other anions (Zhao et al. 2013). Its role in antifolate cancer chemotherapy has been reviewed (Matherly et al. 2014). TMSs 3 and 6 may provide critical interfaces for formation of hPCFT oligomers, facilitated by the GXXXG motifs in TMS2 and TMS4 (Wilson et al. 2015). The extracellular gate has been identified (Zhao et al. 2016), and mechanistic aspects have been considered (Date et al. 2016). Residues in the seventh and eighth TMSs play roles in the translocation pathway and folate binding (Aluri et al. 2017). The mutation, N411K-PCFT, is responsible for HFM (Aluri et al. 2018). PCFT is ubiquitously expressed in solid tumors to which it delivers antifolates, particularly pemetrexed, into cancer cells in a concentrative fashion (Zhao et al. 2018). Substitutions have been identified that lock and unlock PCFT into an inward-open conformation (Aluri et al. 2019). The nanodisc lipid composition influences the cell-free expression of PCFT (Do et al. 2021). Iron deficiency promotes hepatocellular carcinoma metastasis, and the loss of SLC46A1 expression leads to iron deficiency in liver tumor tissues (Wang et al. 2022). Cell-free expression of PCFT in the presence of nanodiscs has been reported (Do and Jansen 2022). Biological and therapeutic applications of the proton-coupled folate transporter have been reviewed (Matherly et al. 2022). FRα and multiple transporters such as PCFT, RFC, OAT4, and OATPs are likely involved in the uptake of methotraxate (MTX), whereas MDR1 and BCRP are implicated in the efflux of MTX from choriocarcinoma cells (Bai et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC46A1 or PCFT of Homo sapiens |
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2.A.1.50.2 | Thymic stromal cotransporter, TSCOT (Kim et al. 2000) | Eukaryota | Metazoa, Chordata | SLC46A2 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.50.3 | solute carrier family 46, member 3 | Eukaryota | Metazoa, Chordata | SLC46A3 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.50.4 | Multidrug efflux transporter, MET, of 507 aas and 12 TMSs (Chahine et al. 2012). Exposure to dietary methotrexate was associated with increased fluid secretion rate and increased flux of methotrexate, but not salicylate. Exposure to methotrexate in the diet resulted in increases in the expression of a multidrug efflux transporter gene (MET; CG30344) in the Malpighian tubules. There were also increases in expression of genes for either a Drosophila multidrug resistance-associated protein (dMRP; CG6214; TC# 3.A.1.208.39) or an organic anion transporting polypeptide (OATP; CG3380; TC# 2.A.60.1.27), depending on the concentration of methotrexate in the diet. MET probably does not export methotrexate (Chahine et al. 2012). |
Eukaryota | Metazoa, Arthropoda | MET of Drosophila melanogaster (Fruit fly) |
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2.A.1.51.1 | Putative permease | Bacteria | Pseudomonadota | Putative transporter of Azoarcus sp. EbN1 (CAI06874) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.51.2 | YjiJ MFS porter, a member of the DUF2118 family in Pfam. |
Bacteria | Pseudomonadota | YjiJ of E. coli (D6IHN4) |
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2.A.1.51.3 | MFS permease |
Bacteria | Deinococcota | MFS permease of Thermus thermophilus (F6DF77) |
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2.A.1.51.4 | Uncharacterized MFS permease |
Bacteria | Pseudomonadota | UP of Pseudomonas aeruginosa |
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2.A.1.52.1 | MFS permease, YihN, of 423 aas and 11 TMSs. It may transport aromatic fluorophores (fluorescent dyes) (Salcedo-Sora et al. 2021). |
Bacteria | Pseudomonadota | YihN of E. coli (P32135) |
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2.A.1.52.2 | YqcE putative transporter |
Bacteria | Pseudomonadota | YqcE pf E. coli (F4TJX1) |
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2.A.1.52.3 | MFS permease |
Bacteria | Actinomycetota | MFS permease of Propionibacterium acnes |
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2.A.1.52.4 | The glycerophosphodiester, glycerophosphocholine uptake porter, GlpU. The cytoplasmic compound is hydrolyzed to α-glycerolphosphate and choline (Großhennig et al. 2013). |
Bacteria | Mycoplasmatota | GlpU of Mycoplasma pneumoniae |
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2.A.1.53.1 | The threonine uptake permease, PhtA (Sauer et al., 2005) (required for maximal growth in macrophages and Acanthamoeba castellanii) | Bacteria | Pseudomonadota | PhtA of Legionella pneumophila (YP_094583) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.53.10 | PhtF of 425 aas |
Bacteria | Pseudomonadota | PhtF of Legionella pneumophila |
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2.A.1.53.11 | PhtG of 432 aas |
Bacteria | Pseudomonadota | PhtG of Legionella pneumophila |
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2.A.1.53.12 | PhtH of 430 aas |
Bacteria | Pseudomonadota | PhtH of Legionella pneumophila |
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2.A.1.53.13 | PhtI of 390 aas |
Bacteria | Pseudomonadota | PhtI of Legionella pneumophila |
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2.A.1.53.14 | PhtK of 410 aas |
Bacteria | Pseudomonadota | PhtK of Legionella pneumophila |
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2.A.1.53.2 | The valine uptake permease, PhtJ (required for maximal growth in macrophages and Acanthamoeba castellanii) (Chen et al., 2008) |
Bacteria | Pseudomonadota | PhtJ of Legionella pneumophila (YP_095910) |
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2.A.1.53.3 | The MFSD1 (SMAP4) transporter (465 aas; 12 TMSs). Expression is increased in mice by amino acid starvation and decreased by a high fat diet (Perland et al. 2016). This lysosomal transporter is essential for liver homeostasis and critically depends on its accessory subunit GLMP (Massa López et al. 2019). MFSD1 is not N-glycosylated but contains a dileucine-based sorting motif needed for its transport to lysosomes. Mfsd1 knockout mice develop splenomegaly and severe liver disease. GLMP (406 aas and at least 2 TMSs, N- and C-terminal) physically interacts with MFSD1 and is a critical accessory subunit. GLMP is essential for the maintenance of normal levels of MFSD1 in lysosomes and vice versa. Glmp knockout mice mimic the phenotype of Mfsd1 knockout mice (Massa López et al. 2019). The two lysosomal integral membrane proteins MFSD1 and GLMP form a tight complex that confers protection of both interaction partners against lysosomal proteolysis. López et al. 2020 refined the molecular interaction of the two proteins and found that the luminal domain of GLMP alone, but not its transmembrane domain or its short cytosolic tail, conveys protection and mediates the interaction with MFSD1. The interaction is essential for the stabilization of the complex. N-glycosylation of GLMP is essential for protection. The interaction of both proteins starts in the endoplasmic reticulum, and quantitatively depends on each other. Both proteins can affect their intracellular trafficking to lysosomes. MFSD1 can form homodimers both in vitro and in vivo (López et al. 2020). MFSD1 facilitates highly selective dipeptide transport in lysosomes (Boytsov et al. 2024). |
Eukaryota | Metazoa, Chordata | MFSDI/GLMP of Homo sapiens (A6NID9) |
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2.A.1.53.4 | Uncharacterized protein of 575 aas and 14 TMSs. |
Eukaryota | Rhodophyta | UP of Cyanidioschyzon merolae |
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2.A.1.53.5 | Putative amino acid transporter of 478 aas and 12 TMSs, CG8602, isoform A. May play a role in macrophage migration in the Drosophila embryo (Dr. Daria Siekhaus, personal communication). |
Eukaryota | Metazoa, Arthropoda | SG8602A of Drosophila melanogaster (Fruit fly) |
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2.A.1.53.6 | MFS uptake permease specific for pyrimidines, PhtC of 422 aas and 12 TMSs. Together with PhtD (TC# 2.A.1.53.6), it contributes to protection of L. pneumophila from dTMP starvation, protects the cell from 5-fluorodeoxyuridine (FUdR) toxicity and is required for growth of L. pneumophila in macrophage (Fonseca et al. 2014). |
Bacteria | Pseudomonadota | PhtC of Legionella pneumophila |
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2.A.1.53.7 | MFS uptake permease, probably specific for pyrimidines, PhtD of 427 aas and 12 TMSs. Together with PhtC (TC# 2.A.1.53.6), it contributes to protection of L. pneumophila from dTMP starvatioin, protects the cell from 5-fluorodeoxyuridine (FUdR) toxicity and is required for growth of L. pneumophila in macrophage (Fonseca et al. 2014). |
Bacteria | Pseudomonadota | PhtD of Legionella pneumophila |
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2.A.1.53.8 | PhtB of 431 aas |
Bacteria | Pseudomonadota | PhtB of Legionella pneumophila |
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2.A.1.53.9 | PhtE of 430 aas |
Bacteria | Pseudomonadota | PhtE of Legionella pneumophila |
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2.A.1.54.1 | The archaeal uptake permease, MMP0835 (function unknown) (31% I, 49% S with PhtA) |
Archaea | Euryarchaeota | MMP0835 of Methanococcus maripaludis (CAF30391) |
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2.A.1.54.2 | UMF-9 homologue of 414 aa |
Bacteria | Thermodesulfobacteriota | UMF9 homologue of Geobacter sulfurreducens (Q747F2) |
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2.A.1.54.3 | Functionally uncharacterized MFS porter of 414 aas |
Bacteria | Bacillota | UP of Syntrophothermus lipocalidus |
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2.A.1.55.1 | Uncharacterized MFS porter of 397 aas and 12 TMSs |
Archaea | Euryarchaeota | UP of Halorubrum distributum |
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2.A.1.55.2 | Uncharacterized protein of 390 aas |
Archaea | Euryarchaeota | UP of Natrinema versiforme |
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2.A.1.55.3 | Uncharacterized protein of 406 aas |
Archaea | Euryarchaeota | UP of Haloterrigena salina |
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2.A.1.55.4 | Putative phthalate porter of 377 aas |
Archaea | Euryarchaeota | UP of Haloferax gibbonsii |
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2.A.1.55.5 | MFS protein of 373 aas and 11 TMSs. The protein is probably N-terminally truncated due to an error, and probably has 12 TMSs in a 6 + 6 TMS arrangement. |
Bacteria | Pseudomonadota | MFS porter of Labrenzia sp. THAF82 |
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2.A.1.56.1 | The 1,3-dihydroxybenzene (resorcinol) uptake permease, MFS_1 (Darley et al., 2007) of 402 aas and 12 TMSs. |
Bacteria | Pseudomonadota | MFS_1 of Azoarcus anaerobius (YP_285101) |
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2.A.1.56.2 | Uncharacterized protein of 405 aas and 12 TMSs. |
Bacteria | Pseudomonadota | UP of Bradyrhizobium japonicum |
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2.A.1.57.1 |
The Ferripyochelin uptake permease, FptX (Michel et al., 2007). Also transports N-acetylglucosamine anhydrous N-acetylmuramyl peptides and is called AmpP or AmpGh1 (Kong et al. 2010). However, it does not play a role in the induction of β-lactam resistance (Zhang et al. 2010). |
Bacteria | Pseudomonadota | FptX or AmpP of Pseudomonas aeruginosa (Q9HWG8) |
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2.A.1.57.2 | The ferric rhizbactin 1021 uptake porter, RhtX (Cuív et al. 2004). |
Bacteria | Pseudomonadota | RhtX of Sinorhizobium meliloti |
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2.A.1.57.3 | Iron-yersiniabactin (Ybt) transporter of 467 aas and 12 TMSs, YbtX (Bobrov et al. 2014). Yersiniabactin can also bind zinc ions with high affinity and feed the Zn2+ into this MFS transporter, YbtX (Bobrov et al. 2014). In fact, the siderophore, Ybt, is required for growth under Zn2+-deficient conditions in a strain lacking ZnuABC (see 3.A.1.15.5 for the E. coli ortholog). This MFS porter is similar to the Irp8 piscibactin secretion porter of Vibrio anguillarum (Lages et al. 2022). |
Bacteria | Pseudomonadota | YbtX of Yersinia pestis |
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2.A.1.57.4 | Siderophore transporter, RhtX/FptX family |
Bacteria | Myxococcota | Siderophore transporter of Myxococcus xanthus |
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2.A.1.57.5 | The iron (Fe3+)·pyridine-2,6-bis(thiocarboxylic acid (PDTC)) uptake transporter, PdtE. Functions with the OMR, PdtK, 1.B.14.8.2 (most similar to 2.A.1.57.4) (Leach and Lewis 2006). |
Bacteria | Pseudomonadota | PdtE of Pseudomonas putida (ABC8353) |
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2.A.1.57.6 | Major facilitator superfamily domain-containing protein 3, MFSD3. Function unknown. The human ortholog has Uniprotein acc # of Q96ES6 with 412 aas and 12 TMSs. |
Eukaryota | Metazoa, Chordata | Mfsd3 of Rattus norvegicus |
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2.A.1.58.1 | The N-acetylglucosamine:H+ symporter, Ngt1 (Alvarez and Konopka, 2007) |
Eukaryota | Fungi, Ascomycota | Ngt1 of Candida albicans (Q5A7S4) |
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2.A.1.58.2 | May contribute to coordination of muscle contraction as regulatory subunit of a nonessential potassium channel complex. Subunit structure: May form a complex with sup-9 and sup-10 where unc-93 and sup-10 act as regulatory subunits of the two pore potassium channel sup-9.
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Eukaryota | Metazoa, Nematoda | Unc-93 of Caenorhabditis elegans (Q93380) |
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2.A.1.58.3 | UNC93-like protein MFSD11 (Major facilitator superfamily domain-containing protein 11; Protein ET) of 449 aas and 12 TMSs It seems to be involved in intracellular transport in mammals and has been suggested to be a sugar:H+ symporter (Zhang et al. 2018). It is expressed in testis, small intestine, spleen, prostate, and ovary, and mutations can give rise to ovarian cancer (Liu et al. 2002). Mfsd11 is abundantly expressed in the mouse brain and plays a potential role in energy homeostasis (Perland et al. 2016). Its transcript is highly enriched in Aedes aegypti during arbovirus infection (Campbell et al. 2011). UNC93A and SV2 (TC# 2.A.1.22.1) may play a role in virus assembly or budding (Campbell et al. 2011). TMEM132C, UNC93A and TTLL2 (the latter two genes being adjacent) are associated with pulmonary function (Son et al. 2015). It may be involved in psoriasis, a common chronic autoimmune inflammatory skin disease (Li et al. 2020). |
Eukaryota | Metazoa, Chordata | MFSD11 of Mus musculus |
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2.A.1.58.4 | MFS permease of 467 aas |
Eukaryota | Viridiplantae, Streptophyta | MFS permease of Oryza sativa |
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2.A.1.58.5 | Duf895 protein of 450 aas |
Eukaryota | Fungi, Ascomycota | Duf895 protein of Verticillium albo-atrum |
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2.A.1.58.6 | MFS permease of 425 aas |
Eukaryota | Evosea | MFS permease of Dictyostellium discoideum |
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2.A.1.58.7 | Unc-93 family homologue B1, Unc-93b1 or Unc93b1, of 597 aas and 12 TMSs, plays a role in innate and adaptive immunity by regulating nucleotide-sensing Toll-like receptor (TLR) signaling (Pelka et al. 2014). It is required for the transport of a subset of TLRs (including TLR3, TLR7 and TLR9) from the endoplasmic reticulum to endolysosomes where they can engage pathogen nucleotides (e.g., of viral nucleic acids) and activate signaling cascades. Unc93B1 may play a role in autoreactive B-cells removal (Isnardi et al. 2008). It induces apoptotic cell death and is cleaved by host and viral proteases (Harris and Coyne 2015). UNC93B1 may play a role in human oral squamous cell carcinomas growth by controlling the secretion of granulocyte macrophage colony-stimulating factor (GM-CSF) (Wagai et al. 2019). UNC93B1 regulates Toll-like receptor stability independently of endosomal TLR transport (Pelka et al. 2018). A missense variant affecting the C-terminal tail of UNC93B1 in dogs is responsible for a Exfoliative Cutaneous Lupus Erythematosus (ECLE) condition (Leeb et al. 2020). Compartmentalization of TLRs in the endosome limits their activation by self-derived nucleic acids and reduces the possibility of autoimmune reactions. UNC93B1 is indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome. Ishida et al. 2021 reported two cryo-EM structures of human and mouse TLR3-UNC93B1 complexes and a human TLR7-UNC93B1 complex. UNC93B1 exhibits structural similarity to other MFS porters. Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions, but the complexes of TLR3 and TLR7 with UNC93B1 differ in their oligomerization state (Ishida et al. 2021). The mammalian trafficking chaperone protein UNC93B1 maintains the ER calcium sensor STIM1 in a dimeric state primed for translocation to the ER cortex (Wang and Demaurex 2022). Gain-of-function human UNC93B1 variants cause systemic lupus erythematosus and chilblain lupus (David et al. 2024; Al-Azab et al. 2024).
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Eukaryota | Metazoa, Chordata | Unc93b1 of Homo sapiens |
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2.A.1.58.8 | MFS permease of 418 aas and 12 TMSs. |
Eukaryota | Evosea | MFS permease of Entamoeba histolytica |
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2.A.1.58.9 | Unc93A of 457 aas and 12 TMSs. |
Eukaryota | Metazoa, Chordata | Unc93A of Homo sapiens |
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2.A.1.59.1 | UMF10a of unknown function, (COG2270). |
Archaea | Euryarchaeota | UMF10a of Methanococcus aeolicus (A6UVW2) |
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2.A.1.59.2 |
UMF10b (in an operon with a sensor kinase/response regulator pair and an 8 TMS rhomboid protease) |
Bacteria | Cyanobacteriota |
UMF10b of Nostoc punctiforme (B2JBG5) |
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2.A.1.59.3 | MFS permease, AF1541 |
Archaea | Euryarchaeota | AF1541 of Archaeoglobus fulgidus (O28731) |
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2.A.1.59.4 | MFS permease, LepA |
Bacteria | Aquificota | LepA of Hydrogenivirga sp.128-5-R1-1 (A8UT57) |
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2.A.1.59.5 | Putative pantothenate:H+ importer of 417 aas and 12 TMSs (Wunderlich 2022). |
Eukaryota | Apicomplexa | Putative pantothenate uptake porter of Plasmodium falciparum |
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2.A.1.6.1 | Citrate:H+ symporter | Bacteria | Pseudomonadota | CitA of Klebsiella pneumoniae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.6.10 | Inner membrane metabolite transport protein YhjE |
Bacteria | Pseudomonadota | YhjE of Escherichia coli |
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2.A.1.6.11 |
Acetate/haloacid transporter, Dehp2, with a possible atypical topology (Tse et al. 2009). Transports acetate, chloroacetate, bromoacetate, 2-chloropropionate, and possibly, with low affinity, glycolate, lactate and pyruvate (based on weak inhibition results). Inducible by chloroacetate (Su and Tsang 2012). This protein is 79% identical to its paralogue, Deh4p (TC# 2.A.1.6.8) which differs in that it shows lower apparent affinity for 2-chloropropionate. |
Bacteria | Pseudomonadota | Dehp2 of Burkholderia caribensis (formerly sp. MBA4) |
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2.A.1.6.12 | The putative thiazole transporter, ThiU. Regulatyed by TPP riboswitch (Rodionov et al. 2002) |
Bacteria | Pseudomonadota | ThiU of Haemophilus influenzae (P44699) |
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2.A.1.6.13 | Acetate/monochloroacetate permease, Deh4p, of 468 aas and 12 TMSs. Transports various carboxylates. Dehalococcoides mccartyi degrades haloacids (Su et al. 2016). |
Bacteria | Chloroflexota | Deh4p of Dehalococcoides mccartyi |
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2.A.1.6.14 | Proline/glycine betaine uptake transporter, ProP, of 466 aas and 12 TMSs. It is not the major proline transporter found in S. aureus (Lehman et al. 2023). |
Bacteria | Bacillota | ProP of Staphylococcus aureus |
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2.A.1.6.2 | α-Ketoglutarate (oxoglutarate):H+ symporter (Seol and Shatkin 1992; Seol and Shatkin 1992). May also export arabinose but not xylose (Koita and Rao 2012). |
Bacteria | Pseudomonadota | KgtP of E. coli (P0AEX3) |
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2.A.1.6.3 | Dicarboxylate:H+ symporter. Transports and serves as a chemoreceptor for β-ketoadipate (Karimian and Ornston 1981). |
Bacteria | Pseudomonadota | PcaT of Pseudomonas putida |
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2.A.1.6.4 | (Proline/glycine-betaine):(H+/Na+) symporter, ProP (also transports taurine, ectoine, pipecolate, proline-betaine, N,N-dimethylglycine, carnitine, and 1-carboxymethyl-pyridinium) (subject to osmotic activation). Transmembrane helix I and periplasmic loop 1 are involved in osmosensing and osmoprotectant transport (Keates et al., 2010). ProP detects the increase in cytoplasmic cation concentration associated with osmotically induced cell dehydration and mediates osmolyte uptake into bacteria (Ozturk et al. 2020). ProP is a 12-TMS protein with an α-helical, cytoplasmic C-terminal domain (CTD) linked to TMS XII. The CTD helix associates with the anionic membrane surface to lock ProP in an inactive conformation. The release of the CTD may activate ProP. Molecular dynamics simulations showed specific intrapeptide salt bridges forming when the CTD associated with the membrane. The salt bridge Lys447-Asp455 weakened CTD-lipid interactions at 0.25 M KCl, and gradual stiffening of the membrane with increasing salinity was obseerved. Thus, salt cations may affect CTD release and activate ProP by increasing the order of membrane phospholipids (Ozturk et al. 2020). ProP forestalls cellular dehydration by detecting environments with high osmotic pressure and mediating the accumulation of organic osmolytes by bacterial cells. Structural determinants and functional significance of dimerization have been described (Ozturk et al. 2023). |
Bacteria | Pseudomonadota | ProP of E. coli (P0C0L7) |
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2.A.1.6.5 | 4-Methyl-o-phthalate:H+ symporter | Bacteria | Pseudomonadota | MopB of Burkholderia cepacia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.6.6 | Shikimate:H+ symporter | Bacteria | Pseudomonadota | ShiA of E. coli | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.6.7 | The citrate/tricarballylate:H+ symporter (CitA or TcuC); probably orthologous to 2.A.1.6.1 (Lewis et al., 2004) | Bacteria | Pseudomonadota | TcuC of Salmonella enterica serovar Typhimurium LT2 (P0A2G3) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.6.8 | The acetate/monochloroacetate (haloacid) permease, Deh4p (Km = 5.5 mμM for acetate; 9 mμM for monochloroacetate) (Yu et al., 2007; Su and Tsang 2012). |
Bacteria | Pseudomonadota | Deh4 of Burkholderia cepacia or sp. MBA4 (Q7X4L6) |
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2.A.1.6.9 | YdfJ. Can function as an inward rectifying K+ channel when expressed in animal cells as measured by whole cell patch clamping. Blocked by barium and protopine (Tang et al., 2011). |
Bacteria | Pseudomonadota | YdfJ of E. coli (P77228) |
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2.A.1.60.1 | The rhizopine related transporter, MocC (could either transport a precursor for rhizopine biosynthesis into bacteroids or the finished product from the bacteroids) (Murphy et al., 1993) | Bacteria | Pseudomonadota | MocC of Sinorhizobium meliloti (Q07609) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.60.2 | Inner membrane protein YbjJ |
Bacteria | Pseudomonadota | YbjJ of Escherichia coli |
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2.A.1.60.3 | The multidrug (quinolone; tetarcycline) resistance pump, TcrA (Chang et al. 2011). |
Bacteria | Pseudomonadota | TcrA of Stenotrophomonas maltophilia (F2WVP9) |
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2.A.1.61.1 | The MccC microcin C51 immunity protein (exports the peptide-nucleotide 'Trojan horse' antibiotic) (Fomenko et al., 2003; Kazakov et al., 2007) | Bacteria | Pseudomonadota | MccC of E. coli (Q83Y57) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.61.2 | MFS porter of 411 aas and 12 TMSs. |
Bacteria | Pseudomonadota | Porter of Bartonella washoensis |
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2.A.1.61.3 | MFS porter of 413 aas and 12 TMSs. |
Bacteria | Chlamydiota | Porter of Parachlamydia acanthamoebae |
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2.A.1.62.1 | The UMF11 homologue |
Bacteria | Bacillota | UMF11 of Staphylococcus aureus (A8YZ14) |
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2.A.1.62.2 |
Putative Macrolide efflux pump (P-MEP), possibly involved in transport of amino acids and their derivatives.
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Bacteria | Fusobacteriota | P-MEP of Fusobacterium sp. 7_1 (C3WVU9) |
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2.A.1.62.3 | UMF11 (links UMF11 with UMF13) |
Bacteria | Bacillota | UMF11 of Bacillus clausii (Q5WGH2) |
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2.A.1.62.4 | Uncharacterized protein of 406 aas and 12 TMSs. Gives an alignment with a ferroportin homolog, 2.A.100.2.1 including almost all of both proteins with a TC BLAST score of e-12. |
Bacteria | Bacillota | UP of Clostridium diolis |
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2.A.1.62.5 | Putative MFS efflux pump of 389 aas and 12 TMSs. Expression of the gene encoding this transporter is governed by a quorum sensing (QS) system, and it impacts the expression of multiple virulence factors, accounting for QS-dependent antibiotic susceptibility (Chang et al. 2022). |
Bacteria | Bacillota | MFS porter of Streptococcus pyogenes |
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2.A.1.63.1 | The UMF12 protein |
Archaea | Euryarchaeota | UMF12 of Methanosarcina barkeri (Q467Y6) |
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2.A.1.63.2 | UMF12 Possible amino acid exporter |
Archaea | Euryarchaeota | UMF12 of Methanosarcina mazei (Q8PRW9) |
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2.A.1.63.3 | Possible nucleotide or oligonucleotide uptake porter, UMF12 |
Bacteria | Deinococcota | UMF12 of Deinococcus radiodurans (Q9RXM0)
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2.A.1.63.4 | MFS carrier |
Eukaryota | Fungi, Ascomycota | MFS carrier of Saccharomyces cerevisiae K7 (P47159) |
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2.A.1.64.1 | The UMF13 protein |
Bacteria | Bacillota | UMF13 of Streptococcus thermophilus (Q5M4L1) |
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2.A.1.64.2 | Uncharacterized protein RP255 | Bacteria | Pseudomonadota | RP255 of Rickettsia prowazekii | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.64.3 | Uncharacterized protein of 611 aas |
Bacteria | Mycoplasmatota | UP of Spiroplasma diminutum |
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2.A.1.65.1 | The putative MFS carrier, Sugar Baby (Sug, isoform D); has a hydrophilic domain between TMSs 3 and 4. Overexpression causes an increased lifespan by 17%. It has 12 TMSs in a 3 + 3 + 6 TMS arrangement. |
Eukaryota | Metazoa, Arthropoda | Sugar Baby of Drosophila melanogaster (Q7KUF9) |
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2.A.1.65.10 | Major facilitator superfamily domain-containing protein 6-like, MfsD6Ls, of 586 aas and 12 TMSs. Mutations can cause pediatric cataracts (Aldahmesh et al. 2012). |
Eukaryota | Metazoa, Chordata | MFSD6L of Homo sapiens |
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2.A.1.65.11 | Duplicated MFS permease (901 amino acyl residues; ~24 TMSs) |
Eukaryota | Viridiplantae, Chlorophyta | Duplicated MFS permease of Chlamydomonas reinhardtii |
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2.A.1.65.12 | MFS_1_like domain-containing protein, MFSD6, of 630 aas and 12 TMSs in a 3 + 3 + 6 TMS arrangement. It seems to regulate neural circuit activity (McCulloch et al. 2017). |
Eukaryota | Metazoa, Nematoda | MfsD6 of Caenorhabditis elegans |
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2.A.1.65.13 | MFSD6 of 791 aas and 12 TMSs in a 3 + 3 + 6 TMS arrangement. Mutations in the mfsd-6 gene influence the regulation of neural circuit activity (McCulloch et al. 2017). MfsD6 may transport sugars. |
Eukaryota | Metazoa, Chordata | MfsD6 of Homo sapiens |
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2.A.1.65.2 | Unknown MFS homologue; e-6 with 2.A.1.5 family members; has a hydrophilic domain between TMSs 3 and 4. | Eukaryota | Metazoa, Arthropoda | UMF14 of Culex quinquefasciatus (B0W435) |
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2.A.1.65.3 | Unknown MFS homologue UMF14 ( 833 aas, 12 TMSs in a 3+9 arrangement ) |
Eukaryota | Metazoa, Arthropoda | UMF14 of Anopheles gambiae (Q7Q0Z9) |
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2.A.1.65.4 | Uncharacterized protein of 474 aas |
Eukaryota | Metazoa, Cnidaria | UP of Nematostella vectensis (Starlet sea anemone) |
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2.A.1.65.5 | MFS porter |
Eukaryota | Metazoa, Arthropoda | MFS porter of Daphnia pulex (E9I268) |
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2.A.1.65.6 | Macrophage MHC Class I receptor 2, Mmr2 or MFSD6. The ortholog of this protein in humans is a also called MFSD6 and is 90% identical to the mouse protein (Bagchi et al. 2020). This disease protein shows increased expression levels with increased energy consumption (Bagchi et al. 2020). |
Eukaryota | Metazoa, Chordata | Mmr2 of Mus musculus (Q8CBH5) |
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2.A.1.65.7 | MFS porter |
Eukaryota | Viridiplantae, Chlorophyta | MFS porter of Chlorella variablis (E1ZG13) |
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2.A.1.65.8 | MFS permease |
Bacteria | Bacillota | MFS permease of Thermoanaerobacter tengcongensis (Q8R7B7) |
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2.A.1.65.9 | Maltose permease | Bacteria | Bacillota | MalA of Geobacillus stearothermophilus |
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2.A.1.66.1 | MFS permease of unknown function (First half resembles 2.A.1.3.7 (e-11) and 2.A.1.15.3 (e-8)). Very likely to be a galactoside/galactose transporter; encoded within a gene cluster with β-galactosidase and galactose metabolic genes. |
Archaea | Thermoproteota | MFS permease of Thermofilum pendens (A1RW34) |
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2.A.1.66.2 |
Putative 4-hydroxybenzoate uptake transporter, MFS_1 (in an operon with 2,3-diketo-5-methylthiopentyl-1-phosphate enolase-phosphatase of the methionine salvage pathway), using S-adenyl methionine (SAM) as substrate. May transport SAM. |
Bacteria | Spirochaetota | MFS1 of Leptospira interrogans (Q8F7L4) |
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2.A.1.66.3 | UMF15 Homologue |
Eukaryota | Bacillariophyta | UMF15 homologue of Thalassiosira pseudonana (B8BU21)
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2.A.1.66.4 | MFS transporter of 531 aas. Present in the membrane of the organelle called the rhoptries which is involved in host invasion and hijacking host cell functions (Peter Bradley, personal communication). |
Eukaryota | Apicomplexa | MFS porter of Toxoplasma gondii |
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2.A.1.66.5 | MFS transporter of 428 aas. Present in the membrane of the organelle called the rhoptries which is involved in host invasion and hijacking host cell functions (Peter Bradley, personal communication). |
Eukaryota | Apicomplexa | Porter of Toxoplasma gondii |
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2.A.1.66.6 | Uncharacterized protein of 646 aas and 12 TMSs |
Eukaryota | Viridiplantae, Chlorophyta | UP of Chlorella variabilis (Green alga) |
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2.A.1.66.7 | Putative MFS carrier of 809 aas and 12 TMSs in a 2 + 4 + 6 TMS arrangement. |
Eukaryota | Apicomplexa | MFS carrier of Plasmodium falciparum |
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2.A.1.66.8 | Pantothenate:H+ symporter, PAT or TMP1 of 565 aas and 12 TMSs in a 6 + 6 TMS arrangement (Wunderlich 2022). |
Eukaryota | Apicomplexa | PAT of Plasmodium falciparum |
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2.A.1.67.1 | MFS permease of unknown function (second half distantly resembles the first half of 2.A.1.41.3/e value of 0.001) |
Bacteria | Actinomycetota | UMF16 of Kribbella flavida (D2PP09) |
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2.A.1.67.2 | MFS porter |
Bacteria | Actinomycetota | MFS porter of Arthrobacter aurescens (A1R564) |
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2.A.1.67.3 | MFS porter |
Bacteria | Pseudomonadota | MFS porter of Erwinia pyrifoliae (D0FNI7) |
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2.A.1.67.4 | MFS porter of 402 aas and 12 TMSs. |
Bacteria | Actinomycetota | MFS porter of Propionibacterium acnes (D1YEI1) |
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2.A.1.67.6 | MfsB (Smlt0548) (B2FL18) of 404 aas and 12 TMSs in a 6 + 6 TMS arrangement. Its function is not known (Boonyakanog et al. 2022). |
Bacteria | Pseudomonadota | MfsB of Stenotrophomonas maltophilia |
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2.A.1.68.1 | The glucose transporter, OEOE_1574; does not transport fructose (Kim et al., 2011). |
Bacteria | Bacillota | OEOE_1574 of Oenococcus onei (Q04DP6) |
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2.A.1.68.2 | MFS porter of 409 aas |
Archaea | Euryarchaeota | MFS porter of Methanofollis ethanolicus |
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2.A.1.68.3 | MFS porter |
Bacteria | Bacillota | MFS porter of Blautia producta |
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2.A.1.69.1 | The UMF17A porter |
Bacteria | Actinomycetota | UMF17A porter of Streptomyces coelicolor (Q9KZY0) |
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2.A.1.69.2 | MFS permease of 438 aas |
Bacteria | Actinomycetota | MFS porter of Geodermatophilus obscurus |
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2.A.1.7.1 | L-Fucose:H+ symporter. The x-ray structure (3.1Å resolution) with an outward open, amphipathic cavity has been solved. Asp46 and Glu135 can undergo cycles of protonation (Dang et al., 2010). |
Bacteria | Pseudomonadota | FucP of E. coli |
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2.A.1.7.10 | The putative glucose porter, GlcP (Rodionov et al., 2010). |
Bacteria | Pseudomonadota | GlcP of Shewanella amazonensis (A1S5F4) |
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2.A.1.7.11 | The putative mannose porter, ManPl (Rodionov et al., 2010). |
Bacteria | Pseudomonadota | ManPl of Shewanella amazonensis (A1S297) |
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2.A.1.7.12 | The putative trehalose porter, TreT (Rodionov et al., 2010) |
Bacteria | Pseudomonadota | TreT of Shewanella frigidimarina (Q07XD1) |
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2.A.1.7.13 | Bypass of stop codon protein 6 | Eukaryota | Fungi, Ascomycota | BSC6 of Saccharomyces cerevisiae S288c | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.7.14 | Protein TsgA, also called GutS, YhfC, YhfH. tsgA i(gutS) gene expression is up-regulated by tellurite and selenite (Guzzo and Dubow 2000). |
Bacteria | Pseudomonadota | TgsA of E. coli |
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2.A.1.7.15 | Major facilitator superfamily domain-containing protein 4-A, MFSD4A, of 526 aas and 12 TMSs. |
Eukaryota | Metazoa, Chordata | MfsD4a of Danio rerio |
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2.A.1.7.16 | The putative mannose porter, ManP (Rodionov D.A., personal communication). Regulated by mannose regulon ManR. |
Bacteria | Bacteroidota | ManP (Q8A5Y0) of Bacteroides thetaiotaomicron |
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2.A.1.7.17 | The putative fructose porter, FruP (Rodionov D.A., personal communication). Regulated by fructose oligosaccharide utilization regulon. |
Bacteria | Bacteroidota | FruP (Q8A6W8) of Bacteroides thetaiotaomicron |
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2.A.1.7.18 | The putative N-acetylglucosamine porter, NagP (Rodionov D.A., personal communication). Regulated by heparin utilization regulon. |
Bacteria | Bacteroidota | NagP (Q89YS8) of Bacteroides thetaiotaomicron |
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2.A.1.7.19 | Probable glucose transporter encoded by a gene sandwiched in between two genes encoding a glucose 1-dehydrogenase and a gluconolactonase. |
Bacteria | Chlamydiota | Glucose permease of Parachlamydia acanthamoebae |
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2.A.1.7.2 | Glucose/galactose porter | Bacteria | Pseudomonadota | Ggp of Brucella abortus (P0C105) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.7.20 | Uncharacterized MFS protein of 392 aas and 12 TMSs. |
Bacteria | Bdellovibrionota | UMFS of Bdellovibrio exovorus |
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2.A.1.7.21 | Uncharacterized protein of the MFS of 505 aas and 12 TMSs |
Eukaryota | Viridiplantae, Chlorophyta | UP of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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2.A.1.7.22 | Uncharacterized protein of 494 aas and 12 TMSs. |
Eukaryota | Viridiplantae, Chlorophyta | UP of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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2.A.1.7.23 | Na+-dependent glucose transporter 1, Mfsd4b, of 491 aas and 12 TMSs. May also serve as a channels for urea in the inner medulla of the kidney. |
Eukaryota | Metazoa, Chordata | Mfsd4b of Xenopus laevis (African clawed frog) |
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2.A.1.7.24 | MFS porter, MFSD4a or SLC60A1, of 514 aas and 12 TMSs. In the mouse, this protein and MFSD9 localize to neurons in the brain, and their mRNA expression levels are affected by diet (Perland et al. 2017). They are associated with cancer and have anti-tumor activities (Yang et al. 2022). It may play a role in the excretion of nitrogen metabolites (Honerlagen et al. 2021). |
Eukaryota | Metazoa, Chordata | MFSD4a of Homo sapiens |
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2.A.1.7.25 | Uncharacterized protein of 894 aas and 19 TMSs in a 7 + 12 TMS arrangement. The first 7 TMSs comprise a CFEM domain, while the last 12 TMSs are homologous to MFS porters. There are many such proteins in the NCBI database, most from fungi. |
Eukaryota | Fungi, Ascomycota | UP of Leptosphaeria maculans |
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2.A.1.7.26 | Na+:glucose co-transporter of 672 aas and about 14 TMSs, SGLT2. It has a Na+ to glucose coupling ratio of 1:1 (Brown et al. 2019). Efficient substrate transport in the mammalian kidney is provided by the concerted action of a low affinity high capacity and a high affinity low capacity Na+/glucose cotransporter arranged in series along kidney proximal tubules. Inhibitors are antidiabetic agents (Li 2019; Singh and Singh 2020). They are also useful as theraputic agents of non-alcoholic fatty liver disease and chronic kidney disease (Kanbay et al. 2020). Marein, an active component of the Coreopsis tinctoria Nutt plant, ameliorates diabetic nephropathy by inhibiting renal sodium glucose transporter 2 and activating the AMPK signaling pathway (Guo et al. 2020). NHE-3 (TC# 2.A.53.2.18) was markedly downregulated, while the Na+-HCO3--cotransporter (NBC-1; TC# 2.A.31.2.12) and SGLT2 were upregulated after kidney transplantation (Velic et al. 2004). Pharmacological inhibition of hSGLT2 by oral small-molecule inhibitors, such as empagliflozin, leads to enhanced excretion of glucose and is widely used in the clinic to manage blood glucose levels for the treatment of type 2 diabetes. Niu et al. 2021 determined the cryogenic electron microscopic structure of the hSGLT2-MAP17 complex in the empagliflozin-bound state to a resolution of 2.95 Å. MAP17 interacts with transmembrane helix 13 of hSGLT2. Empagliflozin occupies both the sugar-substrate-binding site and the external vestibule to lock hSGLT2 in an outward-open conformation, thus inhibiting the transport cycle (Niu et al. 2021). There is no upregulation regarding host factors potentially promoting SARS-CoV-2 virus entry into host cells when the SGLT2-blocker empagliflozin, telmisartan and the DPP4-inhibitor blocker, linagliptin, are used (Xiong et al. 2022). Canagliflozin, dapagliflozin and ipragliflozin significantly inhibit the growth of different cancer cell lines in the micromolar range; SGLT2 inhibitors have antiproliferation, anti-tumorigenesis, and anti-migration effects and may induce apoptosis in cancer cells. Treatment with SGLT2 inhibitors also results in the downregulation of selected genes (Bardaweel and Issa 2022). SGLT2 inhibitor treatment results in symptomatic and functional well-being, especially in relieving pain (Calderon-Rivera et al. 2022). Effects of SGLT2 inhibitors affect the heart and kidney to promote autophagic flux, nutrient deprivation signaling and transmembrane sodium transport (Zannad et al. 2022). Empagliflozin (EMPA), mainly acting on SGLT2, prevented DNA methylation changes induced by high glucose and provided evidence of a new mechanism by which SGLT2i can exert cardio-beneficial effects (Scisciola et al. 2023). A diversifiable synthetic platform for the discovery of new carbasugar SGLT2 inhibitors using azide-alkyne click chemistry has been described (Kitamura et al. 2023). SGLT2 is inhibited by empagliflozin (Raven et al. 2023). SGLT2 inhibitors not only suppress hyperglycemia but also reduce renal, heart, and cardiovascular diseases (Unno et al. 2023). In fact, SGLT2 may also be related to other functions, such as bone metabolism, longevity, and cognitive functions based on mouse models (Unno et al. 2023). Complex effects of different SGLT2 inhibitors on alphaKlotho gene expression (see TC family 8.A.49) and protein secretion in renal MDCK and HK-2 cells have been observed (Wolf et al. 2023). Ferulic acid-grafted chitosan (FA-g-CS) stimulates the transmembrane transport of anthocyanins by SGLT1 and GLUT2 (Ma et al. 2022). SGLT2 Inhibitors are potential anticancer agents (Basak et al. 2023). Analyses of the effects of SGLT2 inhibitors on renal tubular sodium, water and chloride homeostasis as well as their roles in influencing heart failure outcomes has appeared (Packer et al. 2023). The SGLT2 inhibitor, empagliflozin, alleviates cardiac remodeling and contractile anomalies in a FUNDC1-dependent manner in experimental Parkinson's disease (Yu et al. 2023). Type 2 diabetes guidance proposes offering SGLT2-inhibitor therapy to people with established atherosclerotic cardiovascular disease (ASCVD) or heart failure, but this suggestion has been questioned (Young et al. 2023). SGLT2 inhibition in a non-diabetic rat model of salt-sensitive hypertension blunts the development of salt-induced hypertension independent of sex (Kravtsova et al. 2023). SGLT2 inhibitors are safe in humans, but they do not improve outcomes in patients hospitalised with COVID-19 (Vale et al. 2024). Inhibition of SGLT2 protects podocytes in diabetic kidney disease by rebalancing mitochondria-associated endoplasmic reticulum membranes (Li et al. 2024). SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts (Goedeke et al. 2024). Thus, SGLT2i has pleiotropic effects on systemic and heart metabolism, which are distinct from ketone supplementation and may contribute to the long-term cardioprotective benefits of SGLT2i. The molecular mechanism behind the sympatholytic effect of empagliflozin on SGLT2 explains sympathoexcitation in hypertensive heart failure via attenuating subfornical organ endothelial cGAS ubiquitination to amplify neuroinflammation (Zhang et al. 2025). |
Eukaryota | Metazoa, Chordata | GLUT2 of Homo sapiens |
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2.A.1.7.27 | Na+/Glucose co-transporter, SGLT1, SLC60A2 or MfsD4B, of 518 aas and 12 TMSs (Perland et al. 2017). SY009 is a novel SGLT1 inhibitor that exerts effects on the plasma metabolome and bile acids in patients with type 2 diabetes mellitus (Yang et al. 2025). |
Eukaryota | Metazoa, Chordata | MfsD4B of Homo sapiens |
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2.A.1.7.3 | Glucose/Mannose/Xylose: H+ symporter (Paulsen et al., 1998; G.Gosset, personal communication). |
Bacteria | Bacillota | GlcP of Bacillus subtilis |
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2.A.1.7.4 | Rat kidney Na+-dependent glucose (methyl α-glucoside) transporter, NaGLT1 or SGLT1 (glucose:Na+:Na+=1:1) (Horiba et al., 2003). Position 170 of Rabbit Na+/glucose cotransporter (rSGLT1) lies in the Na+ pathway, and modulation of polarity/charge at this site regulates charge transfer and carrier turnover (Huntley et al. 2004). The fine-tuning of glucose uptake mechanisms is rendered by various glucose transporters with distinct transport characteristics. In the pancreatic islet, facilitative diffusion glucose transporters (GLUTs), and sodium-glucose cotransporters (SGLTs) contribute to glucose uptake and represent important components in the glucose-stimulated hormone release from endocrine cells, therefore playing a crucial role in blood glucose homeostasis (Berger and Zdzieblo 2020). SGLT1 and SGLT2 are therapeutic targets for various diseases (Sano et al. 2020), and function in glucose absorption in the small intestine (Vallon 2020). This glucose:Na+ symporter can transport the drug gastrodin, a seditive with a strcture of a phenolic glucoside (Huang et al. 2023). |
Eukaryota | Metazoa, Chordata | NaGLT1 of Rattus norvegicus (BAC57446) |
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2.A.1.7.5 | 2-Deoxy-D-ribose porter, DeoP (Christensen et al., 2003). Plays a role in colonization of the mouse intestine (Martinez-Jéhanne et al. 2009). |
Bacteria | Pseudomonadota | DeoP of Salmonella typhimurium LT-2 (gi 16767076) |
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2.A.1.7.6 | Sucrose permease, ScrT (Rodionov et al., 2010) |
Bacteria | Pseudomonadota | ScrT of Shewanella frigidimarina (ABI73814) |
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2.A.1.7.7 | The Na+-dependent sugar transporter, HP1174 (transports glucose, galactose, mannose and 2-deoxyglucose (Psakis et al. 2009)). (most similar to 2.A.1.7.2; 49% identity) | Bacteria | Campylobacterota | HP1174 of Helicobacter pylori (O25788) |
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2.A.1.7.8 | N-acetylglucosamine porter, NagP (Rodionov et al. 2010). |
Bacteria | Pseudomonadota | NagP of Shewanella oneidensis (Q8EBL0) |
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2.A.1.7.9 | The putative N-acetylgalactosamine porter, AgaP (Leyn et al. 2012). |
Bacteria | Pseudomonadota | AgaP of Shewanella amazonensis (A1S4V0) |
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2.A.1.70.1 | UMF18A, May be a monocarboxylate uptake transporter based on its sequence similarity with families 2.A.1.11 and 2.A.1.13. |
Bacteria | Actinomycetota | UMF18A of Streptomyces coelicolor (Q9L223) |
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2.A.1.70.2 | UMF18B |
Bacteria | Actinomycetota | UMF18B of Saccharomonospora azurea (G4JJZ0) |
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2.A.1.70.3 | UMF18C |
Bacteria | Actinomycetota | UMF18C of Salinispora tropica (A4X2L1) |
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2.A.1.70.4 | Uncharacterized MFS protein of 412 aas and 12 TMSs. |
Bacteria | Deinococcota | UP of Meiothermus timidus |
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2.A.1.70.5 | Uncharacterized MFS porter of 401 aas and 12 TMSs. |
Bacteria | Pseudomonadota | UP of Belnapia rosea |
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2.A.1.70.6 | Uncharacteerized MFS porter of 434 aas and 12 TMSs |
Bacteria | Bacillota | UP of Halalkalibacillus halophilus |
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2.A.1.70.7 | Uncharacterized MFS porter of 401 aas and 12 TMSs. |
Bacteria | Chloroflexota | UP of Dehalococcoidia bacterium |
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2.A.1.70.8 | Uncharacterized MFS porter of 397 aas and 12 TMSs, annotated in Uniprot as ArsP. The encoding gene is next to genes encoding ArsH (Q1LRL2), an NADPH-dependent FMN reductase, ArsC1, an arsenate reductase (Q1LRL1) and an arsenite efflux pump, ArsB or Acr3 of 10 TMSs (ArsB; Q1LRL0; ACR family, TC# 2.A.59). This MFS family shows greatest similarity with families 2.A.1.11 and 2.A.1.13, both which transport anionic speices, for example, oxalate, formate and pyruvate (TC# 2.A.1.11) and monocarboxylates (TC# 2.A.1.13). It is 32% identical and 52% similar to ArsK (TC# 2.A.1.70.9) which is an arsenite/antimonite exporter (Shi et al. 2018). |
Bacteria | Pseudomonadota | ArsP of Cupriavidus metallidurans (Ralstonia metallidurans) |
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2.A.1.70.9 | ArsK, exporter of arsenite, antimonite, trivalent roxarsone and methylarsenite (Shi et al. 2018). Expression of arsK is induced by arsenite [As(III)], antimonite [Sb(III)], trivalent roxarsone [Rox(III)], methylarsenite [MAs(III)] and arsenate [As(V)], and heterologous expression of ArsK in an arsenic-hypersensitive E. coli strain showed that ArsK is essential for resistance to As(III), Sb(III), Rox(III) and MAs(III) but not to As(V), dimethylarsenite [Dimethyl-As(III)] or Cd(II). ArsK reduces the cellular accumulation of As(III), Sb(III), Rox(III) and MAs(III) but not to As(V) or Dimethyl-As(III). An arsenic regulator gene arsR2 is cotranscribed with arsK, and ArsR2 interacts with the arsR2-arsK promoter region without metalloids but is derepressed by As(III), Sb(III), Rox(III) and MAs(III). Thus, ArsK is an arsenic efflux protein and is regulated by ArsR2 (Shi et al. 2018).
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Bacteria | Pseudomonadota | ArsK of Rhizobium radiobacter (Agrobacterium tumefaciens; Agrobacterium radiobacter) |
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2.A.1.71.1 | The Valanimycin-resistance determinant, VlmF (probably a valanimycin:H antiporter (Ma et al., 2000)) |
Bacteria | Actinomycetota | VlmF of Streptomyces viridifaciens (Q9LA76) |
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2.A.1.71.2 | The UMF19a porter |
Bacteria | Actinomycetota | UMF19a porter of Streptomyces coelicolor (Q93J85) |
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2.A.1.71.3 | MFS transporter of 375 aas and 11 TMSs |
Bacteria | Actinomycetota | UP of Patulibacter americanus |
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2.A.1.72.1 | The UMF20A porter |
Bacteria | Actinomycetota | UMF20A of Streptomyces coelicolor (Q9RL01) |
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2.A.1.72.2 | MFS_1 of 429 aas |
Bacteria | Actinomycetota | MFS_1 of Propionimicrobium lymphophilum |
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2.A.1.72.3 | MFS_1 of 390 aas |
Bacteria | Pseudomonadota | MFS_1 of Mesorhizobium loti |
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2.A.1.73.1 | The UMF21A porter |
Bacteria | Actinomycetota | UMF21A porter of Streptomyces coelicolor (Q9L102) |
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2.A.1.73.2 | MFS permease of 397 aas |
Bacteria | Actinomycetota | MFS permease of Actinoplanes friuliensis |
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2.A.1.73.3 | MFS_1, MilK of 442 aas. |
Bacteria | Actinomycetota | MilK of Streptomyces rimofaciens |
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2.A.1.74.1 | UMF22a porter |
Bacteria | Actinomycetota | UMF22 porter of Streptomyces coelicolor (Q9S243) |
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2.A.1.74.2 | MFS_1 of 408 aas |
Bacteria | Bacillota | MFS_1 of Bacillus marmarensis |
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2.A.1.74.3 | MFS_1 of 389 aas |
Bacteria | Pseudomonadota | MFS_1 of Variovorax paradoxus |
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2.A.1.74.4 | MFS_1 of 401 aas |
Bacteria | Pseudomonadota | MFS_1 of Marinobacter santoriniensis |
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2.A.1.75.1 | Probable transporter MCH1. Although the name, "monocarboxylate transporter homologue 1" implies that this system transports monocarboxylates such as lactate, pyruvate and acetate, no evidence for this possibility was obtained (Makuc et al. 2001). Instead, the mch1-5 mutant strain, lacking all 5 such paralogues in yeast showed strongly reduced biomass yields in aerobic glucose-limited chemostat cultures, pointing to the involvement of Mch transporters in mitochondrial metabolism. Indeed, intracellular localization studies indicated that at least some of the Mch proteins reside in intracellular membranes.Thus, the yeast monocarboxylate transporter-homologs perform other functions other than do their mammalian counterparts (Makuc et al. 2001). Possibly they function in intracellular, organellar transport of these acids. |
Eukaryota | Fungi, Ascomycota | MCH1 of Saccharomyces cerevisiae |
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2.A.1.75.2 | MFS putative monocarboxylic acid transporter, UMF23B |
Eukaryota | Fungi, Ascomycota | Mct of Coccidioides posadasii (E9CYW5) |
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2.A.1.75.3 | Uncharacterized major facilitator, UMF23C |
Eukaryota | Fungi, Ascomycota | UMF23C of Candida albicans |
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2.A.1.75.4 | Uncharacterized major facilitator UMF23D |
Eukaryota | Heterolobosea | UMF23D of Naegleria gruberi |
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2.A.1.75.5 | UMF23 permease of 572 aa |
Eukaryota | Viridiplantae, Streptophyta | UMF23 of Arabidopsis thaliana |
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2.A.1.75.6 | Uncharacterized protein of 591 aas and 12 TMSs |
Eukaryota | Viridiplantae, Chlorophyta | UP of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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2.A.1.75.7 | Uncharacterized MFS permease of 530 aas and 12 TMSs. |
Eukaryota | Evosea | UP of Entamoeba histolytica |
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2.A.1.75.8 | PICLORAM RESISTANT30 (PIC30) protein of 601 aas and 12 or 14 TMSs. It is a plasma membrane anion uptake porter, transporting picloram and other picolinate herbicides as well as nitrate, chlorate and chloride anions (Kathare et al. 2019). |
Eukaryota | Viridiplantae, Streptophyta | PIC30 of Arabidopsis thaliana |
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2.A.1.76.1 | Uncharacterized protein Mhp246 |
Bacteria | Mycoplasmatota | Mhp246 of Mycoplasma hyopneumoniae |
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2.A.1.76.2 | Uncharacterized Mycoplama MFS carrier, UMF24B |
Bacteria | Mycoplasmatota | UMF24B of Mycoplasma capricolum |
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2.A.1.76.3 | Uncharacterized MFS carrier, UMF24C |
Bacteria | Bacillota | UMF24C of Lactobacillus salivarius |
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2.A.1.76.4 | MFS carrier of 525 aas and 12 TMSs. |
Bacteria | Mycoplasmatota | MFS porter of Mycoplasma galisepticum |
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2.A.1.77.1 | Unknown Major Facilitator UMF25a |
Bacteria | Planctomycetota | UMF25a of Rhodopirellula baltica |
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2.A.1.77.2 | Unknown Major Facilitator, UMF25b |
Bacteria | Planctomycetota | UMF25b of Planctomyces limnophilus |
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2.A.1.78.1 | UMF26a of 416 aas and 12 TMSs. Encoded by a gene that is adjacent to two ATP hydrolyzing subunits homologous to ABC proteins of the peptide transporters of TC family 3.A.1.5. |
Bacteria | Chlamydiota | UMF26a of Parachlamydia acanthaemoebae (F8KXQ8) |
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2.A.1.78.2 | UMF26b of 419 aas and 12 TMSs |
Bacteria | Chlamydiota | UMF26b of Simkania negevensis (F8L9E4) |
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2.A.1.78.3 |
UMF26c of 457 aas and 12 TMSs |
Bacteria | Planctomycetota | UMF26c of Phycisphaera mikurensis (I0II84) |
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2.A.1.78.4 |
UMF26d of 413 aas and 12 TMSs |
Bacteria | Verrucomicrobiota | UMF26d of Verrucomicrobiae bacterium (B5JEI3) |
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2.A.1.79.1 | MFS permease of 485 aas |
Eukaryota | Rhodophyta | MFS permease of Cyanidioschyzon merolae |
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2.A.1.79.2 | Uncharacterized MFS proter of 724 aas and 12 TMSs with a C-terminal hydrophilic extension. |
Eukaryota | Rhodophyta | UP of Chondrus crispus (Carrageen Irish moss) (Polymorpha crispa) |
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2.A.1.8.1 | Nitrate/H+ symporter (K1);Nitrate/nitrite antiporter (K2). The 3-d structure is available revealing a positively charged pathway for nitrate/nitrite lined with arginine residues with no apparent proton pathway suggesting exchange transport is the primary or sole mechanism. The pathway is between the two halves of the protein and a rocker switch mechanism was proposed (Zheng et al. 2013). In an in vitro reconstituted system, NarK appeared to be a nitrate/nitrite antiporter. High-resolution crystal structures in the nitrate-bound occluded, nitrate-bound inward-open and apo inward-open states have been solved (Fukuda et al. 2015). |
Bacteria | Pseudomonadota | NarK (NarK1-K2) of E. coli |
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2.A.1.8.10 | NO3-/NO2- transporter (NO3- uptake permease; NO2- exporter) (probable NO3-/NO2- antiporter) (stress-induced; Clegg et al., 2006; Jia et al. 2009) |
Bacteria | Pseudomonadota | NarU of E. coli |
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2.A.1.8.11 | The 24 TMS, 2 domain, NarK1-NarK2 porter (NarK1 = a NO3-/H+ symporter; NarK2 = a NO3-/NO2- antiporter). NarK1 is a nitrate/proton symporter with high affinity for nitrate while NarK2 is a nitrate/nitrite antiporter with lower affinity for nitrate (Goddard et al., 2008). Each transporter requires two conserved arginine residues for activity. A transporter consisting of inactivated NarK1 fused to active NarK2 has a dramatically increased affinity for nitrate compared with NarK2 alone, implying a functional interaction between the two domains (Goddard et al., 2008). |
Bacteria | Pseudomonadota | NarK1/NarK2 of Roseobacter denitrificans (Q166T6) |
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2.A.1.8.12 | The root cortical and epidermal cell, high affinity, plasma membrane, NO3- uptake transporter, NRT2.1 (Wirth et al., 2007). Also functions in nitrate sensing and signaling (Miller et al., 2007; Girin et al., 2010). Activity only occurs when NRT2.1 is complexed with NAR2.1 (WR3; 8.A.20.1.1) in a 2:2 tetrameric complex (Yong et al., 2010). NAR2.1 has an N-terminal and a C-terminal TMS and has been annotated as a calcineurin-like phosphoesterase family member (Yong et al., 2010). Ntr transporters may also play a role in gaseous NO2 uptake by leaves (Hu et al. 2014). The Medicago truncatula orthologue has been characterized (Pellizzaro et al. 2014). An NRT2 homologue in wheat has been identifed and partially characterized (Kumar et al. 2022). Nitrate is the main form of inorganic nitrogen that crops absorb, and nitrate transporters 2 (NRT2) are high affinity nitrate uptake porters. When the available nitrate is limiting, the high affinity transport systems are activated. Most NRT2s cannot transport nitrates alone and require the assistance of helper proteins belonging to nitrate assimilation related family (NAR2; TC# 8.A.20.1.1) to complete the transport of nitrate (Zhao et al. 2023). Crop nitrogen utilization efficiency is affected by environmental conditions, and there are differences between different plant varieties. Sorghum bicolor has high stress tolerance and is efficient in soil nitrogen utilization. The S. bicolor genome database was scanned for gene structures, chromosomal localizations, physicochemical properties, secondary structures and transmembrane domains, signal peptides and subcellular localizations, promoter region cis-acting elements, phylogenetic evolution, SNP recognition and annotation, and selection pressure of gene family members (Zhao et al. 2023). Through bioinformatics analysis, 5 NRT2 gene members (designated as SbNRT2-1a, SbNRT2-1b, SbNRT2-2, SbNRT2-3, and SbNRT2-4) and 2 NAR2 gene members (designated SbNRT3-1 and SbNRT3-2) were identified, the number of which was less than that of foxtail millet. SbNRT2/3 could be divided into four subfamilies. All were present in the plasma membrane; SbNRT2 proteins lacked signal peptides, but SbNRT3 proteins contained them. Expression was responsive to plant hormones and stress response elements (Zhao et al. 2023). High-affinity nitrate transporters, SaNRT2.1 and SaNRT2.5, from the Euhalophyte Suaeda altissima have been characterized (Khramov et al. 2024). SaNRT2.1 was expressed in all organs; its expression was not influenced by nitrate supply, while SaNRT2.5 was expressed exclusively in roots; its expression rose about 10-fold under low nitrate. Salinity increased expression of both SaNRT2.1 and SaNRT2.5 under low nitrate (Khramov et al. 2024). |
Eukaryota | Viridiplantae, Streptophyta | NRT2.1 of Arabidopsis thaliana (O82811) |
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2.A.1.8.13 | High affinity nitrate/nitrite antiporter and uptake porter, NrtB (Unkles et al., 1991; 2011; Wang et al. 2008). |
Eukaryota | Fungi, Ascomycota | NrtB of Emericella (Aspergillus) nidulans (Q8X193) |
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2.A.1.8.14 | Nitrate/nitrite uptake porter, NapA (Wang et al., 2000) |
Bacteria | Cyanobacteriota | NapA of Trichodesmium sp. WH 9601 (Q9RA38) |
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2.A.1.8.15 |
Probable nitrate transporter NarT of 388 aas and 12 TMSs in a 6 + 6 TMS arrangement. In Corynebacterium pseudotuberculosis, an insertional mutation in the MFS transporter, NarT, may influence pathogenesis (Hiller et al. 2024).
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Bacteria | Bacillota | NarT of Staphylococcus carnosus |
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2.A.1.8.16 | MFS porter of 430 aas |
Bacteria | Pseudomonadota | MFS porter of Rhizobium loti |
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2.A.1.8.17 | Nitrate/nitrite transporter, NarK2, of 468 aas and 12 TMSs. The narK1 and narK2 genes are located in an operon, narK1K2GHJI, with the structural genes for the nitrate reductase complex. Utilizing an isogenic narK1 mutant, a narK2 mutant, and a narK1K2 double mutant, Sharma et al. 2006 explored the effect on growth under denitrifying conditions. While the ΔnarK1::Gm mutant was only slightly affected, but both the ΔnarK2::Gm and double mutants exhibited poor nitrate-dependent, anaerobic growth although all three strains had wild-type levels of nitrate reductase activity. Nitrate uptake measurements showed that NarK2 has most of the activity. E. coli narK rescued both mutants. |
Bacteria | Pseudomonadota | NarK2 of Pseudomonas aeruginosa |
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2.A.1.8.18 | NRT2.1 high affinity Na+-dependent nitrate uptake porter of 517 aas and 12 TMSs. It functions with the aoxillary protein, NAR2 (TC# 8.A.20.1.2) (Rubio et al. 2019). Functional characterization of the GhNRT2.1e gene revealed its role in improving nitrogen use efficiency in Gossypium hirsutum (Zhang et al. 2023). The high-affinity nitrate transporter 2 (NRT2) gene family proteins have been examined in response to phytohormones and abiotic stresses in alfalfa (Medicago sativa) (Luo and Nan 2024). |
Eukaryota | Viridiplantae, Streptophyta | NTR2.1 of Zostera marina |
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2.A.1.8.2 | Nitrate uptake porter |
Bacteria | Bacillota | NasA of Bacillus subtilis |
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2.A.1.8.3 | Nitrate/nitrite uptake porter |
Bacteria | Cyanobacteriota | NrtP of Synechococcus PCC7002 |
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2.A.1.8.4 | Nitrate transporter |
Eukaryota | Bacillariophyta | Nitrate porter of Cylindrotheca fusiformis |
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2.A.1.8.5 | Nitrate/nitrite transporter/antiporter, CrnA/NrtA (Unkles et al., 1991; Beckham et al. 2010). The nitrate signature sequences (NS1 and NS2) in TMSs 5 and 11 and arg residues in TMSs 2 and 8 may influence substrate binding (Unkles et al., 2012). |
Eukaryota | Fungi, Ascomycota | CrnA of Emericella nidulans |
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2.A.1.8.6 | Nitrate transporter |
Eukaryota | Viridiplantae, Chlorophyta | Nitrate porter of Chlamydomonas reinhardtii |
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2.A.1.8.7 |
High affinity Nitrate/nitrite uptake transporter, Nar4. |
Eukaryota | Viridiplantae, Chlorophyta |
Nar4 of Chlamydomonas reinhardtii (A8J4P3) |
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2.A.1.8.8 | NO2- extrusion, NO3-/NO2- exchange permease, NarK1 |
Bacteria | Deinococcota | NarK1 of Thermus thermophilus HB8 |
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2.A.1.8.9 | NO2- extrusion, NO3-/NO2- exchange permease, NarK2 |
Bacteria | Deinococcota | NarK2 of Thermus thermophilus HB8 |
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2.A.1.80.1 | Uncharacterized MFS permease of 515 aas |
Eukaryota | Rhodophyta | Putative peremease of Galdieria sulphuraria |
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2.A.1.80.2 | MFS_1 of 395 aas |
Bacteria | Myxococcota | MFS1 of Plesiocystis pacifica |
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2.A.1.80.3 | MFS_1 of 398 aas. |
Bacteria | Thermodesulfobacteriota | MFS_1 of Desulfobulbus propionicus |
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2.A.1.80.4 | MFS transporter of 410 aas. |
Bacteria | Pseudomonadota | MFS1 of Octadecabacter antarcticus |
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2.A.1.80.5 | MFS_1 of 401 aas |
Bacteria | Cyanobacteriota | MFS_1 of Crocosphaera watsonii |
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2.A.1.81.1 | The copper (Cu2+) uptake porter, CcoA of 405 aas and 12 TMSs. CcoA-mediated Cu2+ import relies on conserved Met and His residues that could act as metal ligands at the membrane-embedded Cu2+-binding domain (Khalfaoui-Hassani et al. 2016). It provides cytoplasmic Cu needed for cbb3-type cytochrome c oxidase (cbb3-Cox) biogenesis (Khalfaoui-Hassani et al. 2021). Residues important for and/or esstential for function have been identified. CcoA undergoes a thiol:disulfide oxidoreduction cycle, which is important for its Cu import activity (Khalfaoui-Hassani et al. 2021). |
Bacteria | Pseudomonadota | CcoA of Rhodobacter capsulatus |
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2.A.1.81.2 | Putative copper uptake porter, MFS_1 of 420 aas |
Bacteria | Chloroflexota | MFS_1 of Chloroflexus aggregans |
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2.A.1.81.3 | MFS permease of 403 aas. |
Bacteria | Actinomycetota | MFSA permease of Corynebacterium glutamicum |
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2.A.1.81.4 | MFS porter of 350 aas |
Archaea | Nitrososphaerota | MFS porter of Candidatus Caldiarchaeum subterraneum |
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2.A.1.81.5 | Riboflavin uptake transporter of 398 aas and 12 TMSs, RfnT (Gutiérrez-Preciado et al. 2015). |
Bacteria | Pseudomonadota | RfnT of Ochrobactrum anthropi |
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2.A.1.82.1 | The barley copper uptake porter, CT-1 of 749 aas; nearly identical to the wheat orthologue (Li et al. 2013). |
Eukaryota | Viridiplantae, Streptophyta | CT-1 of Hordeum vulgare (F2CRE4) |
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2.A.1.82.2 | The putative copper uptake porter, CT1, of 825 aas. The C-terminal domain of 300 aas is a DUF572 (COG5134) domain. |
Eukaryota | Viridiplantae, Chlorophyta | CT1 of Ostreococcus tauri (Q010B9) |
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2.A.1.82.3 | Synaptic vesicle 2-related protein (SV2-related protein), SVOP or SLC22B4. This protein localizes to neurotransmitter-containing vesicles and has a nucleotide binding site (Yao and Bajjalieh 2009). ATP, GTP, TTP, CTP and NAD biind, with the highest affinity for NAD, in contrast to SV2 (TC# 2.A.1.22.1), which binds both NAD and ATP with equal affinity. May transport nicotinate. |
Eukaryota | Metazoa, Chordata | Sv2p of Mus musculus |
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2.A.1.82.4 | Niacin uptake porter NiaP (Jeanguenin et al. 2012) |
Bacteria | Bacillota | YceI of Bacillus subtilis (O34691) |
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2.A.1.82.5 | Uncharacterized MFS protein of 460 aas |
Eukaryota | Viridiplantae, Chlorophyta | UP of Volvox carteri (Green alga) |
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2.A.1.82.6 | Synaptic vesicle 2-related protein, SVOPL, of 492 aas and 12 TMSs in a 6 + 1 + 5 TMS arrangement. Gene disruption gives rise to neurocognitive disabilities (Nilsson et al. 2017), and mutations can give rise to retinal dystrophies, hereditary blinding disorders (Patel et al. 2018). SVOPL is also a potential cell survival gene that undergoes allelic switching (Boot et al. 2019). |
Eukaryota | Metazoa, Chordata | SVOPL of Homo sapiens |
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2.A.1.83.1 | MFS porter; 1-arseno-3-phosphoglycerate (1As3PGA) exporter, ArsJ. Encoded in an operon concerned with arsenic resistance, encoding the enzymes and transporters of a new pathway of arsenic biotransformation. The adjacent gene encodes a 3-phosphoglycerate dehydrogenase homologue that probably forms the substrate of this MFS porter which could be expelled from the cell (Chen et al. 2016). |
Bacteria | Pseudomonadota | ArsJ of Aliivibrio (Vibrio) salmonicida |
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2.A.1.83.2 | Putative 1-arseno-3-phosphoglycerate exporter, MFS-83. |
Bacteria | Pseudomonadota | MFS-83 of Ferrimonas balearica |
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2.A.1.83.3 | Putative 1-arseno-3-phosphoglycerate exporter of 460 aas (see 2.A.1.83.1). |
Eukaryota | MFS-83 of Ectocarpus siliculosus (Brown alga |
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2.A.1.84.1 | Putative MFS permease of 467 aas and 12 TMSs |
Bacteria | Spirochaetota | MFS permease of Treponema denticola |
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2.A.1.84.2 | Uncharacterized protein of 435 aas and 12 TMSs. |
Bacteria | Actinomycetota | UP of Slackia heliotrinireducens (Peptococcus heliotrinreducens) |
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2.A.1.84.3 | Uncharacterized protein |
Bacteria | Actinomycetota | UP of Streptosporangium roseum |
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2.A.1.86.1 | MFS uptake permease. The gene is adjacent to a putative SAM-dependent methyl transferase, one homologue of which is a puromycin methyl transferase. Perhaps the transport substrate is a drug that is modified by methylation for detoxification purposes. This family is most closely, but distantly related to the AAHS family (2.A.1.15). |
Bacteria | Myxococcota | MFS uptake permease of Myxococcus xanthus |
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2.A.1.86.2 |
Fused protein with N-terminal transmembrane region of 7 putative TMSs and a C-terminal hydrophilic domain homologous to SAM-dependent spermidine synthase. The N-terminus of this protein shows extensive sequence similarity with 2.A.1.86.1 but shows weak similarity with other MFS permeases. |
Bacteria | Pseudomonadota | Fused protein of Thiocapsa marina |
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2.A.1.86.3 | Uncharacterized protein of 512 aas and 7 TMSs. |
Bacteria | Pseudomonadota | UP of Candidatus Thiodiazotropha endoloripes |
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2.A.1.86.4 | Uncharacterized putative S-adenosyl-L-methionine-dependent methyltransferase with a 7 TMS N-terminus (Pegg and Michael 2010). |
Bacteria | Pseudomonadota | UP of Magnetospirillum gryphiswaldense |
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2.A.1.86.5 | Polyamine aminopropyltransferase or spermidine synthase of 516 aas and 7 N-terminal TMSs. |
Bacteria | Pseudomonadota | SpeE of Comamonas testosteroni |
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2.A.1.86.6 | Putative MFS transporter, SVOPL or SLC22B5 (in humans), of 706 aas and 13 TMSs with two repeats of 6 TMSs with the 13th TMS being the extra one. |
Bacteria | Candidatus Tectomicrobia | MFS porter of Candidatus Entotheonella palauensis |
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2.A.1.86.7 | Uncharacterized protein of 212 aas and 6 TMSs. |
Bacteria | Pseudomonadota | UP of Legionella maceachernii (Tatlockia maceachernii) |
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2.A.1.86.8 | Uncharacterized protein of 688 aas and 14 TMSs in a 7 TMS + large hydrophilic domain + 7 more TMSs. |
Bacteria | Thermodesulfobacteriota | UP of Desulfosarcina alkanivorans |
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2.A.1.87.1 | Uncharacterized protein of 435 aas and 12 TMSs in a 6 + 6 arrangement. It most resembles 2.A.1.3.53, an azole resistance protein. Therefore, this protein might be a drug exporter. |
Bacteria | Actinomycetota | UP of Gardnerella vaginalis |
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2.A.1.87.2 | Uncharacterized MFS protein of 431 aas and 12 TMSs. |
Bacteria | Actinomycetota | UP of Arcanobacterium haemolyticum |
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2.A.1.87.3 | Uncharacterized MFS protein of 423 aas and 12 TMSs. |
Bacteria | Pseudomonadota | UP of Kushneria konosiri |
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2.A.1.88.1 | Uncharacterized protein of 434 aas and 12 TMSs. |
Archaea | Candidatus Lokiarchaeota | UP of Lokiarchaeum sp. |
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2.A.1.88.2 | Uncharacterized protein of 430 aas and 12 TMSs. |
Archaea | Candidatus Lokiarchaeota | UP of Lokiarchaeum sp. |
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2.A.1.89.1 | UP of 535 aas and 11 TMSs |
Archaea | Candidatus Lokiarchaeota | UP of Candidatus Lokiarchaeota archaeon CR_4 |
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2.A.1.89.2 | Uncharacteerized protein of 563 aas and 12 TMSs in a 6 + 6 TMS arrangement. |
Archaea | Candidatus Lokiarchaeota | UP of Candidatus Lokiarchaeota archaeon CR_4 |
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2.A.1.9.1 |
High affinity Pi uptake porter, SUL1, Sul-1, SFP2 of 859 aas and 10 TMSs. (also functions in Mn2+ homeostasis); may transport a phosphate·Mn2+ complex (Jensen et al., 2003). Also takes up selenite (Lazard et al., 2010). May be a "transceptor", combining transport and receptor functions (Diallinas 2017).
|
Eukaryota | Fungi, Ascomycota | Pho84 of Saccharomyces cerevisiae (P25297) |
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2.A.1.9.10 | High affinity (25 mμM) phosphate uptake porter, PiPT (Yadav et al. 2010). The high resolution structure has been determined by x-ray crystallography (Pedersen et al. 2013). |
Eukaryota | Fungi, Basidiomycota | PiPT of Piriformospora indica |
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2.A.1.9.11 | Phosphate transporter, PT, of 543 aas and 12 TMSs. It has a micormolar Km for phosphate uptake, is found in the plasma membrane and is induced by low medium phosphate concentrations (Wang et al. 2014). |
Eukaryota | Fungi, Basidiomycota | PT in the ectomycorrhizal fungus, Boletus edulis |
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2.A.1.9.12 | Phosphate transporter and receptor (transceptor) of 543 aas and 12 TMSs. Important for signalling and uptake of phosphate. The majority of terrestrial vascular plants can form mutualistic associations with obligate biotrophic arbuscular mycorrhizal (AM) fungi from the phylum Glomeromycota. This mutualistic symbiosis provides carbohydrates to the fungus, and reciprocally improves plant phosphate uptake. AM fungal transporters can acquire phosphate from the soil through the hyphal networks. Xie et al. 2016 reported a high-affinity phosphate transporter GigmPT that is required for AM symbiosis. GigmPT functions as a phosphate transceptor for the activation of the phosphate signaling pathway as well as the protein kinase A signaling cascade. |
Eukaryota | Fungi, Mucoromycota | PT of Gigaspora margarita |
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2.A.1.9.13 | High-affinity phosphate transporter of 511 aas and 12 TMSs, PHT1. It is root inducible by phosphate starvation but is not expressed in leaves (Ahmadi et al. 2018). |
Eukaryota | Viridiplantae, Streptophyta | PHT1 of Elaeis guineensis var. tenera (Oil palm) |
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2.A.1.9.14 | Pho84 inorganic phosphate transporter of 572 aas and 12 TMSs in a 6 + 6 TMS arrangement. Phosphate starvation upregulates the expression of the pho84 gene as well as varioius phosphatase genes (Innokentev et al. 2024). |
Eukaryota | Fungi, Ascomycota | Pho84 of Schizosaccharomyces pombe (fission yeast) |
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2.A.1.9.2 | Phosphate-repressible, high affinity Pi uptake porter, Pho84 or Pho-5 of 570 aas and 12 TMSs (Versaw 1995). |
Eukaryota | Fungi, Ascomycota | Pho-84 of Neurospora crassa (Q7RVX9) |
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2.A.1.9.3 | Pi uptake porter. Four close paralogues in Medicago truncatula (PT1-4), all localized to roots, show differing affinities for phosphate (Liu et al. 2008). |
Eukaryota | Viridiplantae, Streptophyta | PT1 of Solanum tuberosum |
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2.A.1.9.4 | Pht1;2(1;4) (PT2), a low affinity Pi uptake transporter, functioning throughout the plant (Ai et al., 2009) (76% identical to 2.A.1.9.3). |
Eukaryota | Viridiplantae, Streptophyta | Pht1;2(1;4) of Oryza sativa (Q01MW8) |
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2.A.1.9.5 | Pht1;6 (PT6), a high affinity Pi uptake transporter, functioning thoughout the plant (Ai et al., 2009) (75% identical to 2.A.1.9.3) |
Eukaryota | Viridiplantae, Streptophyta | Pht1;6 (PT6) of Oryza sativa (Q8H6H0) |
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2.A.1.9.6 | Phosphate transporter-5, PT5. Catalyzes phosphate:H+ symport (Liu et al., 2008). |
Eukaryota | Viridiplantae, Streptophyta | PT5 of Medicago truncatula (A5H2U6) |
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2.A.1.9.7 | Organic phosphate (glycerophosphoinositol and glycerophosphocholine, the products of phospholipase-B mediated deacylation of phosphatidylinositol and phosphatidylcholine, respectively) transport protein GIT1 (Almaguer et al. 2006). |
Eukaryota | Fungi, Ascomycota | GIT1 of Saccharomyces cerevisiae |
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2.A.1.9.8 | Putative inorganic phosphate transporter C23D3.12 | Eukaryota | Fungi, Ascomycota | SPAC23D3.12 of Schizosaccharomyces pombe | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.1.9.9 | Inorganic phosphate transporter 1-1 (AtPht1;1; APT2, PHT1) (H+/Pi cotransporter). A Brassica napus homologue, Pht1;4, catalyzes phosphate uptake and affects root architecture (Ren et al. 2014). The phylogeny and expression levels in plant tissues of the proteins of this family in potato have been examined (Liu et al. 2017). The chrysanthemum Pht1;2 is induced in the roots by phosphate starvation (Liu et al. 2018). It is induced by low inorganic phosphate in Spirodela polyrrhiza, a floating plant widely used in biomass utilization and eutrophication phytoremediation (Deng et al. 2021). There are five PHT families in A. thaliana, Pht1 - 5, not all of which are homologous; 57 PHTs are present in soybean (Glycine max), belonging to the PHT1 - 5 families with TC#s (1) 2.A.1.9, (2) 2.A.20, (3) 2.A.29, (4) 2.A.1.14 and (5) 2.A.1.2.61 (Wei et al. 2022). |
Eukaryota | Viridiplantae, Streptophyta | PHT1-1 of Arabidopsis thaliana |
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2.A.1.90.1 | MFS porter, MFR3, putative amino acid transporter of 579 aas and 12 TMSs in a 1 + 3 + 2 + 6 TMS arrangement (Wunderlich 2022). |
Eukaryota | Apicomplexa | MFR3 of Plasmodium falciparum |
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2.A.1.90.2 | Putative amino acid transporter, MFR2, of 711 aas and 12 TMSs in a 1 + 5 + 6 TMS arrangement (Wunderlich 2022). |
Eukaryota | Apicomplexa | MFR2 of Plasmodium falciparum |
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2.A.1.90.3 | MFS porter, MFR4 or ApiAT2, of 516 aas and 12 TMSs in a 1 + 5 + 6 TMS arrangement (Wunderlich 2022). |
Eukaryota | Apicomplexa | MFR4 of Plasmodium falciparum |
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2.A.1.90.4 | Putative amino acid transporter, MFR5 or ApiAT4 of 609 aas and 12 TMSs in a 1 + 5 + 6 TMS arrangement (Wunderlich 2022). |
Eukaryota | Apicomplexa | MFR5 of Plasmodium falciparum |
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2.A.1.90.5 | Uncharacterized MFS porter, NPT1 or ApiAT8, of 577 aas and 12 TMSs in a 1 + 5 + 6 TMS arrangement (Wunderlich 2022). |
Eukaryota | Apicomplexa | NPT1 of Plasmodium falciparum |
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2.A.1.91.1 | MFS porter of unknown function, P115, of 1283 aas and 12 TMSs in a 1 + 2 + 3 + 6 TMS arrangement (Wunderlich 2022). |
Eukaryota | Apicomplexa | P115 of Plasmodium falciparum |
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2.A.1.91.2 | Uncharacterized MFS domain-containing protein, P115, of 984 aas and 12 TMSs in a 1 + 2 + 3 + 6 TMS arrangement. |
Eukaryota | Apicomplexa | P115 of Plasmodium chabaudi chabaudi |
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2.A.1.91.4 | Plasmodium protein of 1061 aas and 10 = 12 TMSs in a 1 + 2 + 3 + 4 - 6 TMS arrangement. |
Eukaryota | Apicomplexa | Conserved protein of Plasmodium ovale curtisi |
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2.A.10.1.1 | 2-keto-3-deoxygluconate:proton symporter (Condemine and Robert-Baudouy 1987). |
Bacteria | Pseudomonadota | KdgT of Erwinia chrysanthemi |
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2.A.10.1.2 | 2-keto-3-deoxygluconate permease (KDG transporter), KdgT |
Bacteria | Pseudomonadota | KdgT of Escherichia coli |
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2.A.10.1.3 | Probable galacturonate uptake porter of 330 aas and 10 TMSs (Pujic et al. 1998). |
Bacteria | Bacillota | Probable galacturonate uptake porter of Bacillus subtilis |
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2.A.10.1.4 | KdgT homologue of 315 aas and 10 TMSs. |
Bacteria | Bacillota | KdgT homologue of Anaerococcus senegalensis |
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2.A.10.1.5 | N-terminal KdgT domain with 10 TMS and a C-terminal N-acetyl transferase (NAT) domain. 462 aas total. |
Bacteria | Bacillota | KdgT of Streptococcus pasteurianus |
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2.A.10.1.6 | Putative 2-keto-3-deoxygluconate:proton symporter of 320 aas and 10 TMSs. This protein shows significant sequence similarity to members of family 2.A.98 (the PSE Famiy). |
Bacteria | Actinomycetota | UP of Gardnerella vaginalis |
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2.A.100.1.1 | The iron exporter Ferroportin1 (Fnp1 or IREG1) |
Eukaryota | Metazoa, Chordata | Ferroportin (IREG1) of Mus musculus |
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2.A.100.1.2 | The probable chloroplast Fe transporter, Mar1 (Conte et al., 2009) |
Eukaryota | Viridiplantae, Streptophyta | Mar1 of Arabidopsis thaliana (Q8W4E7) |
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2.A.100.1.3 | Ferroportin1 or Iron-regulated protein1, 9FPN1, IREG1, ATIREG1; exports Fe2+, Co2+ and Ni2+ (Morrissey et al., 2009) |
Eukaryota | Viridiplantae, Streptophyta | FPN1 of Arabidopsis thaliana (O80905) |
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2.A.100.1.4 | Solute carrier family 40 member 1 (Ferroportin-1; FPN1, SLC40A1, FPN, IREG1, SLC11A3)) (Iron-regulated transporter 1). Transports iron, cobalt, zinc and manganese, magnesium, and maybe copper (Madejczyk and Ballatori 2012). Regulated by its inhibitor, the processed liver antimicrobial peptide, hepcidin (TC# 8.A.37.1.2). Tryptophan 42, a hemochromatosis type 4 disease residue, plays a role in iron export and iron homeostasis as well as hepcidin binding (Le Gac et al. 2013). This protein has been modeled using the MSF EmrD of E. coli (TC# 2.A.1.2.9) (Le Gac et al. 2013). Defects can be corrected by adding the small molecule, hinokitiol (Cioffi et al. 2015; Grillo et al. 2017). The R178Q mutation is a recurrent cause of hemochromatosis and is associated with a novel pathogenic mechanism (Ka et al. 2018). The function of the "gating residues" in the mechanism of iron export have been modeled and studied (Guellec et al. 2019). Optimal conditions for Western blotting for this and other proteins requires that the sample not be boiled (Tsuji 2020). Ferroptosis resists intracellular Vibrio splendidus AJ01 mediated by ferroportin in sea cucumber Apostichopus japonicus (Wang et al. 2024). Alternative splicing generates a novel ferroportin isoform with a shorter C-terminal and intact iron- and hepcidin-binding properties (Juneja et al. 2024). Dual loss and gain of function of the FPN1 iron exporter results in the ferroportin disease phenotype (Uguen et al. 2024).
|
Eukaryota | Metazoa, Chordata | FPN1 or SLC40A1 of Homo sapiens |
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2.A.100.1.5 | Ferroportin of 565 aas and 12 TMSs. |
Eukaryota | Viridiplantae, Chlorophyta | Fpn of Chlorella variabilis (Green alga) |
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2.A.100.1.6 | Uncharacterized ferroportin homolog of 560 aas and 14 TMSs, with two extra TMSs between the two 6 TMS repeat units. |
Eukaryota | Oomycota | UP of Peronospora effusa |
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2.A.100.1.7 | Ferroportin1 (Fpn1) of 562 aas and 12 TMSs (Rafiee et al. 2012). Missense mutations in Fpn1, an intestinal and macrophage iron exporter, have been identified between TMSs 3 and 4 in the zebrafish anemia mutant weissherbst (weh(Tp85c-/-)) and in patients with type 4 hemochromatosis. Thus, ferroportin1 is required for normal iron cycling in both humans and zebrafish (Fraenkel et al. 2005). |
Eukaryota | Metazoa, Chordata | Fpn of Danio rerio (zebrafish) |
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2.A.100.2.1 | Ferroportin of 440 aas and 12 TMSs. Transports Fe2+, Co2+, Mn2+ and Ni2+. The 3-d structures in both the inward and outward facing orientations have been determined, showing similarities to those of MFS permeases (Taniguchi et al. 2015). The Fpn family is a member of the MFS. Fpn-mediated iron efflux is stimulated by extracellular Ca2+ in the physiological range, even though Ca2+ is not transported. Deshpande et al. 2018 determined the crystal structure of Ca2+-bound BbFpn (TC# 2.A.100.2.1), and found that Ca2+ is a cofactor that facilitates a conformational change critical to the transport cycle. They also identified a substrate pocket accommodating a divalent transition metal complexed with a chelator. These findings support a model of iron export by Fpn and suggest a link between plasma calcium and iron homeostasis (Deshpande et al. 2018). |
Bacteria | Bdellovibrionota | Ferroportin of Bdellovibrio bacteriovorus |
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2.A.100.2.2 | Uncharacterized Ferroporin homologue of 592 aas and 12 putative TMSs. |
Eukaryota | Evosea | UP of Acytostelium subglobosum |
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2.A.101.1.1 | Putative transporter, FkbF |
Bacteria | Actinomycetota | FkbF of Streptomyces hygroscopicus var. ascomyceticus (Q9KIE8) |
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2.A.101.1.2 | The putative malonate uptake porter, MatC (An and Kim, 1998) (distantly related to members of the DASS family (2.A.47)) |
Bacteria | Pseudomonadota | MatC of Rhizobium leguminosarum bv trifolii (C6B3K0) |
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2.A.102.1.1 | The putative 4-toluenesulfonate uptake permease, TsaS |
Bacteria | Pseudomonadota | TsaS of Comamonas testosteroni (Q6A553) |
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2.A.102.2.1 | Sulfolactate (sulfite/organosulfonate) exporter,TauE of 256 aas with 8 TMSs in a 4 + 4 TMS arrangement. Catalyzes export of sulfolactate as the terminal step in the metabolism of cysteate (Weinitschke et al. 2007; Mayer et al. 2012). |
Bacteria | Pseudomonadota | TauE of Cupriavidus necator (Ralstonia eutropha) (Q0K020) |
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2.A.102.2.10 | Uncharacterized protein of 250 aas nad 6 TMSs. |
Bacteria | Actinomycetota | UP of Arthrobacter crystallopoietes |
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2.A.102.2.11 | Putative sulfite exporter, the TauE/SafE family protein of 241 aas and 7 or 8 TMSs with a probable 4 + 4 TMS arrangement. |
Bacteria | Actinomycetota | TauE homolog of Adlercreutzia sp. |
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2.A.102.2.12 | TauE/SafE family of putative sulfite exporters. |
Bacteria | Aquificota | TauE homolog of Hydrogenobaculum sp. (metagenome) |
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2.A.102.2.2 | The SafE1 sulfoacetate efflux pump (Krejcík et al., 2008). |
Bacteria | Pseudomonadota | SafE of Neptuniibacter caesariensis (Q2BM66) |
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2.A.102.2.3 | Transporter of unknown function |
Bacteria | Planctomycetota | Uncharacterized permease of Rhodopirellula baltica |
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2.A.102.2.4 | Uncharacterized protein |
Bacteria | Pseudomonadota | Uncharacterized protein of Rhodopseudomonas palustris |
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2.A.102.2.5 | Uncharacterized protein |
Bacteria | Actinomycetota | Uncharacterized protein of Streptomyces coelicolor |
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2.A.102.2.6 | Putative sulfite exporter, TauE or SafE, of 347 aas and 7 - 8 TMSs. |
Bacteria | Spirochaetota | SafE of Leptospira kmetyi |
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2.A.102.2.7 | Uncharacterized protein of 240 aas |
Bacteria | Actinomycetota | UP of Mycobacterium smegmatis |
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2.A.102.2.8 | Uncharacterized protein of 245 aas |
Bacteria | Pseudomonadota | UP of Achromobacter xylosoxidans |
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2.A.102.2.9 | Uncharacterized protein of 291 aas and 8 TMSs. A member of the TSUP or TauE/SafE family. |
Bacteria | Pseudomonadota | UP of E. coli |
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2.A.102.3.1 | Orf of 269 aas and 6 TMSs |
Bacteria | Pseudomonadota | YfcA of E. coli (P0AD30) |
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2.A.102.3.2 | Uncharacterized protein of 253 aas and 8 TMSs |
Bacteria | Actinomycetota | UP of Gordonia amicalis |
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2.A.102.3.3 | Uncharacterized protein of 251 aas and 6 TMSs (Hug et al. 2016). |
Bacteria | Candidatus Peregrinibacteria | UP of Candidatus Peribacter riflensis |
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2.A.102.3.4 | Glycine transporter, YfcA, of 269 aas and 9 TMSs (Deutschbauer et al. 2011). |
Bacteria | Pseudomonadota | YfcA of Shewanella oneidensis |
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2.A.102.4.1 | Orf of 253aas and 8 TMSs |
Archaea | Euryarchaeota | Orf of Pyrococcus abyssi (Q9UYH7) |
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2.A.102.4.10 | Uncharacterized protein of 671 aas and 9 TMSs. TMS1 is N-terminal, followed by a peptidase domain of 350 aas, followed by a transmembrane domain with 8 putative TMSs, homologous to other members of this family. |
Bacteria | Pseudomonadota | UP of Magnetococcus sp. |
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2.A.102.4.11 | Putative permease of 259 aas and 8 TMSs |
Bacteria | Bdellovibrionota | PP of Bdellovibrio bacteriovorus |
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2.A.102.4.12 | Uncharacterized protein of 245 aas and 8 TMSs. |
Bacteria | Bacillota | UP of Lactobacillus rhamnosus |
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2.A.102.4.13 | Acetate transporter of 266 aas and 8 TMSs, SO_1333 (Deutschbauer et al. 2011). |
Bacteria | Pseudomonadota | SO_1333 of Shewanella oneidensis |
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2.A.102.4.14 | Uncharacterized membrane protein of 339 aas and 10 TMSs. The gene encoding this protein is adjacent to the ABC exporter with TC# 3.A.1.148.1. |
Bacteria | Actinomycetota | UP of Microbispora sp. ATCC PTA-5024 |
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2.A.102.4.15 | Uncharacterized protein of 270 aas and 8 TMSs. |
Archaea | Candidatus Bathyarchaeota | UP of candidatus Bathyarchaeota archaeon (marine sediment metagenome) |
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2.A.102.4.2 | Possible organo-sulfur-containing compound transporter (Gristwood et al., 2011) (271aas; 8 TMSs; duplicated). May function with two 4 TMS proteins, PmpA and PmpB of the YedE/YeeE family (TC#9.B.102). |
Bacteria | Pseudomonadota | PmpC of Serratia sp. (E7BBJ3) |
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2.A.102.4.3 | Hypothetical protein |
Archaea | Euryarchaeota | HP of Methanococcus maripaludis |
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2.A.102.4.4 | Hypothetical protein |
Bacteria | Bacillota | HP of Streptococcus pneumoniae |
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2.A.102.4.5 | Putative sulfite exporter of 304 aas and 9 TMSs, TauE/SafE. |
Bacteria | Pseudomonadota | TauE homologue of Thalassiobium sp. |
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2.A.102.4.6 | Uncharacterized protein of the TauE family of 380 aas and 8 TMSs. |
Bacteria | Pseudomonadota | TauE homologue of Bradyrhizobium japonicum |
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2.A.102.4.7 | DUF81 protein of 330 aas and 8 TMSs |
Archaea | Euryarchaeota | DUF81 protein of Halobacterium salinarum |
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2.A.102.4.8 | The putative sulfate transporter, CysZ (Rückert et al., 2005). |
Bacteria | Actinomycetota | CysZ of Corynebacterium glutamicum (Q8NLX4) |
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2.A.102.4.9 | TauE (DUF81) homologue of 322 aas and 9 putative TMSs |
Eukaryota | Rhodophyta | TauE homologue of Galdieria sulphuraria |
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2.A.102.5.1 | Orf of 590 aas and 12 TMSs |
Eukaryota | Viridiplantae, Streptophyta | Orf of Oryza sativa (Q5ZAL4) |
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2.A.102.5.2 | Uncharacterized protein of 480 aas and 8 TMSs. |
Eukaryota | Viridiplantae, Streptophyta | UP of Marchantia polymorpha |
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2.A.102.5.3 | Uncharacterized protein of 10 - 12 TMSs in a 3 - 5 + 2 + 5 TMS arrangement. |
Eukaryota | Fornicata | UP of Giardia intestinalis |
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2.A.102.5.4 | Putative sulfite exporter,TauE/SafE family protein, of 476 aas and 10 TMSs. |
Eukaryota | Viridiplantae, Streptophyta | TauE homolog of Arabidopsis thaliana |
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2.A.102.6.1 | Putative permease of 208 aas and 6 TMSs |
Bacteria | Pseudomonadota | Putative permease of Methylococcaceae bacterium HT3 |
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2.A.102.6.2 | Uncharacterized protein of 174 aas and 4 TMSs |
Eukaryota | Metazoa, Nematoda | UP of Strongylus vulgaris |
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2.A.102.6.3 | Putative sulfite exporter TauE/SafE family protein of 333 aas and 11 TM |
Bacteria | Thermodesulfobacteriota | TauE homologue of Desulfobacterium autotrophicum |
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2.A.102.7.1 | Putative sulfite exporter TauE/SafE family protein of 331 aas and 9 TMSs. |
Bacteria | Pseudomonadota | TauE homolog of Candidatus Filomicrobium marinum |
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2.A.102.7.2 | Uncharacterized protein of 318 aas and 9 TMSs. |
Pseudomonadota | UP of Pseudomaricurvus alcaniphilus |
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2.A.102.7.3 | Putative sulfite exporter TauE/SafE family protein of 307 aas and 9 TM |
Bacteria | Chloroflexota | TauE homologue of Litorilinea aerophila |
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2.A.103.1.1 | Cell division protein, FtsW. May flip lipid II (involved in cell wall synthesis) across the cytoplasmic membrane. R145 and K153 in TMS 4 (of 10) are esesential for this transport activity (Mohammadi et al. 2014). There is some controversy about this transport function (Young 2014; Sham et al. 2014). See TC#2.A.66.4.3 for the alternative explanation. |
Bacteria | Pseudomonadota | FtsW of E. coli (P0ABG4) |
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2.A.103.1.10 | Rod shape-determining protein Rod, of 424 aas and 10 TMSs. |
Bacteria | Bacteroidota | RodA of Lacinutrix venerupis |
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2.A.103.1.11 | Uncharacterized protein of 423 aas and 10 TMSs |
Bacteria | Bacillota | UP of Bacillus marisflavi |
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2.A.103.1.12 | FtsW/RodA/SpoVE family cell cycle protein of 439 aas and 10 TM |
Bacteria | Bacillota | FtsW of Anaerobacillus alkalidiazotrophicus |
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2.A.103.1.2 |
Rod shape determining protein, RodA. A proposed flippase for a lipid-linked disaccharide-pentapeptide cell wall precursor, but this proposal is controversial (Sham et al. 2014; Young 2014). |
Bacteria | Pseudomonadota | RodA of E. coli (P0ABG7) |
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2.A.103.1.3 |
Sporulation protein, SpoVE. |
Bacteria | Bacillota | SpoVE of Bacillus subtilis (P07373) |
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2.A.103.1.4 | FtsW of 524 aas |
Bacteria | Actinomycetota | FtsW of Mycobacterium tuberculosis |
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2.A.103.1.5 | FtsW of 361 aas |
Bacteria | Aquificota | FtsW of Hydrogenobacter thermophilus |
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2.A.103.1.6 | FtsW of 385 aas |
Bacteria | Thermotogota | FtsW of Marinitoga piezophila |
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2.A.103.1.7 | FtsW of 448 aas and 123 TMSs |
Bacteria | Actinomycetota | FtsW of Tropheryma whipplei (strain Twist) (Whipple's bacillus) |
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2.A.103.1.8 | Cell shape-determining protein, MrdB, of 379 aas |
Bacteria | Chlamydiota | MrdB of Chlamydophila psittaci (Chlamydia psittaci) |
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2.A.103.1.9 | Lipid flippase involved in cell envelope biogenesis, FtsW, of 456 aas and 10 TMSs (Bush et al. 2015). |
Bacteria | Actinomycetota | FtsW of Streptomyces coelicolor |
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2.A.104.1.1 | The L-alanine exporter, AlaE (YgaW) of 149 aas and 4 TMSs. (In the DUF1144 or PF06610 superfamily) (Hori et al., 2011). Two charged residues are essential for it's efflux activity (Kim et al. 2016). AlaE is the physiologically most relevant exporter for L-alanine in E. coli. AlaE forms homo-oligomers, and the GxxxG motif in the TMS4 region plays an essential role in AlaE activity but not in AlaE oligomer formation (Ihara et al. 2022). |
Bacteria | Pseudomonadota | AlaE of E. coli (A8ANM6) |
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2.A.104.1.2 | AlaE homologue of 149aas and 4 TMSs. There is a duplicated 2 TMS repeat unit, and immediately following both TMSs 2 and 4, there is a conserved motif, RPYG-W found in both halves of the protein at residue numbers 55 and 122 respectively. Thus, AlaE homologues arose by an intergenic duplication event. |
Bacteria | Pseudomonadota | AlaE homologue of Pelagibacterium halotolerans (G4R961) |
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2.A.104.2.1 | Hypothetical protein (77aas; 2 TMSs). Resembles residues 72-149 (second half) of AlaE. Could be a fragment of the full length protein. |
Archaea | Thermoproteota | HP of an uncultured crenarchaeote (H5SVY7) |
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2.A.104.3.1 | AlaE homologue of 159 aas and 3 or 4 TMSs (KKS95321.1) |
Bacteria | Candidatus Giovannonibacteria | AlaE of Parcubacteria (Giovannonibacteria) bacterium (KKS95321.1) |
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2.A.104.3.2 | AlaE homologue of 150 aas and 4 TMSs (KKP64473.1). |
Bacteria | Candidatus Nomurabacteria | AlaE of Parcubacteria (Nomurabacteria) bacterium GW2011_GWF2_35_12 |
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2.A.105.1.1 | Mitochondrial pyruvate carrier, MPC1/2/3 (MPC1: 130 aas and probably 3 TMSs; MPC2: 129 aas and 3 TMSs; MPC3: 146 aas and 3 TMSs) (Bricker et al., 2012; Herzig et al., 2012). Yeast MPC proteins with 3 TMSs and a matrix-exposed N-terminus are imported by the carrier pathway, using the receptor Tom70, small TIM chaperones, and the TIM22 complex (Rampelt et al. 2020). The TIM9.10 complex chaperones MPC proteins through the mitochondrial intermembrane space using conserved hydrophobic motifs that are also required for the interaction with canonical carrier proteins. Thus, the carrier pathway can import paired and non-paired TMSs and translocate N-termini to either side of the mitochondrial inner membrane, revealing an unexpected versatility of the mitochondrial import pathway for non-cleavable inner membrane proteins (Rampelt et al. 2020). MPC transporters have been reviewed (Cunningham and Rutter 2020). |
Eukaryota | Fungi, Ascomycota | MPC1/2/3 of Saccharomyces cerevisiae |
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2.A.105.1.10 | MPC homologue of 268 aas and 6 - 8 TMSs. |
Eukaryota | MPC homologue of Aureococcus anophagefferens (Harmful bloom alga) |
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2.A.105.1.11 | MPC homologue of 319 aas and 6 - 8 TMSs. |
Eukaryota | Oomycota | MPC homologue of Phytophthora sojae (Soybean stem and root rot agent) (Phytophthora megasperma) |
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2.A.105.1.12 | MPC homologue of 189 aas and 3 - 4 TMSs. |
Eukaryota | Fungi, Ascomycota | MPC homologue of Uncinocarpus reesii |
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2.A.105.1.13 | Mitochondrial pyruvate carrier 1-like, MPC1L (SLC54A3) of 1136 aas and probably 3 TMSs. |
Eukaryota | Metazoa, Chordata | MPC1L of Homo sapiens |
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2.A.105.1.14 | Mitochondrial pyruvate carrier, MPC, of 106 aas and 3 TMSs. |
Eukaryota | Apicomplexa | MPC of Plasmodium falciparum |
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2.A.105.1.15 | Mitochondrial pyruvate carrier, MPC2, of 129 aas and 3 TMSs |
Eukaryota | Apicomplexa | MPC2 of Plasmodium falciparum |
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2.A.105.1.2 | Mitochondrial pyruvate carrier, MPC1/2, SLC4A1/SLC4A2 (Gyimesi and Hediger 2022): (MPC1: 109aas; 2-3 TMSs; MPC2: 127aas; 3 TMSs) (Bricker et al., 2012; Herzig et al., 2012). Aceylation of lys19 and lys26 in MPC2 decreases activity of this transporter. Deficient pyruvate transport activity, mediated in part by acetylation of MPC2, is a contributor to metabolic inflexibility in the diabetic heart (Vadvalkar et al. 2017). Both subunits (MPC1 and 2) contain three TMSs with substantial differences from what was predicted by AlphaFold2 (Li et al. 2022). MPC1,2 and 3 localize tp mitochondrial outer membrane to mediate the transport of pyruvate from the cytosol to mitochondria (Zhao et al. 2024). Mitochondrial pyruvate carrier 1 is a prognostic biomarker in non-small cell lung cancer (Zou et al. 2024). A novel HMGA2/MPC-1/mTOR signaling pathway promotes cell growth via facilitating Cr(VI)-induced glycolysis (Zhao et al. 2024). |
Eukaryota | Metazoa, Chordata | MPC1/2 of Homo sapiens |
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2.A.105.1.3 | Mitochondrial pyruvate carrier (MPC1/2) (MPC1: 107aas; 3 TMSs; MPC2: 154aas; 3 TMSs) (Bricker et al., 2012). |
Eukaryota | Metazoa, Arthropoda | MPC1/2 of Drosophila melanogaster |
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2.A.105.1.4 | MPC1/2 (MPC1: 146aas; 4 TMSs; MPC2: 108aas; 3 TMSs; MPC3?: 110aas; 2-3 TMSs) |
Eukaryota | Viridiplantae, Streptophyta | MPC1/2 of Arabidopsis thaliana |
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2.A.105.1.5 | MPC (117aas; 3 TMSs) |
Eukaryota | Ciliophora | MPC of Paramecium tetraurelia (A0CVJ5) |
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2.A.105.1.6 | MPC (97aas; 3 TMSs) |
Eukaryota | Apicomplexa | MPC of Theileria parva (Q4N4U8) |
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2.A.105.1.7 | MPC (140aas; 3 TMSs) |
Eukaryota | Euglenozoa | MPC of Leishmania braziliensis (A4H7W6) |
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2.A.105.1.8 | MPC homologue of 267 aas and 5 - 8 TMSs. |
Eukaryota | Perkinsozoa | MPC homologue of Perkinsus marinus |
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2.A.105.1.9 | MPC homologue of 349 aas and 8 putative TMSs |
Eukaryota | Perkinsozoa | MPC homologue of Perkinsus marinus |
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2.A.106.1.1 | The Y615 protein | Bacteria | Cyanobacteriota | Y615 of Synechocystis PCC6803 |
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2.A.106.1.2 | Uncharacterized protein of 194 aas and 6 TMSs with two 3-TMS repeats. |
Bacteria | Actinomycetota | UP of Streptomyces griseus |
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2.A.106.1.3 | Uncharacterized protein of 213 aas and 6 TMSs |
Bacteria | Chlorobiota | UP of Chlorobium chlorochromatii |
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2.A.106.1.4 | Uncharacterized protein of 192 aas probably with 6 TMSs in a 3 + 3 TMS repeat unit. |
Bacteria | Pseudomonadota | UP of Acidovorax ebreus |
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2.A.106.1.5 | Chloroplast thylakoid GDT-1-like protein or photosynthesis-affected protein-71, PAM71 or CCHA1 of 370 aas with 6 TMSs in a 3 + 3 TMS arrangement. It takes up Mn2+ and influences both Mn2+ and Ca2+ homeostasis in the chloroplast. It is necessary for photosystem II function due to its Mn2+ uptake activity (Schneider et al. 2016; Hoecker et al. 2017). It is an Mn2+/H+ exchanger, which transport Mn2+ from the chloroplast stroma into the acidic thylakoid lumen (Schneider et al. 2016). It might be a chloroplast-localized Ca2+/H+ antiporter as well (Wang et al. 2016) since it regulates Ca2+, Mn2+ and pH homeostasis and is required for chloroplast development. |
Eukaryota | Viridiplantae, Streptophyta | PAM71 orCCHA1 of Arabidopsis thaliana |
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2.A.106.1.6 | Manganese (Mn2+):proton exchanger, CGLD1, of 340 aas (Schneider et al. 2016; ). |
Eukaryota | Viridiplantae, Chlorophyta | CGLD1 of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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2.A.106.1.7 | Photosynthesis-affected mutant 71, PAM71 homologue, PAM71-HL, of 359 aas and 7 TMSs (Hoecker et al. 2017). Probably a manganese ion transporter; a member of the UPF0016 family. |
Eukaryota | Viridiplantae, Streptophyta | PAM71-HL of Arabidopsis thaliana (Mouse-ear cress) |
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2.A.106.1.8 | Putative DL-lactate uptake porter of 184 aas and 6 - 7 TMSs (Deutschbauer et al. 2011). |
Bacteria | Pseudomonadota | SO_1071 of Shewanella oneidensis |
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2.A.106.2.1 | The PFT27 protein of 323 aas with 7 putative TMSs in a 1 + 3 + 3 TMS arrangement, in which the 3 TMS unit is possibly a repeat seqence. |
Eukaryota | Metazoa, Chordata | PFT27 of Mus musculus |
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2.A.106.2.2 | Ca2+/Mn2+/Mg2+:H+ antiporter, TMEM165 (PT27; TPARL; SLC64A1) of 324 aas and 7 TMSs in a 1 (N-terminal) + 3 + 3 TMS arrangement (Demaegd et al. 2013). It may be both a Ca2+:H+ and a Mn2+:H+ antiporter (Dulary et al. 2016; Stribny et al. 2020), catalyzing uptake of Mn2+ from the cytoplasm into the golgi lumen. TMEM165 has been linked to congenital disorders of glycosylation (CDG) (Foulquier et al. 2012). It may influence glycosylation due to its Mn2+ transport activity that regulates Mn2+ homeostasis in the golgi (Thines et al. 2018). TMEM165 is also required for milk production (Snyder et al. 2019). In humans, both Ca2+ and Mn2+ are required for proper protein glycosylation in cells (Stribny et al. 2020). TMEM165, a Golgi transmembrane protein, is a novel marker for hepatocellular carcinoma, and its depletion impairs invasion activity (Lee et al. 2018). The pathogenicity of TMEM165 variants using structural modeling based on AlphaFold 2 predictions has been presented (Legrand et al. 2023). Mutations in the gene encoding TMEM165 are a cause of a new type of congenital disorder of glycosylation (CDG) (Jankauskas et al. 2024). Comprehensive studies of TMEM165 in different model systems, including mammals, yeast, and fish uncovered the new realm of Mn2+ homeostasis regulation. TMEM165 was shown to act as a Ca2+/Mn2+:H+ antiporter in the medial- and trans-Golgi network, pumping the metal ions into the Golgi lumen and protons outside. Disruption of TMEM165 antiporter activity results in defects in N- and O-glycosylation of proteins and glycosylation of lipids. Impaired glycosylation of TMEM165-CDG arises from a lack of Mn2+ within the Golgi. Nevertheless, Mn2+ insufficiency in the Golgi is compensated by the activity of the ATPase SERCA2. TMEM165 turnover has also been found to be regulated by the Mn2+ cytosolic concentration. Besides causing CDG, the functional involvement of TMEM165 in several other pathologies including cancer and mental health disorders has been described. This systematic review summarizes the available information on TMEM165 molecular structure, cellular function, and its roles in health and disease (Jankauskas et al. 2024). It may catalyze Ca2+ import into lysosomes (Zhang et al. 2025). |
Eukaryota | Metazoa, Chordata | TMEM165 of Homo sapiens (Q9HC07) |
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2.A.106.2.3 | Golgi Ca2+:H+ and Mn2+:H+ antiporter, Gdt1 (GCR-1-dependent translation factor 1) or TMEM165 (Demaegd et al., 2013). Involved in ion homeostasis (Dulary et al. 2016), specifically Mn2+ homeostasis (Thines et al. 2018). |
Eukaryota | Fungi, Ascomycota | Gdt1 of Saccharomyces cerevisiae (P38301) |
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2.A.106.2.4 | The YD68 protein | Eukaryota | Fungi, Ascomycota | YD68 of Schizosaccharomyces pombe | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.106.2.5 | Golgi Ca2+ ion homeostasis protein, TM protein PFT27, of 515 aas and 8 putative TMSs in a 2 (N-terminal) + 3 (middle) + 3 (C-terminal) TMSs. |
Eukaryota | Fungi, Ascomycota | Transmembrane protein PFT27 of Pyrenophora tritici-repentis (Wheat tan spot fungus) (Drechslera tritici-repentis) |
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2.A.106.3.1 | 3 TMS homologue of 89 aas |
Bacteria | Spirochaetota | 3 TMS homologue of Leptonema illini |
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2.A.106.3.2 | 3 TMS homologue of 90 aas |
Bacteria | Bdellovibrionota | 3 TMS homologue of Bdellovibrio bacteriovorus |
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2.A.106.4.1 | Uncharacterized protein of 235 aas |
Archaea | Euryarchaeota | UP of Haloarcula japonica |
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2.A.107.1.1 | The manganese ion efflux pump, MntP (YebN). Regulated by the MntR regulatory protein and the MntS sRNA (Waters et al., 2011). This family has been designated the DUF204 family. |
Bacteria | Pseudomonadota | YebN of E. coli |
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2.A.107.1.2 | The Mth1812 of 184 aas and 6 TMSs. |
Archaea | Euryarchaeota | Mth1812 of Methanobacterium thermoautotrophicum |
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2.A.107.1.3 | DUF204 homologue |
Bacteria | Bacillota | DUF204 homologue of Halobacillus halophilus |
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2.A.107.1.4 | A manganese efflux pump of 184 aas and 6 TMSs. |
Bacteria | Bacillota | Mn2+ exporter of Bacillus altitudinis |
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2.A.107.1.5 | A manganese efflux pumpof 185 aas and 6 TMSs. |
Bacteria | Bacillota | Mn2+ exporter of Bacillus subtilis |
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2.A.107.2.1 | Hypothetical protein of 188 aas |
Bacteria | Bacillota | HP of Halanaerobium hydrogeniformans |
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2.A.107.3.1 | Membrane protein of 210 aas |
Bacteria | Bacillota | Membrane protein of Bacillus subtilis |
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2.A.108.1.1 | High-affinity oxidase-dependent plasma membrane Fe2+-Fe3+ uptake transporter, Ftr1 of 404 aas and 7 TMSs in a 3 + 3 + 1 TMS arrangement with the N-terminus out and the C-termius in (Severance et al. 2004). There are two REXLE (Arg-Glu-Xaa-Leu-Glu) motifs in transmembrane domains 1 and 4, both essential for transport activity, implying the presence of a 3 TMS repeat ((Severance et al. 2004)). Ftr1 may be a "transceptor", combining transport and receptor functions (Diallinas 2017). Bacterial redox-dependent iron transporters with an emphasis on FtrABCD have been reviewed (Banerjee et al. 2022). |
Eukaryota | Fungi, Ascomycota | Fet3 and Ftr1 of Saccharomyces cerevisiae |
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2.A.108.1.2 | Iron-repressible Fe2+ uptake porter, FTR1 (Ziegler et al. 2011) |
Eukaryota | Fungi, Ascomycota | Ftr1 of Candida albicans |
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2.A.108.1.3 | Iron-inducible Fe2+ uptake porter, FTR2 | Eukaryota | Fungi, Ascomycota | Ftr2 of Candida albicans | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.108.1.4 | High-affinity oxidase-dependent vacuolar Fe2+-Fe3+ uptake transporter (Singh et al. 2006) |
Eukaryota | Fungi, Ascomycota | Fet5p and Fth1p of Saccharomyces cerevisiae |
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2.A.108.1.5 | High-affinity oxidase-dependent plasma membrane Fe2+-Fe3+ uptake transporter, Fio1/Fip1 (Frp1) (Singh et al., 2006). Metalloreductase responsible for reducing extracellular iron and copper prior to import. It catalyzes the reductive uptake of Fe3+-salts and Fe3+ bound to catecholate or hydroxamate siderophores. Fe3+ is reduced to Fe2+, which then dissociates from the siderophore and can be imported by the high-affinity Fe2+ transport complex in the plasma membrane. Fio1 is a multicopper oxidase that contains three cupredoxin domains with eleven candidate iron-binding ligands, whereas Frp1 harbors a ferric reductase domain with three-candidate heme-binding ligands. The complex also participates in Cu2+ reduction and Cu+ uptake (Ahmad et al. 2022). |
Eukaryota | Fungi, Ascomycota | Fio1 and Fip1 of Schizosaccharomyces pombe |
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2.A.108.1.6 | Iron transporter, Ftr1 (541 aas) (La Fontaine et al., 2002). FTR1, like its orthologue in S. cerevisiae (9.A.10.1.1), has an exocytoplasmic iron channeling motif and two potential iron permeation motifs in membrane-spanning regions (Terzulli and Kosman 2010). |
Eukaryota | Viridiplantae, Chlorophyta | Ftr1 of Chlamydomonas reinhardtii (AAM45938) |
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2.A.108.1.7 | The Ftr1/Fet3 high-affinity iron uptake system (Larrondo et al., 2007) | Eukaryota | Fungi | Ftr1/Fet3 of Phanerochaete chrysosporium Ftr1 (Q1P9T0) Fet3 (Q1P9T1) |
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2.A.108.1.8 | High affinity iron permease, CaFtr1 (Jung et al. 2008) |
Eukaryota | Fungi, Basidiomycota | CaFtr1 of Cryptococcus neoformans (Q5KJQ5) |
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2.A.108.2.1 | The lead (Pb2+) uptake porter, PbrT | Bacteria | Pseudomonadota | PbrT of Ralstonia metallidurans CH34 (gbCAC28871) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.108.2.10 | Dipartite iron uptake system, FetM (646 aas; 8 TMSs in a 1 + 7 TMS arrangement)/FetP (a periplasmic protein that enhances iron uptake by FetM) (Koch et al. 2011). FetP binds Cu2+ and Mn2+ at two different sites, 1.3 Å apart, in this homodimeric protein, and the 3-d structure with Cu2+ bound to each of the two subunits reveals different geometries at the two sites. FetMP may be an iron permease with an iron scavenging function, and possibly also an iron reducing function (Koch et al. 2011). |
Bacteria | Pseudomonadota | FetMP of E. coli |
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2.A.108.2.11 | Putative heavy metal transporter, Ftr1/Tp34 or Tpd, (TP0972/TP0971). Ftr1 has 448 aas with 9 TMSs while Tp34 has 204 aas with 1 N-terminal TMSs. This antigen is a pathogen-specific membrane immunogen. This periplasmic dimeric protein binds human lactoferrin with submicromolar affinity with a stoichiometry of 2:1 (Deka et al. 2007). It's 3-d structure (1.9 Å resolution) reveals two metal binding sites per monomer with zinc bound to both sites (Deka et al. 2007). |
Spirochaetota | Ftr1/Tdp of Treponema pallidum |
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2.A.108.2.2 | The high-affinity oxidase-dependent iron (ferric/ferrous) transporter, FTR-ChpA |
Bacteria | Pseudomonadota | FTR-ChpA of Brucella melitensis |
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2.A.108.2.3 | The acid-induced, low pH, ferrous iron (Fe2+) uptake transporter, EfeUOB (YcdN); cryptic in E. coli K12 (Cao et al. 2007; Grosse et al., 2006) |
Bacteria | Pseudomonadota | EfeUOB of E. coli O157:H5 |
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2.A.108.2.4 | The Ftr1 (integral membrane transporter)/ P19 (periplasmic iron binding protein) iron uptake system. P19 has distinct copper and iron binding sites and exhibits an immunoglobulin-like fold (Chan et al., 2010). |
Bacteria | Campylobacterota | Ftr1/P19 of Campylobacter jejuni |
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2.A.108.2.5 | Ferrous iron uptake permease, EfeU |
Bacteria | Bacillota | EfeU of Bacillus subtilis |
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2.A.108.2.6 | High affinity Fe2+/Pb2+ permease-like protein. |
Bacteria | Chloroflexota | Permease of Thermobaculum terrenum |
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2.A.108.2.7 | Pb2+ uptake porter of 643 aas, PbtT or FTR1 (Hložková et al. 2013). |
Bacteria | Pseudomonadota | PbtT of Achromobacter xylosoxidans |
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2.A.108.2.8 | Ftr1 protein of 276 aas and 8 TMSs |
Archaea | Thermoproteota | Ftr1 protein of Aeropyrum pernix |
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2.A.108.2.9 | Siderophore-independent iron uptake porter, FtrCAB: FtrC (280 aas, 7 TMSs)/FtrA (183 aas; 1 TMS)/FtrB (110 aas, 0 TMSs) (Mathew et al. 2014). Functions with FtrD, an iron-sulfur cluster-containing ferredoxin of 465 aas. |
Bacteria | Pseudomonadota | FtrCAB of Burkholderia cenocepacia |
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2.A.108.3.1 | Hypothetical protein of 208 aas |
Archaea | Thermoproteota | HP of Sulfolobus islandicus |
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2.A.108.3.2 | Manganese ion transporter, MntH of 250 aas and 6 - 7 TMSs. |
Bacteria | Pseudomonadota | MntH of Rhizobium leguminosarum |
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2.A.108.3.3 | Hypothetical protein |
Archaea | Thermoproteota | HP of Sulfolobus acidocaldarius |
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2.A.109.1.1 | Tellurium resistance protein, TerC of 346 aas and 9 TMSs in a 5 + 4 TMS arrangement. Interactions with several other proteins including TerB have been demonstrated (Turkovicova et al. 2016). |
Bacteria | Pseudomonadota | TerC of E. coli (CAB42997) |
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2.A.109.1.2 | Alx protein of 323 aas and 9 TMSs in a 2 + 3 + 4 TMS arrangement. |
Bacteria | Pseudomonadota | Alx of Neisseria meningitidis (F0N2E7) |
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2.A.109.1.3 | YceF of 262 aas; possibly with 8 TMSs in a 2 + 2 + 2 + 2 TMS arrangement. |
Bacteria | Bacillota | YceF of Bacillus cereus (B5UIP4) |
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2.A.109.1.4 | Putative transporter, YkoY (with 324 aas and 9 TMSs in a 1 + 2 + 2 + 4 TMS arrangement) (Kazanov et al. 2007; Meyer et al. 2011) |
Bacteria | Bacillota | YkoY of Bacillus subtilis (O34997) |
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2.A.109.1.5 | TerC family efflux pump of 210 aas with 6 TMSs in a 3 + 3 TMS arrangement. |
Bacteria | Pseudomonadota | TerC family member of Sinorhizobium fredii |
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2.A.109.1.6 | Uncharacterized protein of 352 aas with 8 TMSs in a 4 + 4 TMS arrangement. |
Eukaryota | Viridiplantae, Streptophyta | UP of Brachypodium distachyon (Purple false brome) (Trachynia distachya) |
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2.A.109.1.7 | Membrane protein induced over 100x by alkaline conditions, Alx or YgjT of 321 aas and 9 TMSs (Stancik et al. 2002). This riboswitch-controlled manganese exporter (Alx) tunes intracellular Mn2+ concentration in E. coli at alkaline pH. A set of acidic residues in the predicted TMSs of Alx play a role in Mn2+ export (Sharma and Mishanina 2023). |
Bacteria | Pseudomonadota | YgjT or Alx of E. coli |
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2.A.109.2.1 | TerC homologue of 286 aas with 8 TMSs in a 2 + 1 + 1 + 2 + 2 TMS arrangement. |
Bacteria | Planctomycetota | TerC homologue of Rhodopirellula baltica |
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2.A.109.2.2 | Hypothetical protein of 300 aas and 7 putative TMSs |
Bacteria | Planctomycetota | HP of Rhodopirellula baltica |
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2.A.109.2.3 |
8 TMS membrane protein including a transmembrane domain homologous to other proteins in the TerC family (2.A.109) with the transmembrane domain having a 4 + 4 TMS arrangement, and a C-terminal domain (residues 622 - 889) with high sequence identity with hemolysin C and all members of the HlyC family (TC# 1.C.126), including some Mg2+ exporters in Cyclin M Mg2+ Exporter (CNNM) (TC family 1.A.112). The hydrophilic N-terminal CBS domain is an integrase domain but may bind ATP (Huang et al. 2021).
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Bacteria | Pseudomonadota | Membrane protein of E. coli |
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2.A.109.3.1 | DUF475; PRK14013 protein (341 aas; 9 or 10 TMSs in a 1 or 2 + 1 + 1 + 2 + 2 + 2 TMS arrangement). |
Archaea | Euryarchaeota | DUF475 protein of Methanocaldococcus vulcanius (C9RH03) |
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2.A.109.3.2 | TerC homolog of 399 aas and 10 TMSs in a 2 + 1 + 1 + 2 + 2 + 2 TMS arrangement. |
Bacteria | Bacillati, Actinomycetota | TerC of Gordonia aichiensis |
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2.A.11.1.1 | [Citrate or D-isocitrate]•M2+ (Mg2+ preferring):H+ symporter, CitM (transports Mg2+, Mn2+, Ni2+, Co2+ & Zn2+). Regulated by the CitS/CitT two component system (Yamamoto et al. 2000; Repizo et al. 2006). |
Bacteria | Bacillota | CitM of Bacillus subtilis |
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2.A.11.1.2 | [Citrate]•M2+ (Ca2+ preferring):H+ symporter, CitH (transports Ca2+, Ba2+ & Sr2+). |
Bacteria | Bacillota | CitH of Bacillus subtilis |
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2.A.11.1.3 | Citrate•Me2+ (Fe2+/Mn2+ preferring):H+ symporter, CitM |
Bacteria | Bacillota | CitM of Streptococcus mutans (AAN58714) |
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2.A.11.1.4 | Citrate-M2+ (Fe3+ preferring): H+ symporter, Cit (transports Fe3+, Ca2+, Pb2+, Ba2+ and Mn2+, but not Mg2+, Ni2+ or Co2+) (Lensbouer et al., 2008). |
Bacteria | Actinomycetota | Cit of Streptomyces coelicolor (Q9S242) |
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2.A.11.1.5 | Uncharacterized transporter YraO | Bacteria | Bacillota | YraO of Bacillus subtilis |
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2.A.11.1.6 | Citrate-inducible divalent cation:citrate uptake transporter, CitH. Can use Ca2+ or Sr2+ but not Mg2+ as the cotransported cation; The CitAB two component sensor kinase/response regulator system mediates induction by citrate (Brocker et al. 2009). |
Bacteria | Actinomycetota | CitH of Corynebacterium glutamicum |
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2.A.11.2.1 | Putative transporter | Bacteria | Bacillota | Putative transporter of Leuconostoc mesenteroides (Q03YV5) |
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2.A.11.2.2 | Uncharacterized protein of 429 aas |
Bacteria | Spirochaetota | UP of Treponema lecithinolyticum |
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2.A.11.2.3 | Uncharacterized protein of 447 aas |
Bacteria | Actinomycetota | UP of Nocardiopsis dassonvillei (Actinomadura dassonvillei) |
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2.A.110.1.1 | The endosomal/lysosomal heme transporter, HRG-1 (SLC48.1) (Yuan et al., 2012) |
Eukaryota | Metazoa, Chordata | SLC48A1 of Homo sapiens |
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2.A.110.1.2 | The worm heme transporter, HRG-1 (Yuan et al., 2012). |
Eukaryota | Metazoa, Nematoda | HRG1 of Caenorhabditis elegans (Q21642) |
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2.A.110.1.3 | HRG-4 heme transporter (Rajagopal et al. 2008). |
Eukaryota | Metazoa, Nematoda | HRG-4 of Caenorhabditis elegans (Q20106) |
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2.A.110.1.4 | Putative heme transporter (151aas; 4 TMSs) |
Eukaryota | Metazoa, Chordata | Heme transporter of Branchiostoma floridae (C3Y137) |
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2.A.110.1.5 | Heme transporter Hrg-6 (Heme-responsive gene 6 protein) (CeHRG-6) |
Eukaryota | Metazoa, Nematoda | Hrg-6 of Caenorhabditis elegans |
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2.A.110.1.6 | HRG homologue |
Eukaryota | Discosea | HRG homologue of Acanthamoeba castellanii |
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2.A.110.2.1 | The LHR1 heme uptake transporter (Huynh et al. 2012). In Leishmania amazonensis, LHR1 is essential for virulence (Miguel et al. 2013). Transport depends on tyrosyl residues in the first three TMSs of the protein (Renberg et al. 2015). |
Eukaryota | Euglenozoa | LHR1 of Leishmania donovani (E9BH93) |
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2.A.110.2.2 | Heme uptake transporter, LHR1 (171aas; 4 putative TMSs) (Huynh et al. 2012). Tyrosyl residues essential for activity are also essential for virulence (Renberg et al. 2015). |
Eukaryota | Euglenozoa | LHR1 of Trypanosoma cruzi (Q4DHZ7) |
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2.A.111.1.1 | Probable Na+/H+ antiporter, NhaE of 489 aa. |
Bacteria | Spirochaetota | NhaE of Leptospira interrogans |
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2.A.111.1.2 |
Na+ /Li+ /H+ antiporter, NhaE (Sousa et al. 2013). |
Bacteria | Pseudomonadota | NhaE of Neisseria meningitidis |
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2.A.111.1.3 | Na+/H+ antiporter, NhaD of 527 aas. Confers resistance to Na+, but not to Li+ (Melo et al. 2005). |
Bacteria | Rhodothermota | NhaD of Rhodothermus marinus (Q4QSA9) |
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2.A.111.2.1 | NhaE homologue of 428 aas and 12 TMSs PF07399; CL0182; IT superfamily). |
Bacteria | Pseudomonadota | NhaE homologue of Roseateles depolymerans |
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2.A.111.2.2 | NhaE homologue of 450 aas and 11-12 TMSs. |
Bacteria | Chlamydiota | NhaE homologue of Chlamydophila caviae |
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2.A.112.1.1 | The human KX blood group antigen (putative amino acid transporter), KX antigen (Suzuki et al. 2013). |
Eukaryota | Metazoa, Chordata | The KX blood group antigen of Homo sapiens |
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2.A.112.1.10 | Uncharacterized XK-related protein of 450 aas |
Eukaryota | Metazoa, Arthropoda | UP of Daphnia pulex (water flea) |
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2.A.112.1.11 | Xkr4 of 650 aas and 10 TMSs in a 2 + 1 + 2 + 2 + 1 + 2 TMS arrangement, suggestive of a 5 TMS repeat unit. Xrk4 catalyzes phosphatidyl serine flipping from the inner leaflet to the outer leaflet of the cell membrane to signal appoptosis. It has a C-terminal caspase recognition signal that may play an important role. Xkr4, 8 and 9 have this activity and have several essential residues in TMS2 and cytoplasmic loop 2 (Suzuki et al. 2014). Xkr4 is activated by caspase-mediated cleavage and binding of the XRCC4 fragment. Zhang et al. 2023 showed that extracellular calcium is a factor needed to activate Xkr4. A constitutively active mutant of Xkr4 was found to induce phospholipid scrambling in an extracellular, but not intracellular, calcium-dependent manner. Other Xkr family members also require extracellular calcium for activation. D123 and D127 of TMS1 and E310 of TMS3 coordinate calcium binding, and the E310K mutation-mediated salt bridge between TMS1 and TMS3 bypasses the requirement for calcium. Disulfide bond formation between these two TMSs also activates phospholipid scrambling without calcium (Zhang et al. 2023). |
Eukaryota | Metazoa, Chordata | Xkr4 of Homo sapiens |
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2.A.112.1.12 | Xkr9 of 650 aas. Catalyzes phosphatidyl serine flipping from the inner leaflet to the outer leaflet of the cell membrane to signal appoptosis. It has a C-terminal caspase recognition signal that may play an important role. Xkr4, 8 and 9 have this activity and have several essential residues in TMS2 and cytoplasmic loop 2 (Suzuki et al. 2014). |
Eukaryota | Metazoa, Chordata | Xkr9 of Homo sapiens |
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2.A.112.1.13 | Xkr8 (XK8, XRG8) is of 395 aas and 6 - 11 apparent TMSs based on hydropathy plots. It catalyzes phosphatidyl serine (PS) flipping from the inner leaflet to the outer leaflet of the cell membrane to signal appoptosis (Sivagnanam et al. 2017). It has a C-terminal caspase recognition sequence that may play a role in apoptosis signalling. Xkr4 TC# 2.A.112.1.11), Xkr8 and Xkr9 (TC# 2.A.112.1.12) have this activity and have several essential residues in TMS2 and cytoplasmic loop 2 (Suzuki et al. 2014). It is a 6 TMS protein that is activated by caspases during apoptosis and promotes phospholipid scrambling, thus exposing PS as an "eat-me-signal" (Suzuki and Nagata 2014). Basigin (BSG; TC# 2.A.23.1.1) and neuroplastin (NPTN; TC# 2.A.23.1.8)) bind to Xkr8 and usher it to the plasma membrane (Suzuki et al. 2016). |
Eukaryota | Metazoa, Chordata | Xkr8 of Homo sapiens |
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2.A.112.1.14 | XKR5 of 686 aas and 5 or 6 TMSs |
Eukaryota | Metazoa, Chordata | XKR5 of Homo sapiens |
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2.A.112.1.15 | XK-related protein of 603 aas and 8 TMSs. |
Eukaryota | Metazoa, Annelida | XK-protein of Capitella teleta (Polychaete worm) |
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2.A.112.1.16 | XK-like protein of 667 aas and 9 TMSs |
Eukaryota | Metazoa, Chordata | XK-like protein of Ciona intestinalis (Transparent sea squirt) (Ascidia intestinalis) |
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2.A.112.1.17 | XK8 or XraB of 404 aas and 9 TMSs |
Eukaryota | Metazoa, Chordata | XK8 of Ciona intestinalis (Transparent sea squirt) (Ascidia intestinalis) |
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2.A.112.1.2 | Cell death abnormality protein 8; phospholipid flippase (in to out) (Suzuki et al. 2013; Chen et al. 2013). |
Eukaryota | Metazoa, Nematoda | ced-8 of Caenorhabditis elegans |
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2.A.112.1.3 | The X Kell blood group precursor-related family member 8 homologue isoform CRAa of 401 aas (XK-related protein 8 or XkR8) (Suzuki et al. 2013). |
Eukaryota | Metazoa, Chordata | XkR8 of Mus musculus |
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2.A.112.1.4 | Uncharacterized protein of 374 aas and ~ 10 TMSs |
Eukaryota | Metazoa, Arthropoda | UP of Culex quinquefasciatus (Southern house mosquito) (Culex pungens) |
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2.A.112.1.5 | XkR8 homologue of 352 aas and 8 - 10 TMSs. |
Eukaryota | Metazoa, Arthropoda | XkR8 homologue of Drosophila melanogaster |
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2.A.112.1.6 | The XK-related protein 2, XKP2 of 440 aas (Calenda et al. 2006). |
Eukaryota | Metazoa, Chordata | XKP2 of Homo sapiens |
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2.A.112.1.7 | The XK-related protein 3, XKR3; XRG3, XTES of 459 aas (Calenda et al. 2006). |
Eukaryota | Metazoa, Chordata | XKR3 of Homo sapiens |
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2.A.112.1.8 | XK protein 6 of 675 aas |
Eukaryota | Metazoa, Platyhelminthes | XK protein of Hymenolepis microstoma (Rodent tapeworm) (Rodentolepis microstoma) |
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2.A.112.1.9 | Uncharacterized protein of 470 aas |
Eukaryota | Metazoa, Chordata | UP of Branchiostoma floridae (Florida lancelet) (Amphioxus) |
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2.A.112.2.1 | XkR8 homologue of 884 aas and 8 - 10 TMSs. |
Eukaryota | Viridiplantae, Chlorophyta | XkR8 homologue of Otreococcus lucimarinus |
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2.A.112.2.2 | Uncharacterized protein of 1119 aas and 10 TMSs. |
Eukaryota | Viridiplantae, Chlorophyta | UP of Bathycoccus prasinos |
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2.A.112.2.3 | Uncharacterized protein of 781 aas and 9 TMSs |
Eukaryota | Viridiplantae, Chlorophyta | UP of Coccomyxa subellipsoidea |
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2.A.112.2.4 | Unchracterized protein of 892 aas |
Eukaryota | Viridiplantae, Chlorophyta | UP of Ostriococcus tauri |
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2.A.112.4.1 | Uncharacterized protein of 652 aas and 8 TMSs |
Eukaryota | Metazoa, Arthropoda | UP of Drosophila grimshawi (Fruit fly) (Idiomyia grimshawi) |
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2.A.112.4.2 | Uncharacterized protein of 694 aas and 9 TMSs. |
Eukaryota | Metazoa, Arthropoda | UP of Solenopsis invicta (Red imported fire ant) (Solenopsis wagneri) |
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2.A.112.4.3 | Uncharacterized protein of 615 aas and 9 TMSs |
Eukaryota | Metazoa, Arthropoda | UP of Aedes aegypti (Yellowfever mosquito) (Culex aegypti) |
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2.A.113.1.1 | Ni2+/Co2+ exporter, RcnA/RcnB (Rodrigue et al., 2005; Iwig et al., 2006). RcnB, a small 1 or 2 TMS protein of the DUF3315 or PF11776 family, regulates the activity of RcnA. |
Bacteria | Pseudomonadota | RcnAB of E. coli |
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2.A.113.1.10 | Nickel/Cobalt uptake porter, NcrC of 231 aas (Marrero et al. 2007). This sequence is proably a partial sequence lacking the C-terminal 3-TMS domain as exists in it's closest homologues such as 2.A.113.1.2. |
Bacteria | Pseudomonadota | NcrC of Serratia marcescens |
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2.A.113.1.11 | NicO homologue of 236 aas and 6 TMSs. |
Bacteria | Bacillota | NicO homologue of Geobacillus thermoleovorans |
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2.A.113.1.12 | NicO homologue of 218 aas and 6 TMSs. |
Archaea | Euryarchaeota | NicO of Haloferax mediterrainei |
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2.A.113.1.13 | NicO homologue of 284 aas and 6 TMSs. |
Bacteria | Thermomicrobiota | NicO of Sphaerobacter thermophilus |
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2.A.113.1.14 | Putative high affinity nickel transporter |
Bacteria | Spirochaetota | Putative Ni2+ transporter of Treponema denticola |
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2.A.113.1.2 | Ni2+ resistance protein, like NcrC |
Bacteria | Pseudomonadota | NcrC homologue of Enterobacter cloaecae (D5CKG5) |
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2.A.113.1.3 | RcnA homologue | Bacteria | Pseudomonadota | RcnA homologue of Ralstonia solanacearum (CAD17703) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.113.1.4 | Urease accessory protein, UreH | Archaea | Euryarchaeota | UreH of Methanocaldococcus jannaschii (Q58492) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.113.1.5 | NiCoT homologue of 6 TMSs with two putative 3 TMS repeats corresponding to TMSs 2-4 and 6-8 in the 8 TMS homologues (B Tsu and DC Yee, unpublished) |
Bacteria | Acidobacteriota | NiCoT homologue of Solibacter usitatus |
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2.A.113.1.6 | NicO homologue of 6 TMSs with TMSs 1-3 corresponding to TMSs 2-4 in the 8 TMS homologues, and TMSs 6-8 corresponding to TMSs 6-8 in the 8 TMS homologues (B Tsu and DC Yee, unpublished). |
Bacteria | Planctomycetota | NicO homologue of Rhodopirellula baltica |
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2.A.113.1.7 | Putative high affinity Ni2+ transporter of 320 aas and 7 TMSs in a 1 3 3 arrangement. |
Bacteria | Pseudomonadota | Nickel transporter of Starkeya novella |
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2.A.113.1.8 | Uncharacterized protein of 244 aas and 6 TMSs. |
Bacteria | Fusobacteriota | UP of Fusobacterium nucleatum |
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2.A.113.1.9 | Uncharacterized protein of 232 aas and 6 TMSs |
Bacteria | Pseudomonadota | UP of Oligotropha carboxidovorans |
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2.A.113.2.1 | High affinity Nickel transporter of 556 aas and 8 or 9 TMSs in a 1 + 4 +3 or 4 TMS arrangement. TMS 1 is N-terminal. distant from the others. Then there are 4 TMSs followed by a hydrophilic regiion with one peak of very weak hydrophobicity. This is followed by 3 clear TMSs. |
Bacteria | Actinomycetota | NicO family member of Streptomyces griseus |
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2.A.113.2.2 | Putative Nickel transporter of 597 aas and 7 TMSs in a 1 (N-terminal) + 3 + 3 arrangement. |
Bacteria | Actinomycetota | NicO family member in Streptomyces ipomoeae |
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2.A.113.2.3 | Uncharacterized protein of 488 aas and 7 TMSs in a clear 1 + 3 + 3 arrangement. |
Bacteria | Cyanobacteriota | UP of Nostoc punctiforme |
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2.A.114.1.1 | Carbon starvation inducible protein CstA (701 aas; 18 TMSs). This protein has been shown to be a pyruvate uptake system, working together with a small protein of 65 aas, YbdD (Hwang et al. 2018). It may also transport peptides. |
Bacteria | Pseudomonadota | CstA of E. coli (P15078) |
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2.A.114.1.10 | BtsT (from the German word for pyruvate: """"Brenztraubensäure"""" transporter) or YjiY of 716 aas and 18 TMSs. It is a high affinity (Km + 16 μM), inducible, specific pyruvate:proton uptake symporter (Kristoficova et al. 2017). Expression of the btsT (yjiY) gene is regulated by the LytS-like histidine kinase, BtsS, a sensor of extracellular pyruvate, together with the LytTR-like response regulator, BtsR (Kristoficova et al. 2017).It may also mediate uptake of specific peptides, thus initiating their metabolism, but this has not been demonstrated directly. It indirectly influences flagellar biosynthesis and virulence. BtsT (YjiY) is required for successful colonization of Salmonella in the mouse gut (Garai et al. 2015). It also influences expression of the mgtC gene to regulate biofilm formation (Garai et al. 2017). |
Bacteria | Pseudomonadota | YjiY of Salmonella enterica; subspecies Typhimurium (strain LT2) |
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2.A.114.1.2 | Carbon starvation protein, CstA (484 aas; 13 TMSs). |
CstA of Anaerococcus prevotii (C7RGN6) |
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2.A.114.1.3 | CstA (579 aas; 15 TMSs) |
CstA of Thermococcus kodakaraensis (Q5JIF7) |
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2.A.114.1.4 | CstA of 483 aas with 12 or 13 putative TMSs. |
Bacteria | Bacillota | CstA of Chlostridium perfringens (Q8XME6) |
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2.A.114.1.5 | CstA of 703 aas and 18 putative TMSs. In C. jejuni, this protein plays a role in starvation responses and peptide uptake. A ΔcstA mutant has reduced use of di- and tri-peptides when used as nitrogen sources. The mutant also has reduced motility and agglutination and shows decreased host-pathogen relationships (Rasmussen et al. 2013). |
Bacteria | Campylobacterota | CstA of Campylobacter jejuni (Q0P9Y2) |
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2.A.114.1.6 | CstA of 511 aas and 14 putative TMSs in a possible 10 4 arrangement. The last 4 TMSs correspond to the DUF4161 domain in CDD. |
Bacteria | Fibrobacterota | CstA of Fibrobacter succinogenes |
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2.A.114.1.7 | CstA of 791 aas and 16 TMSs in an apparent 11 + 5 + 1 arrangement. |
Bacteria | Actinomycetota | CstA of Bifidobacterium animalis |
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2.A.114.1.8 | CstA of 704 aas and 16 TMSs in a 4 + 6 + 6 arrangement. |
Bacteria | Planctomycetota | CstA of Singulisphaera acidiphila |
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2.A.114.1.9 | High affinity (Km 16 mμM) pyruvate:H+ symporter, BtsT (from "Brenztraubensaure", the German word for pyruvate), also called YjiY of 716 aas and 16 - 18 TMSs (Kristoficova et al. 2017). If 16 TMSs, they occur in a 2 + 2 + 5 + 2 (space) +1 + 3 + 1 TMS arrangement, or if 18 TMSs, there are two additional TMSs between the first11 TMSs and the last 5 TMSs. Regulated by Crp as well as the LytS-like histidine sensor kinase, BtsS (YehU) which senses extracellular pyruvate, and it functions with the corresponding LytTR-like response regulator, BtsR (YehT). Although the true inducer is extracellular pyruvate as noted above, it is induced by peptides as cells enter the stationary growth phase, presumably because pyruvate is released from these peptides (Kraxenberger et al. 2012). BtsT forms a complex with the MFS transporter, YhjX (TC# 2.A.1.11.3) and two sensor kinase/response regulator pairs, YehU/YehT and YdpA/YdpB (Behr et al. 2014). Both transporters are also posttranscriptionally regulated by CsrA (Behr et al. 2014). The LytS-type histidine kinase, BtsS, is a 7-transmembrane receptor that binds pyruvate (Qiu et al. 2023). The two proteins, YhjX (TC# 2.A.1.11.3) and YjiY (TC# 2.A.114.1.9) may function together as an oligomer, and confusingly, both have been given the same designation: BtsT (see UniProt entries). |
Bacteria | Cyanobacteriota | BtsT or YjiY of E. coli |
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2.A.115.1.1 | The YitT (UPF0750) efflux transporter of 280 aas and 6 pr 7 N-terminal TMSs. The 3-d structure is known (PDB# 3HLU_A). |
Bacteria | Bacillota | YitT of Bacillus subtilis (P39803) |
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2.A.115.1.2 | The YxkD (UPF0750) membrane protein |
Bacteria | Bacillota | YxkD of Bacillus subtilis (P94357) |
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2.A.115.1.3 | The Hypothetical Protein, HP. 6 TMSs in a 2+2+2 arrangement. |
Bacteria | Pseudomonadota | HP of Rhizobium etli (Q2KCS0) |
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2.A.115.1.4 | DUF161 protein of unknown function (6 TMSs in a 2+2+2 arrangement). |
Bacteria | Pseudomonadota | DUF161 protein of Brucella sp. NF 2653 (E0DTC9) |
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2.A.115.1.5 | Conserved uncharacterized protein of 289 aas; DUF161 + DUF2179 |
Bacteria | Thermodesulfobacteriota | HP of Desulfohalobium retbaense |
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2.A.115.1.6 | DUF2179 protein of unknown function (3 TMSs) |
Bacteria | Thermotogota | DUF2179 protein of Mestoga prima (E0HYB9) |
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2.A.115.1.7 | Uncharacterized protein of 222 aas and 3 N-terminal TMSs. |
Archaea | Euryarchaeota | Uncharacterized 3 TMS protein of Methanoregula boonei (A7I6E8) |
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2.A.115.1.8 | DUF2179 protein of 196 aas |
Bacteria | Thermotogota | DUF2179 protein of Petrotoga mobilis |
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2.A.115.2.1 | The 5 TMS YczE protein. May be distantly related to CirC (5TMSs; 9.B.98.1.4). |
Bacteria | Bacillota | YczE of Bacillus subtilis (E0U2C9) |
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2.A.115.2.10 | Uncharacterized protein of 215 aas |
Archaea | Euryarchaeota | UP of Methanocorpusculum labreanum |
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2.A.115.2.11 | Hypothetical 6 TMS protein, HP |
Bacteria | Mycoplasmatota | HP of Haloplasma contractile (F7PTN4) |
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2.A.115.2.12 | Uncharacterized protein of 212 aas |
Bacteria | Bacillota | UP of Faecalibacterium prausnitzii |
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2.A.115.2.13 | Uncharacterized protein of 205 aas |
Bacteria | Bacillota | UP of Clostridium difficile |
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2.A.115.2.14 | Fusion protein of DUF161 membrane domain of 6 TMSs with a cytidylate kinase 2 domain; 428 aas |
Bacteria | Actinomycetota | Fusion protein of Slackia heliotrinireducens |
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2.A.115.2.15 | Uncharacterized protein of 222 aas |
Bacteria | Deinococcota | UP of Deinococcus radiodurans |
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2.A.115.2.2 | The 5 TMS YyaS protein |
Bacteria | Bacillota | YyaS of Bacillus pseudofirmus (D3FUL0) |
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2.A.115.2.3 | The 5 TMS membrane protein, 5-MP |
Bacteria | Bacillota | 5-MP of Enterococcus faecalis (F2MS25) |
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2.A.115.2.4 | Novobiocin exporter, NbcE, of 195 aas and 4 or 5 TMSs (Pagliai et al. 2010). |
Bacteria | Bacillota | Novobiocin exporter of Lactobacillus brevis |
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2.A.115.2.5 | COG2364 homologue of 221 aas |
Bacteria | Bacillota | COG2364 homologue of Bacillus cereus |
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2.A.115.2.6 | Hypothetical protein of 238 aas |
Bacteria | Actinomycetota | HP of Kytococcus sedentarius |
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2.A.115.2.7 | Hypotheitical protein of 224 aas |
Bacteria | Actinomycetota | HP of Thermobifida fusca |
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2.A.115.2.8 | Hypothetical protein of 222 aas |
Bacteria | Spirochaetota | HP of Brachyspira hyodysenteriae |
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2.A.115.2.9 | Uncharacterized protein of 238 aas |
Bacteria | Bacillota | UP of Eubacterium eligens |
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2.A.116.1.1 | The peptidoglycolipid exporter, GAP (Sondén et al., 2005). |
Bacteria | Actinomycetota | GAP of Mycobacterium smegmatis |
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2.A.116.1.2 | Gap homologue of 237 aas |
Bacteria | Actinomycetota | Gap of Mycobacterium tuberculosis |
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2.A.116.1.3 | Gap homologue of 225 aas |
Bacteria | Actinomycetota | Gap homologue of Streptomyces hydroscopicus |
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2.A.116.1.4 | Gap homologue of 223 aas |
Bacteria | Actinomycetota | Gap homologue of Microlunatus phosphovorus |
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2.A.116.1.5 | Gap homologue of 213 aas |
Bacteria | Actinomycetota | Gap homologue of Catenulispora acidiphila |
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2.A.116.1.6 | Gap homologue of 232 aas |
Archaea | Euryarchaeota | Gap homologue of Methanobacterium formicicum |
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2.A.116.1.7 | Gap homologue of 216 aas |
Bacteria | Actinomycetota | Gap homologue of Gordonia rhizosphera |
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2.A.116.2.1 | Gap homologue of 228 aas |
Bacteria | Cyanobacteriota | Gap homologue of Cyanobium gracile |
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2.A.116.2.2 | Gap homologue of 229 aas |
Bacteria | Cyanobacteriota | Gap homologue of Prochlorococcus marinus |
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2.A.116.3.1 | Gap homologue of 260 aas |
Bacteria | Actinomycetota | Gap homologue of Arthrobacter arilaitensis |
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2.A.116.3.2 | Gap homologue of 229 aas |
Bacteria | Actinomycetota | Gap homologue of Nocardiopsis alba |
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2.A.116.3.3 | Gap homologue of 218 aas |
Bacteria | Bacillota | Gap homologue of Bacillus cereus |
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2.A.116.3.4 | Hypothetical protein of 237 aas |
Bacteria | Bacillota | HP of Clostridium cellulolyticus |
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2.A.117.1.1 | The Chlorhexidine drug-resistance exporter, AceI of 179 aas and 4 TMSs (Hassan et al. 2013) . It is capable of exporting multiple drugs such as benzalkonium, dequalinium, proflavine, and acriflavine. (Hassan et al. 2015). The aceI gene is induced in A. baumannii by the short-chain diamines, cadaverine and putrescine. Membrane transport experiments conducted in whole cells of A. baumannii and Escherichia coli and also in proteoliposomes showed that AceI mediates the efflux of these short-chain diamines (polyamines) such as when energized by an electrochemical gradient (Hassan et al. 2019), suggesting that they are the phsiological substrates of AceI. AceI can form dimers and is regulated at the transcriptional level by AceR (Bolla et al. 2020). |
Bacteria | Pseudomonadota | AceI of Acinetobacter baumannii |
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2.A.117.1.10 | Uncharacterized putative drug exporter of 148 aas and 4 TMSs. |
Bacteria | Pseudomonadota | Transmembrane poir domain-protein of Azospira oryzae (Dechlorosoma suillum) |
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2.A.117.1.11 | Uncharacterized putative drug exporter of 140 aas and 4 TMSs. |
Bacteria | Pseudomonadota | UP of Shewanella hoihica |
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2.A.117.1.12 | The Unknown Bacterial Transmembrane Pair (UBTP) family member of 146 aas and 4 TMSs. Chlorhexidine-unresponsive (Hassan et al. 2013). |
Bacteria | Pseudomonadota | UBTP family member of Burkholderia cenocepacia |
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2.A.117.1.13 | Member of the Proteobacterial Antimicrobial Compound Efflux (PACE) family. This protein is of 140 aas with 4 TMSs. It has been shown to be an active drug exporter, conferring resistance to both proflavine and acriflavine, mediated by an active efflux mechanism (Hassan et al. 2018). |
Bacteria | Pseudomonadota | UBTP2 family member of Vibrio parahaemolyticus |
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2.A.117.1.2 | Chlorhexidine-responsive chlorhexadine exporter of 171 aas and 4 TMSs. |
Bacteria | Pseudomonadota | AceI of Pseudomonas aeruginosa |
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2.A.117.1.3 | Chlorhexidine-responsive putative chlorhxidine exporter of 160 aas and 4 TMSs, AceI (Hassan et al. 2013). It confers resistance to both proflavine and acriflavine by an active efflux mechanism (Hassan et al. 2015). AceR is an activator of aceI gene expression when challenged with chlorhexidine (Liu et al. 2018). This system also exports polyamines (organic diamines) such as cadaverine and putrescine (and possibly spermidine with low affinity). It is induced preferentially by cadaverine and putrescine, and to a much lesser extent by spermidine. An AceI-E15Q mutant is inactive (Hassan et al. 2019). |
Bacteria | Pseudomonadota | AceI of Salmonella typhi |
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2.A.117.1.4 | Chlorhexidine-unresponsive putative drug exporter of 147 aas and 4 TMSs. |
Bacteria | Pseudomonadota | Drug exporter of Pseudomonas aeruginosa |
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2.A.117.1.5 | Chlorhexidine-unresponsive putative drug exporter of 144 aas and 4 TMSs. |
Bacteria | Thermodesulfobacteriota | Drug exporter of Desulfovibrio vulgaris |
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2.A.117.1.6 | Uncharacterized putative drug exporter of 134 aas and 4 TMSs. |
Bacteria | Bacillota | UP of Veillonella parvula |
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2.A.117.1.7 | Uncharacterized putative drug exporter of 147 aas and 4 TMSs. |
Bacteria | Pseudomonadota | UP of Methylobacterium populi |
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2.A.117.1.8 | Uncharacterized putative drug exporter of 179 aas and 4 TMSs. |
Bacteria | Actinomycetota | UP of Micrococcus luteus |
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2.A.117.1.9 | Uncharacterized putative drug exporter of 346 aas and 4 N-terminal TMSs with a long C-terminal hydrophilic domain. |
Bacteria | Pseudomonadota | UP of Pseudomonas fluorescens |
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2.A.117.2.1 | Uncharacterized putative drug exporter of 142 aas and 4 TMSs. |
Bacteria | Pseudomonadota | UP of Rhodobacter spheroides |
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2.A.117.2.2 | Uncharacterized protein of 148 aas and 4 TMSs in a 2 + 2 TMS arrangement. |
Bacteria | Pseudomonadota | UP of Hyphomicrobium sp. (freshwater metagenome) |
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2.A.117.2.3 | PACE efflux transporter protein of 153 aas and 4 TMSs in a 2 + 2 TMS arrangement. |
Bacteria | Planctomycetota | PACE exporter of Planctomycetes bacterium (activated sludge metagenome) |
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2.A.117.3.1 | Uncharacterized protein of 88 aas and 2 TMSs. Its sequence correspondes to the N-terminus of full length homologues and may therefore be a truncated version of a 4 TMS proteins. |
Bacteria | Pseudomonadota | UP of Yangia sp. PrR003 |
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2.A.118.1.1 | Putative arginine transporter | Bacteria | Bacillota | The putative arginine transporter of Enterococcus faecalis (CAC41345) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.118.1.2 | Putative C4 dicarboxylate transporter (DcuC) (based only on similarity) | Bacteria | Pseudomonadota | The putative C4 dicarboxylate transporter of Mesorhizobium sp. BNC1 (EAN06503) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.118.1.3 | Putative C4 dicarboxylate anaerobic carrier |
Bacteria | Bacteroidota | Putative dicarboxylate carrier of Odoribacter splanchnicus |
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2.A.118.1.4 | Putative short chain fatty acid transporter |
Bacteria | Pseudomonadota | SCFA transporter of Vibrio coralliilyticus |
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2.A.118.1.5 | Putative arginine/ornithine antiporter, ArcD |
Bacteria | Pseudomonadota | ArcD of Francisella sp. |
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2.A.118.1.6 | Putative arginine/ornithine antiporter of 503 aas, ArcD. Deletion impairs capsule formation and virulence (Gupta et al. 2013). |
Bacteria | Bacillota | ArcD of Streptococcus pneumoniae |
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2.A.118.1.7 | The probable citruline/ornithine antiporter of 519 aas and 13 TMSs, ArcD (Rimaux et al. 2013). |
Bacteria | Bacillota | ArcD of Lactobacillus sakei |
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2.A.118.1.8 | Possible dicarboxylate transporter of 506 aas and 13 TMSs, YfcC. Its expression affects the glyoxylate shunt and upregulates the glyoxylate shunt enzymes, AceA and AceB (Wang et al. 2014). |
Bacteria | Pseudomonadota | YfcC of E. coli |
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2.A.119.1.1 | The 8 TMS ArsP protein (Wang et al. 2009; Castillo and Saier 2010). Exports organo-arsenicals such as roxarsone and nitrarsone (Shen et al. 2014). |
Bacteria | Campylobacterota | ArsP of Campylobacter jejuni (B5LWZ8) |
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2.A.119.1.2 | The putative 9 or 10 TMS TrkA-C domain protein; DUF318. |
Bacteria | Bacillota | TrkA-C domain protein of Bacillus selenitireducens (A8VTI4) |
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2.A.119.1.3 | The putative 8 TMS MmarC7_1204 protein |
Archaea | Euryarchaeota | The MmarC7_1204 protein of Methanococcus maripaludis (A6VIJ1) |
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2.A.119.1.4 | Uncharacterized protein of 297 aas and 8 TMSs in a 4 + 4 arrangement. |
Bacteria | Pseudomonadota | UP of Xenorhabdus budapestensis |
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2.A.119.1.5 | Uncharacterized protein of 8 TMSs in a 4 + 4 arrangement. |
Bacteria | Pseudomonadota | UP of Pseudomonas aeruginosa |
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2.A.119.1.6 | Zn2+/Cd2+/Cu2+ efflux pump of 491aas and 8 TMSs (Deutschbauer et al. 2011). |
Bacteria | Pseudomonadota | Heavy metal exporter of Shewanella oneidensis |
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2.A.119.2.1 | The 8 TMS Clohylem_07038 protein |
Bacteria | Bacillota | The Clohylem_07038 protein of Clostridium hylemonae (C0C4M2) |
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2.A.119.2.2 | Uncharacterized protein of 316 aas and 8 TMSs. Designated as a member of the DUF2899 family. |
Bacteria | Actinomycetota | UP of Enterorhabdus caecimuris |
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2.A.119.2.3 | Uncharacterized protein of 285 aas with 8 TMSs in a 4 + 4 arrangement. |
Bacteria | Actinomycetota | UP of Collinsella tanakaei |
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2.A.119.2.4 | Uncharacterized protein of 369 aas and 8 TMSs in a 4 + 4 arrangement. |
Bacteria | Bacillota | UP of Acidaminococcus sp. CAG:917 |
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2.A.119.2.5 | Uncharacterized protein of 318 aas and 8 TMSs in a 4 + 4 arrangement. |
Archaea | Euryarchaeota | UP of Methanosarcina barkeri |
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2.A.119.3.1 | The DUF2899 protein with 404 aa and 10 putative TMSs in an apparent 2 + 3 + 2 + 3 arrangement. |
Bacteria | Pseudomonadota | Vibrio harveyi (A6AW26) |
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2.A.119.3.2 | Uncharacterized DUF2899 protein of 280 aas. |
Bacteria | Ignavibacteriota | UP of Ignavibacterium album |
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2.A.119.3.3 | Uncharacterized protein of 419 aas and 10 putative TMSs in a 4 + 2 + 4 TMS arrangement. |
Archaea | Euryarchaeota | UP of Halopelagius longus |
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2.A.119.3.4 | Uncharacterized protein of 390 aas and 11 putative TMSs in a 5 + 2 + 4 arrangement. |
Bacteria | Pseudomonadota | UP of Pseudoalteromonas lipolytica |
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2.A.119.3.5 | Uncharacterized protein of 374 aas and 10 TMSs in a 4 + 2 + 4 TMS arrangement. |
Bacteria | Bacillota | UP of Paeniclostridium sordellii |
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2.A.119.3.6 | Uncharacterized protein of 296 aas and 11 TMSs in a 2 + 3 + 2 + 4 arrangement. |
Bacteria | Pseudomonadota | UP of Grimontia celer |
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2.A.119.3.7 | Uncharacterized protein of 392 aas and 12 TMSs in a 3 + 3 + 2 + 3 + 1 arrangement. |
Bacteria | Pseudomonadota | UP of Albidovulum xiamenense |
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2.A.119.3.8 | Uncharacterized protein of 287 aas and 10 TMSs in a 5 + 5 arrangement. |
Archaea | Candidatus Woesearchaeota | UP of Candidatus Woesearchaeota archaeon |
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2.A.12.1.1 | ATP:ADP antiporter (transports ATP and ADP but not dATP, dADP, ddATP or ddADP), Tlc1 (Daugherty et al., 2004) | Bacteria | Pseudomonadota | ATP/ADP translocase (Tlc1) of Rickettsia prowazekii (spP19568) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.12.1.10 | The microsporidial ATP/ADP exchanger, NTT1 (Km= 11μM; cell surface localized when in the host cell; Tsaousis et al. 2008). | Eukaryota | Fungi, Microsporidia | NTT1 of Encephalitozoon cuniculi (Q8SRA2) |
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2.A.12.1.11 | The microsporidial ATP/ADP exchanger, NTT2 (Km= 20μM; present in spores; localized to the cell surface; Tsaousis et al., 2008). | Eukaryota | Fungi, Microsporidia | NTT2 of Encephalitozoon cuniculi (Q8SUF9) |
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2.A.12.1.12 | The microsporidial ATP/ADP exchanger, NTT3 (Km= 24μM; present in mitosomes; Tsaousis et al., 2008). | Eukaryota | Fungi, Microsporidia | NTT3 of Encephalitozoon cuniculi (Q8SUG0) |
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2.A.12.1.13 | The microsporidial ATP/ADP exchanger, NTT4 (Km= 2μM; present on the cell surface when in the host cell; Tsaousis et al., 2008). | Eukaryota | Fungi, Microsporidia | NTT4 of Encephalitozoon cuniculi (Q8SUG7) |
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2.A.12.1.14 | The nucleotide (ATP/ADP) exchanger NTT1 (Schmitz-Esser et al., 2008) (KMs for ATP and ADP ~ 250 μM) | Bacteria | Thermodesulfobacteriota | NTT1 of Lawsonia intracellularis (B0RZB7) |
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2.A.12.1.15 | High affinity ATP/ADP antiporter of 469 aas and 12 TMSs, NttA. Probably also transporters other nucleotides with low affinity (Vahling et al. 2010). |
Bacteria | Pseudomonadota | NttA of Liberibacter asiaticus (Citrus greening disease) (Liberobacter asiaticum) |
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2.A.12.1.16 | ATP:ADP antiporter of 624 aas and 12 TMSs, AATP1. Transports ATP and ADP in a counterflow reaction. The apparent Km value for ATP was reported to be 28 μM (Neuhaus et al. 1997). In Solanum tuberosum (potato), inhibition of the orthologous AATP1 transporter resulted in greater resistance to the soft rot-causing pathogen, Erwinia carotovora subsp. atroseptica (Linke et al. 2002) and the pathogenic fungus, Alternaria solani (Conrath et al. 2003). |
Eukaryota | Viridiplantae, Streptophyta | Adenylate translocator-1 (AATP1) of Arabidopsis thaliana (gbZ49227) |
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2.A.12.1.17 | Nucleoside triphosphate:H+ symporter. Transports ATP, GTP, CTP and UTP (Tjaden et al. 1999). |
Bacteria | Chlamydiota | Npt2 of Chlamydia trachomatis (gbAE001323) |
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2.A.12.1.18 | NAD+:ADP antiporter, Ntt4 (Haferkamp et al., 2006) | Bacteria | Chlamydiota | Ntt4 of Candidatus Protochlamydia amoeboophila (Q6MDZ0) |
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2.A.12.1.19 | Chloroplast inner envelope ATP/ADP antiporter, AATP2, of 618 aas and 12 TMSs. The apparent Km values for ATP and ADP were reported to be 22 μM and 20 μM, respectively. (Möhlmann et al. 1998). |
Eukaryota | Viridiplantae, Streptophyta | AATP2 of Arabidopsis thaliana (Mouse-ear cress) |
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2.A.12.1.2 | ATP:ADP antiporter, Npt1 (Tjaden et al. 1999). Also transports NAD as a preferred substrate (Fisher et al. 2013). |
Bacteria | Chlamydiota | Npt1 of Chlamydia trachomatis (gbAE001281) |
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2.A.12.1.3 | Nucleotide antiporter (binds and probably transports ATP, dATP, ddATP, ADP, dADP and ddADP (deoxy on the sugar moiety) but not AMP, UTP, CTP or GTP) (Daugherty et al., 2004) | Bacteria | Proteobacteria | Nucleotide antiporter of Caedibacter caryophilus (CAD29686) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.12.1.4 | The nucleotide (CTP, UTP, GDP) (GTP inhibits but is not transported) (Audia and Winkler, 2006) | Bacteria | Pseudomonadota | Tlc4 of Rickettsia prowazekii (Q9ZD47) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.12.1.5 | The GTP/GDP transporter, Tlc5 (Audia and Winkler, 2006) | Bacteria | Pseudomonadota | Tlc5 of Rickettsia prowazekii (O05962) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.12.1.6 | ATP/ADP antiporter, Ntt1 (Haferkamp et al., 2006; Trentmann et al., 2007) | Bacteria | Chlamydiota | Ntt1 of Candidatus protochlamydia amoebophila (Q6MEM5) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.12.1.7 | NTP (all four ribonucleoside triphosphates) antiporter, Ntt2 (Haferkamp et a;., 2006) | Bacteria | Chlamydiota | Ntt2 of Candidatus protochlamydia amoebophila (Q6MEN4) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.12.1.8 | UTP:H+ symporter, Ntt3 (Haferkamp et al., 2006) | Bacteria | Chlamydiota | Ntt3 of Candidatus protochlamydia amoebophila (Q6MEN5) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.12.1.9 | GTP/ATP:H+ symporter, Ntt5 (Haferkamp et al., 2006) | Bacteria | Chlamydiota | Ntt5 of Candidatus protochlamydia amoebophila (Q6MBI2) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.12.2.1 | AAA family homologue of 927 aas with an N-terminal 12 TMS MFS domain and a C-terminal fairly hydrophilic "lipodomain" not recognized by CDD. |
Bacteria | Chlamydiota | AAA family homologue of Chlamydia trachomatis |
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2.A.12.2.2 | AAA family member of 878 aas with an N-terminal 12 TMS MFS domain and a long (~450 aa) hydrophilic extension containing at least one internal HEAT_2 domain. |
Bacteria | Pseudomonadota | AAA family member of Novosphingobium sp. PP1Y |
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2.A.120.1.1 | Putative permease of 349 aas |
Bacteria | Bacillota | PP of Staphylococcus epidermidis |
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2.A.120.1.10 | Putative amino acid transporter, YkvI |
Bacteria | Bacillota | YkvI of Bacillus subtilis |
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2.A.120.1.11 | Putative amino acid uptake porter of 700 aas, BrkK, with a C-terminal Lactamase B domain. |
Bacteria | Bacillota | BrkK of Eubacterium brachy |
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2.A.120.1.12 | Putative alanine:sodium symporter |
Bacteria | Bacillota | Putative transporter of Mogibacterium sp. |
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2.A.120.1.13 | Uncharacterized protein |
Archaea | Thermoproteota | UP of Caldivirga maquilingensis |
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2.A.120.1.14 | Proline transporter, ProT, of 355 aas and 10 TMSs in a 2 + 3 + 2 + 3 TMS arrangement. It is a major proline uptake transporter in S. aureus and is required for infection in skin and soft tissues. In minimal medium it is the major proline uptake porter (Lehman et al. 2023). Its ortholog in S. carnosis (TC# 2.A.120.1.8) is 71% identical to this protein. |
Bacteria | Bacillota | ProT of Staphylococcus aureus |
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2.A.120.1.2 | Putative permease of 372 aas |
Bacteria | Bacillota | PP of Coprococcus catus |
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2.A.120.1.3 | Putative permease of 496 aas |
Bacteria | Bacillota | PP of Clostridium botulinum |
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2.A.120.1.4 | Putative permease of 378 aas |
Bacteria | Pseudomonadota | PP of Sphingopyxis alaskensis |
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2.A.120.1.5 | Putative permease of 378 aas |
Archaea | Euryarchaeota | PP of Pyrococcus horikoshii |
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2.A.120.1.6 | Putative permease of 326 aas |
Bacteria | Bacillota | PP of Caldicellulosiruptor kristjanssonii |
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2.A.120.1.7 | Putative permease of 358 aas |
Bacteria | Bacillota | PP of Desulfotomaculum acetoxidans |
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2.A.120.1.8 | Putative permease of 355 aas, ProT. It is 71% identical to the S. aureus ortholog, ProT (TC# 2.A.120.1.14), which has been shown to be the major proliine uptake transporter in S. aureus and is essential for infections in skin and soft tissues when external proline is provided as a source of this amino acid in minimal growth media (Lehman et al. 2023). |
Bacteria | Bacillota | ProT of Staphylococcus carnosus |
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2.A.120.1.9 | Putative amino acid transporter, YyaD, which possibly plays a role in sporulation. |
Bacteria | Bacillota | YyaD of Bacillus subtilis |
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2.A.121.1.1 | Sulfate transporter, CysZ. Part of the cysteine biosynthetic pathway; allosterically inhibited by the biosynthetic intermediate, sulfite (Zhang et al. 2014). |
Bacteria | Pseudomonadota | CysZ of E. coli (POA6J3) |
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2.A.121.1.2 | CysZ homologue |
Bacteria | Actinomycetota | CysZ homologue of Streptomyces coelicolor |
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2.A.121.1.3 | Uncharacterized protein, CysZ homologue. |
Bacteria | Pseudomonadota | CysZ homologue of Idiomarina loihiensis |
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2.A.121.1.4 | Sulfate uptake porter of 246 aas and 4 or 5 TMSs. CysZ from Pseudomonas denitrificans assembles as a trimer of antiparallel dimers, and the CysZ structures from two other species recapitulate dimers from this assembly. Mutational studies highlighted the functional relevance of conserved CysZ residues (Assur Sanghai et al. 2018). |
Bacteria | Pseudomonadota | CysZ of Pseudomonas denitrificans |
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2.A.121.2.1 | Putative sulfate uptake transporter of 5 TMSs, YAL018c |
Eukaryota | Fungi, Ascomycota | YAL018c of Saccharomyces cerevisiae (P31379) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.121.2.10 | Uncharacterized protein of 367 aas and 4 or 5 TMSs |
Eukaryota | Fungi, Basidiomycota | UP of Tremella mesenterica |
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2.A.121.2.11 | Uncharacterized protein of 288 aas and 4 or 5 TMSs |
Eukaryota | Fungi, Basidiomycota | UP of Phlebiopsis gigantea |
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2.A.121.2.12 | Uncharacterized protein of 282 aas and 5 TMSs. |
Eukaryota | Fungi, Basidiomycota | UP of Neolentinus lepideus |
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2.A.121.2.13 | Uncharacterized protein of 345 aas and 5or 6 TMSs. |
Eukaryota | Fungi, Mucoromycota | UP of Mortierella verticillata |
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2.A.121.2.2 | The Rrt8p protein of 342 aas. |
Eukaryota | Fungi, Ascomycota | Rrt8p of Saccharomyces cerevisiae (Q08219) |
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2.A.121.2.3 | Uncharacterized protein of 429 aas and 5 TMSs. |
Eukaryota | Fungi, Ascomycota | UP of Aspergillus niger (E2PST1) |
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2.A.121.2.4 | CysZ homologue |
Eukaryota | Fungi, Ascomycota | CysZ homologue of Fusarium oxysporum |
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2.A.121.2.5 | The YOL047C protein |
Eukaryota | Fungi, Ascomycota | YOL047C of Saccharomyces cerevisiae (Q08218) |
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2.A.121.2.6 | Putative sulfate uptake porter of 288 aas and 4 or 5 TMSs. |
Eukaryota | Fungi, Ascomycota | CysZ homologue of Neurospora crassa |
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2.A.121.2.7 | Uncharacterized protein of 261 aas and 4 or 5 TMSs. |
Eukaryota | Oomycota | UP of Phytophthora parasitica |
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2.A.121.2.8 | Uncharacterized protein of 226 aas and 4 or 5 TMSs. |
Eukaryota | Fungi, Ascomycota | UP of Ashbya gossypii (Yeast) (Eremothecium gossypii) |
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2.A.121.2.9 | Uncharacterized protein of 309 aas and 5 TMSs |
Eukaryota | Fungi, Ascomycota | UP of Pseudomassariella vexata |
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2.A.121.3.1 | Etoposide-induced protein 2.4, isoform 1, Ei24, or p53-induced gene 8 protein, PIG8. This protein is a apoptosis/autophagy factor (Rømer et al. 2008; Bahk et al. 2010). |
Eukaryota | Metazoa, Chordata | Ei24 or Homo sapiens |
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2.A.121.3.2 | Uncharacterized protein |
Eukaryota | CysZ homologue of Monosiga brevicollis |
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2.A.121.3.3 | Ei24 superfamily homologue |
Eukaryota | Viridiplantae, Streptophyta | Ei24 homologue of Arabidopsis thaliana |
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2.A.121.4.1 | The bacterial 4TMS CysZ homologue |
Bacteria | Campylobacterota | CysZ homologue of Campylobacter coli (E0QD93) |
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2.A.121.4.2 | 5TMS Hypothetical protein, HP |
Bacteria | Campylobacterota | HP of Helicobacter pylori (E6S4S3) |
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2.A.121.4.3 | Unnamed protein |
Bacteria | Pseudomonadota | Unnamed protein of Bartonella clarridgeiae (E6YFT5) |
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2.A.121.4.4 | CysZ homologue |
Bacteria | Pseudomonadota | CysZ homologue of Sideroxydans lithotrophicus |
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2.A.121.4.5 | Uncharacterized protein of 298 aas and 7 TMSs |
Bacteria | Campylobacterota | UP of Nautilia profundicola |
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2.A.121.4.6 | Uncharacterized protein of 231 aas and 5 TMSs |
Bacteria | Spirochaetota | UP of Leptospira interogans |
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2.A.121.4.7 | Uncharacterized protein of 389 aas and 11 TMSs |
Bacteria | Bacteroidota | UP of Bacteroides clarus |
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2.A.121.4.8 | UP of 279 aas and 8 TMSs |
Archaea | Candidatus Lokiarchaeota | UP of Lokiarchaeum sp. GC14_75 |
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2.A.122.1.1 | LrgB (YohK) protein (putative murein hydrolase export regulator; LrgA-associated protein) (7 probable TMSs based on topological analyses. This protein and 2.A.122.1.2 with 8 TMSs appear to derive from a 4 TMS precursor that duplicated to give 8, and LrgB may have lost TMS 1. It does not appear to be a member of the TOG superfamily.). LrgB decreases antibiotic sensitivity (Yang et al., 2005). More recently, it was suggested to be a 3-hydroxypropionate exporter, functioning together with YhoJ ( 1.E.14.1.4) of 132 aas and 4 TMSs (Nguyen-Vo et al. 2020). |
Bacteria | Pseudomonadota | LrgB of E. coli (C6EAH0) |
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2.A.122.1.2 | Putative holin-mediated export regulatory protein, CidB (8 TMSs with an internal repeat of 4 TMSs). It enhances antibiotic sensitivity (Yang et al., 2005). CidA is a holin-like protein (TC# 1.E.14.1.2). The cidABC operon is controlled by CidR, an activator in the presence of acetic acid (Yang et al., 2005). |
Bacteria | Bacillota | CidB of Staphylococcus aureus (H4HJS5) |
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2.A.122.1.3 | Putative antiholin-like protein of 233 aas and 8 TMSs, LrgB (Chu et al. 2013). Proposed to function together with LrgA as a holin/antiholin pair to export autolysins, LytM and LytN. However, the identification of a larger fused plant homologue (9.B.117.1.4) as a plastidic glycolate glycerate transporter (Pick et al. 2013) sheds doubt on this proposal. |
Bacteria | Bacillota | LrgB of Staphylococcus aureus |
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2.A.122.1.4 | Putative murein hydrolase export regulator LrgB of 231 aas and 8 putative TMSs (Ahn et al. 2010). |
Bacteria | Bacillota | Putative murein hydrolase export regulator, LrgB, of Streptococcus mutans |
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2.A.122.1.5 | Putative antiholin of 225 aas and 6 TMSs, LrgB or YwbG (Chen et al. 2015). Inhibits the activity of putative holin, CidA or YwbH (TC# 1.E.14.1.16). |
Bacteria | Bacillota | YwbG of Bacillus subtilis |
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2.A.122.1.6 | Putative antiholin of 231 aas and 8 TMSs, YsbB or LrgB (Chen et al. 2015). Believed to counteract the holin activity of YsbA (TC# 1.E.14.1.17). |
Bacteria | Bacillota | YsbB of Bacillus subtilis |
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2.A.122.1.7 | Putative anit-holin, YxaC of 230 aas and 6-8 TMSs (Chen et al. 2015). |
Bacteria | Bacillota | YxaC of Bacillus subtilis |
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2.A.122.1.8 | Uncharacterized LrgB family protein of 228 aas and 6 TMSs in a 4 + 1 + 1 TMS arrangement. |
Bacteria | Pseudomonadota | UP of Klebsiella pneumoniae |
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2.A.122.2.1 | Plastidic glycolate glycerate transporter, PLGG1, of 512 aas and 12 TMSs (Pick et al. 2013). The last TMSs are homologous to the TMSs in several CidB and LrgB proteins of bacteria. This plant protein may represent a fusion of the bacterial LrgA and LrgB proteins (Yang et al. 2012; Wang and Bayles 2013). Rice OsPLGG1 is the ortholgous plastidic glycolate/glycerate transporter, which is necessary for photorespiration and growth in rice (Shim et al. 2019). Thus, loss of function of rice plastidic glycolate/glycerate translocator 1 impairs photorespiration and plant growth (Shim et al. 2019). |
Eukaryota | Viridiplantae, Streptophyta | PLGG1 of Arabidopsis thaliana |
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2.A.122.2.2 | LrgB1 of 519 aas and 15 putative TMSs. |
Eukaryota | Viridiplantae, Streptophyta | LrgB1 of Oryza sativa |
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2.A.122.2.3 | LrgB2 of 458 aas and 12 - 14 TMSs. |
Eukaryota | Viridiplantae, Streptophyta | LrgB2 of Oryza sativa |
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2.A.122.2.4 | LrgB of 455 aas (Wang and Bayles 2013). |
Eukaryota | Viridiplantae, Chlorophyta | LrgB of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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2.A.122.2.5 | LrgB1 of 455 aas (Wang and Bayles 2013). |
Eukaryota | Bacillariophyta | LrgB1 of Thalassiosira pseudonana (Marine diatom) (Cyclotella nana) |
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2.A.122.2.6 | LrgB2 of 413 aas (Wang and Bayles 2013). |
Eukaryota | Bacillariophyta | LrgB2 of Thalassiosira pseudonana (Marine diatom) (Cyclotella nana) |
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2.A.122.3.1 | Uncharacterized protein of 604 aas and 11 TMSs. |
Eukaryota | Fungi, Ascomycota | UP of Trichoderma harzianum |
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2.A.123.1.1 | Alfalfa Nodulin MtN3 |
Eukaryota | Viridiplantae, Streptophyta | MtN3 of Medicago truncatula (P93332) |
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2.A.123.1.10 | Golgi/E.R. Sweet1 glucose/galactose facilitator (Km ≥ 50mM) (Chen et al. 2010) |
Eukaryota | Metazoa, Nematoda | Sweet1 of Caenorhabditis elegans (O45102) |
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2.A.123.1.11 | The sea squirt sugar transporter, Rga or Sweet1; required for normal development (Hamada et al., 2007; Chen et al., 2010). |
Eukaryota | Metazoa, Chordata | Rga of Ciona intestinalis (F6U696) |
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2.A.123.1.12 | Sugar transporter SWEET1 (Protein saliva) | Eukaryota | Metazoa, Arthropoda | Slv of Drosophila melanogaster |
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2.A.123.1.13 | Bidirectional sugar (sucrose) transporter SWEET11 (AtSWEET11). Oligomerization, probably to the dimeric form, has been demonstrated (Xuan et al. 2013). Important for phloem loading. |
Eukaryota | Viridiplantae, Streptophyta | SWEET11 of Arabidopsis thaliana |
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2.A.123.1.14 | Sugar transporter SWEET1 | Eukaryota | Evosea | slc50a1 of Dictyostelium discoideum | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.123.1.15 | SWEET homologue of 375 aas and 7 TMSs in a 3 + 4 arrangement. |
Eukaryota | Bacillariophyta | SWEET homologue of Phaeodactylum tricornutum |
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2.A.123.1.16 | Uncharacterized protein of 262 aas and 7 TMSs |
Eukaryota | Rhodophyta | UP of Galdieria sulphuraria (Red alga) |
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2.A.123.1.17 | MtN3-like protein of 686 aas and 7-8 TMSs, 1 N-terminal and 7 between residues 380 and 590. |
Eukaryota | Apicomplexa | MtN3-like protein of Plasmodium falciparum |
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2.A.123.1.18 | SWEET2b sugar transporter. Sequesters sugars in root vacuoles. The 3-d structure is known. The subunit consists of two asymetic triple helix bundles (TMSs 1-3 and 5-7) connected by TMS4. SWEET2b is in an apparent inward (cytosolic) open state forming homomeric trimers. TMS4 tightly interacts with the first triple-helix bundle within a protomer and mediates key contacts among protomers (Tao et al. 2015). |
Eukaryota | Viridiplantae, Streptophyta | SWEET2b of Oryza sativa |
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2.A.123.1.19 | Sweet1 (SLC50A1). 99.6% identical to the goat (Capra hircus) mammary gland epithelial homologue which has been characterized (Zhu et al. 2015). |
Metazoa, Chordata | Sweet1 of Ovis aries (sheep) |
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2.A.123.1.2 |
Sweet family member of 305 aas and 7 TMSs. Mediates both low-affinity uptake and efflux of sugars across the membrane. (Wu et al., 2008) |
Eukaryota | Viridiplantae, Streptophyta | Sweet of Citrus clementina |
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2.A.123.1.20 | Uncharacterized protein of 197 aas and 7 TMSs |
Bacteria | Actinomycetota | UP of Acidimicrobium sp. BACL27 |
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2.A.123.1.21 | Uncharacterized duplicated protein of 709 aas and 15 TMSs in a 7 + 7 + 1 arrangement. The protein contains two 7 TMS Sweet domains followed by an Atrophin-1 domain. There is no close homologue in the NCBI database, suggesting that it could be a result of a sequencing artifact. |
Eukaryota | Viridiplantae, Streptophyta | UP of Ananas comosus |
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2.A.123.1.22 | Uncharacterized protein of 1089 aas and 28 TMSs in a 7 + 7 + 7 + 7 arrangement. |
Eukaryota | Oomycota | UP of Phytophthora ramorum (Sudden oak death agent) |
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2.A.123.1.23 | Vacuolar hexose (fructose) transporter of 230 aas and 7 TMSs, Sweet16 (Eom et al. 2015). It plays an iimportant role in cold tolerance (Wang et al. 2018). |
Eukaryota | Viridiplantae, Streptophyta | Sweet16 of Arabidopsis thaliana (Mouse-ear cress) |
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2.A.123.1.24 | Sweet9 of 258 aas and 7 TMSs. Important for nectar secretion (Eom et al. 2015). |
Eukaryota | Viridiplantae, Streptophyta | Sweet9 of Arabidopsis thaliana (Mouse-ear cress) |
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2.A.123.1.25 | Sweet family member of 89 aas and 3 TMSs. Associated with a trehalose phosphatase, possibly suggesting al role in trehalose transport. |
Archaea | Euryarchaeota | Semi-sweet of Methanobacterium lacus |
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2.A.123.1.26 | Sweet13 (Sweet12) of 294 aas and 7 TMSs. Both Sweet13 and 14 transport the plant hormone, gibberellin (GA). A double mutant has a defect in anther dehiscence. This mutant also exhibits altered long distant transport of exogenously applied GA and altered responses to GA during germination and seedling stages (Kanno et al. 2016). In dragon fruit (pitaya; H. undatus) Sweets function in phloem loading, seed filling, nectar secretion, and fruit sweetness development (Jiang et al. 2023). Novel transport-enhancing mutations have been isolated (Narayanan et al. 2024). |
Eukaryota | Viridiplantae, Streptophyta | SWEET13 of Arabidopsis thaliana (Mouse-ear cress) |
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2.A.123.1.27 | SWEET transporter 1 of 262 aas and 7 TMSs. Plays a role in the D. officinale symbiotic germination process (Zhang et al. 2016). This organism provides a traditional chinese medicine. There are 25 SWEET genes in this organism (Hao et al. 2023). Most have 7 TMSs and contain two conserved MtN3/saliva domains. They were divided into four clades, and are found in various tissues. Sixteen were significantly regulated under cold, drought, and MeJA treatment (Hao et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | Sweet transporter of Dendrobium officinale |
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2.A.123.1.28 | Bidirectional sugar transporter, SWEET2a, of 2243 aas and 7 TMSs. It mediates both low-affinity uptake and efflux of sugars across the plasma membrane and plays a role in early seed development in Litchi chinensis (Xie et al. 2019). |
Eukaryota | Viridiplantae, Streptophyta | SWEET2a of Oryza sativa subsp. japonica (Rice) |
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2.A.123.1.29 | Bidirectional sugar transporter SWEET3b of 2252 aas and 7 TMSs. It mediates both low-affinity uptake and efflux of sugars across the plasma membrane and plays a role in early seed development in Litchi chinensis (Xie et al. 2019). |
Eukaryota | Viridiplantae, Streptophyta | SWEET3b of Oryza sativa subsp. japonica (Rice) |
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2.A.123.1.3 | Senescence-associated protein 29, SAG29 (SWEET15) of 292 aas and 7 TMSs. The maize sugar transporters ZmSWEET15a and ZmSWEET15b positively regulate salt tolerance in plant (Wang et al. 2024). |
Eukaryota | Viridiplantae, Streptophyta | SAG29 of Arabidopsis thaliana (Q9FY94) |
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2.A.123.1.30 | Bidirectional sugar transporter SWEET7, of 258 aas and 7 TMSs. It mediates both low-affinity uptake and efflux of sugar across the plasma membrane. AtSWEET7 transports glucose and xylose simultaneously with no inhibition (Kuanyshev et al. 2021).
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Eukaryota | Viridiplantae, Streptophyta | SWEET7 of Arabidopsis thaliana (Mouse-ear cress) |
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2.A.123.1.4 |
Stromal cell protein (SCP) homologue, HsSWEET1 or RAG1AP1. Transports glucose and galactose bidirectionally. Present in the ER, Golgi and plasma membrane (Chen et al., 2010). |
Eukaryota | Metazoa, Chordata | SLC50A1 of Homo sapiens |
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2.A.123.1.5 |
Ruptured pollen Grain-1, Sweet8 or Nodulin MtN3 family protein (essential for pollen viability). (Guan et al., 2008; Chen et al. 2010). |
Eukaryota | Viridiplantae, Streptophyta | RPGI of Arabidoposis thaliana (Q8LFH5) |
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2.A.123.1.6 | Host disease susceptible protein, Xa13 or Os8N3, for bacterial blight (Yang et al., 2006; Chu et al., 2006). Bidirectional sugar transporter, Sweet 11 (Chen et al., 2010) |
Eukaryota | Viridiplantae, Streptophyta | Oryza sativa (Q6YZF3) |
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2.A.123.1.7 | Nec1; predominantly expressed in nectaries; involved in sugar metabolism and nectar secretion (Ge et al., 2000) |
Eukaryota | Viridiplantae, Streptophyta | Nec1 of Petunia hybrida (Q9FPN0) |
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2.A.123.1.8 | Rga (Recombination-activating gene 1) (Hamada et al., 2005) |
Eukaryota | Metazoa, Chordata | Rga of Mus musculus (Q9CXK4) |
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2.A.123.1.9 | Sweet1: bidirectional low affinity glucose uniporter, Km = ~9 mM (Does not transport mannose, fructose or galactose) (Chen et al. 2010). The structure is know, and three regions, each containing several well conserved essential residues, comprise the substrate-binding pocket, the extrafacial gate, and the intrafacial gate (Xuan et al. 2013; Tao et al. 2015). The orthologous SWEET1 in Camellia sinensis (tea) transports glucose, glucose analogues, and other hexoses (Wang et al. 2018). |
Eukaryota | Viridiplantae, Streptophyta | Sweet1 of Arabidopsis thalinana (Q8L9J7) |
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2.A.123.2.1 | The 7 TMS (242aa) bacterial MtN3 homologue |
Bacteria | Mycoplasmatota | MtN3 homologue of Mycoplasma arthritidis (B3PMT4) |
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2.A.123.2.10 | SWEET homologue of 125 aas and 3 TMSs; resembles 2.A.123.2.3 with all 3 TMSs overlapping. |
Oomycota | SWEET homologue of Phytophthora sojae (Soybean stem and root rot agent) (Phytophthora megasperma f. sp. glycines) |
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2.A.123.2.11 | SWEET homologue of 125 aas and 3 TMSs. Closely related to 2.A.123.2.10. |
Eukaryota | Oomycota | SWEET homologue of Phytophthora parasitica |
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2.A.123.2.12 | SWEET homologue of 84 aas and 3 TMSs |
Archaea | Euryarchaeota | SWEET homologue of Methanocella conradii |
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2.A.123.2.13 | Uncharacterized protein of 728 aas and 5 putative TMSs with 4 N-terminal TMSs, where the first 3 are homologous to semisweets of 3 TMSs. The long sequence with one large centrally located peak of hydrophobicity includes several recognized protein domains following the SWEET domain in the following order: Cache-3 - Cache-1 - dimerization interface domain - HAMP domain - followed by two PAS domains. Another protein (UniProt acc #I3IJJ5 of 762 aas), has residues 3 - 635 aas) showing 83% sequence identity with residues 96 - 728 in 2.A.123.2.13. |
Bacteria | Planctomycetota | UP of Candidatus Jettenia caeni |
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2.A.123.2.14 | SemiSWEET of 86 aas and 3 TMSs specific for sucrose. The basic unit of SWEETs may be a 3-TMS unit, and it has been suggested that a functional transporter contains at least four such domains, although this suggestion has not been substantiated (Xuan et al. 2013). |
Bacteria | Pseudomonadota | SemiSWEET of Bradyrhizobium diazoefficiens |
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2.A.123.2.15 | Putative uncharacterized protein of 99 aas and 3 TMSs |
Bacteria | Candidatus Saccharibacteria | Hypothetical protein UW38 of Candidatus Saccharibacteria bacterium |
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2.A.123.2.16 | Facilitated glucose/sucrose/sugar/monoolein transporter of 89 aas and 3 TMSs. The homodimer mediates transmembrane sugar transport down a concentration gradient. Transport is probably effected by rocking-type movements, where a cargo-binding cavity opens first on one and then on the other side of the membrane (Lee et al. 2015). |
Bacteria | Pseudomonadota | Semisweet sugar transporter of E. coli |
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2.A.123.2.2 | 3 TMS MtN3 homologue (85aas) |
Bacteria | Cyanobacteriota | MtN3 of MtN3 of Prochlorococcus marinus (A2BS89) |
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2.A.123.2.3 | Half sized (3 TMS) bacterial MtN3 protein homologue (85aas) |
Bacteria | Fusobacteriota | MtN3 homologue of Fusobacterium mortiferum (C3WG44) |
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2.A.123.2.4 | 3 TMS bacterial MtN3 homologue (96aas) |
Bacteria | Spirochaetota | MtN3 homologue of Leptospira interrogans (Q8F4F7) |
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2.A.123.2.5 | 3 TMS Sweet homologue, MJ_0110 (93aas) |
Archaea | Euryarchaeota | MJ_0110 of Methanocaldococcus jannashii (Q57574) |
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2.A.123.2.6 | SemiSWEET half glucose transporter of 93 aas and 3 TMSs with an N-terminal amphipathic α-helix. The protein occurs as a tight homodimer with the translocation channel between the two monomers. The 3-d structure is known at 2.4 Å resolution revealing the outward open conformation (Xu et al. 2014). The occluded state of the Vibrio sp. N418 SemiSWEET (9.A.58.3.1) has been solved at 1.7 Å resolution (Xu et al. 2014). The presence of these two states argues in favor of a carrier (rocker switch) mechanism rather than a channel-type mechanism (Xu et al. 2014). |
Bacteria | Spirochaetota | SemiSWEET of Leptospira biflexa |
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2.A.123.2.7 | SemiSWEET homologue of 89 aas and 3 TMSs |
Bacteria | Pseudomonadota | SemiSWEET of Rickettsia bellii |
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2.A.123.2.8 | SWEET homologue of 141 aas and 4 putative TMSs. |
Bacteria | Cyanobacteriota | SWEET homologue of Anabaena variabilis |
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2.A.123.2.9 | SWEET homologue of 231 aas and 7 TMSs |
Bacteria | Mycoplasmatota | SWEET homologue of Mycoplasma hyopneumoniae |
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2.A.123.3.1 | SemiSWEET half putative sugar transporter of 97 aas and 3 TMSs with an N-terminal amphipathic α-helix. The protein occurs as a tight homodimer with the translocation channel between the two monomers. The 3-d structure is known at 1.7 Å resolution revealing the occluded conformation (Xu et al. 2014). The outward open state of the Leptospira biflexa SemiSWEET (2.a.123.2.6) has been solved at 2.4 Å resolution (Xu et al. 2014). The presence of these two states argues in favor of a carrier (rocker switch) mechanism rather than a channel-type mechanism (Xu et al. 2014). |
Bacteria | Pseudomonadota | SemiSWEET of Vibrio sp. N418 |
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2.A.123.3.2 | Uncharacterized protein of 107 aas. |
Bacteria | Pseudomonadota | UP of Rhodobacteraceae bacterium KLH11 |
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2.A.123.3.3 | Uncharacterized conserved protein of 273 aas and 7 TMSs containing PQ loop repeats. |
Bacteria | Actinomycetota | UP of Geodermatophilus obscurus |
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2.A.123.3.4 | Uncharacterized protein of 97 aas and 3 TMSs. |
Bacteria | Pseudomonadota | UP of Photobacterium leiognathi |
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2.A.123.4.1 | Membrane protein of 209 aas and 7 TMSs with a putative N-terminal lipid A disaccharide synthase domain. This protein is a member of the "Lipid A Biosynthesis, N-terminal (LAB_N) domain in Pfam/CDD, related to the SWEET family. |
Bacteria | Bacteroidota | Membrane protein of Gramella forsetii |
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2.A.123.4.2 | Uncharacterized protein of 115 aas and 3 TMSs. |
Bacteria | Pseudomonadota | UP of Frateuria aurantia (Acetobacter aurantius) |
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2.A.123.4.3 | Uncharacterized protein (putative lipid A synthesis protein domain) of 115 aas and 3 TMSs. |
Bacteria | Pseudomonadota | UP of Stenotrophomonas maltophilia (Pseudomonas maltophilia) (Xanthomonas maltophilia) |
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2.A.123.5.1 | Uncharacterized protein of 208 aas and 2 N-terminal TMSs. |
Bacteria | Balneolota | UP of Balneolaceae bacterium (soda lake metagenome) |
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2.A.123.5.2 | Uncharacterized protein of 207 aas and 2 or 3 N-terminal TMSs |
Bacteria | Actinomycetota | UP of Serinicoccus sediminis |
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2.A.123.5.3 | Uncharacterized protein of 204 aas and 3 N-terminal TMSs followed by a large hydrophilic domain, characteristic of this subfamily (TC# 2.A.123.5). |
Bacteria | Actinomycetota | UP of Janibacter terrae (hydrocarbon metagenome) |
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2.A.123.5.4 | Uncharacterized protein of 210 aas and 3 N-terminal TMSs. |
Bacteria | Bacteroidota | UP of Chitinophagaceae bacterium (ecological metagenome) |
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2.A.123.5.5 | Uncharacterized protein of 207 aas and 3 or more TMSs |
Euryarchaeota | UP of Methanohalobium evestigatum |
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2.A.124.1.1 | The lysine exporter, LysO of 299 aas and 9 putative TMSs (Pathania and Sardesai 2015). Also exports the toxic lysine antimetabolite, thialysine. Topological analyses of LysO revealed a critical role for a conserved pair of intramembrane solvent-exposed acidic residues (Dubey et al. 2021). |
Bacteria | Pseudomonadota | LysO of E. coli |
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2.A.124.1.2 | Uncharacterized protein of 306 aas and 9 TMSs. |
Bacteria | Bacteroidota | UP of Bacteroides coprophilus |
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2.A.124.1.3 | Uncharacterized protein of 307 aas and 9 TMSs. |
Bacteria | Bacillota | UP of Halanaerobium hydrogeniformans (Halanaerobium sp. (strain sapolanicus)) |
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2.A.124.1.4 | Uncharacterized protein of 206 aas and 7 TMSs. Belongs to the CDD Asp-Al_Ex (asp/ala exchanger) family (TC#2.A.81) |
Bacteria | Bacteroidota | UP of Bacteroides fragilis |
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2.A.124.1.5 | Uncharacterized protein of 297 aas and 8 TMSs. |
Archaea | Thermoproteota | UP of Pyrobaculum aerophilum |
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2.A.124.1.6 | Uncharacterized protein of 198 aas and 6 TMSs. |
Archaea | Thermoproteota | UP of Fervidicoccus fontis |
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2.A.124.1.7 | Uncharacterized protein of 299 aas and 9 TMSs |
Archaea | Thermoproteota | UP of Sulfolobus islandicus |
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2.A.124.1.8 | Lysine-specific transporter, LysT of 302 aas and 8 TMSs (Jorth and Whiteley 2010). |
Bacteria | Pseudomonadota | LysT of Aggregatibacter actinomycetemcomitans |
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2.A.125.1.1 | The riboflavin (Km = 40μM) transporter, RFT1, SLC52A1, of 448 aas and 11 TMSs in a 6 + 5 TMS arrangement (Yonezawa et al. 2008). The C-terminal 150 aas are 92% identical to porcine endogenous retrovirus A receptor 2 (PERV-A receptor 2) and 57% identical to the G-protein-coupled receptor 172A (XP_001519123).RFT1 is also a viral receptor, and the putative structural and functional properties of the GHBh1 receptor have been summarized (Wolf et al. 2023). Vitamin B2/riboflavin transporters play key roles in biochemical oxidation-reduction reactions of carbohydrate, lipid, and amino acid metabolism (Yonezawa et al. 2008, Yao et al. 2010). It may function as a cell receptor for retroviral envelopes similar to the porcine endogenous retrovirus (PERV-A) (Ericsson et al. 2003). The SLC52 family includes RFVT1-3, mutations in which are associated with two diseases, MADD and the Brown-Vialetto-Van Laere syndrome (Ben Mariem et al. 2023). Structure-function relationships have been reported (Ben Mariem et al. 2023).
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Eukaryota | Metazoa, Chordata | RFT1 of Homo sapiens (B5MEV1) |
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2.A.125.1.2 | Solute carrier family 52, riboflavin transporter, member 3 (Riboflavin transporter 2) (hRFVT2, RFVT3). Riboflavin transporter deficiency (RTD) is a rare neurological condition that encompasses the Brown-Vialetto-Van Laere and Fazio-Londe syndromes. Since the discovery of pathogenic mutations in the SLC52A2 and SLC52A3 genes that encode human riboflavin transporters RFVT2 and RFVT3, treatment with high doses of riboflavin have proven to be helpful treatments. Patients exhibit a deteriorating progression of peripheral and cranial neuropathy that causes muscle weakness, vision loss, deafness, sensory ataxia, and respiratory compromise which when left untreated can be fatal (O'Callaghan et al. 2019). Intestinal RFVT3 interacts with TMEM237 (TC# 8.A.121), and this interaction has physiological/biological significance; it seems to be an inducer of RFVT3 synthesis (Sabui et al. 2019). Fluoride induces immunotoxicity by regulating riboflavin transport and metabolism partly through IL-17A in the spleen (Qiao et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC52A3 of Homo sapiens |
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2.A.125.1.3 | Solute carrier family 52, riboflavin transporter, member 2 (Porcine endogenous retrovirus A receptor 1) (PERV-A receptor 1) (Protein GPR172A) (Riboflavin transporter 2) (hRFVT2) (Yonezawa and Inui 2013). Riboflavin transporter deficiency (RTD) is a rare neurological condition that encompasses the Brown-Vialetto-Van Laere and Fazio-Londe syndromes since the discovery of pathogenic mutations in the SLC52A2 and SLC52A3 genes that encode human riboflavin transporters RFVT2 and RFVT3. Patients exhibit a deteriorating progression of peripheral and cranial neuropathy that causes muscle weakness, vision loss, deafness, sensory ataxia, and respiratory compromise which when left untreated can be fatal (O'Callaghan et al. 2019). |
Eukaryota | Metazoa, Chordata | SLC52A2 (RFVT2) of Homo sapiens |
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2.A.125.1.4 | Uncharacterized protein of 701 aas and 11 TMSs. |
Eukaryota | UP of Vitrella brassicaformis |
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2.A.125.1.5 | Uncharacterized protein of 561 aas and 11 TMSs. |
Eukaryota | Heterolobosea | UP of Naegleria gruberi (Amoeba) |
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2.A.126.1.1 | Tmemb_14 family protein of 4 TMSs. Show some sequence similarity with 2.A.7.26.3 |
Bacteria | Chlamydiota | Tmemb_14 protein of Prarchlamydia acanthamoebae |
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2.A.126.1.10 | Uncharacterized protein of 116 aas |
Eukaryota | Kinetoplastida | UP of Trypanosoma brucei |
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2.A.126.1.11 | Uncharacterized protein of 105 aas and 4 TMSs |
Eukaryota | Fungi, Ascomycota | UP of Naumovozyma dairenensis (Saccharomyces dairenensis) |
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2.A.126.1.12 | Uncharacterized protein of 116 aas |
Bacteria | Planctomycetota | UP of Isophaera pallida |
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2.A.126.1.13 | Uncharacterized protein of 105 aas and 4 TMSs |
Eukaryota | Euglenozoa | UP of Trypanosoma vivax |
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2.A.126.1.14 | Putative MDR efflux pump of 153 aas and 4 TMSs |
Eukaryota | Viridiplantae, Streptophyta | Putative porter of Zea mays (Maize) |
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2.A.126.1.15 | Uncharacterized protein of 125 aas and 4 TMSs |
Bacteria | Cyanobacteriota | UP of Nostoc punctiforme |
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2.A.126.1.16 | Chloroplast fatty acid export 2 protein FAX2 of 240 aas and 4 TMSs. |
Eukaryota | Viridiplantae, Streptophyta | FAX2 of Arabidopsis thaliana |
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2.A.126.1.17 | Uncharacterized protein of 129 aas |
Eukaryota | Apicomplexa | UP of Babesia equi |
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2.A.126.1.18 | Transmembrane Protein 14C (TMEM14C) of 112 aas and 4 TMSs. It is a mitochondrial porphyrin (protoporphyrinogen) transporter, essential for haem biosynthesis. It is an SF3B1 splicing target (Steensma et al. 2021). |
Eukaryota | Metazoa, Chordata | TMEM14C of Homo sapiens |
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2.A.126.1.19 | TMEM14A of 99 aas and 4 TMSs. It inhibits apoptosis via negative regulation of the mitochondrial outer membrane permeabilization involved in the apoptotic signaling pathway (). It inhibits N-(4-hydroxyphenyl)retinamide-induced apoptosis through the stabilization of the mitochondrial membrane potential (Woo et al. 2011). |
Eukaryota | Metazoa, Chordata | TMEM14A of Homo sapiens |
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2.A.126.1.2 | Uncharacterized protein of 105 aas |
Eukaryota | Discosea | UP of Acanthamoeba castellanii |
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2.A.126.1.20 | TMEM14B of 114 aas and 4 TMSs. It is a primate-specific protein involved in cortical expansion and folding in the developing neocortex. It may drive neural progenitor proliferation through nuclear translocation of IQGAP1, which in turn promotes G1/S cell cycle transitions (Liu et al. 2017). |
Eukaryota | Metazoa, Chordata | TMEM14B of Homo sapiens |
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2.A.126.1.3 | Uncharacterized protein of 104 aas |
Bacteria | Cyanobacteriota | UP of Anabaena cylindrica |
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2.A.126.1.4 | Uncharacterized protein of 102 aas |
Eukaryota | Evosea | UP of Dictyostelium discoideum |
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2.A.126.1.5 | Uncharacterized protein of 111 aas |
Eukaryota | Metazoa, Arthropoda | UP of Bombyx mori |
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2.A.126.1.6 | Uncharacterized protein of 114 aas and 4 TMSs, TMEM14DP or TMEM14D. |
Eukaryota | Metazoa, Chordata | UP of Homo sapiens |
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2.A.126.1.7 | Uncharacterized protein of 166 aas with 4 TMSs and an N-terminal hydrophilic extension |
Eukaryota | Rhodophyta | UP of Galdieria sulfuraria |
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2.A.126.1.8 | Tmem_14 protein of 110 aas |
Eukaryota | Fungi, Ascomycota | UP of Candida albicans |
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2.A.126.1.9 | Uncharacterized protein of 104 aas |
Eukaryota | Fungi, Ascomycota | UP of Chaetomium globosum |
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2.A.126.2.1 | Uncharacterized protein of 120 aas |
Eukaryota | Viridiplantae, Chlorophyta | UP of Micromonas pusilla |
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2.A.126.2.2 | Uncharacterized protein of 220 aas with 4 TMSs and an N-terminal hydrophilic extension |
Eukaryota | Viridiplantae, Streptophyta | UP of Capsella rubella |
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2.A.126.2.3 | Uncharacterized protein of 120 aas and 4 TMSs |
Eukaryota | Viridiplantae, Chlorophyta | UP of Chlorella variabilis (Green alga) |
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2.A.126.2.4 | Plastid fatty acid export protein 1, FAX1, of 226 aas and 4 TMSs with an N-terminal hydrophlic domain (Li et al. 2015). |
Eukaryota | Viridiplantae, Streptophyta | FAX1 of Arabidopsis thaliana |
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2.A.127.1.1 | PbgA (YejM) of 586 aas and 5 N-terminal TMSs with a C-terminal alkaline phosphatase-like domain (Dalebroux et al. 2015). The globular domains of PbgA resemble the structures of the arylsulfatase protein family and contains a novel core hydrophobic pocket that may be responsible for binding and transporting cardiolipin (Dong et al. 2016). PhoPQ is activated within the intracellular phagosome environment of the host animal, where it promotes remodeling of the outer membrane and resistance to innate immune antimicrobial peptides. Maintenance of the PhoPQ-regulated outer membrane barrier requires PbgA, an inner membrane protein with a transmembrane domain essential for growth, and a periplasmic domain required for PhoPQ-activated increases in outer membrane cardiolipin. Fan et al. 2020 reported the crystal structure of cardiolipin-bound PbgA, adopting a transmembrane fold that features a cardiolipin binding site in close proximity to a long and deep cleft spanning the lipid bilayer. The end of the cleft extends into the periplasmic domain of the protein, which is structurally coupled to the transmembrane domain via a functionally critical C-terminal helix. In conjunction with a conserved putative catalytic dyad situated at the middle of the cleft, structural and mutational analyses suggest that PbgA is a multifunction membrane protein that mediates cardiolipin transport, a function essential for growth, and perhaps catalysis of an unknown enzymatic reaction (Fan et al. 2020). |
Bacteria | Pseudomonadota | PbgA of Salmonella enterica |
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2.A.127.1.10 | Phosphatase PAP2 family protein of 263 aas and 5 TMSs in a 1 + 2 + 2 TMS arrangement. |
Bacteria | Pseudomonadota | PAP2 family protein of Tepidimonas taiwanensis |
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2.A.127.1.11 | LTA synthase family protein of 641 aas and 5 N-terminal TMSs in a 1 + 2 + 2 TMS arrangement. This protein is homologous to TC# 2.A.1.127.1.5 throughout most of its length. The 5 TMS transmembrane region is similar to several other members of this family as well as the second half of the 11 TMS transmembrane region plus the C-terminal hydropilic domain of TC# 2.A.1.127.1.6. |
Bacteria | Pseudomonadota | LTA synthase of Haemophilus influenzae |
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2.A.127.1.12 | Phosphatase PAP2 family protein of 307 aas and 6 TMSs, the first 3 TMSs are distant from each other while the last 3 TMSs are close to each other. |
Bacteria | Verrucomicrobiota | PAP2 family protein of Nibricoccus aquaticus |
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2.A.127.1.13 | Phosphatase PAP2 family protein of 252 aas and 6 TMSs in a 1 + 2 + 3 TMS arrangement. |
Bacteria | Candidatus Cloacimonadota | PAP2 family protein of Candidatus Cloacimonetes bacterium |
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2.A.127.1.14 | Phosphatase PAP2 family protein of 467 aas and 6 TMSs in a 3 + 3 TMS arrangement. |
Bacteria | Candidatus Aminicenantes | PAP2 family protein of Candidatus Aminicenantes bacterium (sediment metagenome) |
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2.A.127.1.15 | PAP2 (acid phosphatase) superfamily protein of 434 aas and 6 or 7 TMSs. |
Bacteria | Nitrospirae | PAP2 family protein of Candidatus Magnetoovum chiemensis |
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2.A.127.1.16 | Phosphatase PAP2 family protein of 226 aas and 6 TMSs |
Bacteria | Pseudomonadota | PAP2 family protein of Solemya velum gill symbiont |
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2.A.127.1.17 | Phosphatase PAP2 family protein of 511 aas and 12 TMSs in a 3 + 3 + 3 + 3 TMS arrangement, where the first and third 3 TMS repeats are separated by larger loops than the second and fourth TMS repeats. |
Bacteria | Pseudomonadota | PAP2 family protein of Alphaproteobacteria bacterium |
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2.A.127.1.18 | Two domain protein with the N-terminal 6 TMS domain corresponding to those of TC families 2.A.127 and 9.B.105, and the second domain correspoonding to those of TC families 4.D.1 and 4.D.2. These two domains are also found adjacent to each other in the same order in another TC entry with TC# 9.B.27.2.12. The protein is annotated in UniProt as an acidPPc domain-containing protein. |
Bacteria | Pseudomonadota | Two domain protein of Fulvimarina sp. |
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2.A.127.1.2 | PbgA protein of 586 aas and 5 N-terminal TMSs. The 3-d structure of the C-terminal alkaline phosphatase-like domain has been solved (Dong et al. 2016). |
Bacteria | Pseudomonadota | PbgA of E. coli |
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2.A.127.1.3 | PbgA of 642 aas and 5 TMSs. |
Bacteria | Pseudomonadota | PbgA of Pseudomonas aeruginosa |
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2.A.127.1.4 | PbgA homologue of 662 aas and 5 N-terminal TMSs. |
Bacteria | Myxococcota | PbgA of Myxococcus xanthus |
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2.A.127.1.5 | Uncharacterized protein of 619 aas and 5 N-terminal TMSs. |
Bacteria | Bacteroidota | UP of Hymenobacter swuensis |
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2.A.127.1.6 | Uncharacterized protein of 896 aas and 11 or 12 TMSs. |
Bacteria | Pseudomonadota | UP of Hydrogenophaga palleronii |
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2.A.127.1.7 | Putative phosphoethanolamine transferase EptBof 518 aas and 3 N-terminal TMSs. |
Bacteria | Pseudomonadota | PE transferase of Thiotrichales bacterium |
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2.A.127.1.8 | Uncharacterized protein of 624 aas and 5 N-terminal TMSs. |
Bacteria | Actinomycetota | UP of Rubrobacter radiotolerans |
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2.A.127.1.9 | Phosphatase PAP2 family protein of 231 aas and 5 TMSs. This protein is homologous to the first half of TC# 2.A.127.1.6 which is not demonstrably homologous to other members of this family. |
Bacteria | Pseudomonadota | PAP2 family protein of Rhodoferax antarcticus |
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2.A.128.1.1 | The 4 TMS VanZ MDR export system confers resistance to teicoplanin and dalbavancin in Streptococcus agalactiae (Lai et al. 2017). |
Bacteria | Bacillota | VanZ of Streptococcus agalactiae |
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2.A.128.1.10 | VanZ homologue of 224 aas and 6 TMSs |
Bacteria | Bacteroidota | VanZ homologue of Flavisolibacter ginsengisoli |
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2.A.128.1.11 | VanZ family proteinof 122 aas and 4 TM |
Bacteria | Bacteroidota | VanZ of Roseivirga seohaensis |
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2.A.128.1.12 | Teicoplanin resistance protein VanZ of 120 aas and 4 TMSs. |
Bacteria | Campylobacterota | VanZ of Campylobacter concisus |
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2.A.128.1.13 | VanZ family proteinof 204 aas and 5 TMSs |
Bacteria | Bacteroidota | VanZ of Parapedobacter indicus |
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2.A.128.1.14 | VanZ family proteinof 125 aas and 4 TM |
Bacteria | Cyanobacteriota | VanZ of Nostoc carneum |
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2.A.128.1.15 | Uncharacterized protein of 247 aas and 8 TMSs, where the first 4 TMSs are homologous to VanZ proteins |
Bacteria | Planctomycetota | UP of Phycisphaerae bacterium |
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2.A.128.1.16 | VanZ family proteinof 119 aas and 4 TMSs. |
Bacteria | Chlorobiota | VanZ of Pelodictyon phaeoclathratiforme |
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2.A.128.1.17 | VanZ like family proteinof 118 aas and 4 TM |
Bacteria | Bacteroidota | VanZ of Flavobacterium terrigena |
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2.A.128.1.18 | VanZ like family proteinof 270 aas and 4 central TM |
Eukaryota | Fungi, Ascomycota | VanZ of Colletotrichum nymphaeae |
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2.A.128.1.19 | VanZ family protein of 202 aas and 5 TMSs in a 1 + 2 + 2 arrangement. |
Bacteria | Bacillota | VanZ of Enterococcus asini |
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2.A.128.1.2 | VanZ homologue of 210 aas and 5 TMSs. |
Bacteria | Bacillota | VanZ of Bacillus cereus |
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2.A.128.1.20 | Teicoplanin resistance protein, VanZ1 of 169 aas and 5 (or 6) putative TMSs in a 1 + 4 arrangement (or in a 6 TMS arrangement). Its synthesis is induced by the antiicrobial peptide, LL-37 (1.C.33.1.10), but not by many other antimicrobials tested (Woods et al. 2018). |
Bacteria | Bacillota | VanZ1 of Peptoclostridium difficile (Clostridium difficile) |
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2.A.128.1.3 | VanZ homologue of 181 aas and 5 TMSs |
Bacteria | Bacillota | VanZ of Listeria grandensis |
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2.A.128.1.4 | VanZ homologue of 143 aas and 4 TMSs |
Bacteria | Bacillota | VanZ of Ruminococcus flavefaciens |
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2.A.128.1.5 | VanZ/RDD domain protein of 386 aas and 9 TMSs |
Bacteria | Bacillota | VanZ/RDD protein of Erysipelothrix rhusiopathiae |
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2.A.128.1.6 | VanZ homologue of 243 aas and 5 TMSs. |
Bacteria | Actinomycetota | VanZ of Amycolatopsis orientalis |
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2.A.128.1.7 | VanZ homologue of 162 aas and 4 TMSs. |
Bacteria | Actinomycetota | VanZ of Streptomyces afghaniensis |
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2.A.128.1.8 | VanZ homologue of 202 aas and 5 TMSs |
Bacteria | Actinomycetota | VanZ of Cellulosimicrobium cellulans |
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2.A.128.1.9 | VanZ homologue of 436 aas and 7 TM |
Bacteria | Mycoplasmatota | VanZ of Mycoplasma sp. CAG:472 |
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2.A.128.2.1 | VanZ family protein of 163 aas and 4 TM |
Bacteria | Planctomycetota | VanZ of Blastopirellula cremea |
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2.A.128.2.2 | Teicoplanin resistance protein, VanZ of 164 aas and 3 or 4 TMSs. |
Bacteria | Bacillota | VanZ of Clostridium acetobutylicum |
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2.A.128.2.3 | UDP-N-acetylmuramoyl-L-alanyl-D-glutamate--2,6-diaminopimelate ligase of 743 aas and an N-terminal hydrophobic domain with 4 TMSs that are homologous to VanZ family members. |
Bacteria | Bacillota | N-terminal VanZ domain protein of Eubacterium sp. An3 |
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2.A.128.2.4 | VanZ family proteinof 135 aas and 4 TMSs. |
Bacteria | Bacillota | VanZ of Cohnella thermotolerans |
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2.A.128.2.5 | Uncharacterized proteinof 203 aas and 6 TMSs. |
Archaea | Euryarchaeota | UP of Methanolobus vulcani |
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2.A.128.2.6 | VanZ family protein of 129 aas andd 4 TMSs |
Bacteria | Actinomycetota | VanZ of Asaccharobacter celatus |
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2.A.128.2.7 | VanZ like family proteinof144 aas and 4 TMSs. |
Archaea | Candidatus Lokiarchaeota | VanZ of Lokiarchaeum sp. |
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2.A.128.2.8 | VanZ family protein of 158 aas and 4 TMSs. |
Bacteria | Verrucomicrobiota | VanZ of Verrucomicrobia bacterium (marine metagenome) |
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2.A.129.1.1 | Bactoprenol-linked glucose translocase of 120 aas and 4 TMSs. Involved in O antigen modification by translocating bactoprenol-linked glucose across the cytoplasmic membrane (Guan et al. 1999). |
Viruses | Heunggongvirae, Uroviricota | GtrA of Shigella phage SfV (Shigella flexneri bacteriophage V) |
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2.A.129.1.10 | GtrA family proteinof 129 aas and 4 TM |
Bacteria | Pseudomonadota | UP of Paracoccus aminovorans |
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2.A.129.1.11 | GtrA family proteinof 138 aas and 4 TMSs. |
Bacteria | Bacillota | GtrA of Lacticigenium naphtae |
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2.A.129.1.2 | Arabinogalactan biosynthesis protein of 121 aas and 4 TMSs. Required for arabinosylation of
arabinogalactan, an essential component of the mycobacterial cell
wall. May act as an anchor protein recruiting AftA, the first
arabinosyl transferase involved in arabinogalactan biosynthesis, rather than a lipid flippase (Kolly et al. 2015). |
Bacteria | Actinomycetota | GtrA of Mycobacterium tuberculosis |
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2.A.129.1.3 | Putative lipid-linked sugar transporter of 216 aas and 6 TMSs. |
Bacteria | Candidatus Wolfebacteria | UP of Candidatus Wolfebacteria bacterium |
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2.A.129.1.4 | GtrA of 203 aas and 4 TMSs. |
Bacteria | Actinomycetota | GtrA of Corynebacterium kroppenstedtii |
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2.A.129.1.5 | Putative flippase GtrA (transmembrane translocase of bactoprenol-linked glucose |
Bacteria | Actinomycetota | GtrA of Nonomuraea pusilla |
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2.A.129.1.6 | GtrA family protein of 142 aas and 4 TMSs. |
Bacteria | Pseudomonadota | GtrA of Azospirillum oryzae |
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2.A.129.1.7 | Lipid-sugar flippase, GtrA, of 128 aas and 4 TMSs. |
Bacteria | Bacillota | GtrA of Staphylococcus aureus |
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2.A.129.1.8 | Putative flippase GtrA (transmembrane translocase of bactoprenol-linked glucose) of 149 aas and 3 or 4 TMSs. |
Bacteria | Bacillota | Putative flippase of Sporobacter termitidis |
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2.A.129.1.9 | Uncharacterized protein of 136 aas and 4 TMSs of the GtrA family. |
Bacteria | Bacillota | UP of Leuconostoc pseudomesenteroides |
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2.A.129.2.1 | GtrA-like protein of 157 aas and 4 TMSs |
Archaea | Candidatus Lokiarchaeota | GtrA-like protein of Lokiarchaeum sp. GC14_75 |
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2.A.129.2.2 | GtrA-like protein of 143 aas and 4 putative TMSs. This protein maybe incomplete, lacking part of its N-terminus. |
Archaea | Candidatus Heimdallarchaeota | Uncharacterized protein of Candidatus Heimdallarchaeota |
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2.A.129.2.3 | GtrA family protein of 137 aas and 4 TMSs |
Bacteria | Pseudomonadota | GtrA of Acidovorax defluvii |
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2.A.129.2.4 | GtrA family protein of 190 aas and 4 TMSs |
Bacteria | Bacillota | GtrA of Vagococcus fluvialis |
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2.A.13.1.1 | The anaerobic C4-dicarboxylate antiporter (aspartate:fumarate antiporter; 433 aas and 12 TMSs), DctA, can catalyze both uptake and exchange (Zientz et al. 1996). The DcuS-DcuR two component system (sensor kinase-response regulator) responds to C4-dicarboxylates in a process that requires formation of a complex of DcuS with C4-dicarboxylate transporter, DctA or DcuB (Wörner et al. 2018). DcuS is in the constitutive "on" state unless complexed with DctA, in which case it becomes fumarate-sensitive (Stopp et al. 2021). |
Bacteria | Pseudomonadota | DcuA of E. coli (P0ABN5) |
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2.A.13.1.2 | Anaerobic C4-dicarboxylate uptake/efflux porter, DcuB. Also catalyzes substrate:substrate antiport (fumarate:malate or fumarate:succinate antiport), but it is also a cosensor for the sensor kinase, DcuS (Kleefeld et al. 2009; Bauer et al. 2011; Chen et al. 2014) It has 12 established TMSs where the loop between TMSs 11 and 12 is the sensor. A central water-filled cavity may provide the transport pathway. The sensory domain of DcuB is composed of cytoplasmic loop XI/XII and a membrane integral region with the regulatory residues Thr396/Asp398 and Lys353. Also transports D-tartrate (Bauer et al. 2011; Kim et al. 2007). The DcuB-DcuS interaction has been reviewed (Unden et al. 2016). The DcuS-DcuR two component system (sensor kinase-response regulator) responds to C4-dicarboxylates in a process that requires formation of the complex of DcuS with C4-dicarboxylate transporters DctA or DcuB (Wörner et al. 2018). |
Bacteria | Pseudomonadota | DcuB of E. coli (P0ABN9) |
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2.A.13.1.3 | C4-dicarboxylate transporter, YhiT (probably transports succinate, fumarate, aspartate, asparagine, carbamoyl phosphate and dihydroorotate; Zaharik et al., 2007) |
Bacteria | Pseudomonadota | YhiT of Salmonella enterica |
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2.A.13.1.4 | Uncharacterized C4-dicarboxylic acid transporter of 445 aas and 11 TMSs. |
Bacteria | Actinomycetota | UP of Saccharothrix espanaensis |
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2.A.13.1.5 | Dicarboxylate transporter, DcuA of 445 aas and 11 TMSs. Takes up aspartate under low (0.3%) oxygen conditions; is regulated in response to oxygen and nitrate mediated by the RacR/RacS sensor kinase/response regulatory pair (Wösten et al. 2017). |
Bacteria | Campylobacterota | DcuA of Campylobacter jejuni |
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2.A.13.1.6 | Dicarboxylate transporter, DcuB of 474 aas and 11 TMSs. Takes up aspartate and secretes succinate. Subject to regulation in response to oxygen and nitrate, mediated by the sensor kinase/response regulator pair, RacR/RacS (Wösten et al. 2017). |
Bacteria | Campylobacterota | DcuB of Campylobacter jejuni |
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2.A.13.2.1 | Uncharacterized protein of 386 aas and 10 TMSs. |
Bacteria | Bacteroidota | UP of Cardinium endosymbiont cEper1 of Encarsia pergandiella |
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2.A.130.1.1 | The Type IX protein secretory system (T9SS) of about 15 components (Lauber et al. 2018). See the family description for details, and the examples cited below for the characteristics and functions, when known, for the 15 potential constituents, which are listed with functional information in the left hand column of this entry (McBride and Zhu 2013). Veith et al. 2017 and Paillat et al. 2023 have reviewed these T9SSs, and have described 18 (or 19) constituents including regulatory proteins. See the family description and Paillat et al. 2023 for details and potential functions and roles. |
Bacteria | Bacteroidota | T9SS of Porphyromonas gingivalis SprA, Sov, 2316 aas, forms a 32 stranded β-barrel and is likely to be the channel for the folded protein substrates. Q7MW38 |
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2.A.130.1.2 | The Type IX secretion system (T9SS) with ~20 putative components, SprA, SprE, SprT, GldK, GldL, GldM, GldN, SprC, SprD, GldB, GldD, GldH, GldI, GldJ, GldA, GldF, GldG, PorV, PorU, and PorZ. The pmf-driven motor (the proton channel) may consist of GldL (like MotA; TC# 2.A.130.1.2) and GldM (like MotB) (Paillat et al. 2023). |
Bacteria | Bacteroidota | About 20 components of the T9SS/gliding motility system of Flavobacterium johnsoniae (Cytophaga johnsoniae). |
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2.A.131.1.1 | Exporter, ArsG, of 234 aas and 6 TMSs, specific for trivalent organoarsenicals, 3-amino-4-hydroxybenzene arsonate, HAPA(III) and 3-amino-benzene arsonate, pAsA(III), both of which are aromatic aminobenezylarsenicals (Chen et al. 2019). These compounds are derived from rosarsone (3-nitro-4-hydrolybenzenearsenate or Rox(V)) and nitarsone (3-nitrobenzene arsenate (Nit(V), respectively both used in feed for domestic animals such as chickens to counteract the disease, coccidiosis and improve feed efficiency (Chen et al. 2019). This system has been incorrectly annotated in the UniProt and NCBI protein databases as the "cytochrome c biogenesis protein transmembrane region", and the "sulfite exporter TauE/SafE family protein", respectively. |
Bacteria | Pseudomonadota | ArsG of Shewanella putrefaciens
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2.A.131.1.2 | Uncharacterized protein of 242 aas and 6 TMSs, annotated incorrectly as a sulfite exporter of the TauE/SafE (TSUP) family |
Bacteria | Bacillota | UP of Salipaludibacillus agaradhaerens |
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2.A.131.1.3 | Uncharacterized protein of 250 aas and 6 TMSs |
Bacteria | Pseudomonadota | UP of Stenotrophomonas rhizophila |
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2.A.131.1.4 | Uncharacterized protein of 245 aas and 6 TMSs. |
Bacteria | Bacillota | UP of Lysinibacillus sphaericus |
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2.A.131.1.5 | Uncharacterized protein of 236 aas and 6 TMSs. |
Bacteria | Bacteroidota | UP of Flavobacteriaceae bacterium BH-SD17 |
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2.A.131.1.6 | Uncharacterized protein of 235 aas and 6 TMSs. |
Bacteria | Candidatus Omnitrophota | UP of Candidatus Omnitrophica bacterium (marine sediment metagenome) |
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2.A.131.1.7 | Uncharacterized protein of 242 aas and 6 TMSs |
Archaea | Euryarchaeota | UP of Methanosarcinales archaeon (oil metagenome) |
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2.A.132.1.1 | The ferrous iron transporter, IroT or MavN, of 638 aas and 8 - 10 TMSs (Portier et al. 2015; Isaac et al. 2015) |
Bacteria | Pseudomonadota | IroT or MavN of Legionella pneumophila |
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2.A.132.1.2 | Uncharacterized protein of 703 aas and probably 10 TMSs with five pairs of TMSs in a 2 + 2 + 2 + 2 + 2 TMS arrangement. |
Bacteria | Pseudomonadota | UP of Rickettsiella grylli |
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2.A.132.1.3 | Uncharacterized protein of 695 aas and 9 - 10 TMSs. |
Bacteria | Pseudomonadota | UP of Legionella geestiana |
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2.A.132.1.4 | Uncharacterized protein of 625 aas and 10 putative TMSs. |
Bacteria | Pseudomonadota | UP of Coxiellaceae bacterium RA15029 |
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2.A.132.1.5 | Putative Fe2+ transporter of 545 aas and 7 or 8 TMSs. It may be C-terminally truncated. |
Bacteria | Pseudomonadota | IroT homologue of Thiotrichales bacterium |
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2.A.132.1.6 | Uncharacterized protein of 736 aas and 9 (or 10) TMSs in a 2 + 2 + 2 + 2 +1 arrangement with large hydrohilic regions between TMSs 2 and 3, and at the C-terminus of the protein. |
Bacteria | Pseudomonadota | UP of Tatlockia micdadei |
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2.A.132.1.7 | Uncharacterized protein of 725 aas and 9 apparent TMSs. |
Bacteria | Pseudomonadota | UP of Legionella feeleii |
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2.A.132.1.8 | Uncharacterized protein of 749 aas and 9 TMSs. |
Bacteria | Pseudomonadota | UP of Candidatus Rickettsiella viridis |
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2.A.133.1.1 | Na+(Li+, K+)/H+ antiporter of 178 aas and 3 TMSs. It's characterization was described by Shao et al. 2018 (see family description). |
Bacteria | Bacillota | RDD family protein of Halobacillus andaensis |
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2.A.133.1.10 | Uncharacterized protein of 240 aas and 3 TMSs. |
Bacteria | Bacteroidota | UP of Nonlabens dokdonensis (Donghaeana dokdonensis) |
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2.A.133.1.11 | Uncharacterized protein in the RDD or YckC Family of 151 aas and 3 N-terminal TMSs |
Bacteria | Bacillota | YckC of Bacillus subtilis |
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2.A.133.1.12 | RDD family protein of 179 aas and 3-4 TMSs |
Bacteria | Bacillota | RDD family protein of Bacillus pumilus (B4AEM5) |
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2.A.133.1.13 | RDD family protein of 159 aas and 3 TMSs. |
Bacteria | Campylobacterota | RDD protein of Helicobacter pylori |
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2.A.133.1.2 | RDD family protein of 133 aas and 3 TMSs |
Archaea | Euryarchaeota | RDD family protein of Methanosarcina barkeri (Q465I3) |
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2.A.133.1.3 | Ser/Thr Kinase (N-terminus) linked to a RDD domain (C-terminus) of 3-4 TMSs (492 aas) |
Bacteria | Cyanobacteriota | S/T kinase/Rdd domain protein of Nodularia spumigena (A0ZK04) |
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2.A.133.1.4 | Human 4TMS RDD protein fused N-terminally to a conserved hydrophilic domain of unknown function (413 aas) |
Eukaryota | Metazoa, Chordata | RDD family protein of Homo sapiens (Q9UBU6) |
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2.A.133.1.5 | YczC of 127 aas and 3 TMSs; RDD family |
Bacteria | Bacillota | YczC of Bacillus subtilis |
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2.A.133.1.6 | RDD family protein of 408 aas and 3 or 4 N-terminal TMSs |
Bacteria | Bdellovibrionota | RDD protein of Bdellovibrio bacteriovorus |
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2.A.133.1.7 | RDD family protein of 157 aas and 3 TMSs |
Bacteria | Pseudomonadota | RDD protein of Vibrio cholerae |
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2.A.133.1.8 | Uncharacterized RDD protein of 310 aas with 4 C-terminal TMSs. |
Bacteria | Pseudomonadota | RDD protein of Stenotrophomonas maltophilia |
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2.A.133.1.9 | RDD family/signal peptidase of 313 aas and 5 TMSs. The first 4 TMSs correspond to the RDD domain-containing family (TC# 2.A.133), while the 5th TMS plus the C-terminal hydrophilic domain corresponds to the signal peptidase domain, belonging to the CAAX peptidease superfamily (TC#s 9.B.1, 9.B.2, 9.B.391 and others (see the CAXX peptidase superfamily). |
Bacteria | Candidatus Levybacteria | Peptidase of Candidatus Levybacteria bacterium |
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2.A.133.2.1 | RDD motif membrane protein 169 aas and 3 or 4 TMSs, required for growth with acetate as a sole carbon source (Deutschbauer et al. 2011). |
Bacteria | Pseudomonadota | RDD protein of Shewanella oneidensi |
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2.A.133.2.2 | Uncharacterized RDD motif-containing protein of 182 aas and 4 TMSs. |
Bacteria | Pseudomonadota | UP of Collimonas fungivorans |
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2.A.133.2.3 | Uncharacterized RDD family protein of 196 aas and 4 TMSs. |
Bacteria | Pseudomonadota | UP of Morococcus cerebrosus |
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2.A.133.2.4 | Uncharacterized RDD domain-containing protein of 157 aas and 3 TMSs |
Bacteria | Actinomycetota | UP of Rhodococcus hoagii |
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2.A.134.1.1 | Na+/K+/Li+:H+ antiporter, NhaM, of 89 aas and 2 or 3 TMSs/polypeptide chain. Four of these subunits may associate to make the complete transporter with ~12 TMSs (Shao et al. 2020). |
Bacteria | Bacillota | NhaM of Halobacillus andaensis |
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2.A.134.1.10 | Uncharacterized protein of 98 aas and probably 3 TMSs. |
Bacteria | Bacillota | UP of Paenisporosarcina sp. |
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2.A.134.1.11 | Uncharacterized protein of 102 aas and probably 3 TMSs in a 2 + 1 TMS arrangement. |
Bacteria | Bacillota | UP of Bacillus paramycoides |
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2.A.134.1.14 | Uncharacterized protein of 109 aas and 4 TMSs in a 2 + 2 TMS arrangement. |
Bacteria | Bacillota | UP of Gorillibacterium sp. (glacier metagenome) |
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2.A.134.1.15 | Uncharacterized protein of 88 aas and 3 predicted TMSs. |
Archaea | Candidatus Woesearchaeota | UP of Candidatus Woesearchaeota archaeon (marine sediment metagenome) |
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2.A.134.1.16 | Uncharacterized protein of 153 aas and 3 TMSs in a 2 + 1 arrangement. |
Bacteria | Bacillota | UP of Lactobacillus florum |
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2.A.134.1.2 | NhaM homologue of 129 aas and 4 TMSs. |
Bacteria | Bacillota | NhaM of Staphylococcus aureus |
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2.A.134.1.3 | Uncharacterized protein of 119 aas and 4 TMSs. May be a fragment. |
Bacteria | Pseudomonadota | UP of Salmonella sp. |
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2.A.134.1.4 | Uncharacterized protein of 106 aas and 3 or 4 TMSs. |
Bacteria | Bacillota | UP of Halobacillus litoralis |
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2.A.134.1.5 | Uncharacterized protein of 101 aas and 4 TMSs in a 2 + 2 TMS arrangement. |
Bacteria | Bacillota | UP of Kurthia zopfii |
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2.A.134.1.6 | Uncharacterized protein of 113 aas and 4 TMSs. |
Bacteria | Bacillota | UP of Staphylococcus pseudintermedius |
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2.A.134.1.7 | Uncharacterized protein of 131 aas and 3 or more likely 4 TMSs. |
Bacteria | Bacillota | UP of Macrococcus brunensis |
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2.A.134.1.8 | Uncharacterized protein of 126 aas and 3 TMSs |
Bacteria | Bacillota | UP of Paenibacillus albus |
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2.A.134.1.9 | Uncharacterized protein of 160 aas and probably 4 (maybe 3) TMSs. |
Bacteria | Pseudomonadota | UP of Acinetobacter sp. |
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2.A.134.2.1 | Uncharacterized protein of 113 aas and 4 TMSs in a 2 + 2 arrangement. |
Bacteria | Bacillota | UP of Salipaludibacillus agaradhaerens |
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2.A.134.3.1 | Uncharacterized protein of 141 aas and 4 TMSs |
Bacteria | Bacillota | UP of Calidifontibacillus azotoformans |
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2.A.134.5.1 | Uncharacterized protein of 196 aas and 3 TMSs. |
Bacteria | Bacillota | UP of Oenococcus oeni |
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2.A.135.1.1 | Heterodimeric inorganic cation antiporter, UmpAB, both subunits belonging to the DUF1538 family. Genomic DNA was screened for novel Na+/H+ antiporter genes from Halomonas zhaodongensis by selection in Escherichia coli KNabc lacking three major Na+/H+ antiporters (Meng et al. 2017). Co-expression of two genes designated umpAB, encoding paired homologous unknown membrane proteins belonging to DUF1538 family, were found to confer E. coli KNabc tolerance to 0.4 M NaCl and 30 mM LiCl, and an alkaline pH resistance at 8.0. UmpAB localizes as a hetero-dimer in the cytoplasmic membrane and exhibits pH-dependent Na+(Li+, K+)/H+ antiport activity at a wide pH range of 6.5 to 9.5 with an optimal pH at 9.0. Neither UmpA nor UmpB showed homology with known single-gene or multi-gene Na+/H+ antiporters, and thus, UmpAB represents a novel two-component Na+(Li+, K+)/H+ antiporter (Meng et al. 2017). |
Bacteria | Pseudomonadota | UmpAB of Halomonas zhaodongensis |
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2.A.135.1.4 | DUF1538 domain-containing protein of 255 aas and 7 TMSs in a 3 + 4 TMS arrangement. |
Bacteria | Pseudomonadota | DUF1538 domain protein of Rhodobacteraceae bacterium |
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2.A.135.1.5 | DUF1538 domain protein of 255 aas and 7 TMSs. This protein brings up 2.A.63.1.3 (residues 10 - 251 (TMSs 1 - 7) aligning with residues 157 - 391 aas (TMSs 4 - 9) in 2.A.63.1.3 which has 14 TMSs. It is possible that these two families are part of a superfamily, but this possibility has not yet been tested rigorously. However, if homologous, this suggests that there was a rearrangement between the two families so that TMSs 1 - 7 in this protein corresponds to TMS 4 - 10 in MnhD (P60686) in the multisubunit Mnh cation exchanger (2.A.63.1.3). The fact that both systems catalyze the same reaction also suggests that these two families are part of a superfamily. |
Bacteria | Pseudomonadota | DUF1538 protein of Halomonas nanhaiensis |
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2.A.135.1.6 | DUF1538 domain-containing protein of 497 aas and 14 TMSs. |
Bacteria | Bacillota | DUF1538 domain protein of Firmicutes bacterium |
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2.A.135.1.7 | DUF1538 domain-containing protein of 230 aas and 7 TMSs. |
Archaea | Euryarchaeota | DUF1538 protein of Methanosarcina sp. MSH10X1 |
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2.A.135.1.8 | DUF1538 domain-containing protein of 250 aas and 7 TMSs. |
Bacteria | Mycoplasmatota | DUF538 protein of Acholeplasmataceae bacterium |
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2.A.14.1.1 | Lactate permease, LctP or LidP (substrates: L-lactate, D-lactate and glycolate) (Núñez et al. 2002). |
Bacteria | Pseudomonadota | LctP (LldP) of E. coli |
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2.A.14.1.2 | Glycolate permease, GlcA or YghK (substrates: L-lactate, D-lactate and glycolate). |
Bacteria | Pseudomonadota | GlcA or YghK of E. coli |
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2.A.14.1.3 | L-lactate permease | Bacteria | Bacillota | LutP of Bacillus subtilis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.14.1.4 | Putative transporter | Archaea | Euryarchaeota | Putative transporter of Methanopyrus kandleri (gi 20095088) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.14.2.1 | Unknown permease | Bacteria | Pseudomonadota | LctP homologue of Sulfolobus solfataricus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.14.2.2 | Lactate porter, LldP, of 569 aas and 15 or 16 TMSs in a 3 + 3 + 3 + 3 + 3 or 4 TMS arrangement (Dörries et al. 2016). |
Bacteria | Thermodesulfobacteriota | LldT of Desulfococcus multivorans |
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2.A.15.1.1 | Glycine betaine:Na+ symporter (also transports dimethylsulfonioacetate and dimethylsulfoniopropionate) |
Bacteria | Bacillota | OpuD of Bacillus subtilis |
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2.A.15.1.10 |
Glycine betaine transporter, BetP. BetP is a transporter with three different functions: betaine transport, osmosensing, and osmoregulation (Krämer and Morbach 2004). The x-ray structure is known (3PO3; 2WIT; Ressl et al., 2009). Regulatory crosstalk in the trimeric BetP has been reported (Gärtner et al., 2011). An extracellular K+ -dependent interaction site modulates betaine-binding (Ge et al., 2011). The porter is trimeric and exhibits structural asymmetry (Tsai et al., 2011). The C-terminal domain is involved in osmosensing and is trimeric like wild-type BetP. The two Na+ binding sites are between TMSs 1 and 8 in the first and second 5 TMS repeats, and between the equivalent TMSs 6 and 3 in the second and first repeats, respectively (Khafizov et al. 2012). interdependent binding of betaine and two sodium ions is observed during the coupling process. All three sites undergo progressive reshaping and dehydration during the alternating-access cycle, with the most optimal coordination of all substrates found in the closed state (Perez et al. 2014). BetP is active and regulated only when negatively charged lipids such as phosphatidyl glycerol are present, and the mechanism has been discussed (Güler et al. 2016). The K+-sensing C-terminal domain results in K+-dependent cooperative betaine-binding (Ge et al. 2011). BetP is a homotrimer lacking exact 3-fold symmetry. The observed differences may be due to crystal packing, or they may reflect different functional states of the transporter, related to osmosensing and osmoregulation (Ziegler et al. 2004). Intracellular K+ alters the conformation of the disordered C- and N-terminal domains to allosterically reconfigure TMSs 3, 8 and 10 to enhance betaine interactions. A map of the betaine binding site, at near single amino acid resolution, revealed a critical extrahelical H-bond mediated by TMS3 with betaine (Tantirimudalige et al. 2022). Hyperosmotic stress allosterically reconfigures the betaine binding pocket in BetP (Tantirimudalige et al. 2022). Both the N- and C-terminal (45 aas) segments participate in autoregulation, transducing changes in K+ concentrations as well as lipid bilayer properties to the integral membrane part of the protein. The C-terminal segment has short helical elements and an orientation that confines interactions (Leone et al. 2022). |
Bacteria | Actinomycetota | BetP of Corynebacterium glutamicum (P54582) |
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2.A.15.1.11 | Glycine betaine transporter BetL (Glycine betaine-Na(+) symporter) | Bacteria | Bacillota | BetL of Listeria monocytogenes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.15.1.12 | The glycine betaine transporter, BetH, of 505 aas and 12 TMSs (Lu et al. 2005). |
Bacteria | Bacillota | BetH of Halobacillus trueperi |
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2.A.15.1.13 | Glycine betaine transporter, OpuD, of 520 aas and 12 TMSs. It may also transport proline, but with low affinity (Wetzel et al. 2011). It is a dominant proline uptake porter, the other being ProT (Lehman et al. 2023). |
Bacteria | Bacillota | OpuD of Staphylococcus aureus |
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2.A.15.1.14 | Trimethylamine uptake transporter of 529 aas and 12 TMSs. Many microbes can utilize TMA as a carbon, nitrogen, and energy source (Gao et al. 2025). TmaT is an Na+/TMA symporter, which possessed high specificity and binding affinity toward TMA. Furthermore, the structures of TmaT and two TmaT-TMA complexes were solved by cryo-EM. TmaT forms a homotrimer structure in solution. Each TmaT monomer has 12 transmembrane helices, and the TMA transport channel is formed by a four-helix bundle. TMA can move between different aromatic boxes, which provides the structural basis of TmaT importing TMA. When TMA is bound in location I, residues Trp146, Trp151, Tyr154, and Trp326 form an aromatic box to accommodate TMA. Moreover, Met105 also plays an important role in the binding of TMA. When TMA is transferred to location II, it is bound in the aromatic box formed by Trp325, Trp326, and Trp329 (Gao et al. 2025). The volatile trimethylamine (TMA) plays an important role in promoting cardiovascular diseases and depolarizing olfactory sensory neurons in humans and serves as a key nutrient source for a variety of ubiquitous marine microbes. |
Bacteria | Pseudomonadati, Bacteroidota | TmaT of Myroides profundi |
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2.A.15.1.2 | Ectosine/glycine betaine/proline:Na+ symporter |
Bacteria | Actinomycetota | EctP of Corynebacterium glutamicum |
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2.A.15.1.3 | Low affinity (0.9 mM), high efficiency, choline/glycine betaine:H+ symporter, BetT (Chen and Beattie, 2007). The choline-glycine betaine pathway plays an important role in bacterial survival in hyperosmotic environments. Osmotic activation of BetT promotes the uptake of external choline for synthesizing the osmoprotective glycine betaine. The cryo-EM structures of Pseudomonas syringae BetT in the apo and choline-bound states shows that BetT forms a domain-swapped trimer with the C-terminal domain (CTD) of one protomer interacting with the transmembrane domain (TMD) of a neighboring protomer (Yang et al. 2024). The substrate choline is bound within a tryptophan prism at the central part of the TMD. The results suggest that in Pseudomonas species, including the plant pathogen P. syringae and the human pathogen P. aeruginosa, BetT is locked at a low-activity state through CTD-mediated autoinhibition in the absence of osmotic stress, and its hyperosmotic activation involves the release of this autoinhibition (Yang et al. 2024). |
Bacteria | Pseudomonadota | BetT of Pseudomonas syringae (Q4ZLW8) |
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2.A.15.1.4 | The high-affinity, proton- or sodium-driven, secondary symporter, BetT. The cytoplasmic C-terminal domain of plays a role in the regulation of BetT activity; C-terminal truncations cause BetT to be permanently locked in a low-transport-activity mode. (Tøndervik and Strøm 2007). |
Bacteria | Pseudomonadota | BetT of E. coli (P0ABC9) |
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2.A.15.1.5 | Glycine-betaine/proline-betaine:Na+ symporter, BetS; BetT, OpuD (Kappes et al. 1996; Boscari et al. 2002; Ziegler et al. 2010). |
Bacteria | Pseudomonadota | BetS of Sinorhizobium meliloti (Q92WM0) |
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2.A.15.1.6 | The glycine betaine, dimethylsulfoniopropionate:Na+ symporter (Ziegler et al., 2010). |
Bacteria | Pseudomonadota | Dddt of Psyohrobacter sp. J466 (D0U567) |
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2.A.15.1.7 | The ectoine/glycine:Na+ symporter, LcoP (Ziegler et al., 2010). |
Bacteria | Actinomycetota | LcoP of Corynebacterium glutamicum (Q8NN75) |
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2.A.15.1.8 | The ectoine/hydroxyectoine:Na+ symporter, EctT (Ziegler et al., 2010). |
Bacteria | Bacillota | EctT of Virgibacillus pantothenticus (Q93AK1) |
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2.A.15.1.9 | High affinity glycine betaine uptake system |
Bacteria | Pseudomonadota | Glycine betaine transporter of Acinetobacter baylyi (Q6F754) |
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2.A.15.2.1 | Carnitine:γ-butyrobetaine antiporter. The x-ray structure is known at 3.5 Å resolution (Schulze et al., 2010). The structure reveals a homotrimer where each protomer has 12 TMSs with 4 L-carnitine molecules outlining the pathway. There is a central binding site and another in the intracellular vestibule (Tang et al. 2010). |
Bacteria | Pseudomonadota | CaiT of E. coli (P31553) |
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2.A.15.2.2 |
The L-carnitine:γ-butyrobetaine antiporter, CaiT. The x-ray structure is known at 2.3 Å resolution (Schulze et al., 2010).
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Bacteria | Pseudomonadota | CaiT of Proteus mirabilis (B4EY22)
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2.A.15.2.3 | Uncharacterized transporter, YeaV, sometimes called CaiT, of 481 or 536 aas with 10 - 12 TMSs. |
Bacteria | Pseudomonadota | YeaV of Escherichia coli |
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2.A.16.1.1 | Tellurite resistance protein, TehA. Encoded in an operon with the gene for a tellurite S-adenosylmethionine-dependent methyl transferase. Together they confer tellurite resistance (Moraes and Reithmeier 2012). High level cell-free expression and specific labeling of TehA from E. coli has been achieved (Klammt et al. 2004). |
Bacteria | Pseudomonadota | TehA of E. coli |
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2.A.16.1.2 |
Tellurite resistance protein TehA homologue of 328 aas and 10 TMSs. An anion channel involved in tellurite resistance. A quasi-symmetrical homotrimer in which each subunit has 10 TMSs and forms a channel. The crystal structure is known at 1.2 A resolution (Chen et al. 2010). The helices are arranged from helical hairpin pairs to form a central 5-helix transmembrane pore that is gated by a conserved phenylalanine residue. Gating is controlled by kinase activation. Selectivity for various anions may be a function of the energetic cost of ion dehydration (Chen et al. 2010). High level cell-free expression and specific labeling of TehA from E. coli has been achieved (Klammt et al. 2004). |
Bacteria | Pseudomonadota |
Tellurite resistance protein TehA homologue of Haemophilus influenzae |
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2.A.16.2.1 | Mae1 malate:proton symport protein. May also transport other dicarboxylates such as oxaloacetate, malonate, succinate and fumarate (Camarasa et al. 2001). May also transport thio-malate (Osawa and Matsumoto 2006). |
Eukaryota | Fungi, Ascomycota | Mae1 of Schizosaccharomyces pombe |
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2.A.16.2.2 | The ATP-dependent subtelomeric helicase, RecQ (2100 aas with a 5 TMS N-terminal domain (residues 43-210). 94% identical to 2.A.16.2.1 (malate transporter) of the same species. | Eukaryota | Fungi, Ascomycota | RecQ of Schizosaccharomyces pombe (Q5EAK4) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.16.2.3 | C4-dicarboxylate transporter/malic acid transport protein, Mae1 of 395 aas and 10 TMSs. It has been overexpressed for the production of L-malate (Liu et al. 2017). |
Eukaryota | Fungi, Ascomycota | Mae1 of Emericella nidulans (Aspergillus nidulans) |
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2.A.16.3.1 | The sulfite efflux (sulfite sensitivity) protein, SSU1. Expression is controlled by the FZF1-4 transcriptional activator; only free sulfite (not complexed sulfite) is exported (Park and Bakalinsky, 2000). Can also export nitrite and nitrate (Cabrera et al. 2014). SSU1 has a putative 10 TMS topology in a (S-L)5 arrangement where S= a small putative TMS and L= a large TMS. |
Eukaryota | Fungi, Ascomycota | SSU1 of Saccharomyces cerevisiae (P41930) |
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2.A.16.3.2 | Sulfite, nitrate exporter of 384 aas, Ssu1 (Cabrera et al. 2014). |
Eukaryota | Fungi, Ascomycota | Ssu1 of Pichia angusta (Yeast) (Hansenula polymorpha) |
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2.A.16.3.3 | Sulfite/nitrate exporter of 392 aas, Ssu2 (Cabrera et al. 2014). |
Eukaryota | Fungi, Ascomycota | Ssu2 of Pichia angusta (Yeast) (Hansenula polymorpha) |
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2.A.16.4.1 | The unknown homologue, UnkH (same topology as 2.A.16.3.1) |
Eukaryota | Fungi, Ascomycota | UnkH of Aspergillus niger (A2QYD7) |
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2.A.16.4.2 | Sulfite efflux pump, Ssul (Sulfite sensitivity protein) (Lechenne et al., 2007). | Eukaryota | Fungi, Ascomycota | Ssul of Arthroderma benhamiea (A3R044) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.16.4.3 | Sulfite efflux pump, Ssul (Lechenne et al., 2007). | Eukaryota | Fungi | Ssul of Aspergillus fumigatus (Q2TJJ2) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.16.4.4 | Uncharacterized transporter MJ0762 | Archaea | Euryarchaeota | MJ0762 of Methanocaldococcus jannaschii | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.16.4.5 | TDT homolouge |
Archaea | Thermoproteota | TDT homologue of Sulfolobus acidocaldarius |
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2.A.16.4.6 | TDT homologue |
Bacteria | Actinomycetota | TDT homologue of Streptomyces coelicolor |
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2.A.16.5.1 | The plant guard cell S (Slow)-type anion channel, SLAC1 (based on activation kinetics of anion channel currents in response to voltage changes); functions in stomatal signalling, controls turgor pressure, and regulates the exchange of water and CO2 (Chen et al. 2010). Also called carbon dioxide insensitive (CDI3) and ozone sensitive (OZS1) (Kollist et al., 2011). Heterotrimeric G proteins regulate guard cell ion channels (Zhang, 2011). Evolutionary studies have been reported (Dreyer et al. 2012). The transmembrane region of guard cell SLAC1 channels detect CO2 signals via an abscisic acid (ABA)-independent pathway (Yamamoto et al. 2016). SLAC1 is activated by the protein kinase OST1 (OPEN STOMATA 1), the Ca2+-dependent protein kinases (CPKs), the GHR1 (GUARD CELL HYDROGEN PEROXIDE-RESISTANT 1) transmembrane receptor-like protein (TC# 1.A.87.2.8), or the PYL5 abscisic acid (ABA) receptor (Q9FLB1) (Wang et al. 2017). The structure of SLAC1 in an inactivated, closed state has been determined (Li et al. 2022). The cytosolic N-terminus and C-terminus are partially resolved and form a plug-like structure which packs against the TM domain. Breaking the interactions between the cytosolic plug and the TMD triggers channel activation. An inhibition-release model is proposed for SLAC1 activation by phosphorylation, that the cytosolic plug dissociates from the TMD upon phosphorylation, and induces conformational changes to open the pore. These findings facilitate an understanding of the regulation of SLAC1 activity and stomatal aperture in plants (Li et al. 2022). |
Eukaryota | Viridiplantae, Streptophyta | SLAC1 of Arabidopsis thaliana |
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2.A.16.5.2 | Slow anion channel homologue-3, SLAH3; nitrate is both a substrate and a gate opener (Geiger et al. 2011). Slow, weak voltage-dependent S-type anion efflux channel involved in maintenance of anion homeostasis (Negi et al. 2008). Binds to the highly selective inward-rectifying potassium channel KAT1 and inhibits its activity. Functions as an essential negative regulator of inward potassium channels in guard cells. Essential for the efficient stomatal closure and opening in guard cells (Zhang et al. 2016). The plasma membrane Glycine soja (soy bean) GsSLAH3 protein contains ten TMSs. GsSLAH3 expression is induced by NaHCO3 treatment, suggesting an involvement to alkaline stress, and ectopic expression of GsSLAH3 in yeast increased sensitivity to alkali treatment (Duan et al. 2017). Overexpression of GsSLAH3 in Arabidopsis thaliana enhanced alkaline tolerance during germination, seedling and adult stages. Transgenic lines improved plant tolerance to KHCO3 rather than high pH treatment. Overexpressing lines accumulated more NO3- than wild type (Duan et al. 2017).
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Eukaryota | Viridiplantae, Streptophyta | SLAH3 of Arabidopsis thaliana |
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2.A.16.6.1 | TDT homologue, TehA of 302aas and 10 TMSs |
Bacteria | Bacillota | TehA of Streptococcus pyogenes (Q9A061) |
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2.A.16.6.2 | TehA homologue of 314aas and 10 TMSs |
Bacteria | Bacillota | TehA of Clostridium butyricum (C4IKV8) |
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2.A.16.6.3 | Uncharacterized protein of 332 aas and 10 TMSs. |
Bacteria | Bacillota | UP of Lactobacillus dextrinicus |
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2.A.17.1.1 | Di- or tripeptide:H+ symporter of 497 aas and 13 or 14 TMSs. DtpT is specific for di- and tripeptides, with the highest affinities for peptides with at least one hydrophobic residue. The effect of the hydrophobicity, size, or charge of the amino acid was different for the amino- and carboxyl-terminal positions of dipeptides. Free amino acids, omega-amino fatty acidss, and peptides with more than three amino acid residues do not interact with DtpT. For high-affinity interaction, the peptides need to have free amino and carboxyl termini, amino acids in the L configuration, and trans-peptide bonds. Comparison of the specificity of DtpT with those of the eukaryotic homologues PepT(1) and PepT(2) showed that the bacterial transporter is more restrictive in its substrate recognition. (Fang et al. 2000). |
Bacteria | Bacillota | DtpT of Lactococcus lactis (P0C2U2) |
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2.A.17.1.2 | The di/tripeptide:H+ symport permease, TppB (DtpA or YdgR) (transports di and tripeptides and peptidomimetics such as aminocephalosporins (Weitz et al., 2007). The transporter has two alternate conformations, one of which is promoted by inhbitor binding (Bippes et al. 2013). |
Bacteria | Pseudomonadota | TppB of E. coli (P77304) |
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2.A.17.1.3 | The dipeptide/tripeptide:H+ symport permease, DtpB (YhiP) (transports glycyl-sarcosine (Gly-Sar) with low affinity (6mM) and the toxic dipeptide, alafosfalin (Harder et al., 2008) | Bacteria | Pseudomonadota | DtpB of E. coli (P36837) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.17.1.4 | DtpD (YbgH) peptide transporter. A projection structure at 19 Å resolution and a high resolution x-ray structure are available; Casagrande et al., 2009; Zhao et al. 2014). Glu21 is the only conserved proton-titratable amino acyl residue (among POTs) that is located in the central cavity, and it is critical for in vivo transport (Zhao et al. 2014). |
Bacteria | Pseudomonadota | DtpD of E. coli (P75742) |
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2.A.17.1.5 | Peptide transporter, YjdL (preference for di-peptides) (Ernst et al., 2009; Gabrielsen et al., 2011; Jensen et al., 2011). The motif, ExxERFxxYY has been shown to be involved in proton translocation, and the nearby K117 may play a dual role in protonation and substrate binding (Jensen et al. 2014). |
Bacteria | Pseudomonadota | YjdL of E. coli (P39276) |
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2.A.17.1.6 | POT famiy di- and tri-peptide porter, DtpT. 3-d structures (PDB:24APS; 5MMT: 5D58' 5D59) are available for an inward open conformation. A hinge-like movement in the C-terminal half facilitates opening of an intracellular gate controlling access to a central peptide binding site. Salt bridges may orchestrate alternating access (Solcan et al., 2012; Quistgaard et al. 2017). |
Bacteria | Bacillota | Peptide porter, DtpT of Streptococcus thermophilus (Q5M4H8) |
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2.A.17.1.7 | Peptide uptake transporter of 496 aas, POT. The 3-d structure has been determined to 1.9Å resolution leading to a proposed mechanism (Doki et al. 2013). Glu310 first may bind the carboxyl group of the peptide substrate. Then deprotonation of Glu310 in the inward open state triggers the release of the bound peptide toward the intracellular space, and salt bridge formation between Glu310 and Arg43 induces the transition state to the occluded conformation. |
Bacteria | Bacillota | POT of Geobacillus kaustophilus |
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2.A.17.1.8 | Proton-coupled oligopeptide uptake transporter of 485 aas and 14 TMSs, DtpT or Pot. Expression of the encoded gene is upregulated upon infection. Transports di- and tripeptides but can not accumulate peptides with a positively charged residue in the C-terminal position. An aromatic residue patch in the active site of the transporter may be responsible for it's unusual specificity (Sharma et al. 2016). |
Bacteria | Pseudomonadota | DtpT of Neisseria meningitidis |
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2.A.17.2.1 | Peptide:H+ symporter | Eukaryota | Fungi, Ascomycota | PTR2-A of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.17.2.2 | Peptide:H+ symporter (dipeptides and tripeptides preferred (Cai et al., 2007). Substrate preference is altered by mutations in the fifth TMS of Ptr2p (Hauser et al. 2013). |
Eukaryota | Fungi, Ascomycota | PTR2 of Saccharomyces cerevisiae |
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2.A.17.2.3 | Dipeptide uptake porter, Ptr2. Transports dipeptides such as Ala-Leu, Ala-Tyr and Tyr-Ala (Belmondo et al. 2014). |
Eukaryota | Fungi, Mucoromycota | Ptr2 of Rhizophagus irregularis (Arbuscular mycorrhizal fungus) (Glomus intraradices) |
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2.A.17.2.4 | Di- and tripeptide uptake transporter, Ptr2 of 577 aas and 12 TMSs. The ptr2 gene showed increased expression upon interaction with the plant-pathogenic fungus Botrytis cinerea, suggesting that it is involved in the mycoparasitic process. Its expression was triggered by nitrogen starvation (Vizcaíno et al. 2006). |
Eukaryota | Fungi, Ascomycota | Ptr2 of Trichoderma harzianum (Hypocrea lixii) |
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2.A.17.2.5 | Oligopeptide transporter of 576 aas and 12 TMSs, PTR22. Transports a variety of peptides as well as derivatives of antifungal agents, such as chlorotetaine and lysyl-cholortetaine (Liu et al. 2018). |
Eukaryota | Fungi, Ascomycota | PTR22 of Candida albicans (Yeast) |
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2.A.17.3.1 | Dual affinity Nitrate/Chlorate symporter, Nrt1.1; CHL1 of 590 aas and 12 TMSs in a 6 + 6 TMS arrangement (Martin et al., 2008). The low affinity form is a homo-dimer and has Thr101 in the non-phosphorylated form; the high affinty form (0.1 micromolar Km) is a monomer and has Thr101 phosphorylated (Sun and Zheng 2015). Rehmannia glutinosa (Chinese foxglove) has 18 ntr1 genes encoding proteins of 419 to 601 aas with 7 - 12 TMSs. They are found primarily in the plasma membranes of various plant tissues (Gu et al. 2021). |
Eukaryota | Viridiplantae, Streptophyta | Ntr1.1/CHL1 of Arabidopsis thaliana |
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2.A.17.3.10 | solute carrier family 15, member 5. Function unknown as of 1/17, but probably a di- and tri-peptide uptake porter (Verri et al. 2016). The tissue expression profile has been reported (Sreedharan et al. 2011).
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Eukaryota | Metazoa, Chordata | SLC15A5 of Homo sapiens |
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2.A.17.3.11 | Solute carrier family 15 member 4 (Peptide transporter 4) (Peptide/histidine transporter 1) (hPHT1; SLC15A4; ) is present in immune cells (Verri et al. 2016). It is a proton-coupled amino-acid transporter that mediates the transmembrane transport of L-histidine and some di- and tripeptides from inside the lysosome to the cytosol, and plays a key role in innate immune responses (Bhardwaj et al. 2006, Kobayashi et al. 2014, Song et al. 2018). It is able to transport a variety of di- and tripeptides, including carnosine and some peptidoglycans peptides (Song et al. 2018; Oppermann et al. 2019). Transport activity is pH-dependent and maximized in the acidic lysosomal environment. It is involved in the detection of microbial pathogens by toll-like receptors (TLRs) and NOD-like receptors (NLRs), probably by mediating transport of bacterial peptidoglycan fragments across the endolysosomal membrane: it catalyzes the transport of certain bacterial peptidoglycan-derived peptides, such as muramyl dipeptide, the NOD2 ligand, and L-alanyl-gamma-D-glutamyl-meso-2,6-diaminoheptanedioate (tri-DAP), the NOD1 ligand (Kobayashi et al. 2014, Song et al. 2018). Byrnes et al. 2022 reviewed three specific mechanisms by which autophagy can regulate metabolism: A) nutrient regeneration, B) quality control of organelles, and C) signaling protein regulation. PHT1 is a histidine/oligopeptide transporter with an essential role in Toll-like receptor innate immune responses. It can act as a receptor by recruiting the adaptor protein TASL which leads to type I interferon production via IRF5 (Custódio et al. 2023). Persistent stimulation of this signalling pathway is involved in the pathogenesis of systemic lupus erythematosus (SLE). The authors presented the Cryo-EM structure of PHT1 stabilized in the outward-open conformation and proposed a model of the PHT1-TASL complex, in which the first 16 N-terminal TASL residues that fold into a helical structure that binds in the central cavity of the inward-open conformation of PHT1. This work suggests the molecular basis of PHT1/TASL mediated type I interferon production (Custódio et al. 2023). PHT1 substrate selectivity, as well as the transport kinetics of the identified substrates have been characterized (Pujol-Giménez et al. 2024). Slc14A4 is an emerging therapeutic target for systemic lupus erythematosus (Wang et al. 2025).
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Eukaryota | Metazoa, Chordata | SLC15A4 of Homo sapiens |
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2.A.17.3.12 | Putative peptide/nitrate transporter At3g25280 |
Eukaryota | Viridiplantae, Streptophyta | At3g25280 of Arabidopsis thaliana |
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2.A.17.3.13 | Probable peptide transporter At1g52190 | Eukaryota | Viridiplantae, Streptophyta | At1g52190 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.17.3.14 | Nitrate transporter 1.6 |
Eukaryota | Viridiplantae, Streptophyta | NRT1.6 of Arabidopsis thaliana |
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2.A.17.3.15 | Nitrate transporter 1.7 |
Eukaryota | Viridiplantae, Streptophyta | NRT1.7 of Arabidopsis thaliana |
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2.A.17.3.16 | Nitrate transporter 1.2 (Nitrate transporter NTL1; NRT1:2; PRT family protein 4.6; NPF4.6; AIT1). Low-affinity proton-dependent nitrate transporter involved in constitutive nitrate uptake but not histidine or dipeptides transport. Involved in (+)-abscisic acid (ABA) transport, but not in gibberellin, indole-3-acetic acid or jasmonic acid import; ABA and nitrate do not compete for substrate uptake (Kanno et al. 2013). Arabidopsis NPF4.6 and NPF5.1 control the leaf stomatal aperture by regulating abscisic acid transport (Shimizu et al. 2021). NPF4.6 is expressed in vascular tissues and guard cells, and it positively regulates stomatal closure in leaves (Shimizu et al. 2021). |
Eukaryota | Viridiplantae, Streptophyta | NRT1.2 of Arabidopsis thaliana |
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2.A.17.3.17 | Transporter for glucosinolates, GTR1, (aliphatic but not indole glucosinolates such as 4-methylthiobutyl glucosinolate, major defence compounds, translocated to seeds on maturation) as well as gibberellic acid and jasmonoyl-L-isoleucine, GTR1 or NPF2.10, of 636 aas and 12 TMSs (Nour-Eldin et al. 2012; Ishimaru et al. 2017). Regulated at the transcriptional level, but also postranslationally. Dimerization of GTR1, possibly induced by dephosphorylation of a Thr residue, regulates its plasma membrane localization, leading to increased transport of glucosinolates and gibberellic acid (Ishimaru et al. 2017). Homologues have been found and characterized in Chinese kale (Jiang et al. 2019). |
Eukaryota | Viridiplantae, Streptophyta | GTR1 of Arabidopsis thaliana |
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2.A.17.3.18 | Nitrate transporter 1.4 |
Eukaryota | Viridiplantae, Streptophyta | NRT1.4 of Arabidopsis thaliana |
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2.A.17.3.19 | Nitrate transporter 1.5 |
Eukaryota | Viridiplantae, Streptophyta | NRT1.5 of Arabidopsis thaliana |
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2.A.17.3.2 | Histidine or peptide:H+ symporter of 585 aas and 12 TMSs. It mediates the transport of di- and tripeptides with high affinity, low capacity (Rentsch et al. 1995). |
Eukaryota | Viridiplantae, Streptophyta | PTR2-B (NTR1) of Arabidopsis thaliana |
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2.A.17.3.20 | High-affinity, proton-dependent glucosinolate-specific transporter-2, GTP2 or NPF2.11. Involved in apoplasmic phloem-loading of glucosinolates and in bidirectional long-distance transport of aliphatic but not indole glucosinolates. May be involved in removal of glucosinolates from the xylem in roots (Nour-Eldin et al. 2012; Andersen et al. 2013). |
Eukaryota | Viridiplantae, Streptophyta | GTR2 of Arabidopsis thaliana |
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2.A.17.3.21 | Low affinity nitrate transporter, Nrt1, of 584 aas and 13 putative TMSs. Two splice variants, Ntr1.1a and Ntr1.1b, have been identified. Under low nitrogen condition, Nrt1.1b accumulates more nitrogen in plants and improves rice growth, but Ntr1.1a had no such effect (Fan et al. 2015). The absorption and long-distance distribution/transport of nitrate is mediated by NRT1.1B in tabacco (Wu et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | Ntr1 of Oryza sativa (Rice) |
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2.A.17.3.22 | Uncharacterized peptide transport protein of 609 aas and 12 TMSs, PTR3-A. |
Eukaryota | Viridiplantae, Streptophyta | PTR3- aof Aegilops tauschii (Tausch's goatgrass) (Aegilops squarrosa) |
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2.A.17.3.23 | Protein NRT1, PTR FAMILY 5.1, NPF5.1 of 583 aas and 12 TMSs in a 6 + 6 TMS arrangement. Mutants defective in NPF5.1 had a higher leaf surface temperature compared to the wild type and, NPF5.1 mediated cellular abscisic acid (ABA) uptake when expressed in a heterologous yeast system (Shimizu et al. 2021). An NRT protein (NPF) from wheat (Triticum aestivum) has been identified and partiallly characterized (Kumar et al. 2022). |
Eukaryota | Viridiplantae, Streptophyta | NPF5.1 of Arabidopsis thaliana (Mouse-ear cress) |
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2.A.17.3.24 | NRT1.13; NPF4.4; PTR family 4.4 of 601 aas and 12 or 13 TMSs in a 6 or 7 + 6 TMS arrangement. In contrast to most NRT1 transporters, NRT1.13 does not have the conserved proline residue between TMSs 10 and 11, an essential residue for nitrate transport activity in CHL1/NRT1.1/NPF6.3 ( TC# 2.A.17.3.1). NRT1.13 showed no nitrate transport activity, but when Ser487 at the corresponding position was converted to proline, NRT1.13 S487P gained nitrate uptake activity, suggesting that wild-type NRT1.13 cannot transport nitrate but can bind it (Chen et al. 2021). Subcellular localization indicated that NRT1.13 is a plasma membrane protein expressed at the parenchyma cells next to xylem in the petioles and the stem nodes. When plants were grown with a normal concentration of nitrate, the nrt1.13 mutant showed no severe growth phenotype, but when grown under low-nitrate conditions, nrt1.13 showed delayed flowering, increased node number, retarded branch outgrowth, and reduced lateral nitrate allocation to nodes. This suggested that NRT1.13 is required for low-nitrate acclimation and that internal nitrate is monitored near the xylem by NRT1.13 to regulate shoot architecture and flowering time. |
Eukaryota | Viridiplantae, Streptophyta | Ntr1.13 of Arabidopsis thaliana |
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2.A.17.3.25 | Protein NRT1/ PTR FAMILY 5.8, NPF5.8 or NAEZT1, of 552 aas and 11 or 12 TMSs. NAET1 and NAET2, function as nicotianamide (nicotinamide NA) transporters required for translocation of both iron and copper to seeds. Chao et al. 2021 showed that NAET1 and NAET2 are predominantly expressed in the shoot and root vascular tissues and mediate secretion of NA out of the cells, resembling the release of neurotransmitters from animal synaptic vesicles (Chao et al. 2021). |
Eukaryota | Viridiplantae, Streptophyta | NPF5.8 of Arabidopsis thaliana (Mouse-ear cress) |
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2.A.17.3.26 | Nicotinamine efflux porter of 563 aas and 11 or 12 TMSs. NAET1 and NAET2 function as a nicotianamide (nicotinamide NA) transporters required for translocation of both iron and copper to seeds. Chao et al. 2021 showed that NAET1 and NAET2 are predominantly expressed in the shoot and root vascular tissues and mediate secretion of NA out of cells, resembling the release of neurotransmitters from animal synaptic vesicles. |
Eukaryota | Viridiplantae, Streptophyta | NAET2 of Arabidopsis thaliana (Mouse-ear cress) |
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2.A.17.3.27 | Vacuolar (tonoplast) glycerate transporter AtNPF8.4 or Npf8.4, of 545 aas and 11 or 12 TMSs. It facilitates shuttling of glycerate between peroxysomes and chloroplasts (Lin and Tsay 2023). It is a tonoplast glycerate uptake system that plays a role of photorespiration in C/N balance (Lin and Tsay 2023). |
Eukaryota | Viridiplantae, Streptophyta | NPF8.4 of Arabidopsis thaliana |
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2.A.17.3.3 | Nitrate (chlorate) or histidine:H+ symporter of 589 aas and 12 TMSs, Ntr1. Its structural gene is specifically expressed in the floral nectaries of Brassica species (Song et al. 2000). |
Eukaryota | Viridiplantae, Streptophyta | RCH2 of Brassica napus |
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2.A.17.3.30 | Brassica rapa selenium (selenicate) transporter NPF2.20 (BrNPF2.20) accounts for Se-enrichment in Chinese cabbage (Hu et al. 2024). Note: The UniProt acc # used is for this protein is for a different Brassica species, but the amino acid sequences of these two orthologs are identical.
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Eukaryota | Viridiplantae, Streptophyta | Selenium transporter NPF2.20 (BrNPF2.20) of Brassica rapa |
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2.A.17.3.4 | Peptide transporter, PTR3-A (induced by histidine, leucine and phenylalanine in cotyledons and lower leaves; involved in stress tolerance in seeds during germination and in defense against virulent bacterial pathogens) (Karim et al., 2007; Karim et al., 2005) | Eukaryota | Viridiplantae, Streptophyta | PTR3-A of Arabidopsis thaliana (Q9FNL7) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.17.3.5 | The nitrate excretion transporter1, NaxT1, og 558 aas and 13 TMSs in a 7 + 6 TMS arrangement (in the plasma membranes of plant cells). |
Eukaryota | Viridiplantae, Streptophyta | NaxT1 of Arabidopsis thaliana (Q9M1E2) |
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2.A.17.3.6 | Chloroplast nitrite uptake system, Nitr1-L (Sugiura et al., 2007) | Eukaryota | Viridiplantae, Streptophyta | Nitr1-L of Arabidopsis thaliana (Q9SX20) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.17.3.7 | The root dipeptide/tripeptide transporter, PTRI (Komarova et al., 2008). Transport is electrogenic and dependent on protons. Leak currents are inhibited by Phe-Ala when this peptide binds at the active site with high affinity (Hammes et al., 2010). |
Eukaryota | Viridiplantae, Streptophyta | PTR1 of Arabidopsis thaliana (Q9M390) |
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2.A.17.3.8 | The germinating pollen dipeptide/tripeptide transporter, PTR5 (Komarova et al., 2008). Transport is electrogenic and dependent on protons. Leak currents are inhibited by Phe-Ala when this peptide binds at the active site with high affinity (Hammes et al., 2010). |
Eukaryota | Viridiplantae, Streptophyta | PTR5 of Arabidopsis thaliana (Q0WR84) |
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2.A.17.3.9 | solute carrier family 15, member 3, SLC15A3, OCTP, PHT2, PHT3, of 581 aas and 12 TMSs in a 3 + 3 + 3 + 3 TMS arrangement. It is a histidine + di- and tri-peptide uptake transporter in immune cells (Verri et al. 2016). The functions, regulation and pathophysiology of PHT2 and PHT1, specifically in immunoregulation have been reviewed (Dong et al. 2023). |
Eukaryota | Metazoa, Chordata | SLC15A3 of Homo sapiens |
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2.A.17.4.1 | Peptide:H+ symporter (transports cationic, neutral and anionic dipeptides including glycylsarcosine (gly-sar) (Søndergaard et al., 2008) as well as anserine (β-alanyl-1-N-methyl-L-histidine) and carnosine (β-alanyl-L-histidine) (Geissler et al., 2010); also transports β-lactam antibiotics, the antitumor agent, bestatin, and various protease inhibitors). It is competitively inhibited by L-4,4'-biphenylalanyl-L-proline (Bip-Pro) with ~10-20µM affinity. Inhibitors/substrates include cefadroxil, Ala-4-nitroanilide and δ-aminolevulinic acid (Knutter et al., 2007). The intracellular loop linking transmembrane domains 6 and 7 of the human dipeptide transporter hPEPT1 includes two amphipathic alpha-helices, with net positive and negative charges which interact and influence conformational changes of hPEPT1 during and after glycylsarcosine transport (Xu et al., 2010). The rabbit orthologue provides the main pathway for dietary nitrogen uptake. Five tyrosyl residues are important for function and/or substrate binding (Pieri et al. 2009). Human PepT1 is modified by N-glycosylation, and all six asparagine residues in the large extracellular loop between transmembrane domains 9 and 10 are subject to N-glycosylation (Chan et al. 2016). Lat1 transports 26 biologically active ultrashort peptides (USPs) into cells as is also true of LAT2 and PEPT1 (Khavinson et al. 2023). The sizes and structures of ligand-binding sites of the amino acid transporters LAT1, LAT2, and of the peptide transporter PEPT1 are sufficient for the transport of the 26 biologically active di-, tri-, and tetra-peptides. Comparative analyses of the binding of all possible di- and tri-peptides (8400 compounds) at the binding sites of the LAT and PEPT family transporters was considered (Khavinson et al. 2023). The 26 biologically active USPs systematically showed higher binding scores to LAT1, LAT2, and PEPT1, as compared with di- and tri-peptides. Most of the 26 studied USPs were found to bind to the LAT1, LAT2, and PEPT1 transporters more efficiently than the previously known substrates or inhibitors of these transporters. Peptides ED, DS, DR, EDR, EDG, AEDR, AEDL, KEDP, and KEDG, and peptoids DS7 and KE17 with negatively charged Asp- or Glu- amino acid residues at the N-terminus and neutral or positively charged residues at the C-terminus of the peptide were found to be the most effective ligands of the transporters under investigation. It can be assumed that the antitumor effect of the KE, EW, EDG, and AEDG peptides could be associated with their ability to inhibit the LAT1, LAT2, and PEPT1 amino acid transporters (Khavinson et al. 2023). |
Eukaryota | Metazoa, Chordata | PepT1 of Rattus norvegicus |
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2.A.17.4.10 | Peptide transporter 3 (Oligopeptide transporter 3) | Eukaryota | Metazoa, Nematoda | Pept-3 of Caenorhabditis elegans | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.17.4.11 | Peptide transporter, Pep1, also called CptB, Opt-2 and Pep-2. It is of 835 aas and 11 TMSs. It transports di-, tri- and tetra-peptides including phenylalanylmethionylarginylphenylalaninamide (FMRFamide) and N-acetylaspartylglutamate, both neuropeptides found throughout the animal kingdom. In contrast to CptA (TC# 2.A.17.4.3), CptB has low-affinity for its substrates (Fei et al. 1998). |
Eukaryota | Metazoa, Nematoda | CptB of Caenorhabditis elegans |
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2.A.17.4.12 | The tonoplast localized protein PtNPF1 participates in the regulation of nitrogen response in diatoms (phytoplankton). It has 775 aas and 12 TMSs in a 6 + 6 TMS arrangement. PtNPF1 is presumably involved in modulating intracellular nitrogen fluxes, managing intracellular nutrient availability. This ability might allow diatoms to fine-tune the assimilation, storage and reallocation of nitrate, conferring upon them a strong advantage in oligotrophic environments (Santin et al. 2023). |
Eukaryota | Bacillariophyta | PtNPF1 of Phaeodactylum tricornutum |
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2.A.17.4.2 | Oligopeptide transporter 1 | Eukaryota | Metazoa, Arthropoda | Oligopeptide transporter of Drosophila melanogaster | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.17.4.3 | High affinity oligopeptide transporter, CPTA. It transports di-, tri- and tetra peptides with low specificity. Neuropeptides (FMRF-amide and N-acetyl-Asp-Glu) are also transported (Fei et al. 1998). |
Eukaryota | Metazoa, Nematoda | CPTA of Caenorhabditis elegans |
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2.A.17.4.4 | The renal brush-border electrogenic, proton-coupled, broad specificity, high affinity, peptide transporter, PepT2 (Rubio-Aliaga et al., 2000). It is competitively inhibited by L-4,4'-Biphenylalanyl-L-Proline (Bip-Pro) with ~10-20µM affinity. Inhibitor/substrates includes cefadroxil, Ala-4-nitroanilide and delta-aminolevulinic acid (Knutter et al., 2007). It transports the fluorescent tracer-dipeptide beta-Ala-Lys-Nepsilon-7-amino-4-methyl-coumarin-3-acetic acid (Ala-Lys-AMCA). Whole-mount preparations from mouse, rat, and guinea pig stomach and small and large intestine were incubated with Ala-Lys-AMCA in the presence or absence of the uptake-inhibitors L-histidine, D-phenylalanyl-L-alanine (D-Phe-Ala), glycyl-L-sarcosine (Gly-Sar), glycyl-L-glutamine (Gly-Gln), benzylpenicillin, and cefadroxil. Fluorescence microscopy revealed that Ala-Lys-AMCA specifically accumulated in both ganglionic layers of the enteric nervous system (ENS) in all regions and species studied (Rühl et al. 2005). This could be inhibited by Gly-Sar, D-Phe-Ala, Gly-Gln, and cefadroxil, but not by free histidine and benzylpenicillin, indicating uptake via PEPT2. Accordingly, dipeptide uptake was completely abolished in PEPT2-deficient mice. |
Eukaryota | Metazoa, Chordata | PepT2 of Mus musculus (Q9ES07) |
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2.A.17.4.5 | The high affinity, low capacity, peptide transporter, PepT2 (SLC15A2) [affinity for glycyl-L-glutamine=18μM] (Romano et al., 2006) | Eukaryota | Metazoa, Chordata | PepT2 of Danio rerio (NP_0010349) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.17.4.6 | Oligopeptide transporter, PepT1 (Slc15A1b) (Bucking and Schulte, 2012) (expressed in freshwater acclimated fish) |
Eukaryota | Metazoa, Chordata | PepT1b of Fundulus heteroclitus (H2DJV9) |
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2.A.17.4.7 | Di-/Tri-peptide porter. 3-d structure (PDB: 2XUT) known revealing a probable alternating access mechanism of transport (Newstead et al., 2011). A second structure shows the protein in an inward open conformation with the peptidommetic, alafosfalin, bound (Guettou et al. 2013). Appears to take up glutathione (Deutschbauer et al. 2011). |
Bacteria | Pseudomonadota | Di-/Tri-peptide permease of Shewanella oneidensis (Q8EKT7) |
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2.A.17.4.8 | Solute carrier family 15 member 2 (Kidney H+:peptide cotransporter) (Oligopeptide transporter, kidney isoform) (Peptide transporter 2, PEPT2) (Verri et al. 2016). Transports opioid peptides (Ganapathy and Miyauchi 2005). It is an electrogenic uphill peptide and peptidomimetic drug transporter, coupling of substrate translocation to a transmembrane electrochemical proton gradient serving as the driving force. In human airways, PEPT2 is localized to bronchial epithelium and alveolar type II pneumocytes, and transport studies revealed that both peptides and peptidomimetic drugs such as antibiotic, antiviral, and antineoplastic drugs are carried by the system. PEPT2 is also responsible for the transport of delta-aminolevulinic acid, which is used for photodynamic therapy and the diagnostics of pulmonary neoplasms (Groneberg et al. 2004). PepT2 in mammals plays essential roles in the reabsorption and conservation of peptide-bound amino acids in the kidney and in maintaining neuropeptide homeostasis in the brain. It is also responsible for the absorption and disposing of peptide-like drugs, including angiotensin-converting enzyme inhibitors, β-lactam antibiotics and antiviral prodrugs. Understanding the structure, function and regulation of PepT2 is of emerging interest in nutrition, medical and pharmacological research. Wang et al. 2022 provided an overview of the structure, substrate preferences and localizations of PepT2 in mammals. As PepT2 is expressed in various organs, its functions in the liver, kidney, brain, heart, lung and mammary gland have been addressed. Regulatory factors that affect the expression and function of PepT2, such as transcriptional activation and posttranslational modification, are also discussed (Wang et al. 2022). Lichtinger et al. 2024 established a mechanistic link between proton binding and peptide recognition, revealing key details underpining secondary active transport in POTs. |
Eukaryota | Metazoa, Chordata | SLC15A2 of Homo sapiens |
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2.A.17.4.9 | Solute carrier family 15 member 1 (Intestinal H+:peptide cotransporter) (Oligopeptide transporter, small intestine isoform) (Peptide transporter 1, PepT1). Takes up oligopeptides of 2 to 4 amino acids with a preference for dipeptides, a major route for the absorption of protein digestion end-products. PepT1 is modified by N-glycosylation, and all six asparagine residues in the large extracellular loop between TMSs 9 and 10 are subject to N-glycosylation. This allows proper association with the plasma membrane and/or stabilization (Chan et al. 2016). Transports opioid peptides (Ganapathy and Miyauchi 2005), can serve as a druh importer and plays a role in inflammatory bowel diseases (Viennois et al. 2018). PEPT1 is upregulated in kidney cancer cell lines, with little expression in normal pancreas. PEPT1 is essential for the growth of pancreatic cancer cells and is therefore a viable drug target (Schniers et al. 2021). Mutation of arginine 282 to glutamate uncouples the movement of peptides and protons by the rabbit PepT1 (Meredith 2004). The structure of the horse ortholog shows that the extracellular domain between TMSs 9 and 10 bridges the NTD and CTD by interacting with TMS1. Deletion of ECD or mutations to the ECD-TMS1 interface impairs transport activity (Shen et al. 2022). |
Eukaryota | Metazoa, Chordata | PepT1 of Homo sapiens |
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2.A.18.1.1 | Auxin:H+ symporter (auxin influx), AUX, AUX1, AUX-1, or LAX (Reinhardt et al., 2003; Carraro et al., 2012). In the PILS (Pin-like) family; members are located in the endoplasmic reticular membrane (Balzan et al. 2014). Expression patterns of PILS family members have been studied (Mohanta et al. 2015). Involved in determination of first pod height (FPH), a quantitative trait in soybean [Glycine max (L.) Merr.] that affects mechanized harvesting (Jiang et al. 2018). Auxin regulates several aspects of plant growth and development and is predominantly synthesized in the shoot apex and developing leaf primordia and from there it is transported to the target tissues e.g. roots. It is essential for root development, root gravitropism, root hair development, vascular patterning, seed germination, apical hook formation, leaf morphogenesis, phyllotactic patterning, female gametophyte development embryo development and the regulation of plant responses to abiotic stresses (Swarup and Bhosale 2019). |
Eukaryota | Viridiplantae, Streptophyta | Aux-1 of Arabidopsis thaliana |
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2.A.18.10.1 | Putative amino acid transporter, AAT or TMEM104 of 496 aas and 11 or 12 TMSs. |
Eukaryota | Metazoa, Chordata | AAT of Homo sapiens (Q8NE00) |
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2.A.18.10.2 | Putative amino acid transporter, AAT |
Eukaryota | Evosea | AAT of Entamoeba histolytica (C4LSN3) |
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2.A.18.10.3 | Putative amino acid transporter, AAT |
Eukaryota | Fornicata | AAT of Giardia intestinalis (C6LXJ3) |
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2.A.18.10.4 | AAAP homologue |
Eukaryota | Ciliophora | AAAP homologue of Tetrahymena thermophilus |
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2.A.18.2.1 | General amino acid permease 1, AAP1 of 485 aas and 11 TMSs. It transports most neutral and acidic amino acids but not aspartate or the basic amino acids. It also transports the L-valine-phenazine-1-carboxylic acid conjugate (L-val-PCA) in Ricinus cotyledons (Xiao et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | AAP1 of Arabidopsis thaliana |
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2.A.18.2.10 | Probable amino acid permease 7 (Amino acid transporter AAP7) | Eukaryota | Viridiplantae, Streptophyta | AAP7 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.2.11 | Transporter for amino acids and GABA, AAT2, of 1564 aas and 12 TMSs, 11 at the N-terminal part of the protein, and 1 at the C-terminus (Wunderlich 2022). |
Eukaryota | Apicomplexa | AAT2 of Plasmodium falciparum |
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2.A.18.2.12 | Transporter of amino acids (e.g., Leu, Met) and/or Ca2+, AAAP3 or ICM1, of 1944 aas and possibly 11 TMSs in a 5 (N-terminal) + 5 (550 to 660) +1 (C-terminal) (Wunderlich 2022). |
Eukaryota | Apicomplexa | AAAP3 of Plasmodium falciparum |
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2.A.18.2.13 | γ-Aminobutyrate transporter, GAT1 of 451 aas and 11 TMSs. |
Eukaryota | Viridiplantae, Streptophyta | GAT1 of Arabidopsis thaliana |
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2.A.18.2.2 | Lysine/histidine transporter, LHT1, of 446 aas and 10 or 11 TMSs (Chen and Bush 1997). It has been reported to be an amino acid-proton symporter with a broad specificity for histidine, lysine, glutamic acid, alanine, serine, proline and glycine 90. It is involved in both apoplastic transport of amino acids in leaves and their uptake by roots (Hirner et al. 2006; Svennerstam et al. 2007; Svennerstam et al. 2008). There is some controversy about which amino acids it can take up, but it may play a role in fungicide uptake (Wu et al. 2021). There are six LHT genes in rice. The four members of cluster 1 show broad amino acid selectivity, while OsLHT5 and OsLHT6 may transport other substrates besides amino acids. The six OsLHT genes have different expression patterns at different developmental stages and in different tissues (Fan et al. 2023). Some OsLHT genes are responsive to PEG, NaCl and cold treatments.
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Eukaryota | Viridiplantae, Streptophyta | LHT1 of Arabidopsis thaliana |
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2.A.18.2.3 | General amino acid transporter 3, AAP3 (transports all neutral, acidic and basic amino acids tested) | Eukaryota | Viridiplantae, Streptophyta | AAP3 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.2.4 | General amino acid transporter 6, AAP6 (transports all neutral and acidic amino acids tested including aspartate, and basic amino acids are transported with low affinity) (Okumoto et al., 2002) | Eukaryota | Viridiplantae, Streptophyta | AAP6 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.2.5 | General amino acid transporter 8, AAP8 (transports all amino acids, but the basic amino acids are transported |
Eukaryota | Viridiplantae, Streptophyta | AAP8 of Arabidopsis thaliana |
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2.A.18.2.6 | Lysine-Histidine Transporter-7 (LHT7) found in mature pollen (Bock et al., 2006) (most like 2.A.18.2.2; 30% identity) |
Eukaryota | Viridiplantae, Streptophyta | LHT7 of Arabidopsis thaliana (Q84WE9) |
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2.A.18.2.7 | Amino acid permease 2 (Amino acid transporter AAP2) | Eukaryota | Viridiplantae, Streptophyta | AAP2 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.2.8 | Lysine histidine transporter-like 8 (Amino acid transporter-like protein 1) | Eukaryota | Viridiplantae, Streptophyta | AATL1 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.2.9 |
Lysine/histidine transporter 2 (AtLHT2) (Amino acid transporter-like protein 2). There are 15 LHTs in maize (Zea mays) (Rabby et al. 2022). |
Eukaryota | Viridiplantae, Streptophyta | LHT2 of Arabidopsis thaliana |
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2.A.18.3.1 | Proline permease 1 | Eukaryota | Viridiplantae, Streptophyta | Prt1 of Arabidopsis thaliana | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.3.2 | Proline/GABA/glycine betaine permease, ProT1, of 414 aas and 11 TMSs. Genome-wide identification of the proline transporter family in non-heading chinese cabbage and functional analysis of BchProT1 under heat stress in this organism (Tian et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | ProT1 of Lycopersicon esculentum |
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2.A.18.3.3 | Proline transporter, ProT2 of 439 aas and 11 TMSs. SlProT1 and SlProT2 genes seem to be more active than the others in response to abiotic stress conditions, but all are active (Akbudak and Filiz 2020). |
Eukaryota | Viridiplantae, Streptophyta | ProT2 of Solanum lycopersicum (Tomato) (Lycopersicon esculentum) |
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2.A.18.4.1 | Neutral amino acid permease | Eukaryota | Fungi, Ascomycota | AAP1 of Neurospora crassa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.4.2 | Aromatic and neutral amino acid permease, PcMtr (Trip et al., 2004) | Eukaryota | Fungi, Ascomycota | PcMtr of Penicillium chrysogenum (AAT45727) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.5.1 | Vesicular γ-aminobutyric acid (GABA) and glycine transporter (Aubrey et al., 2007) |
Eukaryota | Metazoa, Nematoda | UNC-47 of Caenorhabditis elegans |
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2.A.18.5.2 | The vacuolar amino acid transporter AVT1 (catalyzes uptake into yeast vacuoles of large neutral amino acids including tyr, gln, asn, leu and ile) | Eukaryota | Fungi, Ascomycota | AVT1 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.5.3 | The vacuolar GABA and glycine uptake transporter, VGAT. Also called "vesicular inhibitory amino acid transporter" (VIAAT); it is a 2Cl-/γ-aminobutyrate or glycine co-transporter in synaptic vesicles (Juge et al., 2009). GlyT2 and VIAAT cooperate to determine the vesicular glycinergic phenotype (Aubrey et al., 2007). |
Eukaryota | Metazoa, Chordata | VGAT of Mus musculus (O35633) |
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2.A.18.5.4 | Vesicular inhibitory amino acid transporter (GABA and glycine transporter; Solute carrier family 32 member 1; Vesicular GABA transporter; VGAT; hVIAAT). Probably functions by GABA:H+ antiport (Farsi et al. 2016). It localizes to the distal kidney tubule epithelia, especially in the inner medulla and basal portions of the lateral plasma membranes, but not in vesicles or vacuoles (Sakaew et al. 2018). De novo missense variants in SLC32A1 cause developmental and epileptic encephalopathy due to impaired GABAergic neurotransmission (Platzer et al. 2022). |
Eukaryota | Metazoa, Chordata | SLC32A1 of Homo sapiens |
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2.A.18.5.5 | The aggression-related transporter, CG13646 of 527 aas and 11 TMSs. Reduction in expression of CG13646 by approximately half leads to a hyperaggressive phenotype partially resembling that seen in Bully flies (Chowdhury et al. 2017). Members of this family are involved in glutamine/glutamate and GABA cycles of metabolism in excitatory and inhibitory nerve terminals. D. melanogaster provides a model for unraveling unique molecular features of epilepsy elicited by human GABA transporter 1 variants (Kasture et al. 2022). |
Eukaryota | Metazoa, Arthropoda | CG13646 of Drosophila melanogaster |
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2.A.18.6.1 | Neuronal glutamine (System A-like) transporter, GlnT | Eukaryota | Metazoa, Chordata | GlnT of Rattus norvegicus (Q9JM15) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.6.10 | Vacuolar broad specificity amino acid transporter 5 Avt5. Transports histidine, gluatmate, tyrosine, arginine, lysine and serine (Chardwiriyapreecha et al., 2010). |
Eukaryota | Fungi, Ascomycota | Avt5 of Saccharomyces cerevisiae (P38176) |
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2.A.18.6.11 | SLC38 member 6, SNAT6. Na+-dependent synaptic vesicle amino acid release porter (Gasnier, 2004) (transports amino acids,glutamate, glutamine, glycine and γ-amino butyric acid (GABA)). It seems to be the only glutamine transporter in the brain, being present in excitatory neurons, particularly at the synapses (Bagchi et al. 2014). Glutamine uptake via SNAT6 and caveolin (TC# 8.A.26) regulates the glutamine-glutamate cycle (Gandasi et al. 2021). It exhibits a high degree of specificity for glutamine and glutamate, and the presence of these substrates enables formation of SNAT6-caveolin complexes that aid in sodium-dependent trafficking. Interacting partners of SNAT6 include CTP synthase 2 (CTPs2), phosphate-activated glutaminase (Pag; Kvamme et al. 2001), and glutamate metabotropic receptor 2 (Grm2; TC# 9.A.14.7.9) (Gandasi et al. 2021). |
Eukaryota | Metazoa, Chordata | SLC38A6 of Homo sapiens |
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2.A.18.6.12 | Solute carrier family 38, member 8, SLC38A8, expressed only in the eye. This protein is probably a Na+/H+-dependent amino acid (glutamine) transporter which when defective, gives rise to foveal hypoplasia associated with congenital nystagmus and reduced visual acuity, FHONDA (Perez et al. 2014). SLC38A8 mutations exhibit arrest of retinal development at an early stage, resulting in a poorly developed retina with a severe phenotype (Kuht et al. 2020). Severe arrest of foveal development was identified in patients with variants of SLC38A8, and a brief summary of the clinical and genetic characteristics of the pathogenic SLC38A8 variants has been described (Ren et al. 2024). Thus, foveal hypoplasia (FH) can be caused by variants of SLC38A8 (Ren et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC38A8 of Homo sapiens |
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2.A.18.6.13 | Sodium-coupled neutral amino acid transporter 7, SNAT7. Transports L-glutamine in excitatory neurons (but not astrocytes) as the preferred substrate, particularly at synapses, but also transports L-glutamate and other amino acids with polar side chains such as L-histidine and L-alanine (Hägglund et al. 2011). N6-methyladenosine modification of SLC38A7 promotes cell migration, invasion, oxidative phosphorylation, and mitochondrial function in gastric cancer (Hua et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC38A7 of Homo sapiens |
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2.A.18.6.14 | Sodium-coupled neutral amino acid transporter 1 (Amino acid transporter A1; SLC38A1; SNAT1; N-system amino acid transporter 2; Solute carrier family 38 member 1; System A amino acid transporter 1; System N amino acid transporter 1). When overexpressed, it causes Rett syndrome (RTT), an autism spectrum disorder caused by loss-of-function mutations in the gene encoding MeCP2, an epigenetic modulator (transcriptional repressor) of SLC38A1, which encodes a major glutamine transporter (SNAT1). Because glutamine is mainly metabolized in the mitochondria where it is used as an energy substrate and a precursor for glutamate production, SNAT1 overexpression in MeCP2-deficient microglia impairs glutamine homeostasis, resulting in mitochondrial dysfunction as well as microglial neurotoxicity because of glutamate overproduction (Perez et al. 2014). |
Eukaryota | Metazoa, Chordata | SLC38A1 of Homo sapiens |
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2.A.18.6.15 | Neutral amino acid transporter 5 (Solute carrier family 38 member 5, SNAT5) (System N transporter 2, SN2). Transports glutamine, histidine and glycine as well as other amino acids. Present in glial cells where it probably functions in neurotransmitter clearance from synapses (Rodríguez et al. 2014). May also take up cisplatin (Girardi et al. 2020). SLC38A5 is a metabolic regulator of retinal angiogenesis by controlling amino acid nutrient uptake and homeostasis in endothelial cells (Wang et al. 2022). SLC38A5/SNAT5 is a system N transporter that can mediate net inward or outward transmembrane fluxes of neutral amino acids coupled with Na+ (symport) and H+ (antiport). Its preferential substrates are amino acids with side chains containing amide (glutamine, and asparagine) or imidazole (histidine) groups, but also serine, glycine and alanine are transported by the carrier. Expressed in the pancreas, intestinal tract, brain, liver, bone marrow, and placenta, it is regulated at mRNA and protein levels by mTORC1 and WNT/beta-catenin pathways, and it is sensitive to pH, nutritional stress, inflammation, and hypoxia. SNAT5 expression has been found to be altered in pathological conditions such as chronic inflammatory diseases, gestational complications, chronic metabolic acidosis and malnutrition. Growing experimental evidence shows that SNAT5 is overexpressed in several types of cancer cells. Moreover, recently published results indicate that SNAT5 expression in stromal cells can support the metabolic exchanges occurring in the tumor microenvironment of asparagine-auxotroph tumors. Taurino et al. 2023 reviewed the functional roles of the SNAT5 transporter in pathophysiology, and they propose that, due to its peculiar operational and regulatory features, SNAT5 plays pro-cancer roles when expressed either in neoplastic or in stromal cells ofglutamine-auxotroph tumors. |
Eukaryota | Metazoa, Chordata | SLC38A5 of Homo sapiens |
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2.A.18.6.16 | Sodium-coupled amino acid transporter 10, SNAT10. Expressed in several endocrine organs (Sundberg et al. 2008). Transports glutamine, glutamate and aspartate in neuronal and astrocytic cells (Hellsten et al. 2017). |
Eukaryota | Metazoa, Chordata | SLC38A10 of Homo sapiens |
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2.A.18.6.17 | Sodium-coupled neutral amino acid transporter 4 (Amino acid transporter A3) (Na(+)-coupled neutral amino acid transporter 4) (Solute carrier family 38 member 4) (System A amino acid transporter 3) (System N amino acid transporter 3) | Eukaryota | Metazoa, Chordata | SLC38A4 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.6.18 | Putative sodium-coupled neutral amino acid transporter 11, SNAT11 (Forde et al. 2014). |
Eukaryota | Metazoa, Chordata | SLC38A11 of Homo sapiens |
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2.A.18.6.19 | Vacuolar amino acid transporter 7 | Eukaryota | Fungi, Ascomycota | AVT7 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.6.2 | Liver histidine and glutamine specific system N-like, Na+-dependent amino acid transporter, mNAT. Also called SNAT3. SNAT3 trafficking occurs in a dynamin-independent manner and is influenced by caveolin (Balkrishna et al., 2010). |
Eukaryota | Metazoa, Chordata | mNAT of Mus musculus (Q9JLL8) |
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2.A.18.6.20 | Vacuolar amino acid transporter 2 | Eukaryota | Fungi, Ascomycota | AVT2 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.6.21 | Amino acid transporter 10 of 490 aas and 12 TMSs, AATP10 or AAT4.1. Found to be essential for bloodstream-form Trypanosoma brucei through a genome-wide RNAi screen (Schmidt et al. 2018).
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Eukaryota | Euglenozoa | AATP10 of Trypanosoma brucei |
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2.A.18.6.22 | Amino acid transporter 17.2, AAT17.2 of 494 aas and 11 TMSs. Found to be essential for bloodstream-form Trypanosoma brucei through a genome-wide RNAi screen (Schmidt et al. 2018). |
Eukaryota | Euglenozoa | AAT17.2 of Trypanosoma brucei |
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2.A.18.6.23 | Probable amino acid transporter of 378 aas and 10 TMSs. |
Viruses | Bamfordvirae, Nucleocytoviricota | aa transporter of Red seabream iridovirus |
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2.A.18.6.24 | Uncharacterized putative amino acid transporter of 574 aas and 12 TMSs |
Eukaryota | Evosea | UP of Entamoeba histolytica |
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2.A.18.6.25 | Amino acid (probably hydrophobic amino acids, Leu, Ile, Val, Met) uptake transporter, AAT1, of 606 aas and 12 TMSs (Wunderlich 2022). |
Eukaryota | Apicomplexa | AAT1 of Plasmodium falciparum |
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2.A.18.6.3 | System N1, SNAT3 [glutamine/histidine/asparagine/alanine]:[Na+ + H+] sym/antiporter (1 aa + 2 Na+ cotransported against 1 H+ antiported out) (probable orthologue of mNAT). Li+ can substitute for Na+; system N1 can function bidirectionally. SNAT3 is a primarily a glutamine transporter required for amino acid homeostasis. Loss cannot be compensated, suggesting that this transporter is a major route of glutamine transport in the liver, brain, and kidney (Chan et al. 2015). Biallelic variants of SLC38A3 cause epileptic encephalopathy (Marafi et al. 2021). Biallelic variants of SLC38A3 cause epileptic encephalopathy (Marafi et al. 2022). |
Eukaryota | Metazoa, Chordata | SLC38A3 of Homo sapiens |
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2.A.18.6.4 | Plasma membrane System A-like neutral amino acid transporter, SA1, SAT2 or SNAT2 (transports small, neutral aliphatic amino acids including α-(methylamino)isobutyrate, mAIB with Na+ (1:1 stoichiometry; Km = 200-500 μM)). Asparagine 82 controls the interaction of Na+ with the transporter (Zhang and Grewer, 2007). The C-terminal domain regulates transport activity through a voltage-dependent process (Zhang et al., 2011). An 11 TMS topology has been experimentally demonstrated (Ge et al. 2018). |
Eukaryota | Metazoa, Chordata | SAT2 of Rattus norvegicus (Q9JHE5) |
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2.A.18.6.5 | Na+-dependent system A-like transporter, SLC38A2, System A2 or ATA2, SAT2, SNAT2, transports neutral amino acids with decreasing affinity in the order: MeAIB, Ala, Gly, Ser, Pro, Met, Asn, Gln, Thr, Leu and Phe. The neuronal system A2 has been reported to transport Asn and Gln with higher affinity than for other neutral amino acids. ATA2 is stored in the Golgi network and released by insulin stimulus in adipocytes (Hatanaka et al., 2006a). Its levels are regulated by ubiquitin ligase, Nedd4-2, which causes endocytotic sequestration and proteosomal degradation (Hatanaka et al., 2006b). SNAT2 also functions as a mammalian amino acid transceptor (transporter/receptor), acting in an autoregulatory gene expression pathway (Hyde et al., 2007). It also mediates an anion leak conductance that is differentially inhibited by transported substrates (Zhang and Grewer, 2007). It also transports homocysteine (Tsitsiou et al., 2009). It and other SLC proteins belonging to different families and subcellular compartments are subject to induced degradation by heterobifunctional ligands (Bensimon et al. 2020), thus allowing chemical control of transporter protein abundance. . |
Eukaryota | Metazoa, Chordata | SLC38A2 of Homo sapiens |
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2.A.18.6.6 | The vacuolar amino acid transporter, AVT6 (catalyzes efflux from yeast vacuoles of acidic amino acids, Asp and Glu) | Eukaryota | Fungi, Ascomycota | AVT6 of Saccharomyces cerevisiae (P40074) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.6.7 | The Na-dependent alanine/α-(methylamino) isobutyric acid-transporting system A, ATA3 or SNAT4. Transports most neutral short chain amino acids electrogenically. Present only in liver and skeletal muscle. 47% and 57% identical to ATA1 and ATA2, respectively. A 10TMS topology [with N-and C-termini outside and a large N-glycosylated, extracellular loop domain (residues 242-335)] has been established (Shi et al., 2011). (Km(ALA)= 4mM; Na+:Ala= 1:1) (Sugawara et al., 2000) |
Eukaryota | Metazoa, Chordata | ATA3 of Rattus norvegicus (Q9EQ25) |
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2.A.18.6.8 | Second subtype of system N; glutamine transporter, SN2. Prevalent in liver, but detectable in other tissues. Amino acid uptake is coupled to Na+ influx and H+ efflux (Nakanishi et al., 2001) |
Eukaryota | Metazoa, Chordata | SN2 of Rattus norvegicus (Q91XR7) |
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2.A.18.6.9 | Arginine-specific transporter, AAP3 (KM (Arg) = 2μM) | Eukaryota | Euglenozoa | AAP3 of Leishmania donovani (Q86G79) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.7.1 | The vacuolar amino acid transporter, AVT3 (catalyzes efflux from yeast vacuoles of large neutral amino acids such as tyr, gln, asn, leu and ile) | Eukaryota | Fungi, Ascomycota | AVT3 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.7.2 | Vacuolar amino acid transporter 4 | Eukaryota | Fungi, Ascomycota | AVT4 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.7.3 | Vacuolar amino acid transporter 3, Avt3. Catalyzes efflux from vacuoles of large hydrophobic and hydrophilic neutral amino acids, and is required for sporulation. |
Eukaryota | Fungi, Ascomycota | Avt3 of Schizosaccharomyces pombe |
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2.A.18.7.4 | Proline/alanine transporter of 488 aas and 10 TMSs, AAP24. The first 18 amino acids of the negatively charged N-terminal LdAAP24 tail are required for alanine transport and may facilitate the electrostatic interactions of the entire negatively charged N-terminal tail with the positively charged internal loops in the transmembrane domain. This mechanism may underlie regulation of substrate flux rate for this and other transporters (Schlisselberg et al. 2015). |
Eukaryota | Euglenozoa | AAP24 of Leishmania infantum |
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2.A.18.7.5 | Amino acid transporter-6, AAT6 of 488 aas and 11 TMSs. Transports neutral amino acids and the drug, eflornithine (Schmidt et al. 2018). Eflornithine is used in combination with nifurtimox to combat T. brucei disease, and resistance to eflornithine is caused by the deletion or mutation of TbAAT6 which transports eflornithine into the cell (Kasozi et al. 2022).
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Eukaryota | Euglenozoa | AAT6 of Trypanosoma brucei
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2.A.18.8.1 | The electrogenic, proton-dependent amino acid:H+ symporter, PAT1 or LYAAT-1 (Slc36A1). Catalyzes uptake of L-Gly, L-Ala, L-Pro, γ-amino butyrate, and short chain D-amino acids such as proline and hydroxyproline with an aa/ H+ ratio of 1:1 (found in lysosomes) In humans, this is the iminoglycinuria protein (Boll et al., 2004; Miyauchi et al., 2005; Broer, 2008). A disulfide bridge is essential for transport function (Dorn et al., 2009). Transports taurine and β-alanine by H+ symport with low affinity and high capacity across the intestinal brush boarder membrane (Anderson et al., 2009). Exhibits low affinity (Km= 1-10 mM) and transports amino acid-based drugs used to treat epilepsy, schizophrenia, bacterial infections, hyperglycemia and cancer (Thwaites and Anderson, 2011). It is regulated by the Birt-Hogg-Dubé (BHD) syndrome related protein FLCN that has been implicated in the vesicular trafficking processes by interacting with several Rab family GTPases. FLCN binds via its C-terminal DENN-like domain to the recycling transport regulator, Rab11A, and promoted the loading of PAT1 on Rab11A (Zhao et al. 2018). |
Eukaryota | Metazoa, Chordata | mPAT1 of Mus musculus (Q8K4D3) |
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2.A.18.8.2 | Electrogenic, proton-coupled, amino acid symporter 2 (PAT2; Tramdorin-1; SLC36A2) (transports small amino acids: glycine, alanine and proline; found in the ER, not in lysosomes, of neuronal cells in the brain and spinal cord; it can catalyze bidirectional transport depending on the driving force) (Boll et al., 2004; Rubio-Aliaga et al., 2004). SLC36A2 is expressed at the apical surface of the human renal proximal tubule where it functions in the reabsorption of glycine, proline, hydroxyproline and amino acid derivatives with narrower substrate selectivity and higher affinity (Km 0.1-0.7 mM) than SLC36A1. Mutations in SLC36A2 lead to hyperglycinuria and iminoglycinuria. |
Eukaryota | Metazoa, Chordata | PAT2 of Mus musculus (AAH44800) |
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2.A.18.8.3 | Amino acid transporter (low capacity, high affinity) and amino acid-dependent signal transduction protein, Pathetic (Path) (Goberdhan et al., 2005) | Eukaryota | Metazoa, Arthropoda | Path of Drosophila melanogaster (Q9VT04) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.8.4 | H+-coupled amino acid transporter-3 (SLC36A3). SLC36A3 is expressed only in testes and has no known function (Thwaites and Anderson 2011). |
Eukaryota | Metazoa, Chordata | SLC36A3 of Homo sapiens |
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2.A.18.8.5 | H+-coupled amino acid transporter-4; SLC36A4. SLC36A4 is widely distributed and has high-affinity (Km = 2-3 µM) for proline and tryptophan (Thwaites and Anderson 2011). Gut microbiota-derived butyrate may have therapeutic potential in affective disorders characterized by either aberrant serotonergic activity or neuroinflammation due to its role in rescuing the oxidative stress-induced perturbations of tryptophan transport (Rode et al. 2021). |
Eukaryota | Metazoa, Chordata | SLC36A4 of Homo sapiens |
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2.A.18.8.6 | Proton-coupled amino acid transporter 2 (Proton/amino acid transporter 2) (Solute carrier family 36 member 2) (Tramdorin-1) | Eukaryota | Metazoa, Chordata | SLC36A2 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.8.7 | Proton-coupled amino acid transporter 1 (Proton/amino acid transporter 1) (hPAT1 or LYAAT-1) (Solute carrier family 36 member 1). SLC36A1 is expressed at the luminal surface of the small intestine but is also commonly found in lysosomes in many cell types (including neurons), suggesting that it is a multipurpose carrier with distinct roles in different cells including absorption in the small intestine and as an efflux pathway following intralysosomal protein breakdown. SLC36A1 has a relatively low affinity (Km = 1-10 mM) for its substrates, which include zwitterionic amino and imino acids, heterocyclic amino acids and amino acid-based drugs and derivatives used experimentally and/or clinically to treat epilepsy, schizophrenia, bacterial infections, hyperglycaemia and cancer (Thwaites and Anderson 2011). hPAT1 transports the pyridine alkaloids, arecaidine, guvacine and isoguvacine, across the apical membrane of enterocytes and might be responsible for the intestinal absorption of these drug candidates (Voigt et al. 2013). |
Eukaryota | Metazoa, Chordata | SLC36A1 of Homo sapiens |
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2.A.18.8.8 | Putative amino acid permease F59B2.2 | Eukaryota | Metazoa, Nematoda | F59B2.2 of Caenorhabditis elegans | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.18.8.9 | Small, semipolar, amino acid (Ser, Pro, Cys, Ala and Gly) uniporter, NEAAT of 463 aas and 9 - 12 TMSs. It catalyzes electroneutral bidirectional amino acid exchange is response to amino acid concentration gradients (Feng et al. 2019). This transporter is present in thebacteriocyte (symbiosome) membrane which houses the symbiotic bacteria that produce the essential amino acids for the aphid. |
Eukaryota | Metazoa, Arthropoda | NEAAT of Acyrthosiphon pisum (Pea aphid) |
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2.A.18.9.1 | Na+-coupled high affinity, lysosomal arginine transporter and sensor, SLC38A9 (561aas; 11 TMSs) (Gu et al. 2017). Also transports many other amino acids with low affinity and specificity (Rebsamen et al. 2015). The rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar ATPase-dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. Wang et al. 2015 showed that lysosomal SLC38A9 interacts with Rag GTPases and Ragulator in an amino acid-sensitive fashion. SLC38A9 transports arginine, and loss of SLC38A9 represses mTORC1 activation by amino acids, particularly arginine. Overexpression of SLC38A9 or just its Ragulator-binding domain makes mTORC1 signaling insensitive to amino acid starvation but not to Rag activity. Thus, SLC38A9 functions upstream of the Rag GTPases and is probably the arginine sensor for the mTORC1 pathway. Jung et al. 2015 confirmed SLC38A9 to be a Rag-Ragulator complex member, transducing amino acid availability to mTORC1. Lysosomal cholesterol activates TORC1 via an SLC38A9-Niemann-Pick C1 signaling complex (Castellano et al. 2017). The Niemann-Pick C1 (NPC1) protein (TC# 2.A.6.6.1), which regulates cholesterol export from the lysosome, binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function (Castellano et al. 2017). Ragulator and SLC38A9 are each unique guanine exchange factors (GEFs) that collectively push the Rag GTPases toward the active state (Shen and Sabatini 2018). Ragulator triggers GTP release from RagC, thus resolving the locked inactivated state of the Rag GTPases. Upon arginine binding, SLC38A9 converts RagA from the GDP- to the GTP-loaded state, and therefore activates the Rag GTPase heterodimer. Thus, Ragulator and SLC38A9 act on the Rag GTPases to activate the mTORC1 pathway in response to nutrient sufficiency. |
Eukaryota | Metazoa, Chordata | SLC38A9 of Homo sapiens |
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2.A.18.9.2 | SLC38A9 of 549 aas and 111 TMSs. The crystal structure of this lysosomal transporter with arginine bound in the inward facing conformation has been solved (Lei et al. 2018). The bound arginine was locked in a transitional state stabilized by TMS1, which was anchored at the groove between TM5 and TM7. These anchoring interactions were mediated by the highly conserved WNTMM motif in TMS1, and mutations in this motif abolished arginine transport (Lei et al. 2018). |
Eukaryota | Metazoa, Chordata | SLC38A9 of Danio rerio (Zebrafish) (Brachydanio rerio) |
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2.A.19.1.1 | Ca2+:H+ antiporter (also catalyzes Na+:H+ and K+:H+ antiport in processes that have been shown to be physiologically important under certain conditions) (Ivey et al., 1993; Radchenko et al., 2006) | Bacteria | Pseudomonadota | ChaA of E. coli | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.19.10.1 | Putative CaCA family member of 368 aas and 10 TMSs |
Eukaryota | Evosea | UP of Dictyostelium discoideum |
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2.A.19.10.2 | Uncharacterized protein of 518 aas and 10 TMSs |
Eukaryota | Metazoa, Placozoa | UP of Trichoplax adhaerens (Trichoplax reptans) |
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2.A.19.2.1 | Ca2+:H+ antiporter | Bacteria | Cyanobacteriota | Ca2+:H+ antiporter of Synechocystis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.19.2.10 | Vacuolar cation/proton exchanger 1a (Ca(2+)/H(+) exchanger 1a) (OsCAX1a) | Eukaryota | Viridiplantae, Streptophyta | CAX1a of Oryza sativa subsp. japonica | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.19.2.12 | Ca2+/Mg2+/Mn2+:H+ antiporter, CAX or CHA, of 441 aas with a 90 residue hydrophilic N-terminus followed by 11 TMSs (Wunderlich 2022). |
Eukaryota | Apicomplexa | CAX of Plasmodium falciparum |
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2.A.19.2.2 | Vacuolar [Mn2+ or Ca2+]:H+ antiporter, Hum1 (Mn2+ resistance (Mnr1)) protein. Vcx1 has 11 probable TMSs with the N-terminus inside (Segarra and Thomas, 2008). The 3-d structure has been determined at 2.3 Å resolution for the cytosolic facing, substrate bound form, favoring the alternating access mechanism of transport (Waight et al. 2013). |
Eukaryota | Fungi, Ascomycota | Hum1 (Mnr1) of Saccharomyces cerevisiae |
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2.A.19.2.3 | High affinity vacuolar (tonoplast) Ca2+:H+ antiporter (also exports Cd2+ and Zn2+; Shigaki et al., 2005) It is expressed in leaves (Cheng et al., 2005). It determines sensitivity to abscisic acid and sugars during germination and tolerance to ethylene during early seedling development (Zhao et al., 2008). BrCAX1 is involved in Ca2+ transport and Ca2+ deficiency-induced tip-burn in chinese cabbage (Brassica rapa L. ssp. pekinensis) (Cui et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | Cax1 of Arabidopsis thaliana |
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2.A.19.2.4 | Low affinity Ca2+:H+/heavy metal cation (e.g., Mn2+, Mg2+, Cd2+, Ca2+):H+ antiporter, Cax2. The apple (Malus domestiga) ortholog (CAX2L-2) functions positively in modulation of Ba2+ tolerance (Mei et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | Cax2 of Arabidopsis thaliana |
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2.A.19.2.5 | High affinity vacuolar (tonoplast) Ca2+:H+ antiporter (also exports Cd2+ and Zn2+; Shigaki et al., 2005) highly expressed in roots (Cheng et al., 2005) (exhibits phenotypes characteristic of CAX1, but also determines sensitivities to salt, lithium and low pH (Zhao et al., 2008) | Eukaryota | Viridiplantae, Streptophyta | Cax3 of Arabidopsis thaliana (Q93Z81) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.19.2.6 | Algae Ca2+: H+ and Na+:H+ exchanger, CAX1 (mediates stress responses to high Ca2+, Na+ and Co2+). |
Eukaryota | Viridiplantae, Chlorophyta | CAX1 of Chlamydomonas reinhardtii (B6ZCF4) |
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2.A.19.2.7 | Ca2+/H+ antiporter, YfkE (Fujisawa et al., 2009). YfkE is a homotrimer with a subunit size of 451 aas. The 3-d x-ray strcuture is known to 3.1 Å resolution (Wu et al. 2013). The conformational transition is triggered by the rotation of the kink angles of transmembrane helices 2 and 7 and is mediated by large conformational changes in their adjacent transmembrane helices 1 and 6. The inward facing conformation contrasts with the outward facing conformation demonstrated for NCX_Mj (TC# 2.A.19.5.3). The inward facing conformation has a "hydrophobic seal" that closes the external exit (Wu et al. 2013). Intracellular Ca2+ regulation of this H+/Ca2+ antiporter is mediated by a Ca2+ mini-sensor (Lu et al. 2020). The mini-sensor is formed by six tandem carboxylate residues within the transmembrane (TM)5-6 loop on the intracellular membrane surface. Ca2+ binding to the mini-sensor triggers the transition of the transport mode of YfkE from a high-affinity to a low-affinity state. Ca2+ binding to the mini-sensor causes an adjacent segment, the exchanger inhibitory peptide (XIP), to move toward the Ca2+ translocation pathway to interact with TMS 2a in an inward-open cavity. The specific interaction was demonstrated with a synthetic peptide of the XIP, which inhibits YfkE transport and interrupts conformational changes mediated by the mini-sensor. By comparing the apo and Ca2+-bound CAX structures, we propose the following Ca2+ transport regulatory mechanism of YfkE: Ca2+ binding to the mini-sensor induces allosteric conformational changes in the Ca2+ translocation pathway via the XIP, resulting in a rearrangement of the Ca2+-binding transport site in the midmembrane. Since the Ca2+ mini-sensor and XIP sequences are also identified in other CAX homologs, including the mammalian Na+/Ca2+ exchanger (NCX), this study provides a regulatory mechanism for the Ca2+/cation transporter superfamily (Lu et al. 2020). |
Bacteria | Bacillota | YfkE of Bacillus subtilis (O34840) |
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2.A.19.2.8 | The vacuolar Ca2+:H+ exchanger, CAX (Bowman et al., 2011). |
Eukaryota | Fungi, Ascomycota | CAX of Neurospora crassa (O59940) |
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2.A.19.2.9 | Vacuolar cation:proton exchanger, Cax4 (transports Cd2+>Zn2+>Ca2+>Mn2+) (Cheng et al., 2002; Mei et al., 2009). The rice orthologue, Cax4, may transport Ca2+, Mn2+ and Cu2+, and functions in salt stress (Yamada et al. 2014). The A. thaliana protein contributes to Cd2+ resistance (Liao et al. 2019). |
Eukaryota | Viridiplantae, Streptophyta | Cax4 of Arabidopsis thaliana (Q945S5) |
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2.A.19.3.1 | The 10 TMS cardiac Ca2+:3 Na+ antiporter, NCX1 (Ren and Philipson 2013). The Ca2+ sensor (residues 371-508) binds cytoplasmic Ca2+ allosterically to activate exchange activity) (Nicoll et al., 2006; Ren et al., 2006) NCX1 forms homodimers (Ren et al., 2008). It is present in mitochondria where it catalyzes Ca2+ efflux. TMS packing has been analyzed by Ren et al. (2010). Cytoplasmic Ca2+ regulates the dimeric NCX by binding to two adjacent Ca2+-binding domains (CBD1 and CBD2) located in the large intracellular loop between transmembrane segments 5 and 6. John et al. (2011) showed that Ca2+decreases the distance between the cytoplasmic loops of NCX pairs, thereby activating transport. Ser110 in TMS2 plays a role in both Na+ and Ca2+ transport (Ottolia and Philipson 2013). nimodipiine-sensitive NCX1, as well as mitochondrial Ca2+ uptake, plays an important role in clearing somatic Ca2+ after depolarization-induced Ca2+ influx in SCN neurons (Wang et al. 2015). Regulation in suprachiasmatic nucleus neurons has been studied (Cheng et al. 2018). Genetic knockout and pharmacologic inhibitors of NCX1 attenuate hypoxia-induced pulmonary arterial hypertension (Nagata et al. 2020). The main Na+ influx pathway in myocardia in neonates is the NCX transporter (Oshiyama et al. 2022). Cytosolic Ca2+ and Na+ allosterically regulate Na+/Ca2+ exchanger (NCX) proteins to vary the NCX-mediated Ca2+ entry/exit rates in diverse mammalian cell types (Giladi et al. 2024). |
Eukaryota | Metazoa, Chordata | Ca2+ regulated Ca2+:Na+ antiporter (NCX1) of Bos taurus |
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2.A.19.3.2 | Probable Ca2+:3Na+ antiporter, Calx (contains two repeat motifs Calx-α and Calxβ, between the two transmembrane domains, as is true of many Ca2+:Na+ antiporters (Schwarz and Benzer, 1997). CALX activity is inhibited by Ca2+ interaction within its two intracellular Ca2+ regulatory domains CBD1 and CBD2. The Ca2+ inhibition of CALX is achieved by interdomain conformational changes induced by Ca2+ binding at CBD1 (Wu et al., 2011). The exchanger is an essential Ca2+ extrusion mechanism in excitable cells. It consists of a transmembrane domain and a large intracellular loop that contains the two Ca2+-binding domains, CBD1 and CBD2 (de Souza Degenhardt et al. 2021). The two CBDs are adjacent to each other and form a two-domain Ca2+ sensor called CBD12. Binding of intracellular Ca2+ to CBD12 activates NCX but inhibits the NCX of Drosophila, CALX. CALX and NCX CBD12 constructs display interdomain flexibility in the apo state but assume rigid interdomain arrangements in the Ca2+-bound state. CALX-CBD12 preferentially samples closed conformations, whereas the wide-open interdomain arrangement, characteristic of the Ca2+-bound state, is less frequently sampled. These results are consistent with the view that Ca2+ binding shifts the CBD12 conformational ensemble toward extended conformers, which could be a key step in the NCXs' allosteric regulation mechanism (de Souza Degenhardt et al. 2021). |
Eukaryota | Metazoa, Arthropoda | Calx of Drosophila melanogaster |
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2.A.19.3.3 | Plasma membrane sodium:calcium exchanger, NCX3, NAC3 or SLC8A3, controlling Ca2+ homeostasis. Extrudes 1 Ca2+ for 3 extracellular Na+ ions. Potent inhibitors have been identified (Secondo et al. 2015). One such inhibitor of NCX transporters, ORM-10962, exhibits high efficacy and selectivity. Selective NCX inhibition can exert positive as well as negative inotropic effects, depending on the actual operation mode of the NCX (Kohajda et al. 2016). Bepridil is a commonly used medication for arrhythmia and heart failure. It primarily exerts hemodynamic effects by inhibiting Na+/K+ movement and regulating Na+/Ca2+ exchange (Wei et al. 2022). |
Eukaryota | Metazoa, Chordata | SLC8A3 of Homo sapiens |
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2.A.19.3.4 | Sodium/calcium exchanger 1 (Na+/Ca2+-exchange protein 1), CNC NCX1 of 973 aas and 12 TMSs in a 6 + 6 TMS arrangement. The cardiac isoform, CAX1.1, like the archaeal homologues for which high resolution 3-d structures are available (TC#s 2.A.19.5.3 and 2.A.19.8.2), have two aqueous ion permeation channels with cavities that can face the cytoplasm or the external medium (John et al. 2013). It exchanges one Ca2+ ion against three to four Na+ ions, and thereby contributes to the regulation of cytoplasmic Ca2+ levels and Ca2+-dependent cellular processes (Komuro et al. 1992; , Van Eylen et al. 2001; Kofuji et al. 1992). It also contributes to Ca2+ transport during excitation-contraction coupling in muscle. In a first phase, voltage-gated channels mediate the rapid increase of cytoplasmic Ca2+ levels due to release of Ca2+ stores from the endoplasmic reticulum. SLC8A1 mediates the export of Ca2+ from the cell during the next phase, so that cytoplasmic Ca2+ levels rapidly return to baseline. It is also required for normal embryonic heart development and the onset of heart contractions. Both NCX1 and NCX2 play important roles in the motility of the gastric fundus, ileum and distal colon (Nishiyama et al. 2016). An amphipathic α-helix in the NCX1 large intracellular loop controls NCX1 palmitoylation. Thus, NCX1 palmitoylation is governed by a distal secondary structure element rather than by local primary sequence (Plain et al. 2017). The anti-aging gene NM_026333 contributes to proton-induced aging via the NCX1-pathway (Osanai et al. 2018). Dynamic palmitoylation modulates its structure, affinity for lipid-ordered domains, and inhibition by XIP (Gök et al. 2020). Na+/Ca2+ exchanger, NCX1, and canonical transient receptor potential channel 6 (TRPC6) are recruited by STIM1 to mediate Store-Operated Calcium Entry in primary cortical neurons (Tedeschi et al. 2022). SEA0400 is a potent and selective Na+/Ca2+ exchanger (NCX) inhibitor (Iwamoto et al. 2004). Along the proximal tubule and thick ascending limb of the kidney, Ca2+ and Na+ transport occur in parallel, but those processes were dissociated in the distal convoluted tubule (Hakimi et al. 2023). Xue et al. 2023 presented cryo-EM structures of human cardiac NCX1 in both inactivated and activated states, elucidating key structural elements important for NCX ion exchange and its modulation by cytosolic Ca2+ and Na+. They showed that the interactions between the ion-transporting transmembrane (TM) domain and the cytosolic regulatory domain define the activity of NCX. In the inward-facing state with low cytosolic [Ca2+], a TM-associated four-stranded beta-hub mediates tight packing between the TM and cytosolic domains, resulting in the formation of a stable inactivation assembly that blocks the TM movement required for ion exchange. Ca2+ binding to the cytosolic second Ca2+-binding domain (CBD2) disrupts this inactivation assembly which releases its constraint on the TM domain, yielding an active exchanger. Thus, the NCX1 structures provide an essential framework for the mechanistic understanding of the ion transport and cellular regulation of NCX family proteins (Xue et al. 2023). Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400 have been published (Dong et al. 2024). The cryo-EM structure of NCX1.3 in the presence of a specific inhibitor, SEA0400 shows that conserved ion-coordinating residues are exposed on the cytoplasmic face of NCX1.3, indicating that the observed structure is stabilized in an inward-facing conformation. The regulatory calcium-binding domains (CBDs) assemble with the ion-translocation transmembrane domain (TMD). The exchanger-inhibitory peptide (XIP) is trapped within a groove between the TMD and CBD2 and is predicted to clash with gating helices TMs(1/6) at the outward-facing state, thus hindering the conformational transition and promoting inactivation of the transporter. A bound SEA0400 molecule stiffens helix TM2ab and affects conformational rearrangements of TM2ab that are associated with the ion-exchange reaction, thus allosterically attenuating Ca2+-uptake activity of NCX1.3 (Dong et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC8A1 of Homo sapiens |
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2.A.19.3.5 | Sodium/calcium exchanger 2 (Na+/Ca2+-exchange protein 2; NCX2; SLC8A2) of 921 aas and 11 TMSs. Functional inhibition of NCX2 initially causes natriuresis, and further inhibition produces hypercalciuria, suggesting that the functional significance of NCX2 lies in Na+ and Ca+ reabsorption in the kidney (Gotoh et al. 2015). However NCX1-3 are present in the brain where they influence stroke theraputic strategies in a NCX subtype-specific fashion (Shenoda 2015). NCX1 and NCX2 play important roles in the motility of the gastric fundus, ileum and distal colon, but only NCX2 plays a role in the development of diarrhea (Nishiyama et al. 2016). |
Eukaryota | Metazoa, Chordata | SLC8A2 of Homo sapiens |
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2.A.19.4.1 | Rod photoreceptor Ca2+ + K+:4 Na+ antiporter, NCKX1. NCKX1 and heterologously expressed NCKX2 operate at a 4Na+:1Ca2++1 K+ stoichiometry; both NCKX1 and NCKX2 are bidirectional transporters normally extruding Ca2+ from the cell (forward exchange), but also able to carry Ca2+ into the cell (reverse exchange) when the transmembrane Na+ gradient is reversed. Sequence changes have been observed for both NCKX1 and NCKX2 in patients with retinal diseases (Schnetkamp 2004). |
Eukaryota | Metazoa, Chordata | Ca2+ + K+:Na+ antiporter (NCKX1) of Bos taurus |
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2.A.19.4.10 | Sodium/potassium/calcium exchanger 3 (Na+/K+/Ca2+-exchange protein 3), NCKX3, or (Solute carrier family 24 member 3), SLC24A3 (Yang et al. 2013). Palmitoylation is an endogenous regulator of NCKX3 activity (Tao et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC24A3 of Homo sapiens |
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2.A.19.4.11 | Sodium/potassium/calcium exchanger 2 (Na(+)/K(+)/Ca(2+)-exchange protein 2) (Retinal cone Na-Ca+K exchanger) (Solute carrier family 24 member 2) | Eukaryota | Metazoa, Chordata | SLC24A2 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.19.4.12 | Putative Ca2+:cation exchanger of 1524 aas and an apparent duplication with 27 putative |
Eukaryota | Metazoa, Chordata | Putative Ca2+: cation exchanger of Branchiostoma floridae |
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2.A.19.4.13 | Uncharacterized protein of 623 aas. |
Eukaryota | UP of Aureococcus anophagefferens (Harmful bloom alga) |
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2.A.19.4.14 | Ca2+:Na+ exchanger, NCX-9 of 651 aas and 14 TMSs. Plays a role in developmental cell patterning and Ca2+ exchange in mitochondrial (Sharma et al. 2017). |
Eukaryota | Metazoa, Nematoda | NCX-9 of Caenorhabditis elegans |
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2.A.19.4.15 | Putative sodium:calcium symporter of 377 aas and 10 TMSs. |
Viruses | Caudovirales | Na+:Ca2+ symporter of Pseudoalteromonas phage J2-1 |
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2.A.19.4.16 | Uncharacterized protein of 575 aas and 10 TMSs in a 4 + 6 TMS arrangement. |
Eukaryota | Perkinsozoa | UP of Entamoeba histolytica |
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2.A.19.4.2 | The major neuronal Ca2+ + K+:4 Na+ antiporter, NCKX2. NCKX1 and NCKX2 operate with 4Na+:1Ca2++1 K+ stoichiometry; both are bidirectional transporters normally extruding Ca2+ from the cell (forward exchange), but also able to carry Ca2+ into the cell (reverse exchange) when the transmembrane Na+ gradient is reversed. Sequence changes have been observed for both NCKX1 and NCKX2 in patients with retinal diseases (Schnetkamp 2004). |
Eukaryota | Metazoa, Chordata | NCKX2 of Rattus norvegicus |
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2.A.19.4.3 | The sea urchin spermatozoan flagellar K+-dependent Ca2+:Na+ antiporter SuNCKX (Ca2+ + K+:4 Na+ antiporter) | Eukaryota | Metazoa, Echinodermata | SuNCKX of Strongylocentrotus purpuratus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.19.4.4 | K+-dependent Na+/Ca2+ antiporter, NCKX6 (Cai and Lytton, 2004). CCKX6 (NCLX) is an essential component of the mitochondrial Na+/Ca2+ exchanger (Palty et al., 2010; Drago et al., 2011). It usually mediates mitochondrial Ca2+ extrusion (De Marchi et al. 2014). However, the mitochondrial calcium uniporter channel (MCU) and mitochondrial Na+ /Ca2+ exchanger, NCLX, mediate Ca2+ entry into and release from this organelle and couple cytosolic Ca2+ and Na+ fluctuations with cellular energetics (Verkhratsky et al. 2017). Abnormal levels occur in plasma neuron-derived extracellular vesicles of early schizophrenia and other neurodevelopmental diseases (Goetzl et al. 2022). Members of this family have the Glt fold (Ferrada and Superti-Furga 2022). The mitochondrial calcium uniporter (MCU) is involved in an ischemic postconditioning effect against ischemic reperfusion brain injury in mice (Sasaki et al. 2024). Mitochondrial sodium/calcium exchanger (NCLX) regulates basal and starvation-induced autophagy through calcium signaling (Ramos et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC24A6 of Homo sapiens |
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2.A.19.4.5 | The K+-dependent Na+/Ca2+ exchanger, MCKX4 (has 40x higher affinity for K+ than NCKX2 due to a threonine to alanine substitution at position 551 in NCKX2 (Visser et al., 2007)). NCKX4 is highly expressed and regulates Ca2+ transport in ameloblasts during amelogenesis (the formation of tooth enamel). In fact, MCKX4 is critical for enamel maturation (Wang et al. 2014). Residues involved in Na+ binding have been identified (Altimimi et al. 2010). Inhibitors of SLC26A4 that have shown promise in the treatment of different phenotypes of diseases including asthma (Guntupalli et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC24A4 of Homo sapiens |
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2.A.19.4.6 | Trans-Golgi network K+-dependent Na+/Ca2+ antiporter SLC24A5 (NCKX5) (regulates melanogenesis; determines skin color variation) (Ginger et al., 2008). |
Eukaryota | Metazoa, Chordata | SLC24A5 of Homo sapiens |
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2.A.19.4.7 | The endomembrane Ca2+:cation exchanger (CCX, CAX9 or CCX3); transports H+, Na+, K+ and Mn2+; expressed primarily in flowers (Morris et al., 2008). | Eukaryota | Viridiplantae, Streptophyta | CAX9 of Arabidopsis thaliana (Q9LJI2) |
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2.A.19.4.8 | K+ uptake and Na+ transporter, CCX5 (CAX11) (Zhang et al., 2011). |
Eukaryota | Viridiplantae, Streptophyta | CCX5 of Arabidopsis thaliana (O04034) |
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2.A.19.4.9 | Na+/K+/Ca2+ exchanger-1 isoform 1, NCKX-1 |
Eukaryota | Metazoa, Chordata | SLC24A1 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.19.5.1 | Putative Ca2+:H+ or Ca2+:Na+ antiporter with two 5 TMS internal repeats (Sääf et al. 2001). |
Bacteria | Pseudomonadota | ChaB (YrbG) of E. coli |
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2.A.19.5.2 | Cation (Ca2+/Na+):proton antiporter, ChaA or CaxA (confers both Na+ and Ca2+ resistance) (Wei et al., 2007) | Bacteria | Pseudomonadota | ChaA of Alkalimonas amylolytica (Q0ZAI3) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.19.5.3 | Na+:Ca2+ exchanger, NCX_Mj (3-d structure known at 1.9 Å resolution; PDB# 3V5U (Liao et al., 2012). Contains 10 TMSs with two 5 TMS repeats. Four ion binding sites near the center of the protein are present, one specific for Ca2+ and three probably for Na+. Two passageways allow for Na+ and Ca2+ access from the external side. However see a more recent analysis reported for 2.A.19.8.2 (Nishizawa et al. 2013). Transport of both Na+ and Ca2+ requires protonation of D240, but this side chain does not coordinate either ion, implying that the ion exchange stoichiometry is 3:1 and that translocation of Na+ across the membrane is electrogenic although transport of Ca2+ is not (Marinelli et al. 2014). This system has been reviewed and considered to be a model protein for the entire family (Khananshvili 2021). |
Archaea | Euryarchaeota | NCX_Mj of Methanococcus (Methanocaldococcus) jannaschii (Q57556) |
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2.A.19.5.4 | Na+/Ca2+ exchanger. Transport is electrogenic with a likely stoichiometry of 3 or more Na+ for each Ca2+ but K+-independent (Besserer et al. 2012). |
Archaea | Euryarchaeota | MaX1 of Methanosarcina acetivorans |
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2.A.19.6.1 | Vacuolar electrogenic Mg2+, Zn2+, Fe2+, and possibly Cd2+:H+ antiporter, MHX (found in the vascular cylinder; may control the partitioning of Mg2+ and Zn2+ between plant organs). MHX porters are found only in plants and probably have 9 TMSs. Their properties have been reviewed (Gaash et al. 2013). |
Eukaryota | Viridiplantae, Streptophyta | MHX of Arabidopsis thaliana |
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2.A.19.7.1 | Low affinity vacuolar monovalent cation (Na+ (Km=20 mM) or K+(Km=80 mM)):H+ antiporter, Vnx1. (Ca2+ is not transported; plays roles in ion and pH homeostasis) (Cagnac et al., 2007) |
Eukaryota | Fungi, Ascomycota | Vnx1 of Saccharomyces cerevisiae (P42839) |
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2.A.19.7.2 | Uncharacterized protein of 739 aas. |
Eukaryota | Metazoa, Chordata | UP of Ornithorhynchus anatinus (Duckbill platypus) |
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2.A.19.8.1 | Calcium:proton exchanger, CAX(CK31). The function was demonstrated by purification and reconstitution in liposomes (Ridilla et al. 2012). The protein forms dimers in the membrane but can be purified as a monomer. The dimer interface seems to involve TMSs 2 and 6 (Ridilla et al. 2012). |
Bacteria | Pseudomonadota | CAX(CD31) of Caulobacter sp. strain K31 |
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2.A.19.8.2 | Ca2+:H+ antiporter of 405 aas, CAX_Af. The inward facing 3-d structure has been solved to 2.3 Å resolution (Nishizawa et al. 2013). The authors compare this structure to the outward facing 1.9 Å structure of NCX_Mj (TC# 2.A.19.5.3) and suggest that Ca2+ or H+ binds to the cation-binding site mutually exclusively. The first and sixth TMSs alternately create hydrophilic cavities on the intra- and extracellluar sides of the membrane. The inward and outward-facing transitions are triggered by ion binding (Nishizawa et al. 2013). |
Archaea | Euryarchaeota | Ca2+:H+ antiporter CAX_Af of Archaeoglobus fulgidus |
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2.A.19.9.1 | Mg2+ transporter (Mg2+-specific channel-like exchanger) of 550 aas (Preston and Kung 1994; Haynes et al. 2002). Has 10 putative TMSs in a 5 + 5 TMS arrangement and exhibits properties of a channel (Haynes et al. 2002). The mutant form is called 'eccentric' and exhibits backwards swimming behavior (Preston and Kung 1994). |
Eukaryota | Ciliophora | Ca2+-dependent Mg2+ transporter of Paramecium tetraurelia |
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2.A.19.9.2 | Probable Mg2+-specific channel-like exchanger of 625 aas. |
Eukaryota | Ciliophora | Probable Mg2+-specific channel-like exchanger of Tetrahymena thermophila |
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2.A.2.1.1 | Melibiose permease. Catalyzes the coupled stoichiometric symport of a galactoside with a cation (either Na+, Li+, or H+). Based on LacY, a 3-d model has been derived (Yousef and Guan, 2009). Asp55 and Asp59 are essential for Na+ binding. Asp124 may play a critical role by allowing Na+-induced conformational changes and sugar binding. Asp19 may facilitate melibiose binding (Granell et al., 2010). The alternate access mechanism fits better into a flexible gating mechanism rather than the archetypical helical rigid- body rocker-switch mechanism (Wang et al. 2016). Crystal structures of Salmonella typhimurium MelB in two conformations, representing an outward partially occluded and an outward inactive state (Ethayathulla et al. 2014). MelB adopts a typical MFS fold and contains a previously unidentified cation-binding motif. Three conserved acidic residues form a pyramidal-shaped cation-binding site for Na+, Li+ or H+, which is in close proximity to the sugar-binding site. Both cosubstrate-binding sites are mainly contributed by the residues from the amino-terminal domain (Ethayathulla et al. 2014). The Glucose Enzyme IIA protein of the PTS binds MelB either in the absence or presence of a galactoside, and binding decreases the affinity for melibiose, giving rise to inducer exclusion (Saier 1989; Hariharan and Guan 2014). A D55C mutant converted MelBSt to a solely H+-coupled symporter, and together with the free-energy perturbation calculation, Asp59 is the sole protonation site of MelBS of Salmonella typhimurium. Unexpectedly, the H+-coupled melibiose transport exhibited poor activities at greater bulky ΔpH and better activities at reversal ΔpH, supporting the novel theory of transmembrane-electrostatically localized protons and the associated membrane potential are the primary driving forces for H+-coupled symport mediated by MelBSt (Hariharan et al. 2024). MelBSt trapped by camelid single-domain nanobodies (Nbs) retained its physiological functions, and the trapped conformation is similar to that bound by the physiological regulator EIIAGlc (Katsube et al. 2023). |
Bacteria | Pseudomonadota | MelB of E. coli (A7ZUZ0) |
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2.A.2.1.2 |
Probable fucosyl-α-1,6-N-acetylglucosamine uptake porter, AlfD (next to and in an operon with a fucosidase (AlfA) specific for this disaccharide which is present in mammalian glycoproteins, glycolipids and milk (Rodríguez-Díaz et al. 2012). |
Bacteria | Bacillota | AlfD of Lactobacillus casei |
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2.A.2.1.3 | Uncharacterized protein, probably a sugar:H+ symporter of 474 aas and 12 TMSs, YjmB, The gene was from a marine sediment metagenome. |
Archaea | Candidatus Lokiarchaeota | YjmB of Lokiarchaeum sp. GC14_75 |
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2.A.2.2.1 | Lactose permease, LacS. Mediates uptake of β-galactooligosaccharides, lactitol, and a broad range of prebiotic β-galactosides that selectively stimulate beneficial gut microbiota (Andersen et al., 2011). |
Bacteria | Bacillota | LacS of Streptococcus thermophilus |
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2.A.2.2.2 | Raffinose permease | Bacteria | Bacillota | RafP of Pediococcus pentosaceus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.2.2.3 | Galactose permease of 462 aas and 12 TMSs. Transports galactose (Grossiord et al. 2003). |
Bacteria | Bacillota | GalP of Lactococcus lactis |
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2.A.2.3.1 | Glucuronide permease, UidB, GusB, UidP (Liang et al., 2005; Moraes and Reithmeier 2012) |
Bacteria | Pseudomonadota | GusB of E. coli |
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2.A.2.3.10 | Transmembrane protein 180 | Eukaryota | Metazoa, Chordata | TMEM180 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.2.3.11 | Putative transporter |
Eukaryota | Euglenozoa | Putative transporter of Trypanosoma cruzi |
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2.A.2.3.12 | Putative sugar transporter |
Bacteria | Deinococcota | TT_P0219 pf Thermus thermophilus |
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2.A.2.3.13 | Probable sugar transporting MFS-2 symporter of 444 aas and 12 TMSs. |
Archaea | Candidatus Thorarchaeota | MFS carrier of Candidatus Thorarchaeota archaeon |
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2.A.2.3.14 | Probable sugar:cation symporter, MFSD13A or TMEM180, with 517 aas and 12 TMSs with the N- and C-termini reported to be exposed extracellularly (Anzai and Matsumura 2019). It has anti-tumor activity (Yasunaga et al. 2019) and is highly expressed in colorectal cancer (CRC) (Anzai et al. 2021; Shiraishi et al. 2021). It is also a schizophrenia risk factor (Wang et al. 2021). |
Eukaryota | Metazoa, Chordata | TMEM180 of Homo sapiens |
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2.A.2.3.15 | Probable sulfoquinovose importer of 467 aas and 12 TMSs (Denger et al. 2014). Sulphoquinovose (SQ, 6-deoxy-6-sulphoglucose) is the polar headgroup of the plant sulpholipid in the photosynthetic membranes of all higher plants, mosses, ferns, algae, most photosynthetic bacteria, and some non-photosynthetic bacteria. It is part of the surface layer of some Archaea. The estimated annual production of SQ is 10,000,000,000 tonnes (10 petagrams) (Denger et al. 2014). |
Bacteria | Pseudomonadota | Sulfoquinovose importer of E. coli |
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2.A.2.3.16 | MfsD2B or SLC59A2 protein of 504 aas and 12 TMSs (). It is a cation-dependent lipid transporter that specifically mediates export of sphingosine-1-phosphate from red blood cells and platelets (Vu et al. 2017). Sphingosine-1-phosphate is a signaling sphingolipid, and its export from red blood cells into in the plasma is required for red blood cell morphology. It does not transport lysophosphatidylcholine (LPC). |
Eukaryota | Metazoa, Chordata | MfsD2B of Homo sapiens |
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2.A.2.3.17 | Putative sugar: cation symporter, GPH, of 548 aas and 12 TMSs in a 6 + 6 TMS arrangement (Wunderlich 2022). |
Eukaryota | Apicomplexa | GPH of Plasmodium falciparum |
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2.A.2.3.2 | Pentoside permease | Bacteria | Bacillota | XynC (YnaJ) of Bacillus subtilis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.2.3.3 | Isoprimeverose (α-D xylopyranosyl-(1,6)-D-glucopyranose) permease [xylose is not a substrate] (Heuberger et al., 2001) |
Bacteria | Bacillota | XylP of Lactobacillus pentosus |
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2.A.2.3.4 | Probable α-xyloside uptake permease, YicJ (Laikova et al., 2001) | Bacteria | Pseudomonadota | YicJ of E. coli (P31435) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.2.3.5 | Probable β-xyloside uptake permease, YagG (Laikova et al., 2001) | Bacteria | Pseudomonadota | YagG of E. coli (P75683) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.2.3.6 | The putative cellobiose porter, BglT (Rodionov et al. 2010) |
Bacteria | Pseudomonadota | BglT of Shewanella amazonensis (A1S5F2) |
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2.A.2.3.7 | The putative arabinoside porter, AraT (Rodionov et al., 2010) |
Bacteria | Pseudomonadota | AraT of Shewanella sp. MR-4 (Q0HIQ0) |
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2.A.2.3.8 | Major Facilitator Superfamily Domain containing 2A, MFSD2A or SLC59A1 (543aas, 12 TMSs). It is the omega-3-fatty acid transporter that plays a role in thermogenesis via β-adrenergic signaling. It takes up Tunicamycin (TM), a mixture of related species of nucleotide sugar analogs fatty-acylated with alkyl chains of varying lengths and degrees of unsaturation, produced by several Streptomyces species (Bassik and Kampmann, 2011; Reiling et al., 2011). It is a sodium-dependent lysophosphatidylcholine (LPC) symporter expressed at the blood-brain barrier endothelium. It is the primary route for import of docosahexaenoic acid and other long-chain fatty acids into foetal and adult brain, and is essential for mouse and human brain growth and function (Quek et al. 2016). In addition to a conserved sodium-binding site, three structural features were identified: A phosphate headgroup binding site, a hydrophobic cleft to accommodate a hydrophobic hydrocarbon tail, and three sets of ionic locks that stabilize the outward-open conformation. Ligand docking studies and biochemical assays identified Lys436 as a key residue for transport. It forms a salt bridge with the negative charge on the phosphate headgroup. Mfsd2a transports structurally related acylcarnitines but not a lysolipid without a negative charge, demonstrating the necessity of a negative charged headgroup interaction with Lys436 for transport. These findings support a novel transport mechanism by which LPCs are flipped within the transporter cavity by pivoting about Lys436 leading to net transport from the outer to the inner leaflet of the plasma membrane (Quek et al. 2016). Docosahexaenoic acid is an omega-3 fatty acid that is essential for neurological development and function, and it is supplied to the brain and eyes predominantly from dietary sources. This nutrient is transported across the blood-brain and blood-retina barriers as lysophosphatidylcholine. The structure of MFSD2A has been determined using single-particle cryo-EM (Cater et al. 2021). The transporter is in an inward-facing conformation and features a large amphipathic cavity that contains the Na+-binding site and a bound lysolipid substrate. This structure reveals details of how MFSD2A interacts with substrates and how Na+-dependent conformational changes allow for the release of these substrates into the membrane through a lateral gate. This atypical MFS transporter mediates the uptake of lysolipids into the brain. Homozygous variants in the MFSD2A gene cause severe primary microcephaly, brain malformations, developmental delay, and epilepsy (Khuller et al. 2021). Bi-allelic MFSD2A variants cause autosomal recessive primary microcephaly type 15 and broaden the phenotypic spectrum associated with these pathogenic variants, emphasizing the role of MFSD2A in early brain development. Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A have been documented (Bergman et al. 2023). Automated collective variables have been discovered for MFSD2A from molecular dynamics simulations (Oh et al. 2024). |
Eukaryota | Metazoa, Chordata | MFSD2A of Homo sapiens (Q8NA29) |
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2.A.2.3.9 | Inner membrane symporter YihP |
Bacteria | Pseudomonadota | YihP of E. coli |
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2.A.2.4.1 | Liu et al. 2023Sucrose:H+ symporter, Suc1 or Sut1. It provides osmotic driving force for anther dehiscence, pollen germination and pollen tube growth and also transports other glucosides such as maltose and phenylglucosides. Km (sucrose)= 0.5 mM. (Stadler et al., 1999)). In wheat (Triticum aesticum), there are at least three isoforms designated Sut2A, Sut2B and Sut2D (Deol et al. 2013). The ortholog in the common bean, Phaseolus vulgaris (SUT1.1), has been characterized as a high affinity sucrose:H+ symporter (Santiago et al. 2020). SUTs in rice play a role in the apoplastic loading as a major phloem loading strategy (Wang et al. 2021). Some Suts can transport sucrose, glucose, fructose and mannose (Liu et al. 2023).
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Eukaryota | Viridiplantae, Streptophyta | Suc1 of Arabidopsis thaliana |
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2.A.2.4.10 | Proton:glucose symporter A; proton-associated sugar transporter A (PAST-A) (present in brain and deleted in neuroblastoma 5 (DNb-5). Solute carrier family 45 member 1, SLC45A1 (Bartölke et al. 2014). |
Eukaryota | Metazoa, Chordata | SLC45A1 of Homo sapiens |
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2.A.2.4.11 | Sucrose transport protein SUT5 (Sucrose permease 5) (Sucrose transporter 5) (OsSUT5) (Sucrose-proton symporter 5). Sucrose transporter proteins (SUTs) play roles in the phloem loading and unloading of sucrose. The SUT gene family was identified in four Solanaceae species (Capsicum annuum, Solanum lycopersicum, S. melongena, and S. tuberosum) and 14 other plant species ranging from lower and higher plants. The analysis was performed by integration of chromosomal distribution, gene structure, conserved motifs, evolutionary relationship and expression profiles during pepper growth under stresses (Chen et al. 2022). |
Eukaryota | Viridiplantae, Streptophyta | SUT5 of Oryza sativa subsp. japonica |
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2.A.2.4.12 | Sucrose:H+ symporter, SUC5. Also transports biotin and possibly maltose (Pommerrenig et al. 2012). |
Eukaryota | Viridiplantae, Streptophyta | SUC5 of Arabidopsis thaliana |
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2.A.2.4.13 | Scratch, orthologue 1, SCRT; SLC45A2; transports sucrose into pigment-containing vesicles or granules. Mutations give rise to oculocutaneous albinism (Meyer et al. 2011). |
Eukaryota | Metazoa, Arthropoda | SCRT of Drosophila melanogaster |
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2.A.2.4.14 | Melanocyte-specific antigen or melanoma antigen, MatP, Slc45a2, Aim-1, AIM1, at the mouse underwhite locus. Regulated by a melanocyte-specific transcription factor essential for pigmentation, MITF (Du and Fisher 2002). Mutations in MatP in humans cause oculocutaneous albinism type IV (OCA4), an autosomal recessive inherited disorder which is characterized by reduced biosynthesis of melanin pigmentation in skin, hair and eyes. The MATP protein consists of 530 amino acids which contains 12 TMSs (Kamaraj and Purohit 2016). The D93N mutation causes oculocutaneous albinism 4 (OCA4), and the L374F mutatioin correlates with light pigmentation in European populations. Corresponding mutations were produced in the related and well-characterized sucrose transporter from rice, OsSUT1, and transport activity was measured by heterologous expression in Xenopus laevis oocytes and 14C-sucrose uptake in yeast. The D93N mutant had completly lost transport activity while the L374F mutant showed a 90% decrease in transport activity, although the substrate affinity was unaffected (Kamaraj and Purohit 2016). Mutations in MATP protein showed loss of stability and became more flexible, which alter its structural conformation and function (Kamaraj and Purohit 2016). |
Eukaryota | Metazoa, Chordata | Aim1 of Mus musculus |
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2.A.2.4.15 | Putative glycoside transporter of 401 aas and 12 TMSs. |
Eukaryota | Evosea | UP of Entamoeba histolytica |
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2.A.2.4.17 | High affinity sucrose transporter of 617 aas and 12 TMSs, Sut1B. It is regulated by the protein CBF1 (NCBI acc # WJK44481.1) in the pineapple (Ananas comosus). This sucrose transporter AcSUT1B, regulated by AcCBF1, exhibits enhanced cold tolerance in transgenic Arabidopsis (Long et al. 2024).
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Viruses | Orthornavirae, Negarnaviricota | Sucrose transporter, AcSUT1B, of Ananas comosus |
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2.A.2.4.2 | Phloem-localized sucrose:H+ symporter, Sut1 (mediates sucrose uptake or efflux dependent on the sucrose gradient and the pmf; Carpaneto et al., 2005). Sut1 is a sucrose protein symporter. Protons can move in the absence of sucrose (Carpaneto et al., 2010), but upon addition of sucrose, it becomes a symporter. Arg-188 in the rice orthologue and homologues are essential (Sun and Ward 2012). |
Eukaryota | Viridiplantae, Streptophyta | Sut1 of Zea mays (BAA83501) |
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2.A.2.4.3 | Sucrose:H+ symporter, Suc3 or Sut3 of 464 aas. Expressed in cells adjacent to the vascular tissue and in a carpel cell layer). Km (sucrose)= 1.9 mM; maltose is a competitor (Meyer et al., 2000). |
Eukaryota | Viridiplantae, Streptophyta | Suc3 of Arabidopsis thaliana |
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2.A.2.4.4 | The brain proton:associated sugar (glucose) transporter, PAST-A (Shimokawa et al., 2002) | Eukaryota | Metazoa, Chordata | PAST-A of Rattus norvegicus (Q8K4S3) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.2.4.5 | The proton:sucrose uptake symporter, Sut1 (Zhang & Turgeon et al., 2009). |
Eukaryota | Viridiplantae, Streptophyta | Sut1 of Verbascum phoeniceum (D1GC38) |
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2.A.2.4.6 | Vacuolar sucrose;H+ symporter, Suc4, catalyzes sucrose export from vacuoles (Schulz et al., 2011). The interactome of the sucrose transporter, StSUT4, in potato is connected to ethylene and calcium signaling (Garg et al. 2022). |
Eukaryota | Viridiplantae, Streptophyta | Suc4 of Arabidopsis thaliana (Q9FE59) |
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2.A.2.4.7 | Solute carrier family 45, member 4, SLC45A4. Transports sucrose by a proton symport mechanism. Found ubiquitously throughout the tissues of the body (Bartölke et al. 2014). SLC45A4 encodes a mitochondrial putrescine transporter that promotes γ-aminobutyric acid (GABA) de novo synthesis (Colson et al. 2024). The expression of SLC45A4 also has a strong positive correlation with the cellular level of GABA. |
Eukaryota | Metazoa, Chordata | SLC45A4 of Homo sapiens |
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2.A.2.4.8 | solute carrier family 45, member 3, Slc45A3. Sucrose:proton symporter associated with prostate cancer and myelination (Bartölke et al. 2014). Four members of the SLC45 family, SLC45A1-SLC45A4, were differentially expressed in melanoma, but only SLC45A2 and SLC45A3 had prognostic guiding values (Xie et al. 2021). |
Eukaryota | Metazoa, Chordata | SLC45A3 of Homo sapiens |
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2.A.2.4.9 | Solute carrier family 45, member 2, Slc45A2, also called melanocyte-restricted antigen or melanoma antigen, PatP or Aim1. Transports sucrose, glucose and fructose with protons, possibly into vesicular structures that contain melanin (Vitavska et al. 2018). Found in skin and hair; involved in pigmentation (Bartölke et al. 2014). Defects give rise to oculocutaneous albinism (Meyer et al. 2011). One such mutation in dogs, G493D in TMS 11, gives rise to albinisms (Wijesena and Schmutz 2015). OCA type IV (OCA4, OMIM) develops due to homozygous or compound heterozygous mutations in the solute carrier family 45, member 2 (SLC45A2) gene, and many mutations in this human gene have been identified (Inagaki et al. 2006; Tóth et al. 2017). It interacts with 14-3-3 proteins (see TC# 8.A.98). Multiple pathogenic variants in SLC45A2 give rise to oculocutaneous albinism (Lewis and Girisha 2019). Reviewed by Wiriyasermkul et al. 2020. Four members of the SLC45 family, SLC45A1-SLC45A4, were differentially expressed in melanoma, but only SLC45A2 and SLC45A3 had prognostic guiding values (Xie et al. 2021). A 3-bp deletion in the SLC45A2 gene is associated with loss of fleece pigmentation in black-fleeced Suffolk sheep (Tearle et al. 2025). |
Eukaryota | Metazoa, Chordata | SLC45A2 of Homo sapiens |
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2.A.2.5.1 | Saturated and unsaturated oligogalacturonide transporter, TogT (transports di- to tetrasaccharide pectin degradation products which consist of D-galacuronate, sometimes with 4-deoxy-L-threo-5- hexosulose uronate at the reducing position) |
Bacteria | Pseudomonadota | TogT of Erwinia chrysanthemi 3937 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.2.5.2 | The putative rhamnogalacturonide porter, RhiT (Rodionov et al. 2004). |
Bacteria | Pseudomonadota | RhiT of Erwinia carotovora subsp. atroseptica (Q6D188) |
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2.A.2.6.2 | The maltose/maltooligosaccharide transporter, MalI (541 aas) (Lohmiller et al., 2008). |
Bacteria | Pseudomonadota | MalI of Caulobacter crescentus (Q9A612) |
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2.A.2.6.3 | The putative maltose porter, MalT (Rodionov et al., 2010) |
Bacteria | Pseudomonadota | MalT of Shewanella oneidensis (Q8EEC4) |
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2.A.2.7.1 | The insect Bm-re (Bombyx mori red eye) protein; mutants lose ommochromes as well as pigmentation of eggs, eyes, and bodies. May function in pigment transport (Osanai-Futahashi et al., 2012). |
Eukaryota | Metazoa, Arthropoda | Bm-re of Bombyx mori (I0IYT1) |
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2.A.2.7.2 | Bm-re homologue of Tribolium castaneum (Osanai-Futahashi et al., 2012). |
Eukaryota | Metazoa, Arthropoda | Bm-re homologue of Tribolium castaneum (D6W6W0) |
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2.A.2.7.3 | MFSD12, melanosome and lysosome cysteine transporter, of 480 aas and 12 TMSs. It is associated with skin pigmentation in humans, mice, dogs and horses (Crawford et al. 2017; Adhikari et al. 2019; Hédan et al. 2019; Tanaka et al. 2019). Its upregulated expression is observed in melanomas, and elevated MFSD12 levels promote cell proliferation by promoting cell cycle progression (Wei et al. 2019). MFSD12 interference inhibited tumor growth and lung metastasis in melanoma. It mediates the import of cysteine into melanosomes and lysosomes (Adelmann et al. 2020). MFSD12 is required to maintain normal levels of cystine - the oxidized dimer of cysteine - in melanosomes, and to produce cysteinyldopas, the precursors of pheomelanin synthesis made in melanosomes via cysteine oxidation. MFSD12 is necessary for the import of cysteine into melanosomes and, in non-pigmented cells, lysosomes. Loss of MFSD12 reduced the accumulation of cystine in lysosomes of fibroblasts from patients with cystinosis, a lysosomal-storage disease caused by inactivation of the lysosomal cystine exporter, cystinosin (TC# 2.A.43.1.1). Thus, MFSD12 is an essential component of the cysteine importer for melanosomes and lysosomes (Adelmann et al. 2020). |
Eukaryota | Metazoa, Chordata | MFSD12 of Homo sapiens |
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2.A.20.1.1 | Low affinity Pi or phosphate-zinc complex uptake transporter #1, PitA (Km=2 μM) (Me·Pi:H+ symporter) (Beard et al. 2000; Jackson et al. 2008). Also transports tellurite (TeO32-) slowly (Elías et al. 2012; Borghese et al. 2016). |
Bacteria | Pseudomonadota | PitA of E. coli (P0AFJ7) |
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2.A.20.1.2 | Low affinity Pi transporter #2, PitB (Km=30 μM) PitB, like PitA is also a Me·Pi:H+ symporter (Borghese et al. 2016) |
Bacteria | Pseudomonadota | PitB of E. coli |
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2.A.20.1.3 | Bacteria | Actinomycetota | Pit of Mycobacterium bovis |
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2.A.20.1.4 | Probable low-affinity inorganic phosphate transporter | Bacteria | Pseudomonadota | Pit of Rhizobium meliloti |
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2.A.20.1.5 | Putative low affinity Pi transporter PitH1, Sco4138 (Santos-Beneit et al. 2008). |
Bacteria | Actinomycetota | PitH1 of Streptomyces coelicolor. |
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2.A.20.1.6 | Putative low affinity Pi transporter PitH2, Sco1845 (Santos-Beneit et al., 2008). |
Bacteria | Actinomycetota | PitH2 of Streptomyces coelicolor. |
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2.A.20.1.7 | Low affinity inorganic phosphate uptake porter of 335 aas, PitA (Kim et al. 2014; Mechler L, ... Bertram R, personal communication). |
Bacteria | Bacillota | PitA of Staphylococcus aureus |
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2.A.20.2.1 | Pi-repressible Pi:Na+ symporter | Eukaryota | Fungi, Ascomycota | Pho4 of Neurospora crassa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.20.2.10 | Phosphate:sodium symporter of 576 aas, Pho89 (Ahn et al. 2009). |
Eukaryota | Fungi, Ascomycota | Pho89 of Komagataella pastoris (Yeast) (Pichia pastoris) |
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2.A.20.2.11 | Phosphate transporter of 601 aas and 12 TMSs. Pho4. |
Eukaryota | Euglenozoa | Pho4 of Trypanosoma cruzi |
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2.A.20.2.12 | Putative phosphate:sodium symporter of 752 aas and 12 - 14 TMSs. |
Bacteria | Bacteroidota | PNaS family member of Lutibacter sp. |
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2.A.20.2.13 | Putative sodium/phosphate symporter of 534 aas and 12 TMSs. |
Viruses | Bamfordvirae, Nucleocytoviricota | Na+:Phosphate symporter of Emiliania huxleyi virus 84 |
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2.A.20.2.14 | Phosphate uptake transporter of 869 aas and 10 TMSs, 6 N-terminal and 4 C-terminal. Toxoplasma expresses one Pi transporter harboring two PHO4 binding domains (N- and C-terminal) that typify the PiT Family. This transporter named TgPiT, localizes to the plasma membrane, the inward buds of the endosomal organelles termed VAC, and many cytoplasmic vesicles (Asady et al. 2020). It catalyzes Pi:Na+ = 1:2 iselectrogenically. Upon Pi limitation in the medium, TgPiT is more abundant at the plasma membrane. ΔTgPiT parasites accumulate 4-times more acidocalcisomes, storage organelles for phosphate, and exhibit many traits that differ from the wild type organims including poor virulence (Asady et al. 2020). Either PgPiT or PT2 is essential for growth (Cui et al. 2022). |
Eukaryota | Apicomplexa | TgPiT of Toxoplasma gondii |
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2.A.20.2.2 | High affinity Pi:Na+ symporter, Pho89, of 574 aas and possibly 12 TMSs in a 6 + 6 TMS arrangement. |
Eukaryota | Fungi, Ascomycota | Pho89 (YBR296c) of Saccharomyces cerevisiae |
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2.A.20.2.3 | Gibbon ape leukemia virus receptor 2/sodium-dependent phosphate uptake transporter, Pi:Na+ symporter, PiT2, PiT-2, GLVR2, SLC20A2. Mapping of the minimal transporting unit suggested a structure universal to all PiT-related proteins (Battger and Pedersen, 2011).The protein can transport Pi in the absence of Na+, and mutations allow Na+ transport in the absence of Pi. Transmembrane amino acids E(55) and E(575) appear to be responsible for linking Pi import to Na+symport (Bøttger et al. 2006). SLC20A2 variants cause the loss of Pi transport activity in mammalian cells (Sekine et al. 2019). Mutation of SLC20A2 seems to cause hereditary multiple exostoses (Li et al. 2020). It has been associated with Primary Familial Brain Calcification (PFBC) (Wang et al. 2012; Monfrini et al. 2023). Inorganic phosphate exporter heterozygosity in mice leads to brain vascular calcification, microangiopathy, and microgliosis (Maheshwari et al. 2023). |
Eukaryota | Metazoa, Chordata | SLC20A2 of Homo sapiens |
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2.A.20.2.4 | Low affinity housekeeping Pi transporter, PHT2, Pht2;1, Pht2,1, PT2-1 of 587 aas (Młodzińska and Zboińska 2016). The cucumber (Cucumis sativus) ortholog is involved in cucumber growth and metabolism; PT2-1 transcript levels in roots were high when grown in low (limiting) Pi-containing media, but low when grown in high Pi media (Naureen et al. 2018). Expressing Pht2;1 of Pteris vittata enhances phosphate transport in chloroplasts and increases arsenic tolerance in Arabidopsis thaliana (Feng et al. 2021). |
Eukaryota | Viridiplantae, Streptophyta | Pht2;1 of Arabidopsis thaliana |
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2.A.20.2.5 | The Pi:Na+ symporter, PfPit (669 aas; Saliba et al., 2006) |
Eukaryota | Apicomplexa | PfPit of Plasmodium falciparum (Q7YUD6) |
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2.A.20.2.6 | The Pi:(Na+)2 symporter, GLVR1, PiT1 or PiT-1 (Ravera et al., 2007). Mutating the conserved loop region between TMSs 2 and 3 alterred the binding properties of the transporter for Na+/Li+ and phosphate/arenate (Ravera et al. 2013). |
Eukaryota | Metazoa, Chordata | Pit1 of Xenopus tropicalis (Q5BL44) |
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2.A.20.2.7 | Na+-dependent phosphate transporter 1 (PiT-1). Gibbon ape leukemia virus receptor 1 (GLVR-1), Slc20A1 (KM=24μM). The protein has an experimentally tested 12 TMS topology (Farrell et al. 2009). A knock-out mutation of the mouse orthologue results in abnormal endocytosis in the yolk sac visceral endoderm and embyonic death at the 12.5 day stage (Wallingford and Giachelli 2014). PiT1 levels are elevanted in somatotroph adenomas and are positively associated with tumor size, invasive behavior and tumor recurrence in somatotroph adenomas. It may be associated with the activation of the Wnt/betacatenin signaling pathway (Li et al. 2019). The tails are important regulatory domains required for the endocytosis of the Rgt2 and Snf3 glucose sensing receptors triggered by different cellular stimuli (Xiao et al. 2024). Ehrlichia chaffeensis infects and proliferates inside monocytes and macrophages and causes human monocytic ehrlichiosis (HME), an emerging life-threatening tick-borne zoonosis. After internalization, E. chaffeensis resides in specialized membrane-bound inclusions, E. chaffeensis-containing vesicles (ECVs), to evade host cell innate immune responses and obtain nutrients (Li et al. 2024). Host cells recognize E. chaffeensis Ech_1067, a penicillin-binding protein, and then upregulate the expression of PIT1, which transports phosphate from ECVs to the cytosol to inhibit bacterial growth. CTGF (TC# 8.A.87.1.47) regulates mineralization in human mature chondrocyte by controlling Pit-1 and modulating ANK via BMP/Smad signalling (Xiao et al. 2024). PiT1 is the receptor for the endogenous retroviral envelope syncytin-B (TC# 1.G.9.1.3) involved in mouse placenta formation (Mousseau et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC20A1 of Homo sapiens |
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2.A.20.2.8 | Na+:Pi transporter, SPT1 (Li et al., 2011) |
Eukaryota | Viridiplantae, Chlorophyta | SPT1 of Dunaliella viridis (A7U4W2) |
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2.A.20.2.9 | Putative phosphate permease HP_1491 | Bacteria | Campylobacterota | HP_1491 of Helicobacter pylori | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.20.3.1 | Putative Na+-dependent Pi transporter | Archaea | Euryarchaeota | Npt of Methanococcus jannaschii | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.20.3.2 | Low affinity high velocity phosphate transporter, PitA if 320 aas (McCarthy et al. 2014). |
Archaea | Thermoproteota | PitA of Metallosphaera cuprina |
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2.A.20.3.3 | Low affinity phosphate transporter, PitA of 328 aas |
Archaea | Thermoproteota | PitA of Sulfolobus solfataricus |
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2.A.20.3.4 | Low affinity phosphate carrier, PitA of 309 aas. |
Archaea | Euryarchaeota | PitA of Archaeoglobus profundus |
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2.A.20.4.1 | Sulfate:H+ symporter, CysP (Aguilar-Barajas et al., 2011; Mansilla and de Mendoza, 2000) |
Bacteria | Bacillota | CysP (YlnA) of Bacillus subtilis |
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2.A.21.1.1 | Pantothenate:Na+ symporter, PanF (Vallari and Rock 1985; Jackowski and Alix 1990; Reizer et al. 1991). |
Bacteria | Pseudomonadota | PanF of E. coli |
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2.A.21.2.1 | Proline:Na+ symporter, PutP (Jung et al., 2012). Extracellular loop 4 (eL4) controls periplasmic entry of substrate to the binding site (Raba et al. 2014). Interactions between the tip of eL4 and the peptide backbone at the end of TMS 10 participate in coordinating conformational alterations underlying the alternating access mechanism of transport (Bracher et al. 2016). TMS 6 plays a central role in substrate (both Na+ and proline) binding and release on the inner side of the membrane, and functionally relevant amino acids have been identified (Bracher et al. 2016). |
Bacteria | Pseudomonadota | PutP of E. coli |
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2.A.21.2.2 | Sodium/proline symporter (Proline permease) | Bacteria | Bacillota | PutP of Staphylococcus aureus |
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2.A.21.2.3 | L-proline uptake porter, PutP. Proline is used via this system as a carbon and nitrogen source. Induced by proline (Johnson et al. 2008). |
Bacteria | Pseudomonadota | PutP of Pseudomonas aeruginoas |
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2.A.21.2.4 | The high affinity nutritional proline uptake porter, PutP. PutP is inducible by external (but not internal) proline in a poorly defined process dependent on PutR (Moses et al. 2012). |
Bacteria | Bacillota | PutP of Bacillus subtilis |
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2.A.21.2.5 | Proline uptake porter, OpuE (YerK) (von Blohn et al. 1997). Regulated by osmotic stress (high osmolarity). Induction involves σB and σA (Spiegelhalter and Bremer 1998). |
Bacteria | Bacillota | OpuE of Bacillus subtilis |
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2.A.21.2.6 | High affinity proline-specific Na+:proline symporter, PutP (Rivera-Ordaz et al. 2013). Proline is a preferred source of energy for this microaerophilic bacterium. PutP is efficiently inhibited by the proline analogs, 3,4-dehydro-D,L-proline and L-azetidine-2-carboxylic acid. |
Bacteria | Campylobacterota | PutP of Helicobacter pylori |
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2.A.21.2.7 | Sodium:proline symporter of 428 aas and 11 TMSs |
Archaea | Euryarchaeota | Proline uptake porter of Methanosarcina mazei (Methanosarcina frisia) |
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2.A.21.3.1 | Glucose or galactose:Na+ symporter, SGLT1 (galactose > glucose > fucose). Cotransports water against an osmotic gradient (Naftalin, 2008). SGLT1 harbors a water channel (Barta et al. 2022). TMS IV of the high-affinity sodium-glucose cotransporter participates in sugar binding (Liu et al., 2008) and also participates in the uptake of resveratrol, an anti atherosclerosis polyphenol (Chen et al. 2013). hSGLT1 is expressed as a disulfide bridged homodimer via C355; a portion of the intracellular 12-13 loop is re-entrant and readily accessible from the extracellular milieu (Sasseville et al. 2016). Possibly, the extracellular loop between TMS 12 and TMS 13 participates in the sugar transport of SGLT1 (Nagata and Hata 2006). SGLT1 also transports water efficiently. Calculation of the unitary water channel permeability, pf, yielded similar values for cell and proteoliposome experiments. The absence of glucose, Na+, a membrane potential in vesicles, or the directionality of water flow did not grossly altered the pf. Such a weak dependence on protein conformation indicates that a water-impermeable occluded state (glucose and Na+ in their binding pockets) lasts for only a minor fraction of the transport cycle or, alternatively, that occlusion of the substrate does not render the transporter water-impermeable (Erokhova et al. 2016). the ortholog from grass carp (Ctenopharyngodon idellus) of 465 aas and 12 putative TMSs is 80% identical and is found in the anterior and mid intestine (Liang et al. 2020). Sodium-dependent glucose transporter 1 and glucose transporter 2 mediate intestinal transport of quercetrin (Li et al. 2020). Cardiac SGLT1 does not contribute appreciably to overall glucose uptake (Ferté et al. 2021). Collective domain motion facilitates water transport in SGLT1 (Sever and Merzel 2023). Ferulic acid-grafted chitosan (FA-g-CS) stimulates the transmembrane transport of anthocyanins by SGLT1 and GLUT2 (Ma et al. 2022). SLC5A1 and SLC5A3 are involved in glioblastoma cell migration, thereby complementing the migration-associated transportome, suggesting that SLC inhibition may be a promising approach for treatment (Brosch et al. 2022). SGLT1 mediates the absorption of water, yet the mechanism and the effect of inhibitors is not well defined. Sever and Merzel 2023 determined the influence of the energetic and dynamic properties of SGLT1 as they are influenced by selected sugar uptake inhibitors on water permeation. variants of Slc5A1 give rise to Congenital Glucose-Galactose Malabsorption (Hoşnut et al. 2023). Soluble β-glucan fibers modulate blood glucose regulation and intestinal permeability (Marcobal et al. 2024). A small library of glycoderivative putative ligands of SGLT1 has been prepared, and a preliminary biological evaluation has been conducted (D'Orazio and La Ferla 2024). The effectiveness of sodium-glucose co-transporter 2 inhibitors on cardiorenal outcomes has been reviewed (Ali et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC5A1 of Homo sapiens |
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2.A.21.3.10 | Na+-dependent, smf-driven, sialic acid transporter, STM1128 (NanP) (Severi et al., 2010). Also transports the related sialic acids, N-glycolylneuraminic acid (Neu5Gc) and 3-keto-3-deoxy-d-glycero-d-galactonononic acid (KDN) (Hopkins et al. 2013). |
Bacteria | Pseudomonadota | STM1128 (NanP) of Salmonella enterica (Q8ZQ35) |
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2.A.21.3.11 | The alginate oligosaccharide uptake porter, ToaA (Wargacki et al., 2012). |
Bacteria | Pseudomonadota | ToaA in Vibrio splendida (A3UWQ1) |
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2.A.21.3.12 | The alginate oligosaccharide uptake porter, ToaB (Wargacki et al., 2012). |
Bacteria | Pseudomonadota | ToaB in Vibrio splendida (A3UWQ9) |
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2.A.21.3.13 | The alginate oligosaccharide uptake porter, ToaC (Wargacki et al., 2012). |
Bacteria | Pseudomonadota | ToaC in Vibrio splendida (A3UR54) |
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2.A.21.3.14 | Sodium/myo-inositol cotransporter (Na(+)/myo-inositol cotransporter) (Sodium/myo-inositol transporter 1) (SMIT1) (Solute carrier family 5 member 3) | Eukaryota | Metazoa, Chordata | SLC5A3 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.21.3.15 | Sodium/glucose cotransporter 5 (Na+/glucose cotransporter 5) (Solute carrier family 5 member 10) |
Eukaryota | Metazoa, Chordata | SLC5A10 of Homo sapiens |
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2.A.21.3.16 | Sodium/glucose cotransporter 2 (Na+/glucose cotransporter 2; SGLT2) of 672 aas and 14 TMSs. It is a low affinity sodium-glucose cotransporter). It shows increased expression in human diabetic nephropathy. Inhibition causes decreased renal lipid accumulation, inflamation and disease symptoms (Wang et al. 2017). It has a Na+ to glucose coupling ratio of 1:1 (Brown et al. 2019). Efficient substrate transport in the mammalian kidney is provided by the concerted action of a low affinity high capacity and a high affinity low capacity Na+/glucose cotransporter arranged in series along kidney proximal tubules. Inhibitors are antidiabetic agents (Li 2019; Singh and Singh 2020). They are also useful as theraputic agents of non-alcoholic fatty liver disease and chronic kidney disease (Kanbay et al. 2021). Marein, an active component of the Coreopsis tinctoria Nutt plant, ameliorates diabetic nephropathy by inhibiting renal sodium glucose transporter 2 and activating the AMPK signaling pathway (Guo et al. 2020). NHE-3 (TC# 2.A.53.2.18) was markedly downregulated, while the Na+-HCO3--cotransporter (NBC-1; TC# 2.A.31.2.12) and SGLT2 were upregulated after kidney transplantation (Velic et al. 2004). Pharmacological inhibition of hSGLT2 by oral small-molecule inhibitors, such as empagliflozin, leads to enhanced excretion of glucose and is widely used in the clinic to manage blood glucose levels for the treatment of type 2 diabetes. Niu et al. 2022 determined the cryoEM structure of the hSGLT2-MAP17 complex in the empagliflozin-bound state to a resolution of 2.95 Å. MAP17 interacts with transmembrane helix 13 of hSGLT2. Empagliflozin occupies both the sugar-substrate-binding site and the external vestibule to lock hSGLT2 in an outward-open conformation, thus inhibiting the transport cycle (Niu et al. 2022 ). There is no upregulation regarding host factors potentially promoting SARS-CoV-2 virus entry into host cells when the SGLT2-blocker empagliflozin, telmisartan and the DPP4-inhibitor blocker, linagliptin, are used (Xiong et al. 2022). The effectiveness of sodium-glucose co-transporter 2 inhibitors on cardiorenal outcomes has been described (Ali et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC5A2 of Homo sapiens |
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2.A.21.3.17 | Sodium/glucose cotransporter 4 (Na+/glucose cotransporter 4) (hSGLT4) (Solute carrier family 5 member 9). The involvement of aromatic residue pi interactions, especially with Na+ binding, has been examined (Jiang et al. 2012). |
Eukaryota | Metazoa, Chordata | SLC5A9 of Homo sapiens |
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2.A.21.3.18 | Low affinity sodium-glucose cotransporter (Sodium/glucose cotransporter 3) (Na+/glucose cotransporter 3) (Solute carrier family 5 member 4) |
Eukaryota | Metazoa, Chordata | SLC5A4 of Homo sapiens |
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2.A.21.3.19 | The putative arabinose porter, AraP (Rodionov D.A., personal communication). Regulated by arabinose regulon AraR. |
Bacteria | Bacteroidota | AraP (Q8AAV7) of Bacteroides thetaiotaomicron |
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2.A.21.3.2 | Glucose or galactose:Na+ symporter, SglS or SglT of 543 aas and 14 TMSs (Turk et al. 2006). The 3.0 Å structure is known (Faham et al., 2008). Sodium exit causes a reorientation of transmembrane helix 1 that opens an inner gate required for substrate exit (Veenstra et al. 2004; Watanabe et al., 2010). The involvement of aromatic residue pi interactions, especially with Na+ binding, has been examined (Jiang et al. 2012). Its function has been compared with that of LacZ of E. coli (Abramson and Wright 2021). |
Bacteria | Pseudomonadota | SglS of Vibrio parahaemolyticus |
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2.A.21.3.20 | NanT sialic acid transporter of 500 aas (Anba-Mondoloni et al. 2013). |
Bacteria | Bacillota | NanT of Lactobacillus sakei |
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2.A.21.3.21 | Putative sugar:sodium symporter of 571 aas and 15 TMSs, YidK |
Bacteria | Pseudomonadota | YidK of E. coli |
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2.A.21.3.22 | Renal Na+:D-glucose symporter type 1 (Sglt1; Slc5a1) of 662 aas and 14 TMSs. The distribution in renal tissues has been reported (Althoff et al. 2007). Loop 13, which is associated with phlorizin binding, is variable, as is the interaction with this inhibitor in various species. Immunoreaction was observed in the proximal tubular segments PIa and PIIa, the early distal tubule, and the collecting tubule. Thus, Leucoraja, in contrast to the mammalian kidney, employs only SGLT1 to reabsorb D-glucose in the early, as well as in the late segments of the proximal tubule and probably also in the late distal tubule. It differs from the kidney of the close relative, Squalus acanthias, which uses SGLT2 in more distal proximal tubular segments (Althoff et al. 2007). The ortholog in Squalus acanthias (Spiny dogfish), is 88% identical and has been characterized (Althoff et al. 2006). |
Eukaryota | Metazoa, Chordata | Sglt1 of Leucoraja erinacea (Little skate) (Raja erinacea) |
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2.A.21.3.23 | Kidney low affinity SGLT (Slc5a1) Na+:D-glucose symporter of 662 aas and 14 TMSs. Of the mammalian homologues, it most resembles SGLT2 (Althoff et al. 2006). |
Eukaryota | Metazoa, Chordata | SGLT of Squalus acanthias (spiny dogfish shark) |
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2.A.21.3.24 | Putative Na+:Glucose symporter of 507 aas and 14 TMSs. |
Viruses | Heunggongvirae, Uroviricota | Sodium:Glucose symporter of Aeromonas virus 44RR2 |
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2.A.21.3.25 | Na+/Glucose (2:1) symporter, Sglt1, of 658 aas and 14 TMSs, in a 6 + 2 + 6 TMS arrangement (Liang et al. 2021). The mRNA levels of intestinal sglt1 had a positive correlation with dietary starch levels, but the mRNA levels of renal sglt1 were opposite to those of intestinal sglt1 (Liang et al. 2021). |
Eukaryota | Metazoa, Chordata | Sglt1 of Megalobrama amblycephala (blunt snout bream) |
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2.A.21.3.3 | Nucleoside or glucose(?):Na+ symporter | Eukaryota | Metazoa, Chordata | SNST of Oryctolagus cuniculus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.21.3.4 | Glucose:Na+ symporter 3 (low affinity) | Eukaryota | Metazoa, Chordata | SAAT1 of Sus scrofa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.21.3.5 | Myoinositol:Na+ symporter, SMIT1 (Aouameur et al., 2007). | Eukaryota | Metazoa, Chordata | SMIT of Canis familiaris | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.21.3.6 | Myoinositol:Na+ symporter, SMIT2 (also transports D-chiro-inositol, D-glucose and D-xylose) (Coady et al., 2002; Aouameur et al., 2007). A 5-state model includes cooperative binding of Na+, strong apparent asymmetry of the energy barriers, a rate limiting step which is likely associated with the translocation of the empty transporter, and a turnover rate of 21 s-1 (Sasseville et al. 2014). The potential for modulation of plasma myoinositol by variation in SLC5A11 has been assessed (Weston et al. 2022). |
Eukaryota | Metazoa, Chordata | SLC5A11 of Homo sapiens |
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2.A.21.3.7 | Putative sialic acid uptake permease, NanP (D.A. Rodionov, pers. commun.) | Bacteria | Pseudomonadota | NanP of Vibrio fischeri (Q5E733) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.21.3.8 | The putative mannose porter, ManPll (Rodionov et al. 2010). |
Bacteria | Pseudomonadota | ManPll of Shewanella amazonensis (A1S2A8) |
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2.A.21.3.9 | The putative galactose porter, GalPll (Rodionov et al., 2010). |
Bacteria | Pseudomonadota | GalPll of Shewanella pealeana (A8H019) |
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2.A.21.4.1 | The monocarboxylate uptake (H+ symport?) permease, MctP (transports lactate (Km = 4.4 μM), pyruvate (Km = 3.8), propionate, butyrate (butanoic acid), α-hydroxybutyrate, L- and D-alanine (Km = 0.5 mM), and possibly cysteine and histidine) (Hosie et al., 2002). |
Bacteria | Pseudomonadota | MctP of Rhizobium leguminosarum |
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2.A.21.4.2 |
Uncharacterized symporter YodF. It is regulated by the global transcriptional regulator responding to nitrogen availablity, TnrA, suggesting the YodF transports a nitrogenous compound (Yoshida et al. 2003). |
Bacteria | Bacillota | YodF of Bacillus subtilis |
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2.A.21.5.1 | Sodium iodide symporter, NIS (I-:Na+ = 1:2). It also transports other monovalent anions including: ClO3-, SCN-, SeCN-, NO3-, Br-, BF4-, IO4- and BrO3-. It mediates electroneutral active transport of the environmental pollutant perchlorate (Dohan et al., 2007) and inhibits I- uptake. The stoichometry of ClO4-:Na+ uptake is 1 to 1 as perchlorate binds both to the anion and one of the two cation binding sites (Llorente-Esteban et al. 2020). Five beta-OH group-containing residues (Thr-351, Ser-353, Thr-354, Ser-356, and Thr-357) and Asn-360, all of which putatively face the same side of the helix in TMS IX, plus Asp-369, located in the membrane/cytosol interface, play key roles in NIS function and seem to be involved in Na+ binding/translocation (De la Vieja et al. 2007). Thr-354 is essential for iodide uptake (Tatsumi et al., 2010). The G39R mutant (congenital) is inactive. G93 is a pivot for the inwardly to outwardly conformational change (Paroder-Belenitsky et al., 2011). The protein is present as a dimer (Huc-Brandt et al. 2011). Functionally equivalent systems have been reviewed (Darrouzet et al. 2014). Mutations cause congenital I- transport defects (ITD; Li et al. 2013). The physiological, medical and mechanistic features of NIS have been reviewed (Portulano et al. 2014). Mutations in TMS IX can give rise to hypothyroidism (Watanabe et al. 2018). NIS may also have a pump-independent, protumorigenic role in thyroid cancer via its cross-talk with PTEN signaling (Feng et al. 2018). Mutations in its gene gives rise to fetal goitrous hypothyroidism (Stoupa et al. 2020). Iodide transport across thyrocytes constitutes a critical step for thyroid hormone biosynthesis, mediated mainly by the basolateral NIS and the apical anion exchanger pendrin (PDS; SLC26A4; TC# 2.A.53.2.17) (Eleftheriadou et al. 2020). Autoimmunity against NIS for thyroid disease has been documented (Eleftheriadou et al. 2020). The iodide transport defect-causing Y348D mutation in the Na+/I- symporter (NIS) renders the protein intrinsically inactive and impairs its targeting to the plasma membrane (Reyna-Neyra et al. 2021). Mutations in NIS can give rise to congenital hypothyroidism (Zhang et al. 2021). Iodide transport defect is a cause of dyshormonogenic congenital hypothyroidism due to homozygous or compound heterozygous pathogenic variants in the SLC5A5 gene, causing deficient iodide accumulation in thyroid follicular cells (Martín and Nicola 2021). NIS mediates active iodide accumulation in the thyroid follicular cell. Autosomal recessive iodide transport defect (ITD)-causing loss-of-function NIS variants lead to dyshormonogenic congenital hypothyroidism (DCH) due to deficient iodide accumulation for thyroid hormonogenesis (Bernal Barquero et al. 2022). An intramolecular interaction between R130 and D369 is required for NIS maturation and plasma membrane expression (Bernal Barquero et al. 2022). An Inverse agonist of estrogen-related receptor gamma, GSK5182, enhances Na+/I- symporter function in radioiodine-refractory papillary thyroid cancer cells (Singh et al. 2023). The identification of sodium/iodide symporter metastable intermediates provides insights into conformational transition between principal thermodynamic states (Chakrabarti et al. 2023). Advanced differentiated thyroid cancer that is resistant to radioactive iodine therapy may become responsive with a unique treatment combination of chloroquine and vorinostat. This treatment was demonstrated in cellular and animal models of thyroid cancer to inhibit endocytosis of the plasma membrane bound iodine transporter, NIS, and restore iodine uptake (Lechner and Brent 2024). CMTM 6 promotes the development of thyroid cancer by inhibiting NIS activity by activating the MAPK signaling pathway (Chen et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC5A5 of Homo sapiens |
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2.A.21.5.2 |
Na+-dependent multivitamin (pantothenate, biotin, lipoate) transporter (de Carvalho and Quick 2011). Broad specificity. May be useful for drug delivery using biotin-conjugated drugs such as Biotin-Acyclovir (B-ACV) (Vadlapudi et al. 2012). Present in the inclusion membrane that encases Chlamydia trachomatis where it transports vitamins such as biotin (Fisher et al. 2012). May also take up iodide (de Carvalho and Quick 2011). |
Eukaryota | Metazoa, Chordata | SMVT of Rattus norvegicus |
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2.A.21.5.3 | Na+-dependent short chain fatty acid transporter SLC5A8 (tumor suppressor gene product, down-regulated in colon cancer) (substrates: lactate, pyruvate, acetate, propionate, butyrate (Km ≈1 mM)) [propionate:Na+ = 1:3] (Miyauchi et al., 2004). Pyroglutamate (5-oxoproline) is also transported in a Na+- coupled mechanism (Miyauchi et al., 2010). SMCT1 and SMCT2 may transport monocarboxylate drugs (e.g. nicotinate and its derivatives) across the intestinal brush boarder membrane (Gopal et al., 2007; Frank et al. 2008). Wilson et al., 2009 have proposed mechanistic details. SMCT1 can transport urate in a testosterone regulated process (Hosoyamada et al., 2010). It's phsiological functions have been reviewed (Halestrap 2013). The system transports anti-tumor agents, 3-bromopyruvate anddichloroacetate (Su et al. 2016). The mouse ortholog has similar properties (Gopal et al. 2004). |
Eukaryota | Metazoa, Chordata | SLC5A8 of Homo sapiens |
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2.A.21.5.4 | The low affinity (Km (lactate) = 2mM) electroneutral Na+:monocarboxylate (lactate, pyruvate, butyrate, nicotinate) transporter, SMCTn (Plata et al., 2007) | Eukaryota | Metazoa, Chordata | SMCTn of Danio rerio (Q7T384) |
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2.A.21.5.5 | The high affinity (Km (lactate) = 0.2mM) electrogenic Na+ monocarboxylate (lactate, pyruvate, butyrate, nicotinate) transporter, SMCTe (Plata et al., 2007). | Eukaryota | Metazoa, Chordata | SMCTe of Danio rerio (Q3ZMH1) |
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2.A.21.5.6 | Sodium-coupled monocarboxylate transporter 2 (Electroneutral sodium monocarboxylate cotransporter) (Low-affinity sodium-lactate cotransporter) (Solute carrier family 5 member 12) | Eukaryota | Metazoa, Chordata | SLC5A12 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.21.5.7 | Sodium-dependent multivitamin transporter (Na+-dependent multivitamin transporter) (Solute carrier family 5 member 6) of 521 aas and 11 TMSs. It transports biotin (vitamin B7), pantothenate (vitamin B5), α-lipoic acid, and iodide (Holling et al. 2022). Compound heterozygous SLC5A6 variants have been reported in individuals with variable multisystemic disorder, including failure to thrive, developmental delay, seizures, cerebral palsy, brain atrophy, gastrointestinal problems, immunodeficiency, and/or osteopenia. Holling et al. 2022 expanded the phenotypic spectrum associated with biallelic SLC5A6 variants affecting function by reporting five individuals from three families with motor neuropathies. Missense variants p.(Tyr162Cys) and p.(Ser429Gly) did not affect plasma membrane localization of the ectopically expressed multivitamin transporter, suggesting reduced function, such as lower catalytic activity (Holling et al. 2022). |
Eukaryota | Metazoa, Chordata | SLC5A6 of Homo sapiens |
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2.A.21.5.8 | Sodium-coupled transporter, SLC5A11 or cupcake of 600 aas. A mutant lacking this protein is insensitive to the nutritional value of sugars. It is most similar to mammalian sodium/monocarboxylate co-transporters. It was prominently expressed in 10-13 pairs of R4 neurons of the ellipsoid body in the brain and functioned in these neurons for selecting appropriate foods (Dus et al. 2013). |
Eukaryota | Metazoa, Arthropoda | Cupcake of Drosophila melanogaster |
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2.A.21.6.1 | Urea active transporter (also transports polyamines; Uemura et al., 2007; Kashiwagi and Igarashi, 2011). |
Eukaryota | Fungi, Ascomycota | DUR3 of Saccharomyces cerevisiae |
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2.A.21.6.2 | The major transporter for high-affinity urea transport across the plasma membrane of nitrogen-deficient Arabidopsis roots, Dur3 (Kojima et al., 2006; Mérigout et al., 2008). An orthologue of the same function has been characterized in corn (ZmDUR3) (Liu et al. 2014), |
Eukaryota | Viridiplantae, Streptophyta | Dur3 of Arabidopsis thaliana (Q9FHJ8) |
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2.A.21.6.3 | Rice Dur3 (like 2.A.21.6.2; Wang et al., 2012) |
Eukaryota | Viridiplantae, Streptophyta | DUR3 of Oryza sativa (Q7XBS0) |
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2.A.21.6.4 | Probable histatin 5 antimicrobial peptide uptake system. May also take up spermidine and be required for morphogenesis (Mayer et al., 2012). |
Eukaryota | Fungi, Ascomycota | Dur31 of Candida albicans (Q59VF2) |
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2.A.21.6.5 |
Fungal SSS homologue |
Eukaryota | Fungi, Ascomycota | TRP homologue of Neurospora crassa |
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2.A.21.6.6 | Urea transporter, UreA of 693 aas and ~17 TMSs. A three-dimensional model of UreA which, combined with mutagenesis studies, led to the identification of residues important for binding, recognition and translocation of urea, and in the sorting of UreA to the membrane. Residues W82, Y106, A110, T133, N275, D286, Y388, Y437 and S446, located in transmembrane helixes 2, 3, 7 and 11, were found to be involved in the binding, recognition and/or translocation of urea and the sorting of UreA to the membrane. Y106, A110, T133 and Y437 seem to play a role in substrate selectivity, while S446 is necessary for proper sorting of UreA to the membrane (Sanguinetti et al. 2014). A pair of non-optimal codons are necessary for the correct biosynthesis of UreA (Sanguinetti et al. 2019). |
Eukaryota | Fungi, Ascomycota | UreA of Emericella nidulans (Aspergillus nidulans) |
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2.A.21.7.1 | Phenylacetate permease, Ppa | Bacteria | Pseudomonadota | Phenylacetate permease Ppa of Pseudomonas putida | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.21.7.2 | Acetate/glyoxylate/pyruvate permease, ActP or YjcG (Gimenez et al., 2003). Also transports tellurite (TeO32-) (Elías et al. 2015). It may depend on the 2 TMS auxiliary subunit, YjcH (TC#9.B.136.1.1), the gene for which is adjacent to the yjcG gene (Zhuge et al. 2019). Expression of these two genes is coordinately regulated and plays a role in the bacterial growth in macrophage. Intracellular acetate consumption during facultative intracellular bacterial replication within macrophages promotes immunomodulatory disorders, resulting in excessively pro-inflammatory responses of host macrophages (Zhuge et al. 2019). |
Bacteria | Pseudomonadota | ActP (YjcG) of E. coli (NP_418491) |
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2.A.21.7.3 | Pyruvate/acetate/propionate: H+ symporter, MctC (DhlC; cg0953). | Bacteria | Actinomycetota | MctC of Corynebacterium glutamicum (Q8NS49) |
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2.A.21.7.4 | Acetate uptake permease, ActP1; also takes up tellurite (Borghese and Zannoni 2010; Borghese et al. 2011). |
Bacteria | Pseudomonadota | ActP1 of Rhodobacter capsulatus |
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2.A.21.7.5 | Acetate permease ActP-2/ActP2/ActP3 (Borghese and Zannoni 2010; Borghese et al. 2011). Also takes up tellurite (TeO32-) (Borghese et al. 2016). |
Bacteria | Pseudomonadota | ActP2 of Rhodobacter capsulatus |
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2.A.21.8.1 | High affinity neuronal choline:Na+ symporter, CHT1 (chloride-dependent). Present in presynaptic terminals of cholinergic neurons. Has 13 TMSs (Haga 2014). |
Eukaryota | Metazoa, Chordata | CHT1 of Rattus norvegicus |
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2.A.21.8.2 | High affinity choline transporter 1 (Hemicholinium-3-sensitive choline transporter) (CHT1) (Solute carrier family 5 member 7). It is required for synthesis of acetyl choline in cholinergic nerve terminals. It's 13 TMS topology has been verified with an extracellular N-terminus and an intracellular C-terminus. It is likely to be a homooligomer (Okuda et al. 2012). It is defective in hereditary motor neuropathy (Barwick et al. 2012). |
Eukaryota | Metazoa, Chordata | SLC5A7 of Homo sapiens |
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2.A.21.8.3 | Putative porter of 436 aas and 13 TMSs |
Bacteria | Spirochaetota | Porter of Leptospira biflexa |
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2.A.21.9.1 | The nitrogen sensor-receptor domain of the CbrA sensor kinase | Bacteria | Pseudomonadota | CbrA sensor domain of Pseudomonas aeruginosa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.21.9.2 | The proline sensor-receptor domain of the PrlS sensor kinase | Bacteria | Pseudomonadota | PrlS of Aeromonas hydrophila | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.22.1.1 | Serotonin (5-hydroxytryptamine; 5 HT):Na+:Cl- symporter, SERT-A It also transports amphetamines; blocked by cocaine and tricyclic antidepressants such as Prozac; interacts directly with the secretory carrier-associated membrane protein-2 (SCAMP2; O15127) to regulate the subcellular distribution (Muller et al., 2006). The 3 D structure is known ()PDB 5I6X), and it uses an alternating sites mechanism with all 3 substrates bound (Zhang and Rudnick, 2006). Molecular determinants for antidepressants in the human serotonin and norepinephrine A transporters have been identified (Andersen et al., 2011). A conserved asparagine residue in transmembrane segment 1 (TMS1) of the serotonin transporter dictates chloride-coupled neurotransmitter transport (Henry et al., 2011). The formation and breakage of ionic interactions with amino acids in transmembrane helices 6 and 8 and intracellular loop 1 may be of importance for substrate translocation (Gabrielsen et al., 2012). Methylation of the SLC6A4 gene promoter controls depression in men by an epigenetic mechanism (Devlin et al., 2010). The 5HT Km is 0.4 micromolar (Banovic et al. 2010). Regulated allosterically by ATM7 which stabilizes the outward-facing conformation of SERT (Kortagere et al. 2013). Functional and regulatory mechanisms involving the N- and C-terminal hydrophilic domains have been considered (Fenollar-Ferrer et al. 2014). The range of substrates bound and transported has been predicted (Kaufmann et al. 2009). TMS3 may function in substrate and antagonist recognition (Walline et al. 2008). The 3-d x-ray structures with antidepressants bound have been solved, leading to mechanistic predictions; antidepressants lock SERT in an outward-open conformation by lodging in the central binding site, located between TMSs 1, 3, 6, 8 and 10, directly blocking serotonin binding (Coleman et al. 2016). Na+ and cocaine stabilize outward-open conformations of SERT and decrease phosphorylation while agents that stabilize inward-open conformations (e.g., 5-HT, ibogaine) increase phosphorylation. The opposing effects of the inhibitors, cocaine and ibogaine, were each reversed by an excess of the other inhibitor. Inhibition of phosphorylation by Na+ and stimulation by ibogaine occurred at concentrations that induced outward opening and inward opening, respectively (Zhang et al. 2016). SERT is regulated by multiple molecular mechanisms including its physical interaction with intracellular proteins including the ASCT2 (alanine-serine-cysteine-threonine 2; TC# 2.A.23.3.2), co-expressed with SERT in serotonergic neurons and involved in the transport of small neutral amino acids across the plasma membrane (Seyer et al. 2016). SERT transports substituted amphetamine, 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy) (Sealover et al. 2016). A naturally occurring mutation, I425V, associated with obsessive-compulsive disorder and other neuropsychiatric disorders, activates hSERT and eliminates stimulation via the cyclicGMP-dependent pathway (Zhang et al. 2007). The substituted amphetamine, 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy), is a widely used drug of abuse that induces non-exocytotic release of serotonin, dopamine, and norepinephrine through their cognate transporters as well as blocking the reuptake of neurotransmitter by the same transporters. In SERT, Glu394 plays a role in MDMA recognition (Sealover et al. 2016). Intestinal dysbiosis may upregulate SERT expression and contribute to the development of chronic constipation (Cao et al. 2017). Cryo-EM structures of SERT-ibogaine complexes captured in outward-open, occluded and inward-open conformations have been solved (Coleman et al. 2019). Ibogaine binds to the central binding site, and closure of the extracellular gate largely involves movements of TMSs 1b and 6a. Opening of the intracellular gate involves a hinge-like movement of TMS 1a and the partial unwinding of TMS 5, which together create a permeation pathway that enables substrate and ion diffusion to the cytoplasm, thus defining the structural rearrangements that occur from the outward-open to inward-open conformations. SERT and cholecytokinin (CCK) seem to be involved in the pathogenesis of Irrritable Bowl Syndrome (IBS-D) by regulating the brain-gut axis and affecting visceral sensitivity (Qin et al. 2020). Altered SERT function leads to several neurological diseases including depression, anxiety, mood disorders, and attention deficit hyperactivity disorders (ADHD) (Szöllősi and Stockner 2021). The structure and dynamics of the two sodium binding sites indicate that sodium binding is accompanied by an induced-fit mechanism that leads to new conformations (Szöllősi and Stockner 2021). Occlusion of the serotonin transporter is mediated by serotonin-induced conformational changes in the bundle domain (Gradisch et al. 2022). A structural rearrangement of the SERT intracellular gate is induced by Thr276 phosphorylation (Chan et al. 2022). Na+/Cl--dependent neurotransmitter transporters form oligomers. A leucine heptad repeat in TMS2 and a glycophorin-like motif in TMS6 may stabilize the oligomer (Just et al. 2004). Oligomerization of hSERT involves at least two discontinuous interfaces to form an array-like structure containing multimers of dimers (Just et al. 2004). Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. A decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR; decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation (Castillero et al. 2023). Cocaine-regulated trafficking of dopamine transporters in cultured neurons has been revealed using a pH sensitive reporter (Saenz et al. 2023). Two SERT ligands, fluoxetine and escitalopram, enter neurons within minutes, while simultaneously accumulating in many membranes (Nichols et al. 2023). Berberine and evodiamine influence serotonin transporter (5-HTT) expression via the 5-HTT-linked polymorphic region (Hu et al. 2012). Dehydroevodiamine has a dihedral angle of 3.71 degrees compared to 82.34 degrees for evodiamine. Dehydroevodiamine can more easily pass through a phospholipid bilayer than evodiamine because it has a more planar stereo-structure (Luo et al. 2023). SLC6A4 gene variants moderate associations between childhood food insecurity and adolescent mental health (Pilkay et al. 2024). Fetal exposures to many drugs of abuse, e.g., opioids and alcohol (EtOH), are associated with adverse neurodevelopmental problems in early childhood, including abnormalities in activity of the serotonin (5HT) transporter (SERT), which transports 5HT across the placenta. In fact, prenatal opioid and alcohol exposures are association with altered placental serotonin transporter structure and/or expression (Darbinian et al. 2024). |
Eukaryota | Metazoa, Chordata | SERT or SLC6A4 of Homo sapiens |
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2.A.22.1.10 | Serotonin transporter, Mod-5, of 671 aas and 12 TMSs. Functions in thermotaxis memory behavior (Li et al. 2013). |
Eukaryota | Metazoa, Nematoda | Mod-5 of Caenorhabditis elegans |
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2.A.22.1.11 | Serotonin transporter, SERT, of 670 aas and 12 TMSs. it is subject to allosteric regulation involving 2 and possibly 3 distinct allosteric binding sites (Neubauer et al. 2006). Allosteric effectors include the transport inhibitors, duloxetine, RTI-55 and (S)-citalopram, which are antidepressants, and sometimes anti-anxiety and anti-pain medications in humans. |
Eukaryota | Metazoa, Chordata | SERT of Gallus gallus |
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2.A.22.1.12 | Sodium-dependent serotonin (5-HT) transporter, SERT, of 666 aas and 12 TMSs. The pharmacology and potential role in the nervous system have been studied (Camicia et al. 2022). |
Eukaryota | Metazoa, Platyhelminthes | SERT of Echinococcus granulosus |
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2.A.22.1.2 | Noradrenaline (norepinephrine):Na+ symporter (NET1, NAT1, SLC6A2) (also transports 1-methyl-4-tetrahydropyridinium and amphetamines; it is a target of cocaine and amphetamines as well as of therapetics for depression, obsessive-compulsive disorders, and post-traumatic stress disorder. This homooligomeric transporter binds one substrate molecule per transporter subunit (Schwartz et al., 2005; Schlessinger et al., 2011; Andersen et al., 2011). Extracellular loop 3 contributes to substrate and inhibitor selectivity (Lynagh et al. 2013). The highly conserved MELAL and GQXXRXG motifs, located in the second transmembrane domain and the first intracellular loop of hNET, respectively, are determinants of NET cell surface expression, and substrate and inhibitor binding (Sucic and Bryan-Lluka 2007). Based on modeling, the high affinity substrate binding site (S1) of the human norepinephrine transporter has been predicted and then verified by mutational studies (Jha et al. 2020). Proline residues play roles in the expression and function of the human noradrenaline transporter (Paczkowski and Bryan-Lluka 2004). Phosphatidylinositol 4,5-bisphosphate (PIP2) facilitates norepinephrine transporter dimerization and modulates substrate efflux (Luethi et al. 2022). Chemically diverse norepinephrine transporter inhibitors have been identified (Bongers et al. 2023).
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Eukaryota | Metazoa, Chordata | SLC6A2 of Homo sapiens |
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2.A.22.1.3 |
Dopamine:Na+ symporter, DAT (also takes up amphetamines in symport with Na+ which promotes intracellular Na+-dependent dopamine efflux (Khoshbouei et al., 2003)). It is inhibited by cocaine, amphetamines, neurotoxins, antidepressants and ethanol (Chen et al., 2004)]. Zn2+ potentiates uncoupled Cl- conductance (Meinild et al., 2004). A conserved salt bridge between TMSs 1 and 10 constitutes an extracellular gate (Pedersen et al. 2014). The 3-D structure of DAT is known (PDB 4M48; 4XPA). P101 of DAT plays an essential role in DA translocation (Lin and Uhl 2005). DAT is regulated by D3 dopamine receptors (Zapata et al., 2007). P25α (tubulin polymerization-promoting protein, TPPP (UniProt acc # O94811) increases dopamine transporter localization to the plasma membrane (Fjorback et al., 2011). DAT mediates paraquat (an herbicide) neurotoxicity (Rappold et al., 2011). Membrane cholesterol modulates the outward facing conformation and alters cocaine binding (Hong and Amara 2010). Threonine-53 phosphorylation in the rat orthologue (P23977) (Serine 53 in the human transporter) regulates substrate reuptake and amphetamine-stimulated efflux (Foster et al. 2012). DAT is enriched in filopodia and induces filopodia formation (Caltagarone et al. 2015). Dasotraline is an inhibitor of dopamine and norepinephrine reuptake, used for the treatment of attention-deficit/hyperactivity disorder (ADHD) (Hopkins et al. 2015). When in complex with 1-(1-benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB), a psychoactive adictive agonists, DAT can exhibit conformational transitions that spontaneously isomerize the transporter into the inward-facing state, similarly to that observed in dopamine-bound DAT (Sahai et al. 2016). The cytoplasmic N- and C-terminal domains contribute to substrate and inhibitor binding (Sweeney et al. 2016). DAT can exist as a monomer, a cooperative dimer subject to allosteric regulation (Cheng et al. 2017) or an oligomer involving the scaffold domain but not the bundle domain (Jayaraman et al. 2018). Cocaine binds in the S1 site to stabilize an inactive form of DAT (Krout et al. 2017). Dopamine efflux is caused by 3,4-methylenedioxypyrovalerone (MDPV) (Shekar et al. 2017). The cholesterol binding sites observed in the DAT crystal structures may be preserved in all human monoamine transporters (dopamine, serotonin and norepinephrine) and when cholesterol is bound, transport is inhibited (Zeppelin et al. 2018). The cell permeable furopyrimidine, AIM-100, augments DAT oligomerization through an allosteric mechanism associated with the DAT conformational state, and oligomerization-triggered clustering leads to a coat-independent endocytosis and subsequent endosomal retention of DAT (Sorkina et al. 2018). Dysfunction of this transporter leads to disease states, such as Parkinson's disease, bipolar disorder and/or depression (Jayaraman et al. 2018). DAT dysfunction is linked to neuropsychiatric disorders including attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BPD), and autism spectrum disorder (ASD). The DAT Val559 mutation changes the transporter localization and lateral mobility that contributes to ADE and alterations in dopamine signaling underlying multiple neuropsychiatric disorders (Thal et al. 2018). A tight spatial and functional relationship between the DAT/GLT-1 transporters and the Kv7.2/7.3 potassium channel immediately readjusts the membrane potential of the neuron, probably to limit the neurotransmitter-mediated neuronal depolarization (Bartolomé-Martín et al. 2019). Evidence for the association of polymorphisms of DAT1 (SLC6A3) with heroin dependence has been presented (Koijam et al. 2020). A direct coupling between conformational dynamics of DAT, functional activity of the transporter and its oligomerization leading to endocytosis has been documented (Sorkina et al. 2021). Association of the sigma-1 receptor with the dopamine transporter attenuates the binding of methamphetamine via helix-helix interactions (Xu and Chen 2021). Potential partners for DAT, include the transmembrane chaperone 4F2hc (TC# 8.A.9.2.2), the proteolipid M6a (TC# 9.B.38.1.1) and a potential membrane receptor for progesterone (PGRMC2) (TC# 9.B.433.1.1) (Piniella et al. 2021). Two cytoplasmic proteins: a component of the Cullin1-dependent ubiquitination machinery termed F-box/LRR-repeat protein 2 (FBXL2; Q9UKC9), and the enzyme inositol 5-phosphatase 2 (SHIP2; O15357) were also associated. M6a, SHIP2 and Cullin1 were shown to increase DAT activity in coexpression experiments. M6a, enriched in neuronal protrusions (filopodia or dendritic spines), colocalized with DAT in these structures. In addition, the product of SHIP2 enzymatic activity (phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2]) was tightly associated with DAT. PI(3,4)P2 strongly stimulated transport activity in electrophysiological recordings, and conversely, inhibition of SHIP2 reduced DA uptake (Piniella et al. 2021). There are weak associations between DAT mRNA expression and DAT availability in human brains (Pak et al. 2022). Gender differences in cocaine-induced hyperactivity and dopamine transporter trafficking to the plasma membrane have been reported (Deng et al. 2022). The dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson's disease (Vidyadhara et al. 2023). DAT may play a role in Parkinson's disease (Zhou et al. 2023). Dopamine transporter (DAT) deficient rodents have been characterized suggesting perspectives and limitations for neuroscience (Savchenko et al. 2023). Epigenetic analyses of the dopamine transporter gene DAT1 through methylation have reveaed the basis for certain personality traits in athletes (Humińska-Lisowska et al. 2023). Interactions of calmodulin kinase II with the dopamine transporter facilitate cocaine-induced enhancement of evoked dopamine release (Keighron et al. 2023). Known data on the consequences of changes in DAT expression in experimental animals, and results of pharmacological studies in these animals have been reviewed (Savchenko et al. 2023). DAT knockout rats display epigenetic alterations in response to cocaine exposure, and targeting epigenetic modulators, Lysine Demethylase 6B (KDM6B) and Bromodomain-containing protein 4 (BRD4)may be therapeutic in treating addiction-related behaviors in a sex-dependent manner (Vilca et al. 2023). An overview of patient preparation, common imaging findings, and potential pitfalls that radiologists and nuclear medicine physicians should know when performing and interpreting dopamine transporter examinations. Alternatives to 123I-ioflupane imaging for the evaluation of nigrostriatal degeneration are considered (Mercer et al. 2024). The structure of the human dopamine transporter (hDAT) and the mechanisms of inhibition by several agents have been determined (Srivastava et al. 2024). DAT inhibition may be explored as a strategy for ischemic stroke prevention. DA and D1R are involved in the restoration of synaptic dysfunction and neuron protection (Cheng et al. 2024). Cholesterol modulates interactions between psychostimulants and dopamine transporters (Chen 2024). Pyrimidine structure-based compounds are allosteric ligands of the dopamine transporter and may be therapeutic agents for NeuroHIV (Jimenez-Torres et al. 2025). |
Eukaryota | Metazoa, Chordata | DAT (SLC6A3) of Homo sapiens |
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2.A.22.1.4 | Antidepressant- and cocaine-sensitive dopamine transporter, T23G5.5 (Km for dopamine, 1.2 µM; dependent on extracellular Na+ and Cl-; blocked by cocaine and D-amphetamine) (Jayanthi et al. 1998) (interacts with syntaxin 1A to regulate channel activity and dopaminergic synaptic transmission; Carvelli et al., 2008). It is blocked by the neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium ion, and neuron-specific toxin suppressor mutants have been isolated (Nass et al. 2005). Amphetamine exposure during embryogenesis changes expression and function of the dopamine transporter in Caenorhabditis elegans offspring (Ambigapathy et al. 2024). |
Eukaryota | Metazoa, Nematoda | T23G5.5 of Caenorhabditis elegans (Q03614) |
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2.A.22.1.5 | High affinity octopamine transporter, OAT (also transports tyramine and dopamine in the 0.4-3.0 μM range (Donly et al., 2007)). | Eukaryota | Metazoa, Arthropoda | OAT of Trichoplusia ni (Q95VZ4) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.22.1.6 | The dopamine/norepinephrine transporter (SmDAT) (Larsen et al. 2011). |
Eukaryota | Metazoa, Platyhelminthes | DAT of Schistosoma mansoni (E9LD23) |
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2.A.22.1.7 | Dopamine transporter. The 3-d structure is known to 3.0 Å resolution (Penmatsa et al. 2013). The crystal structure, bound to the tricyclic antidepressant nortriptyline, shows the transporter locked in an outward-open conformation with nortriptyline wedged between transmembrane helices 1, 3, 6 and 8, blocking the transporter from binding substrate and from isomerizing to an inward-facing conformation. Although the overall structure is similar to that of its prokaryotic relative LeuT, there are multiple distinctions, including a kink in transmembrane helix 12 halfway across the membrane bilayer, a latch-like carboxy-terminal helix that caps the cytoplasmic gate, and a cholesterol molecule wedged within a groove formed by transmembrane helices 1a, 5 and 7. |
Eukaryota | Metazoa, Arthropoda | Dopamine transporter of Drosophila melanogaster |
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2.A.22.1.8 | Snf-10 transporter. Required for protease-mediated activation of sperm motility. Present in the plasma membrane before activation, but assumes a polarized localization to the cell body region that is dependent on membrane fusions mediated by the dysferlin FER-1 (Fenker et al. 2014). |
Eukaryota | Metazoa, Nematoda | Snf-10 of Caenorabditis elegans |
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2.A.22.1.9 | The sodium-dependent serotonin transporter of 622 aas and 12 TMSs, SERT or SerT. It terminates the action of serotonin by its high affinity reuptake into presynaptic terminals (Demchyshyn et al. 1994). Substrates have been predicted based on modeling studies (Kaufmann et al. 2009). |
Eukaryota | Metazoa, Arthropoda | SerT of Drosophila melanogaster (Fruit fly) |
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2.A.22.2.1 | Proline:Na+ symporter | Eukaryota | Metazoa, Chordata | Proline transporter of Rattus norvegicus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.22.2.10 | Sodium- and chloride-dependent glycine transporter 2 (GlyT-2) (GlyT2) (Solute carrier family 6 member 5). The stoichiometry is Na+:Cl-;Gly = 3:1:1 (Le Guellec et al. 2022). The STAS domain has been solved by x-ray crystalography (PDB# 3LLO). Functions to remove and recycle synaptic glycine from inhibitory synapses. Mutations in GlyT are a common cause of hyperakplexia or startle disease in humans. The ER chaparone, calnexin, facilitates GlyT processing (Arribas-González et al. 2013). An allosteric binding site on GlyT2, for bioactive lipid analgesics has been identified (Mostyn et al. 2019), and it is formed by a crevice between TMSs 5, 7, and 8, and extracellular loop 4. Membrane cholesterol binds to and modulates the function of various SLC6 neurotransmitter transporters, including stabilizing the outward-facing conformation of the dopamine and serotonin transporters. Frangos et al. 2023 investigated how cholesterol binds to GlyT2 (SLC6A5), modulates the glycine transport rate, and influences bioactive lipid inhibition of GlyT2. |
Eukaryota | Metazoa, Chordata | SLC6A5 of Homo sapiens |
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2.A.22.2.11 | Sodium-dependent proline transporter (Solute carrier family 6 member 7) | Eukaryota | Metazoa, Chordata | SLC6A7 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.22.2.12 | Sodium- and chloride-dependent glycine transporter 1 (GlyT-1; GlyT1) (Solute carrier family 6 member 9). The stoichometry seems to be 2:1:1 for Na+:Cl-;glycine (Le Guellec et al. 2022). Inhibitors have been identified and patented (Cioffi 2018). Mutations in the gene encoding GlyT1 are associated with GlyT1 encephalopathy (OMIM #601019), a disease causing severe postnatal respiratory deficiency, muscular hypotonia and arthrogryposis, and result in severe impairment of transporter function (Hauf et al. 2020). . |
Eukaryota | Metazoa, Chordata | SLC6A9 of Homo sapiens |
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2.A.22.2.13 | Sodium-dependent nutrient amino acid transporter 1 (DmNAAT1) |
Eukaryota | Metazoa, Arthropoda | NAAT1 of Drosophila melanogaster | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.22.2.2 | Glycine:Na+ symporter, GlyT1c (glycine/2Na+/1Cl- symporter) or Slc6A9, of 638 aas and 12 TMSs. The cell volume-regulatory mouse glycine transporter (GLYT1) is activated following metallopeptidase- mediated detachment of the oocyte from the zona pellucida (Ortman and Baltz 2023). |
Eukaryota | Metazoa, Chordata | Glycine transporter (GlyT1c) of Rattus norvegicus |
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2.A.22.2.3 | Neutral and cationic amino acid:Na+:Cl- symporter, B0+ or ATB(0,+). The rat homologue (NP_001032633) transports basic and zwitterionic amino acids, but not proline, aspartic acid and glutamic acid (Uchiyama et al, 2008). The stoichiometry of Na+:Cl-:amino acid = 3:1:1 (Le Guellec et al. 2022). SLC6A14 depends on heat shock protein HSP90 for trafficking to the cell surface (Rogala-Koziarska et al. 2019). It is upregulated in some forms of cancer; residues important for function have been identified (Palazzolo et al. 2019). Flagellin from Pseudomonas aeruginosa stimulates the ATB(0,+) transporter for arginine and neutral amino acids in human airway epithelial cells (Barilli et al. 2021). Reshaping the binding pocket selectively reduces access for cationic aas and derivatives (Anderson et al. 2022). Machine learning identified SLC6A14 as a biomarker promoting the proliferation and metastasis of pancreatic cancer via Wnt/β-catenin signaling (Dang et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC6A14 of Homo sapiens |
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2.A.22.2.4 | Gut epithelium absorptive neutral amino acid Na+- or K+-dependent transporter, CAATCH1 (electrogenic; Cl--independent. Substrates: L-proline-preferring + Na+; L-threonine-preferring + K+; also transports L-methionine) (CAATCH1 can also function as an amino acid-gated cation [Na+ and K+] channel.) |
Eukaryota | Metazoa, Arthropoda | Neutral amino acid transporter CAATCH1 of Manduca sexta |
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2.A.22.2.5 | Gut epithelium absorptive neutral amino acid, K+- and Na+-dependent transporter KAAT1 (electrogenic; Cl--dependent; activated by alkaline pH; all zwiterionic amino acids except methyl AIB are substrates). CAATCH1 is 95% identical to KAAT1. Leu > Thr and Pro. | Eukaryota | Metazoa, Arthropoda | Neutral amino acid transporter KAAT1 of Manduca sexta | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.22.2.6 | Glycine:Na+ transporter, GlyT2b (glycine/3Na+/1Cl- symporter, SLC6A5). GlyT2 and VIAAT cooperate to determine the vesicular glycinergic phenotype (Aubrey et al., 2007). Startle disease in Irish wolfhounds is associated with a microdeletion in the glycine transporter GlyT2 gene (Gill et al., 2011). A dominant hyperekplexia (startle disease) mutation Y705C in humans alters trafficking and the biochemical properties of GlyT2 (Gimenez et al. 2012). Structural determinants of the neuronal glycine transporter 2 for the selective inhibitors ALX1393 and ORG25543 have been determined (Benito-Muñoz et al. 2021). The efficacy of the analgesic GlyT2 inhibitor, ORG25543, is determined by two connected allosteric sites (Chater et al. 2023). |
Eukaryota | Metazoa, Chordata | Glycine transporter (GlyT2b) of Mus musculus |
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2.A.22.2.7 | Acetylcholine/choline:Na+ symporter, Snf-6 (interacts with dystrophin which determines its localization to the neuromuscular junction) (Kim et al., 2004) |
Eukaryota | Metazoa, Nematoda | Snf-6 of Caenorhabditis elegans (O76689) |
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2.A.22.2.8 | Cation-dependent nutrient amino acid transporter, AAT1 (L-phe > cys > his > ala > ser > met > ile > tyr > D-phe > thr > gly) (Bondko et al., 2005) | Eukaryota | Metazoa, Arthropoda | AAT1 of Aedes aegypti (Q6VS78) |
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2.A.22.2.9 | The densovirus type-2 (BmDNV-2) receptor; putative amino acid transporter, the densonucleosis refractoriness, Nsd-2 protein, of 625 aas and 11-12 TMSs (Abe et al. 2000). Deletion of the nsd2 gene, encoding this transporter in the midgut membrane, causes resistance to this parvo-like virus as well as bidensovirus (Ito et al. 2008; Ito et al. 2016; Ito et al. 2018). |
Eukaryota | Metazoa, Arthropoda | Nsd-2 of Bombyx mori (B2ZXL8) |
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2.A.22.3.1 | Betaine/GABA:Na+ symporter, BGT1. (Substrates include: betaine, GABA, diaminobutyrate, β-alanine, proline, quinidine, dimethylglycine, glycine, and sarcosine with decreasing affinity in that order). Selective inhibitors have been identified (Kragholm et al. 2013). |
Eukaryota | Metazoa, Chordata | SLC6A12 of Homo sapiens |
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2.A.22.3.10 | Sodium- and chloride-dependent GABA transporter 2 (GAT-2) (Solute carrier family 6 member 13). A deficiency of GAT-2 influences the metabolomics profile of Th1 cells, which provides insight into T cell responses to GAT-2 deficiency in mice (Ding et al. 2021). |
Eukaryota | Metazoa, Chordata | SLC6A13 of Homo sapiens |
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2.A.22.3.11 | Sodium- and chloride-dependent creatine transporter 1 (CT1 or CreaT) (Creatine transporter 1) (Solute carrier family 6 member 8, SLC6A8). The bovine ortholog of the same size, a glycoprotein of about 210 - 230 Da, has been purified to near homogeneity (West et al. 2005). Cooperative Binding of Substrate and Ions Drives Forward Cycling of the Human CT-1. Creatine deficiency disorders have been reviewed (PMID 20301745). Transport of creatine metabolic precursors have also been discussed (Jomura et al. 2022), and the use of SLC6A8 for theraputic purposes has been considered (Kurth et al. 2021). The CreaT2 gene is expressed exclusively in the testes, but CreaT1 is expressed in a variety of tissues (Snow and Murphy 2001). CT1 is present in mouse kidney, skeletal muscle and brown adiose tissue, but not in the pancreas, and levels are suject to organ-specific regulation (Lygate et al. 2022). Variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromeshave been identified (Goldstein et al. 2024). [18F]FDG-PET and [18F]MPPF-PET are brain biomarkers for the creatine transporter Slc6a8 loss of function mutation (Day et al. 2025). |
Eukaryota | Metazoa, Chordata | SLC6A8 of Homo sapiens |
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2.A.22.3.12 | Sodium- and chloride-dependent GABA transporter, Ine (Protein inebriated) (Protein receptor oscillation A) |
Eukaryota | Metazoa, Arthropoda | Ine of Drosophila melanogaster | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.22.3.2 | γ-Aminobutyric acid (GABA):Na+:Cl- symporter, GAT-1 (Stoichiometry, GABA:Na+ = 1:2 where both Na+ binding sites, Na1 and Na2, have been identified. Na2 but not Na1 can accommodate Li+ (Zhou et al., 2006)). Cai et al. 2005 have reported that N-glycosylation increases the stability, trafficking and GABA-uptake of GABA transporter 1. Glutamine 291 is essential for Cl- binding (Ben-Yona et al., 2011). Four human isoforms have been identified, GAT-1, GAT-2, GAT-3, and GAT-4, all about 70% identical to each other (Borden et al., 1992). GAT-2 transports γ-aminobutyric acid and β-alanine (Christiansen et al, 2007) It also concentratively takes up β-alanine and α-fluoro-β-alanine (Liu et al., 1999). GAT1 is capable of intracellular Na+-, Cl-- and GABA-induced outward currents (reverse GABA transport; GABA efflux) (Bertram et al., 2011). An acidic amino acid residue in transmembrane helix 10 conserved in the Neurotransmitter:Sodium:Symporters is essential for the formation of the extracellular gate of GAT-1 (Ben-Yona and Kanner, 2012). It is required for stringent gating and tight coupling of ion- and substrate-fluxes in the GABA transporter family (Dayan et al. 2017). GAT-1 is the target of the antiepileptic drug, tiagabine (Kardos et al. 2010). The monomeric protein has been purified fused to GFP (Hu et al. 2017). The methodology involving the reconstitution of GABA, glycine and glutamate transporters has been described (Danbolt et al. 2021). Neurodevelopmental phenotypes have been associated with pathogenic variants of SLC6A1 (Kahen et al. 2021). 4-Phenylbutyrate restores GABA uptake and reduced seizures in SLC6A1 patient variants (Nwosu et al. 2022). The cryo-EM structure of full-length, wild-type human GAT1 in complex with its clinically used inhibitor, tiagabine, has appeared (Motiwala et al. 2022). Inhibition of GAT1 prolongs the GABAergic signaling at the synapse and is a strategy to treat certain forms of epilepsy. Nayak et al. 2023 presented the cryoEM structure of Rattus norvegicus GABA transporter 1 (rGAT1) at a resolution of 3.1 Å. The structure revealed rGAT1 in a cytosol-facing conformation, with a linear density in the primary binding site that accommodates a molecule of GABA, a displaced ion density proximal to Na site 1 and a bound chloride ion. A unique insertion in TM10 aids the formation of a compact, closed extracellular gate (Nayak et al. 2023). The molecular basis for substrate recognition and transport by human GABA transporter GAT1 has been determined (Zhu et al. 2023). These investigators reported four cryogenicEM structures of human GAT1 at resolutions of 2.2–3.2 Å. GAT1 in substrate-free form or in complex with the antiepileptic drug tiagabine exhibits an inward-open conformation. In the presence of GABA or nipecotic acid, inward-occluded structures are captured. The GABA-bound structure reveals an interaction network bridged by hydrogen bonds and ion coordination for GABA recognition. The substrate-free structure unwinds the last helical turn of transmembrane helix TM1a to release sodium ions and substrate (Zhu et al. 2023) who have identified associations between the 3D structure and variant pathogenicity, variant functions, and phenotypes in SLC6A1-related disorders. |
Eukaryota | Metazoa, Chordata | SLC6A1 of Homo sapiens |
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2.A.22.3.3 | The taurine:Na+ symporter, TauT or SLC6A6, (also transports β-alanine and γ-aminobutyric acid (GABA) (Tomi et al., 2008; Anderson et al., 2009). Regulation of the cellular content of taurine in mammalian cells has been reviewed (Lambert 2004). Biallelic mutation of the TauT-encoding gene is linked to early retinal degeneration (Preising et al. 2019). Oral taurine administration of retinal degeneration and cardiomyopathy reverses the phenotype (Ansar et al. 2019). Overexpression of SLC6A6 suppresses neointimal formation by inhibiting vascular smooth muscle cell proliferation and migration via Wnt/beta-catenin signaling (Rong et al. 2023). |
Eukaryota | Metazoa, Chordata | SLC6A6 of Homo sapiens |
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2.A.22.3.4 | Creatine:Na+ symporter | Eukaryota | Metazoa, Chordata | Creatine transporter of Oryctolagus cuniculus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.22.3.5 | Renal apical membrane creatine:Na2+:Cl- symporter (CRT) (Garcia-Delgado et al., 2007) | Eukaryota | Metazoa, Chordata | CRT of Rattus norvegicus (P28570) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.22.3.6 | γ-aminobutyric acid (GABA):Na+:Cl- symporter GAT-1 (stoichiometry = 1:2:1) (Jiang et al., 2005) | Eukaryota | Metazoa, Nematoda | GAT-1 of Caenorhabditis elegans (AAT02634) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.22.3.7 | The GABA transporter, GAT4 (single mutations render this transporter C1- independent) (Zomot et al., 2007) | Eukaryota | Metazoa, Chordata | GABA transporter GAT4 of Mus musculus (Q8BWA7) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.22.3.8 | Mouse GABA, β-alanine, fluoro-β-alanine and taurine transporter-3 (GAT3) (Liu et al. 1999). Orthologous to rat and human GAT2; 72% identical to GAT4 (2.A.22.3.7) (takes up GABA with high affinity into presynaptic terminals). Also takes up the carnitine precursor, gamma-butyrobetaine (Nakanishi et al., 2011). |
Eukaryota | Metazoa, Chordata | GAT3 of Mus musculus (P31649) |
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2.A.22.3.9 | Sodium- and chloride-dependent GABA transporter 3 (GAT-3) (Solute carrier family 6 member 11). Expression of GAT-3 was selectively decreased within the amygdala of alcohol-choosing rats, and a knockdown of this transcript reversed choice preference of rats that originally chose a sweet solution over alcohol. GAT-3 expression was selectively decreased in the central amygdala of alcohol-dependent people as well. Thus, impaired GABA clearance within the amygdala contributes to alcohol addiction (Augier et al. 2018). |
Eukaryota | Metazoa, Chordata | SLC6A11 of Homo sapiens |
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2.A.22.4.1 | High affinity tryptophan:Na+ symporter, TnaT, of 501 aas and 12 TMSs (Androutsellis-Theotokis et al., 2003). The Km for Tryptophan is 145 nM; tryptamine and serotonin weakly inhibited with Ki values of 200 and 440 μM, respectively. An evolutionarily conserved role of adjacent transmembrane segments 7 and 8 has been proposed (Kniazeff et al. 2005). |
Bacteria | Bacillota | TnaT of Symbiobacterium thermophilum |
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2.A.22.4.2 | The amino acid (leucine):2 Na+ symporter, LeuTAa (Yamashita et al., 2005). LeuT possesses two ion binding sites, NA1 and NA2, both highly specific for Na+ but with differing mechanisms of binding (Noskov and Roux, 2008). X-ray structures have been determined for LeuT in substrate-free outward-open and apo inward-open states (Krishnamurthy and Gouaux, 2012). Extracytoplasmic substrate binding at an allosteric site controls activity (Zhao et al. 2011). It has been proposed that the 5 TMS repeat derived from a DedA domain (9.B.27; Khafizov et al. 2010). Mechanistic aspect of Na+ binding have been studied (Perez and Ziegler 2013). Structural studies of mutant LeuT proteins suggest how antidepressants bind to biogenic amine transporters (Wang et al. 2013). The detailed mechanism was studied by Zhao and Noskov, 2013. Uptake involves movement of the substrate amino acid from the outward facing binding site, S1, to the inward facing binding site, S2, coupled with confrmational changes in the protein (Cheng and Bahar 2013). The complete substrate translocation pathway has been proposed (Cheng and Bahar 2014). The inward facing conformation of LeuT has been solved (Grouleff et al. 2015). Substrate-induced unlocking of the inner gatemay determinethe catalytic efficiency of the transporter (Billesbølle et al. 2015). Of the two Na+ binding sites, occupation of Na2 stabilizes outward-facing conformations presumably through a direct interaction between Na+ and transmembrane helices 1 and 8 whereas Na+ binding at Na1 influences conformational change through a network of intermediary interactions (Tavoulari et al. 2015). TMS1A movements revealed a substantially different inward-open conformation in lipid bilayer from that inferred from the crystal structure, especiallly with respect to the inner vestibule (Sohail et al. 2016). Partial unwinding of transmembrane helices 1, 5, 6 and7 drives LeuT from a substrate-bound, outward-facing occluded conformation toward an inward-facing open state (Merkle et al. 2018). A conserved tyrosine residue in the substrate binding site is required for substrate binding to convert LeuT to inward-open states by establishing an interaction between the two transporter domains (Zhang et al. 2018). The X-ray structure of LeuT in an inward-facing occluded conformation has revealed the mechanism of substrate release (Gotfryd et al. 2020). This involves a major tilting of the cytoplasmic end of TMS5, which, together with release of the N-terminus but without coupled movement of TM1) opens a wide cavity towards the second Na+ binding site. The X-ray structure of LeuT in an inward-facing occluded conformation has been solved, revealing the mechanism of substrate release (Gotfryd et al. 2020). In nine transporters having the LeuT fold, the bundle (first two TMSs of each 5 TMS repeat) rotates relative to the hash (third and fourth TMSs). Motions of the arms (fifth TMS) to close or open the intracellular and outer vestibules are common, as is a TMS1a swing, with notable variations in the opening-closing motions of the outer vestibule. These analyses suggest that LeuT-fold transporters layer distinct motions on a common bundle-hash rock (Licht et al. 2024). Thus, conformational movements in LeuT-fold transporters rock (Licht et al. 2024)! | Bacteria | Aquificota | LeuTAa of Aquifex aeolicus (2A65_A) |
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2.A.22.4.3 | The methionine/alanine uptake porter, MetPS (Trotschel et al., 2008) (MetP is the transporter; MetS is an essential auxiliary subunit). | Bacteria | Actinomycetota | MetPS of Corynebacterium glutamicum |
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2.A.22.5.1 | Hypothetical Na+-dependent permease | Archaea | Euryarchaeota | MJ1319 of Methanococcus jannaschii | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.22.5.2 | The 11 TMS Na+-dependent tyrosine transporter, Tyt1 (Quick et al., 2006) | Bacteria | Fusobacteriota | Tyt1 of Fusobacterium nucleatum (Q8RHM5) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.22.5.3 | Neurotransmitter:sodium symporter of 455 aas, MhsT. The x-ray structures of two occluded inward-facing states with bound Na+ ions and L-tryptophan have been solved (4US4; Malinauskaite et al. 2014). These structures provide insight into the cytoplasmic release of Na+. The switch from outward- to inward-oriented states is centered on the partial unwinding of transmembrane helix 5, facilitated by a conserved GlyX9Pro motif that opens an intracellular pathway for water to access the Na+2 site. Solvation through this TMS 5 pathway may facilitate Na+ release from the Na+2 site to the inward-open state (Malinauskaite et al. 2014). TMS5 plays a role in the binding and release of Na+ from the Na+2 site and in mediating conformational changes (Stolzenberg et al. 2017). MhsT of Bacillus halodurans is a transporter of hydrophobic amino acids and a homologue of the eukaryotic SLC6 family of Na+ -dependent symporters for amino acids, neurotransmitters, osmolytes, and creatine. A non-helical region in TMS 6 of hydrophobic amino acid transporter MhsT mediates substrate recognition (Focht et al. 2020). |
Bacteria | Bacillota | MhsT of Bacillus halodurans |
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2.A.22.5.4 | Uncharacterized protein of 427 aas and 12 TMSs. |
Archaea | Euryarchaeota | UP of Thermococcus profundus |
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2.A.22.5.5 | Na+-dependent hypotaurine transporter of 454 aas and 11 TMSs (Deutschbauer et al. 2011). |
Bacteria | Pseudomonadota | Hypotaurine uptake porter of Shewanella oneidensis |
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2.A.22.6.1 | Na+/Amino acid transporter 1, SIT1/IMINO (SLC6A20). Transports imino acids such as proline (Km=0.2 mM), pipecolate, and N-methylated amino acids such as MeAIB and sarcosine (Na+-dependent, Cl--stimulated, pH-independent, voltage-dependent) (Li+, but not H+ can substitute for Na+) (Takanaga et al., 2005). It is a 2Na+/1Cl--proline cotransporter (Bröer et al., 2009). To identify new inhibitors of the proline transporter SIT1, its expression in Xenopus laevis oocytes was optimized. Trafficking of SIT1 was augmented by co-expression of angiotensin-converting enzyme 2 (ACE2) in oocytes, but there was no strict requirement for co-expression of ACE2. A pharmacophore-guided screen identified tiagabine as a potent non-competitive inhibitor of SIT1 (Bröer et al. 2024). The cryo-EM structure of ACE2-SIT1 bound with tiagabine was determined. The inhibitor binds close to the orthosteric proline binding site with its size extends into the cytosolic vestibule. This causes the transporter to adopt an inward-open conformation, in which the intracellular gate is blocked. This study provides the first structural insight into inhibition of SIT1 and generates tools for a better understanding of the ACE2-SIT1 complex (Bröer et al. 2024). |
Eukaryota | Metazoa, Chordata | SIT1 of Rattus norvegicus (Q64093) |
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2.A.22.6.10 | Uncharacterized protein of 1608 aas and 12 TMSs in a 3 + 4 + 5 TMS arrangement with long hydrophilic extensions at the N- and C-termini. |
Eukaryota | Metazoa, Arthropoda | UP of Aedes albopictus (Asian tiger mosquito) |
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2.A.22.6.11 | Putative amino acid transporter, NSS1, of 1132 aas with 16 TMSs in a 3 (residues 460 - 530) + 13 TMSs (C-terminal) with a hydrophilic N-terminal 430 aas (Wunderlich 2022). |
Eukaryota | Apicomplexa | NSS1 of Plasmodium falciparum |
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2.A.22.6.2 | Synaptic vesicle neutral amino acid:Na+ symporter NTT4/XT1/BOAT3 (SLC6A17) (catalyzes uptake of neurotransmitters into presynaptic vesicles (Zaia and Reimer, 2009). |
Eukaryota | Metazoa, Chordata | NTT4 of Rattus norvegicus (P31662) |
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2.A.22.6.3 | B(O)AT1 or BOAT (SLC6A19; Hartnup's disease protein) is a kidney and intestinal apical membrane epithelial transporter for Na+-dependent, Cl--independent reabsorption of neutral amino acids. Many neutral L-amino acids bind with ~0.5 mM affinities; Leu is the preferred substrate, but all large, neutral, non-aromatic, L-amino acids bind to this transporter. Uptake of leucine is sodium-dependent. In contrast to other members of the neurotransmitter transporter family, this one does not appear to be chloride-dependent. Activity is enhanced by collectrin (Tmem27), a collecting duct transmembrane (1 TMS) glycoprotein (Q9HBJ8) (Danilczyk et al., 2006). The mouse orthologue is (Q9D687) (Broer et al., 2004; 2008) which is deficient due to mutation(s) in its structural gene, and it forms a complex with collectrin and the brush border carboxypeptidase angiotensin-converting enzyme 2 (ACE2; Q9BYF1). Mutations in Hartnup disorder protein, such as B0AT1(R240Q), decrease complex formation (Kraut and Sachs 2005) and lead to neutral aminoaciduria and in some cases pellagra-like symptoms (Kowalczuk et al., 2008; Singer et al. 2012). Collectrin is expressed at high levels in the simple embryonic kidney (the pronephros) of amphibians such as Xenopus (McCoy et al. 2008). ACE2 plays an important role in amino acid transport by acting as a binding partner of SLC6A19 in the intestine, regulating its trafficking, expression on the cell surface and catalytic activity (Kowalczuk et al. 2008, Camargo et al. 2009). ACE2 is also the cellular receptor for SARS-CoV and SARS-CoV-2 ( causitive agent of COVID-19). Yan et al. 2020 presented cryoEM structures of full-length human ACE2 in the presence of B0AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resolution of 2.9 angstroms. The ACE2-B0AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues (Yan et al. 2020). SLC6A19 inhibition facilitates urinary neutral amino acid excretion and lowers the plasma phenylalanine concentration (Wobst et al. 2024).Structural dynamics of SLC6A19 in simple and complex lipid bilayers have been reported (Dehury et al. 2025). |
Eukaryota | Metazoa, Chordata | SLC6A19 of Homo sapiens |
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2.A.22.6.4 | The neutral amino acid transporter, B0AT3 (Slc6a18); XT2 (55% identical to 2.A.22.6.3). The SLC6A18 transporter Is most likely a Na+-dependent glycine/urea antiporter responsible for urea secretion in the proximal straight tubule: The influence of this urea secretion on glomerular filtration ratehas been discussed (Bankir et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC6A18 of Homo sapiens |
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2.A.22.6.5 | solute carrier family 6, member 16 | Eukaryota | Metazoa, Chordata | SLC6A16 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.22.6.6 | Sodium-dependent vesicular neutral amino acid transporter SLC6A17 (Sodium-dependent neurotransmitter transporter NTT4/BOAT3) (Solute carrier family 6 member 17) (Hägglund et al. 2013). |
Eukaryota | Metazoa, Chordata | SLC6A17 of Homo sapiens |
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2.A.22.6.7 | Sodium-dependent neutral amino acid transporter B(0)AT2 (Sodium--dependent neurotransmitter transporter NTT73) (Sodium-coupled branched-chain amino-acid transporter 1) (Solute carrier family 6 member 15; Slc6a15). It is mainly expressed in neurons and plays a role in depression and stress vulnerability (Santarelli et al. 2015). The mouse ortholog (acc # Q8BG16) is 91.5% identical. It exhibits preference for methionine and the branched-chain amino acids, leucine, valine and isoleucine. It also transport s low-affinity substrates such as alanine, phenylalanine, glutamine and pipecolic acid (Bröer et al. 2006), and it mediates the saturable, pH-sensitive and electrogenic cotransport of proline and sodium ions with a stoichiometry of 1:1, and may play a role as a transporter for neurotransmitter precursors into neurons. In contrast to other members of the neurotransmitter transporter family, it does not appear to be chloride-dependent. The structure of B0AT2 enabled the discovery of tiagabine as an inhibitor (Kukułowicz et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC6A15 of Homo sapiens |
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2.A.22.6.8 | Sodium- and chloride-dependent transporter XTRP3 (Sodium/amino-acid transporter 1) (Solute carrier family 6 member 20) (Transporter rB21A homologue) |
Eukaryota | Metazoa, Chordata | SLC6A20 of Homo sapiens |
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2.A.22.6.9 | Sea bass amino acid uptake porter, SLC6A19 or B0AT1 of 634 aas. Levels depend on diet (Rimoldi et al. 2015). |
Eukaryota | Metazoa, Chordata | SLC6A19 of Dicentrarchus labrax (European seabass) (Morone labrax) |
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2.A.22.7.1 | Amino acid/GABA uptake porter, NSS3, of 1439 aas and 16 TMSs with an N-terminal hydrophilic region (residues 1 - 480), + 3 TMSs (residues 481 - 590), + 10 TMSs (residues 720 - 1170) + 3 TMSs (residues 1290 - 1430) (Wunderlich 2022). |
Eukaryota | Apicomplexa | NSS3 of Plasmodium falciparum |
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2.A.23.1.1 | Glutamate/aspartate:H+ symporter, GltP or GltT; has 8 TMSs with 2 re-entrant loops as for GltPh (TC# 2.A.23.1.5). GltP residues involved in substrate binding and transport have been identified, especially in transmembrane helices VII and VIII (Rahman et al. 2016). |
Bacteria | Pseudomonadota | GltP of E. coli |
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2.A.23.1.10 | Organic acid uptake porter, DctA of 444 aas and 8 - 10 putative TMSs. Based on mutant analyses, it may transport succinate, benzoate, acetate, fumarate and malate (Nam et al. 2003). A dctA mutant colonized tobacco roots to a lesser extent than the wild-type during early seedling development. Colonization by the dctA mutant, as compared to the wild type, also reduced the level of systemically induced resistance against the soft rot pathogen Erwinia carotovora SCC1 (Nam et al. 2006). |
Bacteria | Pseudomonadota | DctA of Pseudomonas chlororaphis (Pseudomonas aureofaciens) |
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2.A.23.1.11 | Dicarboxylate transporter, DctA of 458 aas and 10 TMSs. Transports L-aspartate, succinate and fumarate. Functions under high oxygen conditions although constitutively synthesized (Wösten et al. 2017). |
Bacteria | Campylobacterota | DctA of Campylobacter jejuni |
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2.A.23.1.12 | DAACS family amino acid uptake system, All0342, possibly an acidic amino acid transporter, that also catalyzes amino acid efflux (including γ-amino isobutyrate) by a passive mechanism (Pernil et al. 2015). |
Bacteria | Cyanobacteriota | All0342 of Anabaena (Nostoc) strain PCC7120 |
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2.A.23.1.14 | Sodium:glutamate cotransporter (symporter), Glt, of 430 aas and probably 9 TMSs in a 3 + 3 + 3 TMS arrangement. Several 3-d structures are known (Jensen et al. 2013). The binding and transport of L- and D-aspartate have been studied, revealing that both the L- and D-aspartate bound GltTk structures with only minor rearrangements in the structure of the binding site (Arkhipova et al. 2019). A conserved methionine residue plays a role in the ion symport process, apparently by influencing the specific kinetics in the binding reaction, which, while influential for the turnover rate, does not fundamentally explain the ion-coupling mechanism (Zhou et al. 2021). The 3-d structure is available (PDB # 6XWO). It has a covalent trimeric transporter structure with an interconnecting rigid scafford domain (trimerization domain) on the inside. This seems to be a unique structure for a transporter (Colucci et al. 2023). The structure of the P208R mutant is also known (Colucci et al. 2023). |
Archaea | Euryarchaeota | Glt of Thermococcus (Pyrococcus) kodakarensis |
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2.A.23.1.15 | Glutamate:Na+ symporter, Glt, of 425 aas and 10 TMSs. Pyrococcus horikoshii amino acid transporter GltPh revealed, like other channels and transporters, activity mode switching, previously termed wanderlust kinetics (Jiang et al. 2024). Structural states were attributed to a functional timeline, allowing six structures to be solved from a single molecule, and an inward-facing state, IFSopen-1, to be determined as a kinetic dead-end in the conformational landscape (Jiang et al. 2024). |
Archaea | Euryarchaeota | Glt of Pyrococcus horikoshii |
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2.A.23.1.2 | Glutamate/aspartate:Na+ + H+ symporter | Bacteria | Bacillota | GltT of Bacillus stearothermophilus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.23.1.3 | C4-dicarboxylate transporter (substrates: fumarate, D- and L-malate, succinate, succinamide, orotate, iticonate, mesaconate). This protein is 85% identical to the Sinorhizobium melitoti ortholog, mutants of which have an alterred substrate specificity and inability to support N2 fixing symbiosis (Yurgel and Kahn 2005). |
Bacteria | Pseudomonadota | DctA of Rhizobium leguminosarum |
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2.A.23.1.4 | The L-cystine/L-selenocystine:H+ symporter, TcyP (YhcL) (Burguière et al., 2004) |
Bacteria | Bacillota | TcyP (YhcL) of Bacillus subtilis (P54596) |
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2.A.23.1.5 |
Archaeal aspartate transporter, Gltph (GltPh) (3-D structure known; 3V8F and 3V8G) (Boudker et al., 2007; Yernool et al., 2004). Cotransports aspartate with 2 Na+ (Ryan et al., 2009) or 3 Na+ (Groeneveld and Slotboom, 2010) or 1Na+ plus 1 H+ plus 1 K+ (Machtens et al. 2015). Reyes et al. (2009) have solved the structure of the inward facing state by cysteine crosslinking. The loop between TMSs 3 and 4 plays an essential role in transport (Compton et al., 2010). Gltph shows opposite movement of the external gate upon binding cotransported sodium compared with substrate (Focke et al., 2011). The transport pathway and the conformational changes involved have been suggested based on modeling studies (Stolzenberg et al. 2012; Wang et al. 2018). Individual transport domains may alternate between periods of quiescence and periods of rapid transitions. The switch to the dynamic mode may be due to separation of the transport domain from the trimeric scaffold which precedes domain movements across the bilayer (Akyuz et al. 2013). This spontaneous dislodging of the substrate-loaded transport domain is approximately 100-fold slower than subsequent transmembrane movements and may be rate determining in the transport cycle. Interactions between the transporter and specific lipids in artificial membranes have revealed effects on activity, and mechanisms have been proposed (McIlwain et al. 2015). The system can also function as an anion channel (Machtens et al. 2015). Millisecond dynamics have been described (Matin et al. 2020). |
Archaea | Euryarchaeota | Gltph of Pyrococcus horikoshii (LXFHA) |
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2.A.23.1.6 | The dicarboxylate (succinate, fumarate, malate and oxaloacetate):H+ symporter, DctA (probably 3H+ are transported per succinate taken up (Groeneveld et al., 2010). |
Bacteria | Bacillota | DctA of Bacillus subtilis (P96603) |
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2.A.23.1.7 | Aerobic dicarboxylate transporter, DctA. Interacts with the DcuS sensor kinase (Witan et al., 2012). The interaction of DctA with DcuS has been studied extensively and reviewed (Unden et al. 2016). |
Bacteria | Pseudomonadota | DctA of E. coli (P0A830) |
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2.A.23.1.8 | Cystine transporter, YdjN, of 463 aas. Also transports L-selenaproline (L-selenazolidine-4-carboxylic acid) and L-selenocystine, both toxic analogues that inhibit growth of urinary tract pathogenic E. coli (Deutch et al. 2014). |
Bacteria | Pseudomonadota | YdjN of E. coli |
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2.A.23.1.9 | Fumarate:H+ symporter of 442 aas and 14 established TMSs, DctA. Responsible for the transport of dicarboxylates such as succinate, fumarate, and malate. The 3-d structure has been solved (Geertsma et al. 2015). It reveals an inward facing transmembrane domain of two 7 TMS intertwined inverted repeats similar to that of UraA as well as a STAS domain (Geertsma et al. 2015). |
Bacteria | Deinococcota | Fumarate transporter of Deinococcus geothermalis |
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2.A.23.2.1 | Glutamate/aspartate:Na+ symporter, GLAST or EAAT1, Structural rearrangements have been probed by Leighton et al., 2006). EAAT1 interacts directly with the Na+, K+-ATPase (TC #3.A.3.1) (Rose et al., 2009). CEAT1 couples glutamate uptake to the symport of 3 Na+ and 1 H+ followed by the antiport of 1 K+. It can function as an uncoupled anion, water and/or urea channel (Vandenberg et al., 2011). Large collective motions regulate the functional properties of EAAT1 trimers (Jiang et al., 2011). The reentrant helical hairpin loop, HP1, functions during the transport cycle as the proposed internal gate. HP1 is packed against transmembrane domain, TMS 2 and TMS5 in its closed state, and two residues located in TM2 and HP2 of EAAT1 are in close proximity (Zhang et al. 2014). In EAAT1, R388 is a critical element for the structural coupling between the substrate translocation and the gating mechanisms of the EAAT-associated anion channel, and conversion to E or D creates a constitutively open anion channel (Torres-Salazar et al. 2015). |
Eukaryota | Metazoa, Chordata | Glutamate/aspartate permease (excitatory amino acid transporter-1, EAAT1) of Rattus norvegicus |
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2.A.23.2.10 | Excitatory amino acid transporter (Sodium-dependent glutamate/aspartate transporter), Gkt-1 of 503 aas and 9 - 11 TMSs (Radice and Lustigman 1996). |
Eukaryota | Metazoa, Nematoda | Glt-1 of Caenorhabditis elegans |
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2.A.23.2.11 | EAAT homologue, a glutamate/aspartate preferring transporter of 483 aas. TMS8 includes residues important for substrate and cation binding (Wang et al. 2013). |
Eukaryota | Metazoa, Arthropoda | EAAT homoloue of Culex quinquefasciatus (Southern house mosquito) (Culex pungens) |
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2.A.23.2.12 | Dicarboxylic acid over dicarboxylic amino acid preferring EAAT3 homologue of 483 aas (Wang et al. 2013). |
Eukaryota | Metazoa, Arthropoda | EAAT3 homologue of Culex quinquefasciatus (Southern house mosquito) (Culex pungens) |
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2.A.23.2.2 | Glutamate/aspartate:Na+ symporter, GLT1; GLUT-R; EAAT2. Interacts directly with the Na+, K+-ATPase (TC #3.A.3.1) (Rose et al., 2009). Cotransports glutamic acid with three Na+ followed by countertransport of K+ (Teichman et al., 2009). The C-terminal 74aa domain regulates transport activity (Leinenweber et al., 2011). Hippocampal glutamate transporter 1 (GLT-1) levels parallel memory training (Heo et al., 2011). GLT-1 is regulated by MAGI-1 (Zou et al., 2011). Venom from the spider Parawixia bistriata and a purified compound (Parawixin1) stimulate EAAT2 activity and protect retinal tissue from ischemic damage (Mortensen et al. 2015). Determinants of this stimulation are at the interface of the trimerization and substrate transport domains ((Mortensen et al. 2015). TMS4 of GLT-1 undergoes a complex conformational shift during substrate translocation (Rong et al. 2016). Both reentrant loops determine the cation specificity (Silverstein et al. 2018). A tight spatial and functional relationship between the DAT/GLT-1 transporters and the Kv7.2/7.3 potassium channel immediately readjusts the membrane potential of the neuron, probably to limit the neurotransmitter-mediated neuronal depolarization (Bartolomé-Martín et al. 2019).
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Eukaryota | Metazoa, Chordata | Glutamate permease (excitatory amino acid transporter-2, EAAT2) of Rattus norvegicus |
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2.A.23.2.3 | Glutamate/aspartate/cysteine:Na+ symporter, EAAC1; EAAT3, SLC1A1 (Li+ can replace Na+; EAAC1 also mediates glutamate-independent anion conductance.) Cotransports glutamic acid with three Na+ followed by countertransport of K+(Teichman et al., 2009). The 50 residue 4B-4C loop (following TMS4) binds Na+ (Koch et al., 2007). (The dicarboxylic aminoaciduria protein in humans; NP_004161; Bröer, 2008a; 2008b). Neutralizing aspartate 83 modifies substrate translocation (Hotzy et al., 2012). An SLC1A1 deletion segregates with schizophrenia and bipolar schizoaffective disorder in a 5-generation family (Myles-Worsley et al. 2013). Thr101 in TMS3 is essential for Na+ binding (Tao et al. 2010). Klotho, a 1012 aa protein with N- and C-terminal TMSs, is a regulator of the excitatory amino acid transporters EAAT3 and EAAT4 (Almilaji et al. 2013). The 3 Na+ binding sites in SLC1A porters have been identified, and both reentrant loops determine cation selectivity (Silverstein et al. 2018). |
Eukaryota | Metazoa, Chordata | SLC1A1 of Homo sapiens |
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2.A.23.2.4 | Aspartate/taurine (not glutamate):Na+ symporter, dEAAT2 (mediates both uptake and heteroexchange of its two substrates, both dependent on external Na+ (with taurine outside and Asp inside)); L-glutamate is transported with low affinity and efficiency (Besson et al., 2005). |
Eukaryota | Metazoa, Arthropoda | dEAAT2 of Drosophila melanogaster (E1JHQ6) |
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2.A.23.2.5 | solute carrier family 1 (glutamate transporter), member 7 | Eukaryota | Metazoa, Chordata | SLC1A7 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.23.2.6 | Excitatory amino acid transporter 1 (EAAT1) (Sodium-dependent glutamate/aspartate transporter 1) (GLAST-1) (Solute carrier family 1 member 3). Mutations cause episodic ataxia type 6 (EA6) (Choi et al. 2016; Iwama et al. 2017). EAAT1 regulates the extent and duration of glutamate-mediated signals by the clearance of glutamate after synaptic release. It also has an anion channel activity that prevents additional glutamate release. This system may be important for the pathophysiology of schizophrenia (Parkin et al. 2018). Substrate-induced structural rearrangements occur between the TMS4b-4c loop and TMS7 during the transport cycle (Zhang et al. 2019). GLAST serves as a cell surface biomarker for astrocytes (Kumar et al. 2021). It interacts with NHERF1 and NHERF2 (see TC# 8.A.24.1.1) which modify its cell surface expression (Sato et al. 2013). The inhibitor, UCPH-101 slows substrate translocation rather than substrate or Na+ binding, confirming a non-competitive inhibitory mechanism. However, it only partially inhibits wild-type ASCT2 with relatively low affinity (Dong et al. 2023). Perivascular fibroblasts expressing SLC1A3 are essential for penile erection in mice because they reduce norepinephrine availability, thereby promoting dilation of the corpora cavernosa. The number of SLC1A3+ perivascular fibroblasts decreased in aged mice, which reduced penile blood flow (Guimaraes et al. 2024). Vitamin D3 supplementation promotes Slc1A3 activity, increasing amino acid digestion and absorption in fish, contributing to the overall productivity of aquaculture (Zhang et al. 2022). |
Eukaryota | Metazoa, Chordata | SLC1A3 of Homo sapiens |
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2.A.23.2.7 | Excitatory amino acid transporter 2, EAAT2 (Glutamate/aspartate transporter II) (Sodium-dependent glutamate/aspartate transporter 2) (Solute carrier family 1 member 2). This system may be important for the pathophysiology of schizophrenia (Parkin et al. 2018). Amino acids in the TMS2 of EAAT2 are essential for membrane-bound localization, substrate binding, transporter function and anion currents (Mai et al. 2021). The distance between the TMS3-TMS4 loop and TMS7 changes when substrates are transported (Qu et al. 2021). SLC1A2 and SLC1A3 encode the glial glutamate transporters EAAT2 and EAAT1, which are not only the predominant glutamate uptake carriers in the brain, but also function as anion channels. Two homologous mutations, which substitute prolines in the center of the fifth TMS by arginine (P289R EAAT2, P290R EAAT1) cause epileptic encephalopathy (SLC1A2) or with episodic ataxia type 6 (SLC1A3). Both mutations impair glutamate uptake and increase anion conduction (Suslova et al. 2023). Additionally, the P312R mutation generates an anion conducting state that is accessible in the outward facing apo state that is the main determinant of the increased anion conduction of EAAT transporters carrying this mutation. The kinase LRRK2 is required for the physiological function and expression of the glial glutamate transporter EAAT2 (SLC1A2) (Di Iacovo et al. 2025). |
Eukaryota | Metazoa, Chordata | SLC1A2 (EAAT2) of Homo sapiens |
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2.A.23.2.8 | Excitatory amino acid transporter 4, EAAT4 (Sodium-dependent glutamate/aspartate transporter) (Solute carrier family 1 member 6). Klotho, a 1012 aa protein with N- and C-terminal TMSs, is a regulator of the excitatory amino acid transporters EAAT3 and EAAT4 (Almilaji et al. 2013). Phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, enhanced Cl- currents via EAAT4, but this increased Cl- current was not thermodynamically coupled to glutamate transport. These PMA-enhanced Cl- currents were partially blocked by staurosporine, chelerythrine, and calphostin C, the three PKC inhibitors, implying that PKC-mediated phsophorylation was responsible (Fang et al. 2006). Epispdic ataxia (EA6) is caused by mutations in SLC1A3 encoding this glutamate transporter that is also an anion channel (Graves et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC1A6 of Homo sapiens |
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2.A.23.2.9 | Putative sodium-dependent excitatory amino acid transporter Glt-3 | Eukaryota | Metazoa, Nematoda | Glt-3 of Caenorhabditis elegans | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.23.3.1 | Neutral amino acid (alanine, serine, cysteine, threonine):Na+ symporter. Also transports homocysteine (Jiang et al., 2007). AscT1 is the Syncytin-1 (Q9UQF0) receptor. Syncytin-1, of 538 aas with 4-7 TMSs, is a viral fusion protein and is involved in the development of multiple sclerosis (Antony et al. 2007). Mutation causes nuerological problems including global developmental delay, severe progressive microcephaly, seizures, spasticity and thin corpus callosum (CC) (Heimer et al. 2015). Alkoxy hydroxy-pyrrolidine carboxylic acids (AHPCs) and hydroxy-l-proline act as selective high-affinity inhibitors of the SLC1 family neutral amino acid transporters, SLC1A4 and SLC1A5 (Lyda et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC1A4 of Homo sapiens |
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2.A.23.3.2 | Insulin-activated, Na+-dependet amino acid (serine, alanine, glutamate, glutamine and other neutral amino acids):amino acid antiporter (Ndaru et al. 2019). Also transports homocysteine (Jiang et al., 2007). V-9302 is a selective and potent competitive small molecule antagonist of glutamine uptake via ASCT2. Blockage of ASCT2 activity with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo (Schulte et al. 2018). The glutamine transporter ASCT2 plays a role in antineoplastic therapy (Teixeira et al. 2021). |
Eukaryota | Metazoa, Chordata | Insulin-dependent amino acid transporter B of Mus musculus, AscT2 |
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2.A.23.3.3 | Broad-specificity amino acid:Na+ symporter, LAT1, M7V1, RDR, RDRC, or SLC1A5 (transports most neutral, zwitterionic and dibasic amino acids either uptake or bidirectional transport) (Scalise et al. 2018). Required for intracellular multiplication of Legionella pneumophila (Wieland et al., 2005). SLC7A5 with accessory protein SLC3A2 (the heavy chain; TC# 8.A.9.2.2) mediates bidirectional transport of amino acids and regulates mTOR and autophagy (Nicklin et al., 2009; Estrach et al. 2014). LAT1 is the sole transport competent subunit of the heterodimer (Napolitano et al. 2015). l-Leucine inhibits uptake of LAT1 substrates as well as cell growth, and it potentiates the efficacy of bestatin and cisplatin, even at low concentrations (25 muM) (Huttunen et al. 2016). Transports certain thyroid hormones and their derivatives (Krause and Hinz 2017). It interacts with scaffold proteins and is glycosylated on two asn residues, N163 and N212. Also serves as the receptor by a group of retroviruses (Scalise et al. 2018). Syncytin-1 interacts with the ASCT2 receptor (Štafl et al. 2021). Discoidin domain receptor 1 promotes hepatocellular carcinoma progression through modulation of the SLC1A5 and the mTORC1 signaling pathway (Pan et al. 2022). LAT1 expression is alterred in patients with pediatric scoliosis (development of skeletal deformities) (Demura et al. 2022). The expression of SLC1A5 is upregulated in glioblastoma tissues compared with low-grade gliomas. SLC1A5 knockdown inhibits glioma cell proliferation and invasion, and reduces the sensitivity of ferroptosis via the GPX4-dependent pathway (Han et al. 2022). It acts as a cell surface receptor for Feline endogenous virus RD114, Baboon M7 endogenous virus, and type D simian retroviruses. LAT1 plays a role in the activation of pathogenic T cell subsets under inflammatory conditions (Ogbechi et al. 2023). SLC1A5 is a novel biomarker associated with ferroptosis (Chen et al. 2023). Vitamin D3 supplementation promotes Slc1A5 activity, increasing amino acid digestion and absorption in fish, contributing to the overall productivity of aquaculture (Zhang et al. 2022). Lat1 plays a role in human cancer progression, and other SLC transporters also play roles (Hushmandi et al. 2024). LAT1 is a target for breast cancer diagnosis and therapy (Zhou et al. 2025). JAM-A (junctional adhesion molecule-A) promotes breast cancer progression via regulation of amino acid transporter LAT1 (Magara et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC1A5 of Homo sapiens |
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2.A.23.3.4 | Uncharaterized protein of 409 aas and 10 TMSs. |
Bacteria | Spirochaetota | UP of Treponema denticola |
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2.A.24.1.1 | Citrate:Na+ symporter, CitS. Kebbel et al. 2013 presented the three-dimensional map of dimeric CitS obtained with electron crystallography. Each monomer has 13 alpha-helical transmembrane segments; six are organized in a distal helix cluster and seven in the central dimer interface domain. Based on structural analyses and comparison to VcINDY, a molecular model with assigned helices, a model with internal structural symmetry was proposed. Projections of CitS in several conformational states induced by the presence and absence of sodium and citrate as substrates were also proposed. Citrate binding induces a defined movement of alpha helices within the distal helical cluster. Kebbel et al. 2013 proposed a substrate translocation site and conformational changes that are in agreement with the "alternating access" model. The loop between TMSs VIII and IX folds into an amphipathic surface helix (Sobczak and Lolkema 2005). |
Bacteria | Pseudomonadota | CitS of Klebsiella pneumoniae |
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2.A.24.1.2 | CitS or CitT of Salmonella enterica (typhi) of 446 aas with 11 or 12 TMSs. It shows narrow substrate specificity and is very specific, transporting only citrate and to a low extent citromalate (Bandell et al. 1997). Also Na+ can be replaced by Li+, but only at very high concentrations. |
Bacteria | Pseudomonadati, Pseudomonadota | CitS of Salmonella enterica |
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2.A.24.2.1 | L-Malate permease | Bacteria | Bacillota | MaeP of Streptococcus bovis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.24.2.2 | Malate:lactate antiporter (substrates include: S-lactate, R-lactate, S-malate and S-citramalate) | Bacteria | Bacillota | MaeP of Lactococcus lactis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.24.2.3 | Malate:Na+ symporter | Bacteria | Bacillota | YufR of Bacillus subtilis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.24.2.4 | L-malate/citrate:H+ symporter (electroneutral) | Bacteria | Bacillota | CimH (YxkJ) of Bacillus subtilis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.24.2.5 | Citrate:acetate antiporter, CitW | Bacteria | Pseudomonadota | CitW of Klebsiella pneumoniae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.24.3.1 | Electrogenic citrate:L-lactate exchanger, CitP or CitN (Pudlik and Lolkema 2012). |
Bacteria | Bacillota | CitN of Lactococcus lactis |
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2.A.24.3.2 | Citrate:lactate antiporter (substrates include: citrate, S-citramalate, S-malate, 2-hydroxylisobutyrate and R-lactate) | Bacteria | Bacillota | CitP of Leuconostoc mesenteroides | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.25.1.1 | Alanine (or glycine):Na+ symporter | Bacteria | Pseudomonadota | DagA of Alteromonas haloplanktis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.25.1.10 | Putative Ala/Gly transporter of 476 aas and 11 TMSs, YaaJ |
Bacteria | Pseudomonadota | YaaJ of E. coli |
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2.A.25.1.2 |
Alanine:Na+ (or H+) symporter (Kamata et al. 1992; Kanamori et al. 1999). The sequence as reported appears to lack the first 45 aas and the first two tMSs, probably because of incorrect initiation codon selection. |
Bacteria | Bacillota | Acp of thermophilic bacterium PS-3 |
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2.A.25.1.3 | Alanine:Na+ symporter, AgcS (Moore and Leigh, 2005) | Archaea | Euryarchaeota | AgcS of Methanococcus maripaludis (CAF31067) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.25.1.4 | The putative glycine porter, GlyP. Regulated by Glycine riboswitch (Rodionov et al. 2011) |
Bacteria | Pseudomonadota | GlyP of Shewanella oneidensis (Q8EII1) |
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2.A.25.1.5 |
Amino-acid carrier protein, AlsT. Negatively regulated by TnrA (Yoshida et al. 2003). |
Bacteria | Bacillota | AlsT of Bacillus subtilis |
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2.A.25.1.6 | Putative bifunctional protein of 748 aas and 12 TMSs with an N-terminal sodium:alanine symporter domain and a C-terminal phosphatidylserine decarboxylase proenzyme domain. |
Bacteria | Spirochaetota | Bifunctional protein of Leptospira biflexa |
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2.A.25.1.7 | Putative alanine/glycine transporter of 443 aas and 11 TMSs. |
Bacteria | Pseudomonadota | PP of Anaplasma phagocytophilum |
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2.A.25.1.8 | Putative alanine/glycine transporter of 447 aas and 11 TMSs. |
Bacteria | Bacillota | Putative transporter of Clostridium novyi |
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2.A.25.1.9 | Probable Glycine/alanine/asparagine/glutamine uptake porter, AgcS (Bualuang et al. 2014). |
Bacteria | Pseudomonadota | AgcS of Pseudomonas aeruginosa |
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2.A.26.1.1 | Branched chain amino acid: Na+ symporter | Bacteria | Pseudomonadota | BraB of Pseudomonas aeruginosa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.26.1.10 | Branched chain amino acid transporter 2 of 439 aas and 12 TMSs, BrnQ (Guardiola et al. 1974). The brnQ gene can be mutated to give rise to threonine tolerance (Radi et al. 2022). However the wild type protein takes up threonine (in addition to leucine, isoleucine and valine) but with low affinity and high flux (Khozov et al. 2023). |
Bacteria | Pseudomonadota | BrnQ of E. coli |
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2.A.26.1.2 | Ile/Val:H+ symporter | Bacteria | Pseudomonadota | BraZ of Pseudomonas aeruginosa | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.26.1.3 | Branched chain amino acid:H+ symporter | Bacteria | Bacillota | BrnQ of Lactobacillus delbrueckii | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.26.1.4 | The branched chain amino acid transporter BrnQ (transports Leu, Ile, Val, Phe, and Met) (Braun et al., 2008). |
Bacteria | Chlamydiota | BrnQ of Chlamydia trachomatis (O84558) |
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2.A.26.1.5 | LIVCS family member of 429 aas and 12 TMSs. |
Bacteria | Bacillota | LIV transporter of Blautia hydrogenotrophica |
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2.A.26.1.6 | Uncharacterized protein of 430 aas and 12 TMSs. |
Bacteria | Campylobacterota | UP of Arcobacter butzleri |
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2.A.26.1.7 | LIV transporter of 411 aas and 12 TMSs |
Bacteria | Mycoplasmatota | LIV transporter of Mycoplasma sp. |
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2.A.26.1.8 | LIV transporter of 445 aas and 12 TMSs. |
Bacteria | Thermodesulfobacteriota | lIV transporter of Desulfovibrio desulfuricans |
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2.A.26.1.9 | Branched chain amino acid (Leucine, Isoleucine, Valine) transporter of 456 aas and 12 TMSs, BrnQ (Trip et al. 2013). |
Bacteria | Bacillota | BrnQ of Lactococcus lactis |
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2.A.27.1.1 | Glutamate:Na+ symporter, GltS, of 401 aas and 12 TMSs. It transports L- and D-glutamate, α-methylglutamate and homocysteate. Swapping the order of the two halves (repeat units) does not decrease activity (Dobrowolski and Lolkema, 2010). |
Bacteria | Pseudomonadota | GltS of E. coli (P0AER8) |
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2.A.27.1.2 | Glutamate:Na |
Bacteria | Cyanobacteriota | GltS of Synechocystis PCC6803 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.27.1.3 |
Probable L-glutamate/N-acetylglutamate uptake porter, GltS. Involved in N-acetylglutamate catabolism as a carbon and nitrogen source (Johnson et al. 2008). |
Bacteria | Pseudomonadota | GltS of Pseudomonas aereuginosa |
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2.A.27.1.4 | Sodium/glutamate symporter, GltS, YbfA, JemA, of 401 aas and 12 TMSs. Note, the Na+:Glutamate symporter with TC# 2.A.27.1.1 is also called GltS. YbfA regulates the sensitivity of E. coli K12 to plantaricin BM-1 via the BasS/BasR two- component regulatory system (Chen et al. 2021). |
Bacteria | Pseudomonadota | GltS of E. coli |
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2.A.27.1.5 | sodium:glutamate symporter of 476 aas and 12 TMSs, GltS. It has a Km for glutamate of 5 μM, but has low affinity for Na+. Glutamate uptake is inhibited by glu, gln, asp and asn (Boonburapong et al. 2012). |
Bacteria | Cyanobacteriota | GltS |
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2.A.27.2.1 | Glutamate:sodium symporter, GltS (Boonburapong et al. 2012). |
Bacteria | Cyanobacteriota | GltS of Snyechococcus sp. ATCC27264 (Agmenellum guadruplicatum) |
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2.A.27.2.2 |
Archaeal GltS homologue |
Archaea | Euryarchaeota | GltS of Methanosarcina mazei |
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2.A.28.1.1 | Organic acid/(conjugated) bile acid (taurocholate):Na+ symporter. Taurine conjugates > glycine conjugates > unconjugated bile salts. The initial effect on hepatic bile flow of cholestatic agents such as thorazine and estradiol 17beta-glucuronide are on water flow and not bile salt export pump-mediated bile acid transport (Javitt 2020). |
Eukaryota | Metazoa, Chordata | Liver bile acid uptake system of Rattus norvegicus |
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2.A.28.1.10 | BASS family homologue |
Bacteria | Myxococcota | BASS family homologue of Myxococcus xanthus |
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2.A.28.1.11 | Apical sodium-dependent bile acid transporter, SBAT of 546 aas and 9 - 12 TMSs. It is essential for survival of a carcinogenic liver fluke Clonorchis sinensis in the bile (Dai et al. 2020). |
Eukaryota | Metazoa, Platyhelminthes | SBAT of Clonorchis sinensis |
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2.A.28.1.2 | Liver/ileal bile acid:Na+ symporter, ASBT, ISBT or NTCP2 (SLC10A2) of 348 aas and 7 TMSs (Mareninova et al. 2005) (essential for liver or intestinal bile acid transport and homeostasis (Rao et al., 2008). This BART superfamily protein has been modeled in 3-dimensions using the 3-D structure of bacteriorhodopsin (a TOG superfamily member) (Zhang et al. 2004). TMS4 forms part of the substrate translocation pathway (Khantwal and Swaan, 2008); TMS7 plays a role in substrate binding and translocation (González et al., 2012); TMS1 contributes to substrate translocation and protein stability (da Silva et al., 2011), and TMS2 coordinates Na+ translocation (Sabit et al. 2013). NTCP serves as the Hepatitis B Virus (HBV) receptor, and drugs developed to target NTCP induce autophagy and may provide therapy for HBV (Zhang et al. 2015). Decreased activity leads to luminal bile salt concentrations and either increased eletrolyte secretion or decreased reabsolption (van der Mark et al., 2014). Function and stability depend on N-glycosylation (Muthusamy et al. 2015). Specific inhibitors are known (Slijepcevic and van de Graaf 2017). It has a 7 TMS topology (Banerjee and Swaan 2006). Chronic hepatitis B, C and D viruses (HBV, HCV and HDV) infect the liver and cause cancer. The three viruses are exclusively hepatotropic, and NTCP mediates the transport of bile acids and plays a key role in HBV HCV and HDV entry into hepatocytes. It modulates HCV infection by regulating innate antiviral immune responses in the liver (Eller et al. 2018). The S-acylation status of hASBT regulates its function, metabolic stability, membrane expression, and phosphorylation state (Ayewoh et al. 2020). The GXXXG/A motifs in TMS2 and TMS7 are important for proper folding and sorting of NTCP, and they indirectly affect glycosylation, homodimerization, and bile acid transport, as well as its HBV/HDV receptor function (Palatini et al. 2021). Structural plasticity is a feature of rheostat positions in the human Na+/taurocholate cotransporting polypeptide (NTCP) (Ruggiero et al. 2022). A monoclonal antibody against human NTCP blocks Hepatitis B virus infection (Takemori et al. 2022). NTCP interacts directly with the first 48 residues of the N-myristoylated N-terminal preS1 domain of the hepatitis viral large protein. 3-d structural analyses suggest that members of the SLC10 family share a common mechanism of bile acid transport, but the NTCP structure displays an additional pocket formed by residues that are known to interact with preS1 (Park et al. 2022). Genetic variants of NTCP gene influence hepatitis B vaccine failure (Chen et al. 2022). Enhanced oral absorption and liver distribution of polymeric nanoparticles can be achieved through traveling the enterohepatic circulation pathways of bile acids using ASBT (Wang et al. 2022). Novel inhibitors of NTCP have been identified (Song et al. 2024). |
Eukaryota | Metazoa, Chordata | NTCP of Homo sapiens |
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2.A.28.1.3 | The organic anion:Na+ symporter, SOAT (transports estrone-3-sulfate (Km= 31 μM) and dehydropiandrosterone sulfate (Km = 30 μM) but not taurocholate, estradiol-17β-glucuronide or ouabain) (Geyer et al., 2004) | Eukaryota | Metazoa, Chordata | SOAT of Rattus norvegicus (Q70EX6) |
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2.A.28.1.4 | The organic anion:Na+ symporter, SOAT (probable paralogue of 2.A.28.1.3); a 7 TMS protein with the N-terminus out and the C-terminus in. Transports dehydroepiandrosterone sulfate, estrone-3-sulfate, and pregnenolone sulfate with Km values of 30, 12 and 11 μM, respectively. Sulfoconjugated taurolithocholate is also a substrate. Cholate, taurocholate and chenodeoxycholate are not substrates. (Geyer et al., 2007). It is expressed in the CNS (Sreedharan et al. 2011). |
Eukaryota | Metazoa, Chordata | SLC10A6 of Homo sapiens |
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2.A.28.1.5 | solute carrier family 10 (sodium/bile acid cotransporter family), member 3 |
Eukaryota | Metazoa, Chordata | SLC10-3 of Bos taurus (Q0V8N6) |
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2.A.28.1.6 | solute carrier family 10 (sodium/bile acid cotransporter family), member 5 |
Eukaryota | Metazoa, Chordata | SLC10A5 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.28.1.7 | Solute carrier family 10 (sodium/bile acid cotransporter family), member 4. The rat orthologue is found in cholinergic neurons of the brain together with the vesicular acetyl choline transporter, VAChT (TC# 2.A.1.2.28), and the high affinity choline transporter, CHT1 (TC#s 2.A.21.8.1 & 2) (Geyer et al. 2008). It is a protease-activated bile acid transporter (Abe et al. 2013). It has also been reported to be a vesicular monoaminergic and cholinergic associated transporter that is important for dopamine homeostasis and neuromodulation in vivo, and it may play a role in neurotransmitter release at the neuromuscular junction (Larhammar et al. 2015; Patra et al. 2015). It's loss in mice results in cognitive impairment (Melief et al. 2016). |
Eukaryota | Metazoa, Chordata | SLC10A4 of Homo sapiens |
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2.A.28.1.8 | P3 protein (Solute carrier family 10 member 3) | Eukaryota | Metazoa, Chordata | SLC10A3 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.28.1.9 | Sodium/bile acid cotransporter (Cell growth-inhibiting gene 29 protein; Na+/bile acid cotransporter; Na+/taurocholate transport protein; NTCP; Solute carrier family 10 member 1). Transports steroids and xenobiotics, including HMG-CoA reductase inhibiitors (statins). This protein is the hepatitis B and D virus receptor (Yan et al. 2012). Specific inhibitors are known and include cyclosporin A (Wu et al. 2020, Slijepcevic and van de Graaf 2017). hNTCP-membrane vesicles effectively prevent viral infection, spreading, and replication in a human-liver-chimeric mouse model of HBV infection (Liu et al. 2018). The dye, indocyaine green (ICG), is a substrate, and NTCP and ICG form a reporter system with applications in cancer biology, robust drug-drug interactions, and drug screening in HBV/HDV infections (Wu et al. 2020). Structural plasticity is a feature of rheostat positions in the Human Na+/taurocholate cotransporting polypeptide (NTCP) (Ruggiero et al. 2022). Findings on protein-protein interactions (PPIs) between NTCP and cofactors relevant for entry of the virus/NTCP receptor complex have been summarized (Zakrzewicz and Geyer 2023). Hepatitis B virus (HBV) is a globally prevalent human DNA virus responsible for over 250 million cases of chronic liver infections, leading to conditions such as liver inflammation, cirrhosis and hepatocellular carcinoma (HCC). Sodium taurocholate co-transporting polypeptide (NTCP) is highly expressed in human hepatocytes and functions as a bile acid (BA) transporter. NTCP is the receptor that HBV and its satellite virus, hepatitis delta virus (HDV), use to enter hepatocytes. HBV entry into hepatocytes is tightly regulated by various signaling pathways, and NTCP plays an important role in the initial stage of HBV infection. NTCP acts as an initiation signal, causing metabolic changes in hepatocytes, facilitating the entry of HBV into hepatocytes. Li et al. 2024 examined the regulatory mechanisms governing HBV pre-S1 binding to liver membrane NTCP, the role of NTCP in HBV internalization, and the transcriptional and translational regulation of NTCP expression. Additionally, they discussed clinical drugs targeting NTCP, including combination therapies involving NTCP inhibitors. Sodium taurocholate co-transporting polypeptide (NTCP) has been identified as an entry receptor for hepatitis B virus (HBV). Manganese is a potent inducer of lysosomal activity that inhibits de novo hepatitis B virus (HBV) infection (Yu et al. 2025).
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Eukaryota | Metazoa, Chordata | SLC10A1 of Homo sapiens |
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2.A.28.2.1 | The chloroplastic glucosinolate uptake porter, BAT5 (Gigolashvili et al., 2009) [glucosinolates are thioglucosides of amino acid derivatives. These bitter natural pesticides are present in most plants of the order Brassicales among others]. |
Eukaryota | Viridiplantae, Streptophyta | BAT5 of Arabidopsis thaliana (Q3EA49) |
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2.A.28.2.2 | Chloroplast envelope membrane pyruvate:Na+ symporter, called Bile acid:sodium symporter, protein 2, BASS2 (widely distributed in all land plants tested) (Furumoto et al., 2011). |
Eukaryota | Viridiplantae, Streptophyta | BASS2 of Flaveria trinervia (E0D3H5) |
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2.A.28.2.3 | Chloroplast envelope membrane pyruvate:Na+ symporter, BASS2. (Orthologous to 2.A.28.2.2) (Furumoto et al., 2011; Furumoto 2016). The wheat ortholog functions in salt tolerance (Zhao et al. 2016). |
Eukaryota | Viridiplantae, Streptophyta | BASS2 pf Arabidopsis thaliana (Q1EBV7) |
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2.A.28.2.4 | Na+:bile acid symporter (AstB). The 3-d structure is available (3ZUX). |
Bacteria | Pseudomonadota | AstB of Neisseria meningitidis (Q9K0A9) |
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2.A.28.2.5 | Putative Na+ symporter |
Bacteria | Bacillota | YqcL of Paenibacillus sp. JDR-2 (C6CWW0) |
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2.A.28.2.6 | Probable macrolide resistance porter (very similar to the orthologue in B. brevis) (Margolles et al. 2005). |
Bacteria | Actinomycetota | Macrolide resistance protein of Bifidobacterium longum |
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2.A.28.2.7 | Putative Na+ symporter (10 TMSs) |
Archaea | Euryarchaeota | Putative Na+ symporter of Halomicrobium mukohataei (C7NY93) |
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2.A.28.2.8 | Putative integral membrane protein |
Bacteria | Actinomycetota | Putative integral membrane protein of Streptomyces coelicolor |
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2.A.28.2.9 | Sodium bile acid symporter family protein, ASBT, of 307 aas and 10 TMSs. The 3-d structure has been solved (4N7W and 4N7X) (Zhou et al. 2014). This structure has been used to model the yeast Acr3 protein (TC# 2.A.59.1.1) which is in a distinct family of the BART superfamily (Wawrzycka et al. 2016). |
Bacteria | Pseudomonadota | ASBT of Yersinia frederiksenii |
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2.A.28.3.1 | Solute carrier family 10, member 7 protein (358 aas. Present in the plasma membrane with 10 established TMSs with the N- and C-termini in the cytoplasm (Godoy et al. 2007)) (Zou et al., 2005). Slc10a7 KO mice exhibit moderate skeletal dysplasia (osteochondrodyplasia), characterized by markedly shortened and mildly bowed limbs (Brommage et al. 2014). SLC10A7 plays roles in glycosaminoglycan synthesis and skeletal development, and mutants in its gene can cause skeletal dysplasia in mice and humans (Dubail et al. 2018). It plays a role in bone mineralization and transport of glycoproteins to the extracellular matrix (Ashikov et al. 2018). However it has been reported to not show transport activity towards bile acids and steroid sulfates (including taurocholate, cholate, chenodeoxycholate, estrone-3-sulfate, dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate) (Godoy et al. 2007). SLC10A7 regulates O-GalNAc glycosylation and Ca2+ homeostasis in the secretory pathway (Durin et al. 2025). |
Eukaryota | Metazoa, Chordata | SLC10A7 of Homo sapiens |
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2.A.28.3.2 | Putative Na+-dependent transporter | Eukaryota | Viridiplantae, Streptophyta | Putative transporter of Arabidopsis thaliana (Q9LYM5) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.28.3.3 | Putative Na+-dependent transporter |
Bacteria | Pseudomonadota | Putative transporter of Paracoccus denitrificans |
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2.A.28.3.4 | Putative Na+-dependent transporter, YfeH (332 aas; 7-10 TMSs) | Bacteria | Pseudomonadota | YfeH of E. coli (P39836) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.28.3.5 | Putative Na+-dependent transporter (322 aas; 8-10 TMSs) | Bacteria | Lentisphaerota | Transporter of Lentisphaera araneosa (A6DUG7) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.28.3.6 | Fusion Protein of 928aas: N-terminal Cysteine proteinase/Cathepsin F (residues 1-578/Peptidase CIA family) C-terminal BART sugar family domain (579-928). |
Eukaryota | Viridiplantae, Chlorophyta | Protease/transporter fusion protein of Ostreococcus tauri (Q01E11) |
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2.A.28.3.7 | RCh1p transporter (SLC10 family). Regulates cytosolic Ca2+ homeostasis (Jiang et al., 2012). Rch1p is part of the low-affinity calcium uptake system (LACS) system and does not functionally interact with Cch1p (Alber et al. 2013). It regulates O-GalNAc glycosylation as well as Ca2+ homeostasis in the secretory pathway: insights into SLC10A7-CDG (congenital disorders of glycosylation) (Durin et al. 2025). |
Eukaryota | Fungi, Ascomycota | RCh1p of Candida albicans (Q59UQ7) |
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2.A.28.4.1 | Uncharacterized protein of 360 aas with an N-terminal hydrophobic domain of 4 - 5 TMSs homologous to members of this family. The C-terminal hydrophilic domain may be related to TC# 1.C.96, and 1.C.96 may be related to 1.C.5 in the aerolysin superfamily. |
Metazoa, Mollusca | UP of Crassostrea gigas (Pacific oyster) (Crassostrea angulata) |
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2.A.29.1.1 | Mitochondrial ATP/ADP antiporter 2 (SLC25A5; ANT2) of 298 aas and 6 TMSs; it facilitates exchange of ADP and ATP between the cytosol and mitochondrial matrix (inhibited by carboxyatractyloside and bongkrekate) (Clémençon et al. 2013). Modification of lysyl residues with fluorescamine induces Ca2+ permeability (Buelna-Chontal et al. 2014). Ca2+ induces oxidative stress, which increases lipid peroxidation and ROS generation, collapses the transmembrane potential and releases cytochrome c (Correa et al. 2018). Thus, pore opening in the inner mitochondrial membrane results from the binding of Ca2+ to the adenine nucleotide translocase. It is methylated by FAM173A, a mitochondrial lysine-specific methyltransferase that targets ANTs 2 and 3, and affects mitochondrial respiration (Małecki et al. 2019). |
Eukaryota | Metazoa, Chordata | SLC25A5 of Homo sapiens |
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2.A.29.1.10 | Solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 6. It is an ADP/ATP exchanger called ANT3 and is of 298 aas with 6 TMSs (Clémençon et al. 2013). Its activation promotes progression and chemoresistance in multiple myeloma, dependent on PINK1 transport (Hu et al. 2025). |
Eukaryota | Metazoa, Chordata | SLC25A6 of Homo sapiens |
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2.A.29.1.2 | Mitochondrial ADP/ATP carrier 1 (AAC1); ADP/ATP translocase 1; adenine nucleotide translocator 1 (ANT1); adPEO, Sengers syndrome (SLC25A4). Valine 181 is critical for the nucleotide exchange activity (De Marcos Lousa et al. 2005). Mice have three ANTs, and if all three are knocked out, the mitochondrial permeability transition pore (MPTP) can not form, although with only two eliminated, it still can, suggesting the an ANT is an essential constituent of the MPTP (Karch et al. 2019). The MPT provides a mechanism of skeletal muscle atrophy that operates through mROS emission and caspase-3 activation (Burke et al. 2021). Inhibition of carnitine palmitoyltransferase 1A aggravates fatty liver graft injury by promoting the mitochondrial permeability transition (Xue et al. 2021). Upon protein kinase C (PKC) inactivation, the cytoprotective compound, bisindolylpyrrole, can induce prolonged transient MPTP, causing apoptosis in a cyclophilin D (CypD)-dependent manner through the VDAC1/2-regulated ANT-associated pore (Koushi et al. 2020). ANT1 mediates H+ transport, but only in the presence of long-chain fatty acids (FA), as already known for UCPs. It depends on FA chain length and saturation, implying that FA transport is confined to the lipid-protein interface. Purine nucleotides with the preference for ATP and ADP inhibited H+ transport, as do inhibitors of ATP/ADP transport, carboxyatractyloside and bongkrekic acid (Kreiter et al. 2021). Constraints imposed by ANT and cyclophilin D, putative components or regulators of the MPT pore, are associated with the enhanced resistance to Ca2+-induced MPT (Sartori et al. 2022). |
Eukaryota | Metazoa, Chordata | SLC25A4 of Homo sapiens |
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2.A.29.1.3 | Adenine nucleotide transporter, ANT, or ATP:ADP carrier AAC1 (one of three paralogues). Transports heme and heme precursor protoporphyrin IX (PP IX) as well as ATP and ADP (Azuma et al. 2008). |
Eukaryota | Fungi, Ascomycota | AAC1 of Saccharomyces cerevisiae (P04710) |
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2.A.29.1.4 | The Hydrogenosome ADP/ATP carrier (Van der Giezen et al., 2002) | Eukaryota | Fungi, Chytridiomycota | Hydrogenosome ADP/ATP carrier of Neocallimastix frontalis (AAK 71468) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.1.5 | ADP (Km = 40 µM)/ATP (Km = 100 µM) antiporter, ACC1 (three isoforms, AAC1, 2 and 3 were characterized where AAC3 has higher affinities (10-22 µM) (Haferkamp et al., 2002). | Eukaryota | Viridiplantae, Streptophyta | ACC1 of Arabidopsis thaliana (P31167) |
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2.A.29.1.6 | The Endoplasmic Reticular Adenine Nucleotide Transporter, ER-ANT1 (probable ATP:ADP exchanger; Leroch et al., 2008) | Eukaryota | Viridiplantae, Streptophyta | ER-ANT1 of Arabidopsis thaliana (Q0WQJ0) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.1.7 | ADP:ATP carrier 2, Aac2 (Lethal with loss of Sal1, (2.A.29.23.2) but independent of its AAC activity (Kucejova et al., 2008)). The x-ray structure suggests a novel domain-based alternating-access transport mechanism (Ruprecht et al. 2014). |
Eukaryota | Fungi, Ascomycota | Aac2 of Saccharomyces cerevisiae (P18239) |
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2.A.29.1.8 | Mitochondrial ADP/ATP carrier-4, ANT4, of 315 aas and 6 TMSs. It may serve to mediate energy generating and energy consuming processes in the distal flagellum, possibly as a nucleotide shuttle between flagellar glycolysis, protein phosphorylation and mechanisms of motility (Kim et al. 2007). |
Eukaryota | Metazoa, Chordata | SLC25A31 of Homo sapiens |
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2.A.29.1.9 | ADP/ATP carrier #3, AAC3 (90% identical to 2.A.29.1.7) (#2)). Prolines in TMSs 1,3, and 5 are important for function (Babot et al., 2012). The x-ray structure suggests a novel domain-based alternating-access transport mechanism (Ruprecht et al. 2014). Although the transporter catalyzes the translocation of substrate, the substrate also facilitates interconversion between alternating states (Brüschweiler et al. 2015). |
Eukaryota | Fungi, Ascomycota | ADP/ATP exchanger-3 (ACC3) of Saccharomyces cerevisiae (P18238) |
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2.A.29.10.1 | Flavin adenine dinucleotide (FAD) carrier (FADC; FLX1) (catalyzes FAD export from the mitochondrion) (Bafunno et al., 2004) | Eukaryota | Fungi, Ascomycota | FLX1 of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.10.10 |
Mitochondrial NAD /NADP carrier, NDT2; counter exchange substrates include ADP and AMP (Palmieri et al., 2009). |
Eukaryota | Viridiplantae, Streptophyta | NDT2 of Arabidopsis thaliana (Q8RWA5) |
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2.A.29.10.11 |
Chloroplastic (plastidic) NAD/NADP carrier, NDT1; of 312 aas and 6 or 7 TMSs. It catalyzes counter exchange (antiport) of substrates: ADP and AMP (Palmieri et al., 2009). |
Eukaryota | Viridiplantae, Streptophyta | NDT1 of Arabidopsis thaliana (O22261) |
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2.A.29.10.12 | Mitochondrial carrier, AMC1; MC2, (unknown substate) of 360 aas and 6 or 7 TMSs. |
Eukaryota | Apicomplexa | AMC1 of Plasmodium falciparum |
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2.A.29.10.2 | Mitochondrial folate transporter, hMFT | Eukaryota | Metazoa, Chordata | SLC25A32 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.10.3 |
Chloroplast folate/folate derivative transporter, AtFOLT1 (Bedhomme et al., 2005; Haferkamp and Schmitz-Esser 2012) |
Eukaryota | Viridiplantae, Streptophyta | AtFOLT1 of Arabidopsis thaliana (CAH65737) |
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2.A.29.10.4 | Mitochondrial pyrimidine nucleotide transporter, RIM2 (transports TTP (Km= 200 μM), UTP (Km= 400 μM) and CTP (Km= 440 μM). Catalyzes electroneutral TTP/TMP and TTP/TDP antiport. Deoxy pyrimidine nucleotides are also transported) (Marobbio et al., 2006). Pyrimidine trinucleotide transporter, RIM2 (transports TTP, CTP and UTP) (Todisco et al., 2006) | Eukaryota | Fungi, Ascomycota | RIM2 of Saccharomyces cerevisiae (P38127) |
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2.A.29.10.5 | The mitochondrial NAD+ uptake transporter, Ndt1 (also transports (d)AMP and (d)GMP but not α-NAD+, NADH, NADP+, or NADPH. Transport is saturable with an apparent Km of 0.38mM for NAD+). (70% identical to Ndt2 which also takes up NAD+). The main role of Ndt1p and Ndt2p is to import NAD+ into mitochondria by unidirectional transport or by exchange with intramitochondrially generated (d)AMP and (d)GMP (Todisco et al., 2006) | Eukaryota | Fungi, Ascomycota | Ndt1 of Saccharomyces cerevisiae (P40556) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.10.6 | solute carrier family 25 (pyrimidine nucleotide carrier ), member 36 | Eukaryota | Metazoa, Chordata | SLC25A36 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.10.7 | solute carrier family 25 (pyrimidine nucleotide carrier), member 33 | Eukaryota | Metazoa, Chordata | SLC25A33 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.10.8 | Mitochondrial nicotinamide adenine dinucleotide transporter 2, NDT2 (Mitochondrial NAD+ transporter 2) (Todisco et al. 2006). |
Eukaryota | Fungi, Ascomycota | YEA6 of Saccharomyces cerevisiae |
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2.A.29.10.9 | ADP/ATP-specific mitochondrial carrier (MC) in mitosomes (reduced mitochondria incapable of ATP synthesis) (Williams et al., 2008). | Eukaryota | Fungi, Microsporidia | MC in Antonospora locustae (Q4VFZ9) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.11.1 | The Plastid (Amyloplast) ADP-glucose transporter Brittle endosperm 1 (BT1) (Kirchberger et al., 2007). | Eukaryota | Viridiplantae, Streptophyta | BT1 of Zea mays | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.11.2 | The Adenine nucleotide uniporter, BT1 (Leroch et al., 2005). | Eukaryota | Viridiplantae, Streptophyta | BT1 of Solanum tuberosum (Q9ZNY4) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.11.3 | The plastid ADP-glucose transporter, Nst1 (~90% identical to and probably orthologous with 2.A.29.11.1.) (Haferkamp, 2007). | Eukaryota | Viridiplantae, Streptophyta | Nst1 of Hordeum vulgare (Q6E5A5) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.11.4 | Adenine nucleotide (ATP, ADP) carrier, ANT1; BRITTLE-1. Present in both mitochondria and plastids (Haferkamp and Schmitz-Esser 2012). |
Eukaryota | Viridiplantae, Streptophyta | ANT1 of Arabidopsis thaliana |
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2.A.29.11.5 | Hydrogenosome ATP/ADP antiporter, HMP31 (Tjaden et al., 2004) | Eukaryota | Parabasalia | HMP31 of Trichomonas gallinae (AAP30846) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.11.6 | ADP:ATP carrier-2 of 6 TMSs and 401 aas. |
Eukaryota | Parabasalia | Carrier of Trichomonas vaginalis |
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2.A.29.11.7 | Mitochondrial carrier of 304 aas and 6 TMSs. |
Eukaryota | Parabasalia | Carrier of Trichomonas vaginalis |
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2.A.29.11.8 | Putative Thiamine-pyrophosphate (TPP):nucleotide antiporter, TPC or DNG, of 576 aas and 6 TMSs with 1 TMS (N-terminal) + 5 TMSs (residues 380 -576) (Wunderlich 2022). |
Eukaryota | Apicomplexa | TPC of Plasmodium falciparum |
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2.A.29.12.1 | Grave’s disease carrier (GDC) protein. Transports coenzyme A and/or a coenzyme A precursor (Vozza et al. 2016). SLC25A16 is the human orthologue. |
Eukaryota | Metazoa, Chordata | GDC of Bos taurus |
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2.A.29.12.2 | Mitochondrial exchange transporter for Coenzyme A and adenosine 3', 5'-diphosphate, SLC25A42 (also transports dephospho-Coenzyme A, and ADP; Fiermonte et al. 2009). SLC25A42 deficiency leads to a congenital disease with a heterogeneous clinical presentation, including myopathy, developmental delay, lactic acidosis, encephalopathy and other symptoms (Heckmann et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC25A42 of Homo sapiens |
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2.A.29.12.3 | solute carrier family 25; mitochondrial carrier; Graves disease autoantigen, member 16. It is a Coenzyme A transporter (Gutiérrez-Aguilar and Baines 2013). |
Eukaryota | Metazoa, Chordata | SLC25A16 of Homo sapiens |
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2.A.29.12.4 | Mitochondrial Coenzyme A carrier protein, LEU5 or Leu-5 (Gutiérrez-Aguilar and Baines 2013). |
Eukaryota | Fungi, Ascomycota | LEU5 of Saccharomyces cerevisiae |
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2.A.29.12.5 | Coenzyme A transporter of 331 aas (Zallot et al. 2013). |
Eukaryota | Viridiplantae, Streptophyta | Coenzyme A transporter of Arabidopsis thaliana |
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2.A.29.12.6 | Coenzyme A transporter of 325 aas (Zallot et al. 2013). |
Eukaryota | Viridiplantae, Streptophyta | Coenzyme A transporter of Arabidopsis thaliana |
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2.A.29.12.7 | Dephospho-coenzyme A (dPCoA) carrier, dPCoAC, of 365 aas and 6 TMSs. dPCoA is the best substrate, but ADP and dADP are also transported. Coenzyme A is not transported but is a strong competive inhibitor (Vozza et al. 2016). Formerly called "alternative testis transcripts open reading frame A". |
Eukaryota | Metazoa, Arthropoda | dPCoAC of Drosophila melanogaster (Fruit fly) |
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2.A.29.13.1 | Succinate/fumarate antiporter, Sfc1, of 322 aas; essential for growth on ehtanol and acetate (Palmieri et al. 1997; Palmieri et al. 2006). |
Eukaryota | Fungi, Ascomycota | ACR1 of Saccharomyces cerevisiae |
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2.A.29.14.1 | Mitochondrial Ca2+-activated aspartate/glutamate antiporter carrier with Ca2+-binding EF-hand domain, Aralar of 678 aas and possibly 6 TMSs. The microRNAs, miR-302b and miR-372, regulate mitochondrial metabolism via the SLC25A12 transporter, which controls MAVS-mediated antiviral innate immunity (Yasukawa et al. 2020). Thus, miRNAs modulate the innate immune response by altering mitochondrial dynamics and metabolic demand. |
Eukaryota | Metazoa, Chordata | SLC25A12 of Homo sapiens |
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2.A.29.14.10 | Calcium-binding mitochondrial carrier protein Aralar1 of 690 aas. |
Eukaryota | Fungi, Ascomycota | Aralar1 of Verticillium alfalfae (Verticillium wilt of alfalfa) (Verticillium albo-atrum) |
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2.A.29.14.11 | Uncharacterized protein of 1149 aas with 7 N-terminal TMSs; only the N-terminal 360 aas are homologous to other members of the MC family. |
Eukaryota | Oomycota | UP of Aphanomyces invadans |
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2.A.29.14.2 | Mitochondrial Ca2+-activated aspartate/glutamate antiporter carrier with a Ca2+-binding EF-hand domain, Citrin of 675 aas and about 8 TMSs, 2 near the N-terminus and 6 nearer the C-terminus of the rotein. Defects in humans cause type II citrullinemia. Citrin deficiency is a rare metabolic disorder prevalent in East and Southeast Asia that affects liver or neurological function throughout various life stages. Early diagnosis and dietary management can improve prognosis for infant onset disease (Tsai et al. 2024). Patients with a history of cholestasis caused by citrin deficiency during infancy have a greater incidence of ADHD than the general population, suggesting that metabolic disturbances during early childhood in individuals with citrin deficiency may have a long-term negative impact on their neurocognitive function (Tsai et al. 2024). A basic understanding of the etiology of citrin deficiency has been presented (Walker 2024). |
Eukaryota | Metazoa, Chordata | SLC25A13 of Homo sapiens |
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2.A.29.14.3 | Mitochondrial glutamate carrier 1 (GC1); glutamate:H+ symporter 1 (SLC25A22). It plays a role in glucose-stimulated insulin secretion by β-cells (Casimir et al., 2009), and is responsible for migrating partial seizures in neonatal infancy (MPSI), a severe condition with few known etiologies (Poduri et al. 2013). Early infantile epileptic encephalopathy (EIEE) is a heterogeneous group of severe forms of age-related developmental and epileptic encephalopathies with onset during the first weeks or months of life. EIEE type 3 is caused by variants affecting the function of SLC25A22, which is also responsible for epilepsy of infancy with migrating focal seizures (EIMFS). Lemattre et al. 2019 reported a family with a less severe phenotype of EIEE type 3. Functional studies showed that glutamate oxidation was defective. There are three groups according to the severity of the SLC25A22-related disorders. The variants were classified according to the location of the mutation, depending on the protein domain; patients with two variants located in helical transmembrane domains presented a severe phenotype, whereas patients with at least one variant outside helical transmembrane domains presented a milder phenotype. Thus, there seems to be a continuum of disorders related to SLC25A22 (Lemattre et al. 2019). |
Eukaryota | Metazoa, Chordata | SLC25A22 of Homo sapiens |
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2.A.29.14.4 | Yeast mitochondrial aspartate/glutamate antiporter, Agc1 (Cavero et al., 2003) (also catalyzes glutamate uniport and glutamate:proton symport (Palmieri et al. 2006). Comprised of 902 aas; has a 500 residue N-terminal hydrophilic domain as well as a C-terminal 100 residue hydrophilic domain. Both domains are uniquely found in members of the 2.A.29.14 subfamily. |
Eukaryota | Fungi, Ascomycota | Agc1 of Saccharomyces cerevisiae (NP_015346) |
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2.A.29.14.5 | solute carrier family 25 (glutamate carrier), member 18 | Eukaryota | Metazoa, Chordata | SLC25A18 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.14.6 | Solute carrier family 25, member 40, SLC25A40 of 338 aas and 6 TMSs. This mitochondrial inner membrane transporter can be mutated (Y125C) to give hypertriglyceridemia (Rosenthal et al. 2013). It may also be involved in primary Sjögren's syndrome (pSS), a prevalent and disabling form of fatigue (Norheim et al. 2014). SLC25A40 facilitates anticancer drug resistance in human leukemia K562 cells (Kudo et al. 2023). |
Eukaryota | Metazoa, Chordata | SLC25A40 of Homo sapiens |
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2.A.29.14.7 | solute carrier family 25, member 44, SLC25A44 of 314 aas and 6 TMSs in a 3 + 3 arrangement. The GBA-370Rec Parkinson's disease risk haplotype harbors a potentially pathogenic variant in the SLC25A44 mitochondrial gene (Goldstein et al. 2021). |
Eukaryota | Metazoa, Chordata | SLC25A44 of Homo sapiens |
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2.A.29.14.8 | Solute carrier family 25 member 39 | Eukaryota | Metazoa, Chordata | SLC25A39 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.14.9 | MC family homologue of 327 aas and 6 TMSs |
Eukaryota | Viridiplantae, Chlorophyta | MCP homologue of Ostreococcus lucimarinus |
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2.A.29.15.1 | Oxaloacetate/malonate/sulfate/thiosulfate transporter, OAC1 | Eukaryota | Fungi, Ascomycota | Oxaloacetate carrier (OAC1) of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.15.2 | solute carrier family 25, member 35 | Eukaryota | Metazoa, Chordata | SLC25A35 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.15.3 | solute carrier family 25, member 34 | Eukaryota | Metazoa, Chordata | SLC25A34 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.16.1 | Reported to be a deoxynucleotide (enzyme), the deoxynucleotide carrier (DNT) (all four dNDPs and less efficiently, all four dNTPs are transported, but not dNMPs, NMPs or nucleosides). It is also a thiamin pyrophosphate (TPP) transporter responsible for Amish lethal microencephaly brain development retardation (MCPHA) and α-ketoglutarate acidurua when defective (Arco and Satrústegui, 2005; Lindhurst et al., 2006; Iacopetta et al., 2010). SLC25A19 is required for NADH homeostasis and mitochondrial respiration (Jiang 2024). |
Eukaryota | Metazoa, Chordata | SLC25A19 of Homo sapiens |
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2.A.29.16.2 | The thiamin pyrophosphate (TPP) transporter, Tpc1; catalyzes thiamin pyrophosphate/thiamin monophosphate excange (Palmieri et al. 2006). Also transports pyrophosphate, ADP, ATP and other nucleotides (Iacopetta et al., 2010). |
Eukaryota | Metazoa, Arthropoda | Tpc1 of Drosophila melanogaster (Q7K0L7) |
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2.A.29.16.3 | Uncharacterized mitochondrial carrier C1604.04 | Eukaryota | Fungi, Ascomycota | SPBC1604.04 of Schizosaccharomyces pombe | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.17.1 | Peroxisomal ATP/ADP/AMP antiporter, Ant1 (Ypr128cp) (Palmieri et al. 2006). |
Eukaryota | Fungi, Ascomycota | Ant1 of Saccharomyces cerevisiae (AAB68270) |
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2.A.29.18.1 | Mitochondrial S-adenosylmethionine (SAM) carrier, Sam5p or PET8 (Marobbio et al., 2003). Catalyzes the exchange of SAM for S-adenosylhomoserine as well as biotin and lipoate transport (Palmieri et al. 2006). |
Eukaryota | Fungi, Ascomycota | Sam5p of Saccharomyces cerevisiae (P38921) |
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2.A.29.18.2 | The plastid S-Adenosylmethionine importer, SAMT1 (regulates plastid biogenesis and plant development; catalyzes the counter-exchange of SAM with SAM and with S-adenosylhomocysteine) (Bouvier et al., 2006). Also present in the mitochondrion (Haferkamp and Schmitz-Esser 2012). |
Eukaryota | Viridiplantae, Streptophyta | SAMT1 of Arabidopsis thaliana (Q94AG6) |
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2.A.29.18.3 | Solute carrier family 25 (S-adenosylmethionine (SAM) carrier), member 26 of 275 aas and 6 TMSs. It is responsible for the uptake of SAM into mitochondria and when defective by mutation gives rise to combined oxidative phosphorylation deficiency 28 (COXPD28) (Ji et al. 2021).
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Eukaryota | Metazoa, Chordata | SLC25A26 of Homo sapiens |
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2.A.29.18.4 | Uncharacterized protein of 369 aas and 6 TMSs |
Eukaryota | Viridiplantae, Chlorophyta | UP of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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2.A.29.18.5 | Inner membrane mitochondrial magnesium exporter, Mme1 of 347 aas and 6 (- 8?) TMSs. Deletion of MME1 significantly increased steady-state mitochondrial Mg2+ concentrations, while overexpression decreased them. Measurements of Mg2+ exit from proteoliposomes reconstituted with purified Mme1 provided definite evidence that Mme1 is an Mg2+ exporter (Cui et al. 2015). |
Eukaryota | Fungi, Ascomycota | Mme1 of Saccharomyces cerevisiae |
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2.A.29.18.6 | Inner membrane mitochondrial magnesium exporter, Mme1 of 347 aas and 6 (- 8?) TMSs. Deletion of MME1 significantly increased steady-state mitochondrial Mg2+ concentrations, while overexpression decreased them. Measurements of Mg2+ exit from proteoliposomes reconstituted with purified Mme1 provided definite evidence that Mme1 is an Mg2+ exporter (Cui et al. 2015). The G-M-N motif determines ion selectivity, probably together with the negatively charged loop at the entrance of the channel, thereby forming the selectivity filter (Sponder et al. 2013). |
Eukaryota | Fungi, Ascomycota | Mme1 of Saccharomyces cerevisiae |
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2.A.29.18.7 | Putative mitochondrial carrier, MTM1 or MC3 of 380 aas and 6 or 7 TMSs. |
Eukaryota | Apicomplexa | MTM1 of Plasmodium falciparum |
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2.A.29.18.8 | Mitochondrial carrier protein, SamC or PET8, probably takes up S-adenosyl-methionine (SAM) and exports S-adenosyl-homocysteine (SAH) of 256 aas and 6 TMSs. |
Eukaryota | Apicomplexa | SamC of Plasmodium falciparum |
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2.A.29.18.9 | Mitochondrial carrier, MME1 or MC1, (substrate unknown) of 330 aas and 6 TMSs. |
Eukaryota | Apicomplexa | MME1 of Plasmodium falciparum |
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2.A.29.19.1 | Mitochondrial ornithine carrier 2 (ORC2 or OrnT2) (transports ornithine, citrulline, lysine, arginine, histidine); HHH syndrome (SLC25A2). Catalyzes ornithine:citrulline antiport and ornithine:H+ antiport (Tonazzi and Indiveri, 2011). |
Eukaryota | Metazoa, Chordata | SLC25A2 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.19.2 |
Mitochondrial ornithine transporter (ornithine/citrulline exchanger), SLC25A15 or Orc1. Catalyzes a vital step in the urea cycle, interconnecting the cytosolic and mitochondrial components for the cycle (Moraes and Reithmeier 2012). |
Eukaryota | Metazoa, Chordata | SLC25A15 of Homo sapiens |
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2.A.29.2.1 | Oxoglutarate/malate antiporter, OMA, or malate/aspartate shuttle, MAS. Also transports porphyrin derivatives: Fe-protoporphyrin IX, coproporphyrin III, hemin, etc. (Kabe et al., 2006). Plays roles in the malate-aspartate shuttle, (MAS), the oxoglutarate-isocitrate shuttle, OIS, and gluconeogenesis. Functional residues have been identified (Cappello et al. 2007). The MAS plays a pivotal role in transporting cytosolic reducing equivalents - electrons - into the mitochondria for energy conversion at the electron transport chain (ETC) and in the process of oxidative phosphorylation (Koch et al. 2024). Inherited bi-allelic pathogenic variants in five of the seven components of the MAS have been described and cause a wide spectrum of symptoms including early-onset epileptic encephalopathy (Koch et al. 2024). |
Eukaryota | Metazoa, Chordata | Oxoglutarate/malate carrier of Bos taurus |
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2.A.29.2.10 | The dicarboxylate-tricarboxylate carrier (PfDTC) catalyzes oxoglutarate-malate, oxoglutarate-oxaloacetate, or oxoglutarate-oxoglutarate exchange as well as with several di- and tri-carboxylates (Nozawa et al., 2011). |
Eukaryota | Apicomplexa | DTC of Plasmodium falciparum (Q8IB73) |
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2.A.29.2.11 | solute carrier family 25 (mitochondrial carrier; oxoglutarate/malate carrier), member 11 |
Eukaryota | Metazoa, Chordata | SLC25A11 of Homo sapiens (Q9CR62) |
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2.A.29.2.12 | Solute carrier family 25 member 52 (Mitochondrial carrier triple repeat protein 2) | Eukaryota | Metazoa, Chordata | SLC25A52 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.2.13 | Mitochondrial 2-oxoglutarate/malate carrier protein (OGCP) (Solute carrier family 25 member 11) | Eukaryota | Metazoa, Chordata | SLC25A11 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.2.14 | Solute carrier family 25 member 51 (Mitochondrial carrier triple repeat protein 1). This is a transporter for the uptake of NADP+ into mitochondria (Goyal and Cambronne 2023). |
Eukaryota | Metazoa, Chordata | SLC25A51 of Homo sapiens |
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2.A.29.2.15 | Uncharacterized protein of 309 aas and 6 TMSs. |
Eukaryota | Foraminifera | UP of Reticulomyxa filosa |
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2.A.29.2.16 | The mitochondrial dicarboxylate-tricarboxylate carrier protein (DTC) of 298 aas and 6 TMSs (Picault et al. 2002). The ortholog of Gastrodia elata has been cloned, sequenced and partially characterized (Zhao et al. 2023). |
Eukaryota | Viridiplantae, Streptophyta | DTC of Arabidopsis thaliana |
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2.A.29.2.2 | Dicarboxylate (succinate/fumarate/ malate/α-ketoglutarate/ oxaloacetate) antiporter | Eukaryota | Metazoa, Chordata | Dicarboxylate transporter of Rattus norvegicus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.2.3 | Dicarboxylate:Pi antiporter (Pi, malate, succinate, oxaloacetate, sulfate, sulfite) | Eukaryota | Fungi, Ascomycota | Dicarboxylate:Pi antiporter of Saccharomyces cerevisiae | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.2.4 | Mammalian oxodicarboxylate carrier (ODC; SLC25A21; 607571) (transports C5-C7 oxodicarboxylates including 2-oxoadipate and 2-oxoglutarate in an antiport reaction; also transports less well: pimelate, 2-oxopimelate, 2-amino adipate, oxaloacetate, and citrate) (Defects cause 2-oxoadipate acidemia, an inborn error of metabolism) |
Eukaryota | Metazoa, Chordata | SLC25A21 of Homo sapiens |
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2.A.29.2.5 | 2-oxodicarboxylate carrier 2 (ODC2) (transports the same substrates as human ODC except that 2-amino adipate is not transported while malate is) (Palmieri et al. 2006). |
Eukaryota | Fungi, Ascomycota | ODC2 of Saccharomyces cerevisiae (Q99297) |
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2.A.29.2.6 | Plant dicarboxylate/tricarboxylate carrier, DTC, transports dicarboxylates (such as malate, oxaloacetate, oxoglutarate, and maleate) and tricarboxylates (such as citrate, isocitrate, cis-aconitate, and trans-aconitate) | Eukaryota | Viridiplantae, Streptophyta | DTC of Nicotiana tabacum | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.2.7 | Mitochondrial dicarboxylate carrier (DIC; SLC25A10; 606794) transports malate, succinate, phosphate, sulfate, thiosulfate |
Eukaryota | Metazoa, Chordata | SLC25A10 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.2.8 | 2-oxodicarboxylate carrier 1 (ODC1) transports C5-C7 oxodicarboxylic acid (2-oxoadipate, 2-oxoglularate, adipate, glutarate, 2-oxopimelate, oxaloacetate, citrate and malate) (functions by a strict antiport mechanism (Palmieri et al., 2001). | Eukaryota | Fungi, Ascomycota | ODC1 of Saccharomyces cerevisiae (Q03028) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.2.9 | The dicarboxylate carriers, DIC1 (transports malate, oxaloacetate and succinate as well as phosphate, sulfate and thiosulfate at high rates: 2-oxoglutarate is a poor substrate (Palmieri et al., 2007)). |
Eukaryota | Viridiplantae, Streptophyta | DIC1 of Arabidopsis thaliana (Q9SJY5) |
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2.A.29.20.1 | Peroxisomal adenine nucleotide carrier, PMP34 (ANC; SLC25A17). Probably specific for multiple cofactors like coenzyme A (CoA), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN) and nucleotide adenosine monophosphate (AMP), and to a lesser extend for nicotinamide adenine dinucleotide (NAD+), adenosine diphosphate (ADP) and adenosine 3',5'-diphosphate (PAP). May catalyze the transport of free CoA, FAD and NAD+ from the cytosol into the peroxisomal matrix by a counter-exchange mechanism. Inhibited by pyridoxal 5'-phosphate and bathophenanthroline in vitro (Visser et al. 2002; Agrimi et al. 2012). |
Eukaryota | Metazoa, Chordata | SLC25A17 of Homo sapiens |
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2.A.29.20.2 | Peroxisomal adenine nucleotide carrier 2, PNC2. Transports ATP, ADP and NAD+ (Linka and Esser 2012). |
Eukaryota | Viridiplantae, Streptophyta | PNC2 of Arabidopsis thaliana |
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2.A.29.20.3 | Peroxisomal nucleotide (ATP, ADP, AMP) carrier-1, PNC1 (Haferkamp and Schmitz-Esser 2012). |
Eukaryota | Viridiplantae, Streptophyta | PNC1 of Arabidopsis thaliana |
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2.A.29.21.1 | Mitochondrial GTP/GDP exchange carrier (Ggc1) [also transports deoxyGTP and deoxyGDP as well as ITP and IDP but less well than GTP and GDP] [KM(GTP)=1 μM; KM(GDP)=5 μM]. Inhibited by pyridoxal-5-P, bathophenanthroline and tannic acid but not by inhibitors of the ATP-ADP carrier (Vozza et al., 2004). GGC appears to be intrinsically plastic with structural plasticity asymmetrically distributed among the three homologous domains (Sounier et al. 2015). Chaparone proteins TIM8.13 and TIM9.10 bind to Ggc1 to facilitate membrane insertion (Sučec et al. 2020). |
Eukaryota | Fungi, Ascomycota | Ggc1 of Saccharomyces cerevisiae (NP_010083) |
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2.A.29.22.2 | The Mitosome (crypton) ADP/ATP carrier (Chan et al., 2005) |
Eukaryota | Evosea | Mitosome ADP/ATP carrier of Entamoeba histolytica (AAK69775) |
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2.A.29.23.1 | Mitochondrial ATP-Mg2+/inorganic phosphate antiporter [3 isoforms in humans with 3 EF-hand CA2+ binding motifs in their N-terminal domain: Q6KCM7, Q9BV35, and Q6NUK1] (Fiermonte et al., 2004) | Eukaryota | Metazoa, Chordata | SLC25A25 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.23.10 | Hydrogenosome carrier of 262 aas and 6 TMSs. Referred to as AAC3 (Rada et al. 2011). |
Eukaryota | Parabasalia | Carrier of Trichomonas vaginalis |
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2.A.29.23.11 | Mitochondrial carrier, AMC3 or MC6, ATP/ADP antiporter, of 590 aas and 6 TMSs in a 2 + 2 + 2 TMS arrangement. |
Eukaryota | Apicomplexa | AMC3 of Plasmodium falciparum |
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2.A.29.23.2 | Mg2+-ATP/Pi carrier, Sal1 (Ca2+ binding carrier, CMC1; supressor of AAC2 lethality (EF hand Ca2+ binding motif at N-terminus). ADP:ATP carrier 2 (Kucejova et al., 2008; Traba et al., 2008) | Eukaryota | Fungi, Ascomycota | Sal1 of Saccharomyces cerevisiae (P48233) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.23.3 | Chloroplast thylakoid ATP/ADP antiporter, TAAC (Thuswaldner et al., 2007; Haferkamp et al., 2011). Also transports 3'-phosphoadenosine 5'-phosphosulfate (PAPS), made in the mitochondria and exported to the cytoplasm where it is involved in several aspects of sulfur metabolism, including the biosynthesis of thiols, glucosinolates, and phytosulfokines, and therefore also named PAPST1 (Gigolashvili et al. 2012). Expression of the PAPST1 gene is regulated by the same MYB transcription factors that also regulate the biosynthesis of sulfated secondary metabolites, glucosinolates. |
Eukaryota | Viridiplantae, Streptophyta | TAAC of Arabidopsis thaliana (Q9M024) |
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2.A.29.23.4 | The mitochondrial adenine nucleotide transporter, ADNT1 (At4g01100) (prefers AMP and ADP to ATP; not inhibited by bongkrekate or carboxyatractyloside; loss yields reduced root growth and respiration) (Palmieri et al., 2008b). | Eukaryota | Viridiplantae, Streptophyta | ADNT1 of Arabidopsis thaliana (O04619) |
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2.A.29.23.5 | Solute carrier family 25 (mitochondrial carrier; ATP-M2+/phosphate carrier), member 23 of 468 aas and 6 TMSs, SLC25A23, APC2, MCSC2, SCaMC-3. Variants are generated by alternative splicing (Del Arco 2005; Bassi et al. 2005). Glucagon regulation of oxidative phosphorylatioin requires an increase in matrix adenine nucleotides involving SCaMC-3 (Amigo et al. 2013). SLC25A23 augments mitochondrial Ca2+ uptake, interacts with MCU, and induces oxidative stress-mediated cell death (Hoffman et al. 2014). It also counteracts the PARP-1-dependent fall in mitochondrial ATP caused by excitotoxic insults in neurons (Rueda et al. 2015). CaMCs play a role in glutamate excitotoxicity and Ca2+ regulation of respiration (Rueda et al. 2016). |
Eukaryota | Metazoa, Chordata | SLC25A23 of Homo sapiens |
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2.A.29.23.6 | solute carrier family 25, member 41 | Eukaryota | Metazoa, Chordata | SLC25A41 of Homo sapiens | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.23.7 | solute carrier family 25, member 43. May play a role in Paget's bone disease (Gutiérrez-Aguilar and Baines 2013). Also regulates cell cycle progression and proliferation through a putative mitochondrial checkpoint (Gabrielson et al. 2015). |
Eukaryota | Metazoa, Chordata | SLC25A43 of Homo sapiens |
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2.A.29.23.8 | Calcium-binding mitochondrial carrier protein SCaMC-1 (Mitochondrial ATP-Mg/Pi carrier protein 1; Mitochondrial Ca2+-dependent solute carrier protein 1; Small calcium-binding mitochondrial carrier protein 1; Solute carrier family 25 member 24). The crystal structure of the N-terminal Ca2+-binding domain has been determined and shown to undergo a large conformational change when Ca2+ binds (Yang et al. 2014). Fontaine progeroid syndrome (FPS, OMIM 612289) is a genetic disorder stemming from pathogenic variants in the SLC25A24 gene. It encompasses Gorlin-Chaudry-Moss syndrome and Fontaine-Farriaux syndrome (Pannier et al. 2024). |
Eukaryota | Metazoa, Chordata | SLC25A24 of Homo sapiens |
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2.A.29.23.9 | Mitochondrial transporter for 3′-phospho-adenosine 5′-phosphosulfate and adenosine 5′-phosphosulfate (APS), YPR011c. Sulfate and phosphate are also transported using an antiport mechanism (Todisco et al. 2014). Inhibited by bongkrekic acid. Deletion mutants are thermal sensitive and have less methionine and glutathione. The gene is induced by thermal stress conditions (Todisco et al. 2014). |
Eukaryota | Fungi, Ascomycota | YPR011c of Saccharomyces cerevisiae |
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2.A.29.24.1 | Brain mitochondrial carrier protein 1, BMCP1 (participates in mitochondrial proton leak) (also called uncoupling protein-5 (UCP5)) (Sanchis et al., 1998). Transports protons and chloride ions; activated by fatty acids and inhibited by purine nucleotides similarly to UCP1-3 (Hoang et al. 2012); H+ transport may be activated while Cl- transport may be inhibited by faty acids (Hoang et al. 2015). Unc5 also transports sulfur anions (sulfate, sulfite, thiosulfate), inorganic phosphate, dicarboxylates (malonate, malate, citamalate, aspartate, gultamate) and tricarboxylates (Gorgoglione et al. 2019). It catalyzes fast anion:anion exchange and slow uniport. Sulfate and thiosulfate are the most high affinity substrates (Gorgoglione et al. 2019). |
Eukaryota | Metazoa, Chordata | SLC25A14 of Homo sapiens |
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2.A.29.24.2 | Kidney mitochondrial carrier protein, KMCP1 (Haguenauer et al., 2005). The expression patterns and functions of different UCP homologs have been reviewed (Monteiro et al. 2021). |
Eukaryota | Metazoa, Chordata | KMCP1 of Mus musculus (NP_080508) |
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2.A.29.24.3 |
solute carrier family 25, member 27; UCP4. Transports protons and chloride ions; activated by fatty acids and inhibited by purine nucleotides similarly to UCP1-3 (Hoang et al. 2012). H+ transport may be activated while Cl- transport may be inhibited by fatty acids (Hoang et al. 2015). MFN2 deficiency affects calcium homeostasis in lung adenocarcinoma cells via downregulation of UCP4 (Zhang et al. 2023). |
Eukaryota | Metazoa, Chordata | SLC25A27 of Homo sapiens |
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2.A.29.24.4 |
solute carrier family 25, member 30; Kidney MCP1, KMCP1 or UCP6 (uncoupling protein 6). It also transports sulfur anions (sulfate, sulfite, thiosulfate), inorganic phosphate and dicarboxylates (malonate, malate, citamalate, aspartate) (Gorgoglione et al. 2019). It catalyzes fast anion:anion exchange and slow uniport. Sulfate and thiosulfate are the most high affinity substrates (Gorgoglione et al. 2019). |
Eukaryota | Metazoa, Chordata | SLC25A30 of Homo sapiens |
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2.A.29.25.1 | The mitochondrial presenilin-associated protein (PSAP; MTCH1) binds to the PDZ domain (a QFYI motif) C-terminus of presenilin. It contains 2 solcar repeats and is 389 aas long. It is most similar to 2.A.29.23.1 and 2.A.29.12.1. There are 2 human isoforms, mitochondrial carrier homologues, MTCH1 and MTCH2, possibly involved in apoptosis (Xu et al., 1999, 2002). Its transport function is unknown (Xu et al., 1999, 2002). Surprisingly, this protein has been reported to be targetted to the outer mitochonrdial membrane (Gutiérrez-Aguilar and Baines 2013). Two proapoptotic PSAP isoforms generated by alternative splicing differ in the length of a hydrophilic loop located between two predicted transmembrane domains. Both isoforms are expressed in human and rat tissues. PSAP probably contains multiple mitochondrial targeting motifs dispersed along the protein (Lamarca et al. 2007). |
Eukaryota | Metazoa, Chordata | MTCH1 of Homo sapiens (Q9NZJ7) |
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2.A.29.25.2 | The mitochondrial carrier homologue-2 (MTCH2). Binds the BH3-interacting domain death agonist, BID. Regulated (induced) by the hepatocyte growth factor receptor, HGF/SF or Met. It has been proposed that its transport function has been lost (Robinson et al., 2012). Surprisingly, this protein has been reported to be targetted to the outer mitochondrial membrane (Gutiérrez-Aguilar and Baines, 2013). MTCH2 is a mitochondrial outer membrane protein insertase (Guna et al. 2022). It is required for insertion of biophysically diverse tail-anchored (TA), signal-anchored, and multipass proteins, but not outer membrane beta-barrel proteins. Scramblases play a pivotal role in facilitating bidirectional lipid transport across cell membranes, thereby influencing lipid metabolism, membrane homeostasis, and cellular signaling (Bartoš et al. 2024). MTCH2, an insertase, has a membrane-spanning hydrophilic groove resembling those that form the lipid transit pathway in known scramblases. Bartoš et al. 2024 showed that MTCH2 reduces the free energy barrier for lipid movement along the groove and therefore can function as a scramblase. The scrambling rate of MTCH2 in silico is similar to that of voltage-dependent anion channel (VDAC), a recently discovered scramblase of the outer mitochondrial membrane, suggesting a potential complementary physiological role for these mitochondrial proteins. Other insertases which possess a hydrophilic path across the membrane like MTCH2, can also function as scramblases (Bartoš et al. 2024). |
Eukaryota | Metazoa, Chordata | MTCH2 of Homo sapiens (Q9Y6C9) |
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2.A.29.26.1 | Viral mitochondrial carrier-like protein, L276 (VMC) for dATP and dTTP (237 aas) (Monné et al., 2007). |
Viruses | Bamfordvirae, Nucleocytoviricota | VMC of Mimiviridae mimivirus (Q5UPV8) |
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2.A.29.27.1 | The ATP exchanger/symporter, LcnP (secreted via the bacterial Dot/Icm type IV secretion system into macrophages, and assembled in the mitochondrial inner membrane (Dolezal et al., 2012)). |
Bacteria | Pseudomonadota | LcnP of Legionella pneumophila (Q5WSP6) |
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2.A.29.28.1 | The thiamin pyrophosphate (TPP) carrier, TPC1 (Marobbio et al., 2002). | Eukaryota | Fungi, Ascomycota | TPC1 of Saccharomyces cerevisiae (NP_011610) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.28.2 | Uncharacterized protein of 326 as and 6 TMSs. |
Eukaryota | Fungi, Ascomycota | UP of Kazachstania naganishii |
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2.A.29.29.1 | The citrate/oxoglutarate carrier, Yhm2 (Castegna et al., 2010; Mayor et al., 1997). Ymh2 also transports oxaloacetate, succinate, and fumarate, but not malate or isocitrate. It may function in antioxidation (Castegna et al., 2010). |
Eukaryota | Fungi, Ascomycota | Yhm2 of Saccharomyces cerevisiae (Q04013) |
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2.A.29.3.1 | Uncoupling protein (H+; halide anions; protonated or anionic fatty acids) | Eukaryota | Metazoa, Chordata | Uncoupling carrier of Bos taurus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2.A.29.3.2 |
Mitochondrial brown fat uncoupling protein 1 (UCP1 or UCP-1) is also called thermogenin and obesity protein (SLC25A7). It mediates adaptive thermogenesis (Azzu and Brand, 2009). It transports protons and chloride ions and is activated by fatty acids while being inhibited by purine nucleotides (Hoang et al. 2012). It functions as a long-chain fatty acid (LCFA) anion/H+ symporter, but the LCFA anion can not dissociate due to hydrophobic interactions, so it is, in effect, an H+ carrier (Fedorenko et al. 2012). Thermogenic Brown adipose tissue cells with increased UCP1 activity also have increased ATP sythase activity to allow maintenance of normal ATP levels (Guillen et al. 2013). Zhao et al. 2017 showed that fatty acids (FA) can directly bind UCP1 at a helix-helix interface site composed of residues from TMSs H1 and H6. The FA acyl chain appears to fit into the groove between H1 and H6 while the FA carboxylate group interacts with the basic residues near the matrix side of UCP1 (Zhao et al. 2017). UCP1 mediates liver injury in mice and humans by modulating mitochondrial ATP production and cell apoptosis via the ERK signaling pathway (Liu et al. 2017). Activation is achieved by retinoids of UCP1 (Tomás et al. 2004). Expression of its structural gene is influenced by emodin (Cheng et al. 2021). Repeated oral administration of flavan-3-ols induces browning in mice adipose tissues through sympathetic nerve activation, and this involves increased synthesis of UCP-1, CD137 (TC# 9.B.87.4.2) and TMEM26 (TC# 9.B.422.1.1) (Ishii et al. 2021). UCP1 has been described in detail as a sophisticated energy valve involving loose and tight conformations and H+ transport (Klingenberg 2017). H+ transport is electrophoretic and depends on fatty acids. By alternating opening of the gates, the fatty acid takes H+ from cytosol and release it to the matrix (Klingenberg 2017). ucp1, and ucp3, biomarkers for cardiac damage, were significantly upregulated by Tl+ in Danio rerio. (Chang et al. 2023). The cryo-EM structure of the GTP-inhibited state of UCP1, like its nonconducting state, has been solved (Jones et al. 2023). The purine nucleotide cross-links the transmembrane helices of UCP1 with an extensive interaction network, providing a structural basis for understanding the specificity and pH dependency of this regulatory mechanism. The analyses indicate that inhibitor binding prevents the conformational changes that UCP1 uses to facilitate proton leak (Jones et al. 2023). As noted above, UCP1 conducts protons through the inner mitochondrial membrane to uncouple mitochondrial respiration from ATP production, thereby converting the electrochemical gradient of protons into heat. UCP1 is activated by endogenous fatty acids and synthetic small molecules, such as 2,4-dinitrophenol (DNP), and is inhibited by purine nucleotides, such as ATP. Kang and Chen 2023 presented the structures of human UCP1 in the nucleotide-free state, the DNP-bound state and the ATP- bound state. The structures show that the central cavity of UCP1 is open to the cytosolic side. DNP binds inside the cavity, making contact with TMS2 and TM6. ATP binds in the same cavity and induces conformational changes in TMS2, together with the inward bending of TMSs 1, 4, 5 and 6 of UCP1, resulting in a more compact structure of UCP1. The binding site of ATP overlaps that of DNP, suggesting that ATP competitively blocks the functional engagement of DNP, resulting in the inhibition of the proton-conducting activity of UCP1 (Kang and Chen 2023). Mitochondrial H+ leak and thermogenesis involves the function and regulation of uncoupling protein 1 and the ADP/ATP carrier, the two proteins that mediate mitochondrial H+ leak. (Bertholet and Kirichok 2022). Polyphenol compound 18a modulates UCP1-dependent thermogenesis to counteract obesity (Wen et al. 2024). Ibuprofen induced UCP1 activity in liposomes, isolated brown fat mitochondria and UCP1-expressing HEK293 cells (Cavalieri et al. 2022). |
Eukaryota | Metazoa, Chordata | UCP1 of Homo sapiens |
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2.A.29.3.3 |
The uncoupling protein, UCP1 or PUMP1 (functions to relieve oxidative stress, and to allow efficient photosynthesis (Sweetlove et al., 2006). In some plants, it is activated in response to cold stress and may control reactive oxygen species (Valente et al. 2012). In addition to protons, it transports a variety of anions including aspartate, glutamate, cysteine sulfinate, cysteate, dicarboxylates (malate, oxaloacetate, oxaloglutarate), phosphate, sulfate and thiosulfate. It functions preferentially as an anion exchanger, but more slowly as an anion uniporter. A primary function may be aspartate/glutamate antiport, thereby contributing to the export of reducing equivalents from the mitochondria in photorespiration. (Monné et al. 2018). |
Eukaryota | Viridiplantae, Streptophyta | UCP1 of Arabidopsis thaliana |
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2.A.29.3.4 |
Human UCP2; implicated in a variety of physiological and pathological processes including protection from oxidative stress, negative regulation of glucose sensing systems and the adapta |