TCID | Description | Domain | Kingdom/Phylum | Example |
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1.A.1.1.1 | 2 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). |
Bacteria | Actinobacteria | Skc1 (KcsA) of Streptomyces lividans |
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). |
Eukaryota | Metazoa | Voltage-sensitive Na+ channel of Rattus norvegicus |
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 | Na+ channel of Blattella germanica (O01307) |
1.A.1.10.11 | Sodium channel of 2215 aas, 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 | VmNa of Varroa destructor |
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). |
Eukaryota | Metazoa | SCN2A of Homo sapiens |
1.A.1.10.13 | Voltage-sensitive Na+ channel of 2821 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). |
Eukaryota | Metazoa | Na+ channel of Drosophila melanogaster |
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 | CAV2 of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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). |
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). |
Eukaryota | Metazoa | Na+ channel of Aedes aegypti (Yellowfever mosquito) (Culex aegypti), the most prevalent vector of dengue and yellow fever viruses. |
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 | PARA sodium channel of Anopheles gambiae (African malaria mosquito) |
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 | FPC1 of Periplaneta americana (American cockroach) (Blatta americana) |
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 | Nav1.4-beta subunits of Electrophorus electricus (Electric eel) (Gymnotus electricus) |
1.A.1.10.2 | Na+ channel, α-subunit, SCAP1 | Eukaryota | Metazoa | SCAP1 from Aplysia californica (P90670) |
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 | PaFPC1 of Periplaneta americana (American cockroach) (Blatta americana) |
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 | NaV of Myzus persicae. |
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).
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Eukaryota | Metazoa | Nav1.5 of Homo sapiens (Q14524) |
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).
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Eukaryota | Metazoa | NaV1.4 of Homo sapiens (P35499) |
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). |
Eukaryota | Metazoa | Nav1.7 of Homo sapiens (Q15858) |
1.A.1.10.6 | Tetrodotoxin-resistant voltage-gated Na+ channel of dorsal ganglion sensory neurons, Nav1.8 (Akopian et al., 1996). 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). |
Eukaryota | Metazoa | Nav1.8 of Rattus norvegicus |
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; Martinez-Moreno et al. 2020). |
Eukaryota | Metazoa | Nav1.1 of Homo sapiens (P35498) |
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). |
Eukaryota | Metazoa | Nav1.6 of Homo sapiens (Q9UQD0) |
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). .
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Eukaryota | Metazoa | Nav1.9 of Homo sapiens (Q9UI33) |
1.A.1.11.1 | Voltage-sensitive Ca2+ channel (transports Ca2+, Ba2+ and Sr2+) | Eukaryota | Metazoa | 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 | Cch1/Mid1 of Saccharomyces cerevisiae |
1.A.1.11.11 | The Cav1.4 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). |
Eukaryota | Metazoa | Cav1.4 of Homo sapiens |
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).
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Eukaryota | Metazoa | Cav3.1d of Mus musculus (Q9WUT2) |
1.A.1.11.13 | Two-pore Ca2+ channel protein 1, TPC1 (Km(Ca2+))=50 µM; voltage gated; 461 aas; 6TMSs) (Hashimoto et al., 2004; Kurusu et al, 2004; 2005) | Eukaryota | Viridiplantae | TPC1 of Oryza sativa (Q5QM84) |
1.A.1.11.14 | Voltage-dependent calcium channel, α-1 subunit (1911aas), CyCaα1 | Eukaryota | Metazoa | 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 | NALCN of Homo sapiens (Q6P2S6) |
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 | 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 | Cch1/Mid1 of Cryptococcus neoformans |
1.A.1.11.18 | The nicotinic acid adenine dinucleotide phosphate (NAADP)- dependent two pore Ca2+- channel, TPC3 (Brailoiu et al., 2010). |
Eukaryota | Metazoa | Two pore Ca2+ channel 3, TPC3 of Bos taurus (C4IXV8) |
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). |
Eukaryota | Metazoa | TPC2 of Homo sapiens (Q8NHX9) |
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 | DHPR of Oryctolagus cuniculus |
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 | Eg1-19 of Caenorhabditis elegans (A8PYS5) |
1.A.1.11.21 | Voltage-gated Ca2+ channel, Egl-19, isoform a |
Eukaryota | Metazoa | Egl-19 of C. elegans (G5EG02) |
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 | Tpcn1 of Mus musculus |
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 | Mid1 of Schizosaccharomyces pombe |
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 |
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). |
Eukaryota | Metazoa | TPC1 of Homo sapiens |
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). |
Eukaryota | Viridiplantae | TPC1 of Arabidopsis thaliana |
1.A.1.11.27 | Voltage-dependent P/Q-type Ca2+ channel subunit α1A, CACNA1A (CACH4; CACN3; CACNL1A4) of 2,505 aas. 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 encephalopathu 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). |
Eukaryota | Metazoa | CACNA1A Ca2+ channel of Homo sapiens |
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 | VDCC of Caenorhabditis elegans |
1.A.1.11.29 | Voltage-gated calcium channel (VDCC) of 3097 aas and 24 TMSs, Cav7 (Wheeler and Brownlee 2008). |
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). |
Eukaryota | Metazoa | R-type Ca2+ channel of Mus musculus |
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). |
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). |
Bacteria | Proteobacteria | CAv1.3 of Homo sapiens |
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). |
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). |
Eukaryota | Kinetoplastida | Ca2+ channel of Leishmania donovani |
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 | Longamoebia | Calcium channel of Acanthamoeba castellanii |
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 | Kinetoplastida | Ca2+ channel of Trypanosoma cruzi |
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). |
Eukaryota | Metazoa | CACNA1C of Homo sapiens (2221 aas; Q13936) |
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). |
Eukaryota | Metazoa | CACNA1H of Homo sapiens (2353 aas; Q95180) |
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). |
Eukaryota | Metazoa | α-Cav1.2 of Mus muscultus (2139 aas; Q01815) |
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).
|
Eukaryota | Metazoa | Ca2+ channel CRA_c of Homo sapiens (Q9P0X4) |
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). |
Eukaryota | Metazoa | Cav2.1 of Rattus norvegicus (P54282) |
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). |
Eukaryota | Metazoa | Cav2.2 of Mus musculus (O55017) |
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 | Phycodnaviridae | Kcv1 K+ channel of Chlorella virus PBCV-1 |
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 | Phycodnaviridae | ATCV1 (KCVS/KCVNTS) of Acanthocystis turfacea chlorella virus (A7K9J5) |
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). |
Viruses | Phycodnaviridae | Kesv of Ectocarpus siliculosus virus 1 (Q8QN67) |
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 | Phycodnaviridae | Kcv of Paramecium bursaria Chlorella virus |
1.A.1.12.5 | Potassium ion channel protein of 86 aas and 2 TMSs (Greiner et al. 2018). |
Viruses | Phycodnaviridae | K+ channel protein of Micromonas pusilla virus SP1 |
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 |
|
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 | Proteobacteria | Kch of E. coli |
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) |
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) |
1.A.1.13.3 | Divalent cation (Ca2+, Mg2+, Mn2+, Ni2+)-activated K+ channel, TuoK (contains a RCK domain) (Parfenova et al., 2007) | Archaea | Euryarchaeota | 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 | Firmicutes | BikC of Bacillus subtilis (Q795M8) |
1.A.1.13.5 | Putative 2 TMS ion channel protein (N-terminus) with C-terminal TrkA_N (NADB Rossman) domain. |
Bacteria | Actinobacteria | Ion channel protein of Streptomyces coelicolor |
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 | Cyanobacteria | K+ channel of Synechocystis PCC6803 |
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 | Cyanobacteria | K+ channel of Synechocystis PCC6803 |
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) |
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 | Proteobacteria | KchA of Helicobacter pylori |
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. |
Bacteria | Firmicutes | NaChBac of Bacillus halodurans |
1.A.1.14.2 | Voltage-gated Na+ channel, NavPZ (Koishi et al., 2004) | Bacteria | Proteobacteria | 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 | Firmicutes | 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 | Proteobacteria | VGSC of Silicibacter pomeroyi (56676695) |
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 | Proteobacteria | NavCh of Arcobacter butzleri (A8EVM5) |
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 | Proteobacteria | Nav of Magnetococcus marinus (also called sp. strain MC-1) |
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 | Firmicutes | Nav of Caldalkalibacillus thermarum |
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). |
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 |
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). |
Eukaryota | Metazoa | KCNQ1 K+ channel of Mus musculus |
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). |
Eukaryota | Metazoa | KCNQ2 K+ channel of Homo sapiens (O43526) |
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 | KCNQ3 K+ channel of Homo sapiens (O43525) |
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). |
Eukaryota | Metazoa | KCNQ4 K+ channel of Homo sapiens |
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. |
Eukaryota | Metazoa | KCNQ5 of Mus musculus |
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 acylposition 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). Activated KCNQ1 channel promotes fibrogenic response in hereditary gingival fibromatosis via clustering and activation of Ras (Gao et al. 2020). |
Eukaryota | Metazoa | KCNQ1 of Homo sapiens (P51787) |
1.A.1.15.7 | Ion channel transporter of 296 aas and 5 putative TMSs. |
Bacteria | Terrabacteria group | Ion channel of Mycoplasma sp. Pen4
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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). |
Eukaryota | Metazoa | SkCa2 of Homo sapiens |
1.A.1.16.2 | The intermediate conductance, Ca2+-activated K+ channel, Kcnn4, SK4, Sk4, Smik, Ik1 hIK1, IKCa or KCa3.1, also called the Gardos channel (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). 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). 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 may be present in mitochondria (Parrasia et al. 2019). |
Eukaryota | Metazoa | hIK1 of Homo sapiens (AAC23541) |
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). |
Eukaryota | Metazoa | SK of Drosophila melanogaster (Q7KVW5) |
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 | KCNL-2 of Caenorhabditis elegans |
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 | TSKCa of Psetta maxima (Turbot) (Pleuronectes maximus) |
1.A.1.16.6 | Small conductance calcium-activated K+ channel of 543 aas. KCNN1 or SK |
Eukaryota | Metazoa | SK of Homo sapiens |
1.A.1.16.7 | Small conductance calcium-activated potassium channel protein 3 of 736 aas and 6 TMSs, SK3 or KCNN3. |
Eukaryota | Metazoa | KCNN3 of Homo sapiens |
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. |
Archaea | Crenarchaeota | KvAP of Aeropyrum pernix (Q9YDF8) |
1.A.1.17.2 | Voltage-gated K+ channel, Kv (Santos et al., 2008). | Bacteria | Firmicutes | Kv of Listeria monocytogenes (Q8Y5K1) |
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). |
Eukaryota | Metazoa | TRESK-1 of Mus musculus (AAQ91836) |
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). |
Eukaryota | Metazoa | TRASK-2 of Homo sapiens |
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). |
Eukaryota | Metazoa | CatSper of Homo sapiens |
1.A.1.19.2 | Sperm-associated cation channel, CatSper2 (6 TMS Ca2+ channel) | Eukaryota | Metazoa | CatSper2 of Homo sapiens (26051223) |
1.A.1.19.3 |
Alkalinization-activated Ca2+-selective channel, 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 | CatSper of Mus musculus |
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 | Shab11 of Drosophila melanogaster |
1.A.1.2.10 | Voltage-gated K+ channel, chain A, Shaker-related, Kv1.2 (Crystal structure known, Long et al., 2007; Chen et al. 2010). 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). |
Eukaryota | Metazoa | Kv1.2 of Homo sapiens (P16389) |
1.A.1.2.11 | Voltage-gated K+ channel, Shab-related, Kv2.1 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. |
Eukaryota | Metazoa | Kv2.1/Kv2.2 of Homo sapiens |
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, per cent 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). .
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Eukaryota | Metazoa | Kv1.1 of Homo sapiens (Q09470) |
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). |
Eukaryota | Metazoa | Kv3.3 of Homo sapiens (Q14003) |
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 | Kv1 of Octopus vulgaris (H2EZS9) |
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 | 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 | 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 retentio (Ottschytsch et al. 2005). |
Eukaryota | Metazoa | Kcng3 or Kv10.1of Rattus norvegicus |
1.A.1.2.18 | Potassium voltage-gated channel subfamily F member 1 (Voltage-gated potassium channel subunit Kv5.1) (kH1) | Eukaryota | Metazoa | 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). |
Eukaryota | Metazoa | KCND3 of Homo sapiens |
1.A.1.2.2 | Voltage-sensitive K+ channel |
Eukaryota | Metazoa | Shaw2 of Drosophila melanogaster |
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. Has an important 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 | Shk-1 of Caenorhabditis elegans |
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 | Shal of Caenorhabditis elegans |
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 | jShak1 of Polyorchis penicillatus (Hydromedusa; jellyfish) |
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 | KCNC2 of Homo sapiens |
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).
|
Eukaryota | Metazoa | KCNC1 of Homo sapiens |
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 | Kv2.2 of Homo sapiens |
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 | KCNG4 of Homo sapiens |
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). |
Eukaryota | Metazoa | KCNG1 of Homo sapiens |
1.A.1.2.28 | Potassium voltage-gated channel subfamily D member 1, Kv4.1 of 647 aas and 6 TMSs. 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 must include the intracellular T1-T1 tetramerization domains interface (Wang and Covarrubias 2006).
|
Eukaryota | Metazoa | Kv4.1 of Homo sapiens |
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). |
Eukaryota | Metazoa | Kv1.6 of Homo sapiens |
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 | Shal2 of Drosophila melanogaster |
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 | Haloplasmatales | K+ channel of Haloplasma contractile |
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 involved in the blocking effect of the antidepressant, metergoline, on C-type inactivation has been reported (Bai et al. 2018). 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 | KCNA4 of Homo sapiens |
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). |
Eukaryota | Metazoa | Kv1.3 homomers and Kv1.3/Kv1.5 heteromers of Homo sapiens (P22001) |
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), and (2) cytoplasmic Ca2+ binding proteins known as K+ channel interacting proteins (KChIPs; TC#5.B.1.1.7; 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 small ubiquitin-like modifier) two distinct sites on Kv4.2, increases surface expression and decreases current amplitude (Welch et al. 2019). |
Eukaryota | Metazoa | Kv4.2 of Homo sapiens (Q9NZV8) |
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. |
Eukaryota | Metazoa | Shaker of Drosophila melanogaster (CAA29917) |
1.A.1.2.7 | Electrically silent lens epithelium K+ channel (Delayed rectifier K+ channel α-subunit, Kv9.1 (Shepard & Rae, 1999)) |
Eukaryota | Metazoa | Kv9.1 of Homo sapiens |
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 | KVS-1 (α)/ MPS-1 (MiRPβ) of Caenorhabditis elegans |
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 | Kv2.3r of Rattus norvegicus (P97557) |
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). |
Eukaryota | Metazoa | H-ERG of Homo sapiens (Q12809) |
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). |
Eukaryota | Metazoa | Erg2 of Rattus norvegicus |
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 | Erg3 of Rattus norvegicus |
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). |
Eukaryota | Metazoa | EAG1 of Rattus norvegicus (Q63472) |
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). |
Eukaryota | Metazoa | KCNH3 of Homo sapiens |
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 | Eag of Drosophila melanogaster |
1.A.1.20.7 | Cyclic nucleotide-gated K+ channel, CNGC or CNG1 of 894 aas and 6 TMSs (Wheeler and Brownlee 2008). |
CNG1 of Chlamydomonas reinhardtii |
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1.A.1.20.8 | Aureochrome 1-like protein of 370 aas and a probable C-terminal 2 TMS ion channel domain. |
Eukaryota | Raphidophyceae | Aureochrome 1 of Chattonella antiqua |
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 | Eag2 of Homo sapiens |
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 | Firmicutes | NaK channel of Bacillus cereus (2AHYB) (Q81HW2) |
1.A.1.21.2 | Two pore domain potassium channel family protein of 122 aas and 2 TMSs. |
Bacteria | Chloroflexi | K+ channel of Anaerolineales bacterium |
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 |
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 | Proteobacteria | 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 | SYM8 of Pisum sativum |
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 | CASTOR of Lotus japonicus (Q5H8A6) |
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 | POLLUX of Lotus japonicus (Q5H8A5) |
1.A.1.23.4 | putative ion channel (N-terminal domain) protein with C-terminal TrkA-N domain (DUF1012); NAD-binding lipoprotein. |
Bacteria | Actinobacteria | Ion channel protein of Streptomyces coelicolor |
1.A.1.24.1 | The cyclic nucleotide regulated K+ channel, CNR-K+ channel (412 aas) | Bacteria | Proteobacteria | CNR-K+ channel of Rhodopseudomonas palustris (Q02006) |
1.A.1.24.2 | K+ channel protein homologue |
Bacteria | Proteobacteria | K+ channels protein homologue of Stigmatella aurantiaca (Q08U57) |
1.A.1.24.3 | Putative 6 TMS potassium channel |
Bacteria | Proteobacteria | Potassium ion channel of Myxococcus xanthus |
1.A.1.24.4 | Putative K+ channel |
Bacteria | Cyanobacteria | K channel of Cyanotheca (Synechococcus) sp PCC8801 |
1.A.1.24.5 | Cyclic nucleotide-gated K+ channel of 459 aas. |
Bacteria | Proteobacteria | Channel of Labenzia aggregata |
1.A.1.24.6 | Uncharacterized ion channel protein of 276 aas and 6 TMSs |
Bacteria | Bacteroidetes | UP of Flavobacterium psychrolimnae |
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 | Proteobacteria | MlotiK1 of Mesorhizobium loti (Q98GN8) |
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.1.27.1 | Putative 4 TMS ion channel protein. TMSs 1-2 may not be homologous to TMSs 3-4 which probably form the channel. |
Bacteria | Actinobacteria | Hypothetic VIC family member of Streptomyces coelicolor |
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 | Actinobacteria | Putative ion channel of Streptomyces coelicolor |
1.A.1.27.3 | Uncharacterized protein of 114 aas |
Bacteria | Proteobacteria | UP of Rhizobium meliloti |
1.A.1.27.4 | Uncharacterized protein of 148 aas and 3 or 4 TMSs |
Bacteria | Proteobacteria | UP of Marinobacter hydrocarbonoclasticus |
1.A.1.28.1 | Putative K+ channel |
Bacteria | Proteobacteria | Putative K+ channel of Klebsiella varicola (D3RJS6) |
1.A.1.28.2 | Putative K+ channel |
Bacteria | Proteobacteria | Putative K+ channel of Pseudomonas fluorescens (C3K1P0) |
1.A.1.28.3 | Thylakoid membrane 6 TMS voltage-sensitive K+ channel, SnyK; important for photosynthesis (Checchetto et al. 2012). |
Bacteria | Cyanobacteria | SynK of Synechocystis sp. |
1.A.1.28.4 | Putative voltage-dependent K+ channel |
Bacteria | Proteobacteria | K+ channel of Vibrio alginolytcus |
1.A.1.28.5 | Putative voltage-dependent K+ channel |
Bacteria | Proteobacteria | K+ channel of E. coli |
1.A.1.28.6 | Putative voltage-dependent K+ channel |
Bacteria | Proteobacteria | K+ channel of Acinetobacter baumannii |
1.A.1.28.7 | Uncharacterized protein of 228 aas and 6 TMSs |
Archaea | Euryarchaeota | UP of Methanoculleus bourgensis (Methanogenium bourgense) |
1.A.1.28.8 | Two pore domain potassium channel family protein of 246 aas and 6 TMSs. |
Bacteria | Planctomycetes | Putative K+ channel of Planctomycetes bacterium |
1.A.1.29.1 | The 2 - 4 TMS K+ channel, LctB (Wolters et al. 1999). |
Bacteria | Firmicutes | LctB of Bacillus stearothermophilus |
1.A.1.29.2 | Uncharacterized protein of 481 aas and 2 TMSs. (Pfam CL0030) |
Archaea | Euryarchaeota | UP of Pyrococcus furiosus |
1.A.1.29.3 | Uncharacterized protein of 326 aas and 2 TMSs |
Bacteria | Proteobacteria | UP of Pseudoalteromonas luteoviolacea |
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 |
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 |
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 |
1.A.1.29.7 | Putative K+ channel of 317 aas and 2 TMSs with a central P-loop. |
Archaea | DPANN group | K+ channel of Candidatus Woesearchaeota archaeon (marine sediment metagenome) |
1.A.1.3.1 | Large conductance, voltage- and Ca2+-activated K+ calcium-dependent potassium (BK) 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). |
Eukaryota | Metazoa | Ca2+-activated K+ channel of Drosophila melanogaster |
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).
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Eukaryota | Metazoa | Kcma1 of Homo sapiens |
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). |
Eukaryota | Opisthokonta | BKCa or MaxiK channel of Rattus norvegicus (Q62976) |
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. |
Eukaryota | Metazoa | BK K+ channel of Caenorhabditis elegans (Q95V25) |
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). |
Eukaryota | Metazoa | Slo2 of Rattus norvegicus (Q9Z258) |
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). |
Eukaryota | Metazoa | Slo3 of Mus musculus (O54982) |
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). |
Eukaryota | Metazoa | Slo2.1 of Homo sapiens |
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 | Slo2.2 of Homo sapiens |
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 | Slo-2 of Caenorhabditis elegans |
1.A.1.3.9 | Voltage-gated calcium-activated potassium channel of 862 aas and 6 or 7 TMSs. |
Eukaryota | Entamoebidae | VIC protein of Entamoeba histolytica |
1.A.1.30.1 | Uncharacterized putative chloride channel protein of 219 aas and 2 TMSs. |
Viruses | UP of Vibrio phage 1.081.O._10N.286.52.C2 |
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1.A.1.31.1 | Uncharacterized VIC superfamily member of 230 aas and 6 or 7 TMSs (Anwar and Samudrala 2018). |
Eukaryota | Entamoebidae | UP of Entamoeba histolytica |
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). |
Eukaryota | Viridiplantae | AKT1 of Arabidopsis thaliana |
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 | Akt1 of Physcomitrella patens (A5PH36) |
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 | KCN11 of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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.1.4.2 | 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 | KDC1 of Daucus carota |
1.A.1.4.3 | Inward rectifying, pH-independent K+ channel, KZM1 (Philippar et al., 2003) | Eukaryota | Viridiplantae | 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). |
Eukaryota | Viridiplantae | GORK of Arabidopsis thaliana (CAC17380) |
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 | SKOR of Arabidopsis thaliana (AAF26975) |
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).
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Eukaryota | Viridiplantae | AKT2/KAT2 of Arabidopsis thaliana |
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). |
Eukaryota | Viridiplantae | KAT1 of Arabidopsis thaliana (Q39128) |
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). | Eukaryota | Viridiplantae | SPIK of Arabidopsis thaliana (Q8GXE6) |
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 | KC1 of Arabidopsis thaliana (P92960) |
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 | CNG channel of Ictalurus punctatus |
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. Associated withfamiial sinus bradycardia (Boulton et al. 2017). Activation of Hcn4 by cAMP has been reviewed (Porro et al. 2020). |
Eukaryota | Metazoa | Hcn4 of Homo sapiens (Q9Y3Q4) |
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). |
Eukaryota | Metazoa | HCN2/HCN4 channels of Homo sapiens |
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). |
Eukaryota | Metazoa | CNGA3 of Homo sapiens (Q16281) |
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 | CNGA3 of Oncorhynchus mykiss (G9BHJ0) |
1.A.1.5.14 | Probable cyclic nucleotide-gated ion channel 6 (AtCNGC6) (Cyclic nucleotide- and calmodulin-regulated ion channel 6) | Eukaryota | Viridiplantae | CNGC6 of Arabidopsis thaliana |
1.A.1.5.15 | Cyclic nucleotide gated K+ channel of 650 aas |
Eukaryota | Heterolobosea | Channel of Naegleria gruberi |
1.A.1.5.16 | Cyanobacterial cyclic nuceotide K+ channel of 454 aas (Brams et al. 2014). |
Bacteria | Cyanobacteria | Channel of Trichodesmium erythraeum |
1.A.1.5.17 | Cyclic nucleotide-gated K+channel 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). |
Bacteria | Spirochaetes | Channel of Spirochaeta thermophila |
1.A.1.5.18 | Cyclic nucleotide-gated cation (CNG) channel of 665 aas. |
Eukaryota | Metazoa | CNG of Drosophila melanogaster |
1.A.1.5.19 | TAX-2 cyclic nucleotide-gated cation channel-B (CNGB) of 800 aas (Wojtyniak et al. 2013). |
Eukaryota | Metazoa | TAX-2 CNGB of Caenorhabditis elegans |
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). |
Eukaryota | Metazoa | HCN of Mus musculus |
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 | TAX-4 CNGA of Caenorhabditis elegans |
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 | Intramacronucleata | PAK2.1 of Paramecium tetraurelia |
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 | Intramacronucleata | PAK11-MAC of Paramecium tetraurleia |
1.A.1.5.23 | Cyclic nuceotide-gated Na+ channel of 729 aas and 6 putative TMSs, CNGC19. Constitutively expressed in roots but Induced in leaves and shoots under conditions of salt (NaCl) stress (Kugler et al. 2009). |
Eukaryota | Viridiplantae | CNGC19 of Arabidopsis thaliana |
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). |
Eukaryota | Viridiplantae | CNGC20 of Arabidopsis thaliana |
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 | CNGC18 of Arabidopsis thaliana (Mouse-ear cress) |
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). |
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 | CNG-1 of Caenorhabditis elegans |
1.A.1.5.29 | spHCN1 is a 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 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). 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). |
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 (Zhong et al., 2002). 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 5Å, 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 TMS4 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 structure, undergoing conformational rearrangements (Maity et al. 2015). Moreover, structural heterogeneity of CNGA1 channels has been demonstrated (Maity et al. 2016). |
Eukaryota | Metazoa | CNG of Homo sapiens |
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 | Ih channel of Panulirus interruptus (California spiny lobster) (Palinurus interruptus) |
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 | Spirochaetes | LliK of Leptospira licerasiae |
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).
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Eukaryota | Metazoa | HCN1 of Homo sapiens |
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) |
Eukaryota | Metazoa | HCN2 of Strongylocentrotus purpuratus (Purple sea urchin) |
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 | Cng-3 of Caenorhabditis elegans |
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). |
Bacteria | Spirochaetes | SthK of Spirochaeta thermophila |
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 | CNGC17 of Arabidopsis thaliana (Mouse-ear cress) |
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 | CNGA2 complex of Mus musculus CNGA2 (Q62398) CNGA4 (AAI07349) CNGB1b (NP_001288) |
1.A.1.5.5 | The cyclic nucleotide- and voltage-gated ion (K+, Rb+, Cs+) channel, CNGC1 (inward rectifying) (functions in heavy metal and cation transport, as does CNGC10) (Dreyer and Uozumi, 2011; Zelman et al., 2012). |
Eukaryota | Viridiplantae | CNGC1 of Arabidopsis thaliana (O65717) |
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 | CNGC2 of Arabidopsis thaliana (O65718) |
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 | HLM1 of Arabidopsis thaliana |
1.A.1.5.8 | The non-selective cation transporter involved in germination, CNGC3 (Gobert et al., 2006; Zelman et al., 2012). |
Eukaryota | Viridiplantae | CNG3 of Arabidopsis thaliana (Q9SKD7) |
1.A.1.5.9 | The cyclic nucleotide-gated K+ channel, Sp-tetraKCNG (2238 aas) (Galindo et al., 2007) | Eukaryota | Metazoa | 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) |
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). |
Eukaryota | Fungi | Tok1 outward rectifier K+ channel of Saccharomyces cerevisiae |
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 | TOK1 of Candida albicans (Yeast) |
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 | AtTPK4 of Arabidopsis thaliana (AAP82009) |
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 | KCO1 of Arabidopsis thaliana |
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). | Eukaryota | Viridiplantae | TPK1 of Nicotiniana tobacum (A9QMN9) |
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 | TPK5 of Arabidopsis thaliana |
1.A.1.7.6 | Potassium inward rectifier (Kir)-like channel 3 (AtKCO3) | Eukaryota | Viridiplantae | 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. |
Eukaryota | Viridiplantae | TPK3 of Arabidopsis thaliana |
1.A.1.7.8 | Putative K+ channel of 96 aas nd 2 TMSs. |
Viruses | Phycodnaviridae | K+ channel of Yellowstone lake phycodnavirus 2 |
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 | TOK1 of Neosartorya fumigata (Aspergillus fumigatus) |
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 | TWIK-1 of Mus musculus |
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 | TASK-2 of Homo sapiens |
1.A.1.8.3 | The 2P-domain K+ channel, TWIK 2 (functions in cell electrogenesis (Patel et al., 2000). | Eukaryota | Metazoa | TWIK2 of Homo sapiens (Q9Y257) |
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). |
Eukaryota | Metazoa | 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) | Eukaryota | Metazoa | KCNK16 of Homo sapiens |
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).
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Eukaryota | Metazoa | KCNK9 or TASK3 of Homo sapiens |
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 | KCNK15 of Homo sapiens |
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 | TREK-2A of Danio rerio (Zebrafish) (Brachydanio rerio) |
1.A.1.9.14 | Open rectifier K+ channel 1, isoform D of 1001 aas and 6 TMSs, Ork1. |
Eukaryota | Metazoa | ORK1 of Drosophila melanogaster (Fruit fly) |
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). |
Eukaryota | Metazoa | TASK1 or KCNK3 of Homo sapiens (AAG29340) |
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 | TRAAK of Mus musculus (O88454) |
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 """"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, termed """"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 | TREK-2 of Rattus norvegicus |
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 | TWK-18 of Caenorhabditis elegans (Q18120) |
1.A.1.9.6 | The pH-sensitive 2 pore (4 TMS) K+ channel, 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). |
Eukaryota | Metazoa | TASK-4 of Homo sapiens |
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 | Sup-9 of Caenorhabditis elegans (O17185) |
1.A.1.9.8 | TWiK family of potassium channels protein 9 | Eukaryota | Metazoa | twk-9 of Caenorhabditis elegans |
1.A.1.9.9 | TWiK family of potassium channels protein 12 | Eukaryota | Metazoa | Twk-12 of Caenorhabditis elegans |
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. |
Eukaryota | Metazoa | GluR-K1 of Rattus norvegicus |
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). |
Eukaryota | Viridiplantae | GLR3.3/GLR3.4 receptor of Arabidopsis thaliana |
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 uponpore transplantation (Hoffmann et al. 2006). |
Eukaryota | Metazoa | Grik2 of Rattus norvegicus (P42260) |
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 | NMDA receptor of Xenopus laevis (Q91977) |
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). |
Eukaryota | Metazoa | GluR-2 of Homo sapiens (P42262) Drug effects, regulatory protein modulators and positive allosteric modulators have been reviewed (Fu et al. 2019). |
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 | Ir25a of Drosophila melanogaster |
1.A.10.1.15 | Glutamate ionotropic receptor homologue |
Eukaryota | Metazoa | Glutamate receptor in Daphnia pulex (water flea) |
1.A.10.1.16 | Olfactory ionotropic receptor, Ir93a of 842 aas |
Eukaryota | Metazoa | Ir93a of Panulirus argus (spiny lobster) |
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 | Ir76b of Drosophila melanogaster |
1.A.10.1.18 | Calcium channel of 551 aas, Glr1 (Wheeler and Brownlee 2008). |
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 | Olfactory receptor of Aedes albopictus (Asian tiger mosquito) (Stegomyia albopicta) |
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 | GluR-D of Rattus norvegicus |
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) |
Eukaryota | Metazoa | NMDAR of Homo sapiens |
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 | Glr-1 of Caenorhabditis elegans |
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 | NR1 of Aplysia californica (California sea hare) |
1.A.10.1.23 | Ionotropic glutamate receptor, GluR1 (GluR-1, GluR1-flip; GRIA1; GluH1; CTZ) 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).
|
Eukaryota | Metazoa | GluR-1 of Homo sapiens |
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). |
Eukaryota | Viridiplantae | GLR3.6 of Arabidopsis thaliana |
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).
|
Eukaryota | Metazoa | NMDAR of Drosophila melanogaster (Fruit fly) |
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 | Ir21a of Drosophila melanogaster |
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 | Ir21a of Aedes aegypti (yellow fever mosquito) |
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). |
Eukaryota | Metazoa | GRIK5 of Homo sapiens |
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 | NMDA receptor, Grin C2, of Homo sapiens |
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). |
Eukaryota | Metazoa | GluR3 of Homo sapiens (P42263) |
1.A.10.1.5 | The homomeric cation channel/glutamate receptor/kainate 1, GluR5 (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). |
Eukaryota | Metazoa | GluR5 of Rattus norvegicus |
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). |
Eukaryota | Metazoa | NR1/NR2A or NR2B or NR2C of Rattus norvegicus |
1.A.10.1.7 | The glutamate receptor 1.1 precursor (Ligand-gated channel 1.1, AtGLR1 (Kang and Turano, 2003)) | Eukaryota | Viridiplantae | 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 | GluR δ2 of Mus musculus (Q61625) |
1.A.10.1.9 | The ionotropic glutamate receptor kainate 4 precursor (Glutamate receptor, KA-1 or EAA1) (Kamboj et al., 1994) | Eukaryota | Metazoa | KA1 of Homo sapiens (Q16099) |
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 | Cyanobacteria | GluR0 of Synechocystis sp. PCC6803 |
1.A.10.2.2 | Probable Ionotropic glutamate receptor (GluR) |
Bacteria | Bacteroidetes/Chlorobi group | GluR homologue of Algoriphagus sp. PR1 (A3I049) |
1.A.10.2.3 | Probably Ionotropic glutamate receptor (GluR) |
Bacteria | Bacteroidetes/Chlorobi group | GluR homologue of Chlorobium luteolum (Q3B5G3) |
1.A.10.2.4 | Probable Ionotropic glutamate receptor (GluR) |
Bacteria | Proteobacteria | GluR homologue of Vibrio fischeri (B5FDH7) |
1.A.10.2.5 | Uncharacterized protein of 1003 aas and 5 - 7 TMSs |
Eukaryota | Viridiplantae | UP of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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 |
1.A.10.3.2 | Ligand-gated ion channel of 448 aas and 4 TMSs in a 3 + 1 TMS arrangement. |
Viruses | Varidnaviria | LIC of Only Syngen Nebraska virus 5 |
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 |
1.A.100.1.2 | Putative viroporin of 118 aas and 1 or 2TMSs |
Viruses | Mononegavirales | Putative Viroporin of Joinjakaka virus |
1.A.100.1.3 | Putative viroporin of 90 aas and 1 TMS |
Viruses | Mononegavirales | Putative viroporin of Kotonkan virus |
1.A.101.1.1 | Pex11 of 236 aas and possibly 3 TMSs (Mindthoff et al. 2015). |
Eukaryota | Fungi | Pex11 of Saccharomyces cerevisiae |
1.A.101.1.2 | Pex11 of 247 aas. |
Eukaryota | Metazoa | Pex11 of Homo sapiens |
1.A.101.1.3 | Pex11 of 248 aas |
Eukaryota | Viridiplantae | Pex11 of Arabidopsis thaliana |
1.A.101.1.4 | Pex11 of 222 aas |
Eukaryota | Kinetoplastida | Pex11 of Leishmainia major |
1.A.101.1.5 | Pex11 of 234 aas |
Eukaryota | Metazoa | Pex 11 of Drosophila melanogaster (Fruit fly) |
1.A.101.1.6 | Pex11C-like protein of 199 aas |
Eukaryota | Metazoa | Pex11C-like protein of Mombyx mori |
1.A.101.1.7 | Uncharacterized glycosomal protein of 220 aas |
Eukaryota | Kinetoplastida | UP of Leishmania major |
1.A.101.2.1 | Putative Pex11 of 355 aas |
Eukaryota | Fungi | Pex11 homologue of Aspergillus niger |
1.A.101.2.2 | Putative Pex11 homologue of 315 aas |
Eukaryota | Fungi | Pex11 homologue of Cryptococcus neoformans (Filobasidiella neoformans) |
1.A.101.2.3 | Uncharacterized protein of 327 aas |
Eukaryota | Fungi | UP of Bipolaris oryzae |
1.A.101.2.4 | Pex11 homologue of 290 aas |
Eukaryota | Fungi | Pex11 homologue of Sphaerulina musiva (Poplar stem canker fungus) (Septoria musiva) |
1.A.101.2.5 | Uncharacterized protein of 188 aas |
Eukaryota | Oomycetes | UP of Aphanomyces astaci |
1.A.101.3.1 | Uncharacterized protein of 317 aas |
Eukaryota | Fungi | UP of Wallemia mellicola (Wallemia sebi |
1.A.101.3.2 | Uncharacterized protein of 410 aas |
Eukaryota | Fungi | UP of Serpula lacrymans (Dry rot fungus) |
1.A.101.3.3 | Uncharacterized protein of 334 aas |
Eukaryota | Fungi | UP of Rhodosporidium toruloides (Yeast) (Rhodotorula gracilis) |
1.A.101.3.4 | Uncharacterized protein of 228 aas |
Eukaryota | Fungi | UP of Mucor circinelloides (Mucormycosis agent) (Calyptromyces circinelloides) |
1.A.101.4.1 | Uncharacterized glycosomal protein of 225 aas |
Eukaryota | Kinetoplastida | UP of Leishmania braziliensis |
1.A.101.4.2 | Uncharacterized protein of 253 aas |
Eukaryota | Kinetoplastida | UP of Leishmania braziliensis |
1.A.101.4.3 | Uncharacterized protein of 247 aas |
Eukaryota | Kinetoplastida | UP of Trypanosoma cruzi |
1.A.101.5.1 | Uncharacterized protein of 252 aas |
Eukaryota | Isochrysidales | UP of Emiliania huxleyi |
1.A.101.5.2 | Uncharacterized protein of 252 aas |
Eukaryota | Oomycetes | UP of Saprolegnia diclina |
1.A.101.5.3 | Uncharacterized protein of 421 aas |
Eukaryota | Isochrysidales | UP of Emiliania huxleyi |
1.A.101.6.1 | Pex11 of 240 aas |
Eukaryota | Intramacronucleata | Pex11 of Tetrahymena thermophila |
1.A.101.6.2 | Uncharacterized protein of 289 aas |
Eukaryota | Intramacronucleata | UP of Paramecium tetraurelia |
1.A.101.6.3 | Pex11 domain containing protein of 235 aas |
Eukaryota | Intramacronucleata | Pex11 of Oxytricha trifallax |
1.A.101.6.4 | Peroxin Pex11 of 243 aas |
Eukaryota | Viridiplantae | Pex11 of Physcomitrella patens (Moss) |
1.A.101.7.1 | Uncharacterized protein of 244 aas |
Eukaryota | Fungi | UP of Kazachstania africana (Yeast) (Kluyveromyces africanus) |
1.A.101.7.2 | Pex25 of 294 aas |
Eukaryota | Fungi | Pex25 of Saccharomyces cerevisiae |
1.A.101.7.3 | Pex27 of 376 aas and 2 predicted TMSs. |
Eukaryota | Fungi | Pex27 of Saccharomyces cerevisiae |
1.A.101.8.1 | Uncharacterized protein of 206 aas |
Eukaryota | Bacillariophyta | UP of Thalassiosira oceanica (Marine diatom) |
1.A.101.8.2 | Uncharacterized protein of 360 aas |
Eukaryota | Bacillariophyta | UP of Phaeodactylum tricornutum |
1.A.101.8.3 | Uncharacterized protein of 252 aas |
Eukaryota | Oomycetes | UP of Pythium ultimum |
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 | Orthomyxoviridae | PB1-F2 of Influenza virus A |
1.A.102.1.2 | Influenza A virus PB1-F2 protein of 57 aas |
Viruses | Negarnaviricota | PB1-F2 of INfluenza A virus |
1.A.102.1.3 | PB1-F2 protein of 57 aas and 0 TMSs |
Viruses | Negarnaviricota | PB1-F2 of Influenza A virus (A/chicken/Dongguan) |
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 | PB1F2 of influenza A virus |
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 | Mononegavirales | SH of Parainfluenza Virus 5 (Simian Virus 5) |
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 |
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 | Proteobacteria | FlhA of E. coli |
1.A.104.1.2 | Flagellar biosynthesis protein FlhA of 728 aas and 8 TMSs in a 4 + 4 TMS arrangement.. |
Bacteria | PVC group | FlhA of Spartobacteria bacterium |
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 | MLKL of Homo sapiens |
1.A.105.1.2 | Mixed lineage kinase domain-like protein, MLKL, of 711 aas and 4 N-terminal TMSs. |
Eukaryota | Metazoa | MLKL of Balaenoptera acutorostrata scammoni (whale) |
1.A.105.1.3 | Mixed lineage kinase domain-like protein, MLKL, isoform X1 of 503 aas. |
Eukaryota | Metazoa | MLKL of Acanthaster planci |
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. 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). |
Eukaryota | Metazoa | TMCO1, a CLAC channel of Homo sapiens |
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 | Entamoebidae | CLAC channel of Entamoeba histolytica |
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 | Amoebozoa | TMCO1 of Dictyostelium discoideum (Slime mold) |
1.A.106.1.2 | TMCO1 of 183 aas and 3 TMSs |
Eukaryota | Metazoa | TMCo1 of Hydra vulgaris (Hydra) (Hydra attenuata) |
1.A.106.1.3 | TMCO1 or Anon-37B-2 of 177 aas and 3 TMSs. |
Eukaryota | Metazoa | TMCO1 of Drosophila melanogaster (Fruit fly) |
1.A.106.1.4 | TMCO1 of 177 aas and 3 TMSs |
Eukaryota | Metazoa | TMCO1 of Schistosoma japonicum (Blood fluke) |
1.A.106.1.5 | TMCO1 homologue of 201 aas and 3 TMSs |
Eukaryota | Apicomplexa | TMCO1 homologue of Toxoplasma gondii |
1.A.106.1.6 | Uncharacterized protein of 199 aas and 3 TMSs |
Eukaryota | Viridiplantae | UP of Zea mays (Maize) |
1.A.106.1.7 | Uncharacterized protein of 219 aas and 3 TMSs |
Eukaryota | Apicomplexa | UP of Eimeria tenella (Coccidian parasite) |
1.A.106.1.8 | Uncharacterized protein of 196 aas and 3 TMSs |
Bacteria | Proteobacteria | UP of Arabidopsis thaliana |
1.A.106.1.9 | Uncharacterized TMCO1 homologue of 192 aas and 3 TMSs. |
Eukaryota | Viridiplantae | UP of Chlamydomonas reinhardtii |
1.A.106.2.1 | TMCO1 homologue of 167 aas and 3 TMSs |
Archaea | Candidatus Korarchaeota | TMCO1 homologue of Korarchaeum cryptofilum |
1.A.106.2.2 | Uncharacterized protein of 174 aas and 3 TMSs |
Archaea | Euryarchaeota | UP of Thermococcus nautili |
1.A.106.2.3 | Uncharacterized protein of 191 aas and 3 TMSs. |
Archaea | Euryarchaeota | UP of Methanobrevibacter smithii |
1.A.106.2.4 | Uncharacterized protein of 301 aas and 4 TMSs |
Archaea | Euryarchaeota | UP of Halorubrum saccharovorum |
1.A.106.2.5 | Uncharactized protein of 193 aas and 3 or 4 TMSs |
Archaea | Euryarchaeota | UP of Ferroglobus placidus |
1.A.107.1.1 | Pore-forming Hemoglobin-α of 142 aas (Morrill and Kostellow 2016). |
Eukaryota | Metazoa | Hemoglobin-α of Homo sapiens |
1.A.107.1.2 | Pore-forming hemoglobin-β of 147 aas (Morrill and Kostellow 2016). |
Eukaryota | Metazoa | Hemoglobin-β of Homo sapiens |
1.A.107.1.3 | Pore-forming myoglobin of 154 aas (Morrill and Kostellow 2016). |
Eukaryota | Metazoa | Myoglobin of Homo sapiens |
1.A.107.1.4 | Pore-forming neuroglobin of 151 aas (Morrill and Kostellow 2016). |
Eukaryota | Metazoa | Neuroglobin of Homo sapiens |
1.A.107.1.5 | Pore-forming cytoglobin of 154 aas (Morrill and Kostellow 2016). |
Eukaryota | Metazoa | Cytoglobin of Homo sapiens |
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 | FGF2 of Homo sapiens |
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 | FGF23 of Homo sapiens |
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 | IL1α of Homo sapiens |
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 | IL1beta of Homo sapiens |
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 | Proteobacteria | AmtB of E. coli (P69681) |
1.A.11.1.2 | High affinity ammonia/methylammonia uptake carrier, Amt1 or AmtA (Walter et al., 2008) | Bacteria | Actinobacteria | Amt1 of Corynebacterium glutamicum (P54146) |
1.A.11.1.3 | Low affinity (KM > 3mM) ammonia uptake carrier, AmtB (Walter et al., 2008) | Bacteria | Actinobacteria | 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 | Proteobacteria | AmtB of Azospirillum brasilense (P70731) |
1.A.11.1.5 | Ammonia channel (Ammonia transporter) | Bacteria | Aquificae | 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 | Dictyosteliida | 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 | Kinetoplastida | Amt of Trypanosoma cruzi |
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 | Firmicutes | NrgA of Streptococcus mutans |
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 | Amt1 of Arabidopsis thaliana (P54144) |
1.A.11.2.10 | Putative ammonium transporter 2 | Eukaryota | Metazoa | 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) |
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 | Florideophyceae | Amt1 of Chondrus crispus (Carrageen Irish moss) (Polymorpha crispa) |
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). |
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 | Phycodnaviridae | NH3 transporter of Ostreococcus tauri virus RT-2011 |
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 | Amt2 of Arabidopsis thaliana |
1.A.11.2.3 | High-affinity ammonia/methylammonia transporter, Amt1(Paz-Yepes et al., 2007) | Bacteria | Cyanobacteria | 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 | LeAMT1;1 of Lycopersicon esculentum (P58905) |
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 | Cyanobacteria | AmtB of Synechococcus sp CC9311 (Q0IDE4) |
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 | Amt1;4 of Arabidopsis thaliana (Q9SVT8) |
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) |
1.A.11.2.8 | Amt1;1, a proposed NH4+:H+ sumporter (Ortiz-Ramirez et al., 2011) |
Eukaryota | Viridiplantae | Amt1;1 of Phaseolus vulgaris (E2CWJ2) |
1.A.11.2.9 | Eukaryota | Dictyosteliida | 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 | 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 | 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 | Amt1 of Hebeloma cylindrosporum (Q8NKD5) |
1.A.11.3.4 | Low affinity ammonia transporter, Amt2 (Javelle et al., 2001, 2003b) | Eukaryota | Fungi | 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 | Mep2 of Candida albicans (Q59UP8) |
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). |
Eukaryota | Metazoa | RhCG of Homo sapiens (Q9UBD6) |
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).
|
Eukaryota | Metazoa | Rhr-1 of Caenorhabditis elegans |
1.A.11.4.11 | Rh protein of 478 aas and 11 TMSs. It is a primary contributor to ammonia excretion, and poor expression changes the expression levels of many enzymes (Si et al. 2018). |
Eukaryota | Metazoa | Rh protein of Portunus trituberculatus (the swimming crab) |
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). Regulated by Wnt/β-catenin signalling, a pathway frequently deregulated in many cancers and associated with tumorigenesis (Merhi et al. 2015). |
Eukaryota | Metazoa | RhBG of Homo sapiens (Q9H310) |
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 and fluoroethylamine. 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 | The RhAG/RhCE/RhD, complex of Homo sapiens |
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 | Proteobacteria | RH50 of Nitrosomonas europaea (Q82X47)
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1.A.11.4.5 | Kidney rhesus glycoprotein p2 (Rhp 2). Transports NH3 and methylammonium (Nakada et al., 2010). |
Eukaryota | Metazoa | Rhp2 of Triakis scyllium (D0VX38) |
1.A.11.4.6 | Rhesus-like glycoprotein A (Rh50-like protein RhgA) |
Eukaryota | Dictyosteliida | RhgA of Dictyostelium discoideum |
1.A.11.4.7 | Ammonium transporter of 391 aas and 12 TMSs. 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 | Firmicutes | Ammonium transporter of [Clostridium] papyrosolvens |
1.A.11.4.8 | NH3 (NH4+) 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 | Rhag of Anabas testudineus (climbing perch) |
1.A.11.4.9 | NH3 (NH4+) 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). |
Bacteria | Proteobacteria | Rhcg2 of Anabas testudineus (climbing perch) |
1.A.110.1.1 | OTOP1 of 600 aas and 12 TMSs in a 5 + 5 + 2 arrangement. OTOP1 is a 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). |
Eukaryota | Metazoa | OTOP1 of Mus musculus |
1.A.110.1.10 | Otop3 of 600 aas and 12 TMSs. 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 has been reviewed (Danmaliki and Hwang 2020). |
Eukaryota | Metazoa | Otop3 of Gallus gallus (chicken) |
1.A.110.1.2 | OTOP1 H+ channel of 612 aas and 10 TMSs (Tu et al. 2018). |
Eukaryota | Metazoa | OTOP1 of Homo sapiens |
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 | OTOP2 of Homo sapiens |
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 | OTOP3 of Homo sapiens |
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). |
Eukaryota | Metazoa | OTOP1 of Danio rerio (Zebrafish) (Brachydanio rerio) |
1.A.110.1.6 | OtoPetrin-like (Otpl6) of 581 aas and 12 TMSs. |
Eukaryota | Metazoa | Otpl6 of Caenorhabditis elegans |
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 | OTOP, isoform D of Drosophila melanogaster (Fruit fly) |
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 | Putative Otop protein of Schistosoma mansoni (Blood fluke) |
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 | OTOP3 of Xenopus tropicalis |
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 | MTGM of Homo sapiens |
1.A.111.1.2 | MRTM homologue of 108 aas and 2 TMSs. |
Eukaryota | Fungi | MTGM of Aspergillus niger |
1.A.111.1.3 | MTGM homologue of 113 aas and 2 TMSs. |
Eukaryota | Fungi | MTGM homologue of Saccharomyces cerevisiae |
1.A.111.1.4 | MTGM homologue of 74 aas |
Eukaryota | Viridiplantae | MTGM of Glycine max |
1.A.111.1.5 | Reactive oxygen species modulator 1 homologue, Romo1 family member of 128 aas. |
Eukaryota | Dictyosteliida | Romo1 of Dictyostelium discoideum |
1.A.111.1.6 | MTGM protein of 80 aas. |
Eukaryota | Bangiophyceae | MTGM of Galdieria sulfuraria |
1.A.111.1.7 | MTGM homologue of 149 aas |
Eukaryota | Intramacronucleata | MTGM homologue of Tetrahymena thermophius |
1.A.111.1.8 | Uncharacterized protein of 165 aas and 2 TMSs. |
Eukaryota | Apicomplexa | UP of Theileria annulata |
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 |
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). |
Eukaryota | Metazoa | Cyclin M2, CNNM2, of Mus musculus (Q3TWN3) |
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 | CNNM3 of Mus musculus |
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 | CNNM3 of Homo sapiens |
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 | CNNM4 of Homo sapiens |
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 | CNNM1 of Homo sapiens |
1.A.112.1.6 | Putative Mg2+ exporter of 875 aas and 5 TMSs, CNNM2 or ACDP2 (Chen et al. 2018). |
Eukaryota | Metazoa | CNNM2 of Homo sapiens |
1.A.112.1.7 | Uncharacterized protein of 734 aas and 5 N-terminal TMSs. |
Eukaryota | Kinetoplastida | UP of Trypanosoma cruzi |
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 |
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 | Firmicutes | MpfA of Staphylococcus aureus |
1.A.112.2.2 | Uncharacterized protein of 434 aas with an N-terminal 4 TMSs, YrkA. |
Bacteria | Firmicutes | YrkA of Bacillus subtilis (Q45494) |
1.A.112.2.3 | Probable Mg2+ exporter of 452 aas. It does not exhibit hemolysin activity (Sałamaszyńska-Guz and Klimuszko 2008). |
Bacteria | Proteobacteria | TylC-like protein of Campylobacter jejuni |
1.A.112.2.4 | Uncharacterized protein of 444 aas and 4 TMSs, YhdP. Mutations in yhdP increase the activity of sigmaW, suggesting that this protein may be an MDR exporter (Turner and Helmann 2000). |
Bacteria | Firmicutes | YhdP of Bacillus subtilis |
1.A.112.2.5 | CorC homologue, YfjD, of 428 aas and 4 TMSs. In a two gene operon with YpjD, a putative cytochrome c assembly protein (P64432; TC# 9.B.14.3.6). |
Bacteria | Proteobacteria | YfjD of E. coli |
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 |
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 | Proteobacteria | CorB of Pseudomonas bauzanensis |
1.A.112.2.8 | HlyC/CorC family transporter of 354 aas and 4 TMSs. |
Bacteria | Actinobacteria | CorC domain protein of Micromonospora peucetia |
1.A.112.2.9 | Uncharacterized protein of 329 aas and 4 TMSs. |
Bacteria | Verrucomicrobia | UP of Verrucomicrobia bacterium] |
1.A.113.1.1 | The small integral membrane protein 22 of 81 aas and 1 TM |
Eukaryota | Metazoa | Small integral membrane protein 22 of Stegastes partitus |
1.A.113.1.2 | Small integral membrane protein 5 isoform X1 of 119 aas and 1 TM |
Eukaryota | Metazoa | Small integral membrane protein 5 isoform X1 of Anolis carolinensis |
1.A.113.1.3 | ELN homologue of unknown function with 158 aas and 2 TMSs |
Eukaryota | Metazoa | ELN homologue of Alligator mississippiensis (American alligator) |
1.A.113.1.4 | Small integral membrane DUF4713 protein 22 of 83 aas and 1 TM |
Eukaryota | Metazoa | Small membrane protein-22 of Sorex araneus |
1.A.113.1.5 | Small integral membrane protein 18 of 111 aas and 1 TM |
Eukaryota | Metazoa | Protein 18 of Phascolarctos cinereus |
1.A.113.2.1 | Uncharacterized protein of 112 aas and 1 TMS. |
Eukaryota | Metazoa | UP of Scleropages formosus (Asian bonytongue) |
1.A.113.2.2 | Uncharacterized protein of 112 aas and 1 TMS. |
Eukaryota | Metazoa | UP of Empidonax traillii |
1.A.113.2.3 | Uncharacterized protein of 108 aas and 1 TMS. |
Eukaryota | Metazoa | UP of Electrophorus electricus (Electric eel) (Gymnotus electricus) |
1.A.113.3.1 | Uncharacterized protein of 109 aas and 1 TMS. |
Eukaryota | Metazoa | UP of Apis mellifera |
1.A.113.3.2 | Uncharacterized protein of 77 aas and 1 TMS. |
Eukaryota | Metazoa | UP of Anopheles gambiae (African malaria mosquito) |
1.A.113.3.3 | Uncharacterized protein of 84 aas and 1 TMS. |
Eukaryota | Metazoa | UP of Harpegnathos saltator (Jerdon's jumping ant) |
1.A.113.3.4 | Uncharacterized protein of 81 aas and 1 TMS |
Eukaryota | Metazoa | UP of Helicoverpa armigera |
1.A.113.3.5 | Uncharacterized protein of 97 aas and 1 TMS |
Eukaryota | Metazoa | UP of Nasonia vitripennis (Parasitic wasp) |
1.A.113.3.6 | Uncharacteerized protein of 84 aas and 1 TMS |
Eukaryota | Metazoa | UP of Nicrophorus vespilloides (Boreal carrion beetle) |
1.A.113.3.7 | Uncharacterized protein of 87 aas and 1 TMS |
Eukaryota | Metazoa | UP of Laodelphax striatella (small brown planthopper) |
1.A.113.3.8 | Uncharacterized protein of 192 aas and 2 putative TMSs. |
Eukaryota | Metazoa | UP of Folsomia candida (Springtail) |
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 | Endoregulin of Homo sapiens |
1.A.113.5.2 | ELN homologue of 78 aas and 1 TMS. |
Eukaryota | Metazoa | ELN homologue of Nothobranchius furzeri |
1.A.113.5.3 | ELN homologue of 75 aas and 1 TMS. |
Eukaryota | Metazoa | ELN of Larimichthys crocea (large yellow croaker) |
1.A.113.5.4 | Bacterial ELN homologue of unknown function with 101 aas and 1 TMS |
Bacteria | Proteobacteria | ELN homologue of Desulfobacteraceae bacterium |
1.A.113.5.5 | ELN homologue of 85 aas and 1 TMS |
Bacteria | Thermotogae | ELN homologue of Thermotoga sp. |
1.A.113.5.6 | Small integral membrane protein 6 of 56 aas and 1 TMS, ELN. |
Eukaryota | Metazoa | ELN of Mus musculus |
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). |
Eukaryota | Metazoa | PACC1 of Homo sapiens |
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 | TMEM206 of Danio rerio (Zebrafish) (Brachydanio rerio) |
1.A.114.1.3 | TMEM206 of 469 aas and 2 TMSs. |
Eukaryota | Metazoa | TMEM206 of Amphimedon queenslandica |
1.A.114.1.4 | TMEM206-like protein of 382 aas and 2 TMSs. |
Eukaryota | Metazoa | TMEM206 of Saccoglossus kowalevskii |
1.A.114.1.5 | TMEM206 of 254 aas and 2 TMSs. |
Eukaryota | Metazoa | TMEM206 of Callorhinchus milii |
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 | Ayr1 of Saccharomyces cerevisiae |
1.A.115.1.2 | NAD-binding protein of 261 aas and 1 TM |
Archaea | Euryarchaeota | NAD BP of Euryarchaeota archaeon |
1.A.115.1.3 | SDR family of NAD(P)-dependent oxidoreductases of 287 aas and 0 TM |
Bacteria | Actinobacteria | SDR family protein of Allonocardiopsis opalescens |
1.A.115.1.4 | Uncharacterized protein of 188 aas and 3 putative TMSs. |
Eukaryota | Fungi | UP of Botrytis elliptica |
1.A.115.1.5 | SDR family oxidoreductase of 250 aas and 1 TM |
Bacteria | Proteobacteria | SDR family protein of Pseudomonas abietaniphila |
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 | Nidovirales | Viroporin of Porcine reproductive and respiratory syndrome virus (PRRSV) |
1.A.116.1.2 | E (envelope) protein of 80 aas and 1 TMS. |
Viruses | Nidovirales | E protein of Kibale red colobus virus 1 |
1.A.116.1.3 | ORF2b of 70 aas and 1 TMS |
Viruses | Nidovirales | ORF2b of Rodent arterivirus |
1.A.116.1.4 | E protein of 74 aas and 1 TMS |
Viruses | Nidovirales | E protein of African pouched rat arterivirus |
1.A.116.1.5 | E protein of 76 aas and 1 TM |
Viruses | Nidovirales | E protein of Mikumi yellow baboon virus 1 |
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 | Nidovirales | GP2a protein of Equine arteritis virus (strain Bucyrus) (EAV) |
1.A.116.1.7 | ORF4a of 79 aas and 1 TMS. |
Viruses | Nidovirales | ORF4a of Simian hemorrhagic fever virus |
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 | Nidovirales | M-protein of Guangdong chinese water skink coronavirus |
1.A.117.1.2 | Membrane glycoprotein of 222 aas and 3 or 4 TMSs |
Viruses | Nidovirales | M-protein of Severe acute respiratory syndrome coronavirus 2 |
1.A.117.1.3 | M-protein of 268 aas and 3 N-terminal TMSs |
Viruses | Nidovirales | M protein of Common moorhen coronavirus HKU21 |
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 | Nidovirales | M-protein of the transmissible gastroenteritis virus (TGEV) |
1.A.117.1.5 | Matrix (M) protein of 219 aas and 3 N-terminal TMSs. |
Viruses | Nidovirales | M protein (MERS) of betacoronavirus England 1 |
1.A.117.1.6 | Membrane (M)-protein of 275 aas and 3 (+ 2 or 3 possible) TMSs |
M-protein of Bottlenose dolphin coronavirus |
||
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 | Viridiplantae | M of Avian infectious bronchitis virus (strain DE072) (IBV) |
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 | Kalata-B1 of Oldenlandia affinis (P56254) |
1.A.118.1.2 | Cyclotide, Cycloviolacin O8 |
Eukaryota | Viridiplantae | Cycloviolacin O8 of Viola odovata (P58440) |
1.A.118.1.3 | The Varv peptide A/Kalata-B1 |
Eukaryota | Viridiplantae | Varv of Viola odorata (Q5USN7) |
1.A.118.1.4 | Cyclotide Oak6 |
Eukaryota | Viridiplantae | Oak6 of Oldenlandia affinis (D8WS37) |
1.A.119.1.1 | The drought stress-inducible putative membrane protein, TMPIT1 |
Eukaryota | Viridiplantae | TMPIT1 of Triticum dicoccoides (G0ZL54) |
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) |
|
1.A.119.1.11 | Uncharacterized protein of 409 aas and 7 TMSs. |
Eukaryota | Viridiplantae | UP of Chlorella variabilis |
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 |
1.A.119.1.2 | The TMEM120A or TACAN protein , of 343 aas and 7 TMSs. May function in adipogenesis (Batrakou et al. 2015). TACAN is 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). |
Eukaryota | Metazoa | TACAN of Homo sapiens |
1.A.119.1.3 | TACAN-like protein (homologue) of 199 aas and 7 TMSs |
Eukaryota | Metazoa | TACAN of Arabidopsis thaliana (thale cress) |
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 | UP of Schistosoma curassoni |
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 | UP of Dibothriocephalus latus |
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 | UP of Nippostrongylus brasiliensis |
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 | UP of Schistocephalus solidus |
1.A.119.1.8 | TMPIT-like protein of 355 aas and 7 TMSs |
Eukaryota | Viridiplantae | TMPIT protein of Dunaliella salina |
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 | TMEM120 of Chlorella sorokiniana |
1.A.12.1.1 | Organellar chloride (anion selective) channel, p64 (outwardly rectifying) (437 aas and 1 TMS). 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 | CLIC5 or p64 of Bos taurus |
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). |
Eukaryota | Metazoa | CLIC1 or NCC27 of Homo sapiens |
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 | CLIC-5A of Homo sapiens (Q53G01) |
1.A.12.1.4 | Organellar chloride channel CLIC-6 (704 aas) [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]. | Eukaryota | Metazoa | CLIC-6 of Homo sapiens (Q96NY7) |
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 | CLIC2 of Homo sapiens (O15247) |
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 | CLIC4 of Homo sapiens (Q9Y696) |
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 | CLIC3 of Homo sapiens (O95833) |
1.A.12.2.1 | The plant Cl- intracellular channel protein DHAR1 (glutathione dehydrogenase/dehydroascorbate reductase) (Elter et al., 2007) | Eukaryota | Viridiplantae | DHAR1 of Arabidopsis thaliana (NP_173387) |
1.A.12.2.2 | Putative Glutathione S-transferase. Pore formation has not been demonstrated in prokaryotes. |
Bacteria | Spirochaetes | Probable glutathione S-transferase of Leptospira interrogans |
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 | Proteobacteria | Stringent starvation protein A of E. coli (P0ACA3) |
1.A.12.3.2 | Glutathione S-transferase, YfcF of 214 aas. Pore formation has not been demostrated. |
Bacteria | Proteobacteria | YfcF of E. coli |
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 | Riboviria | nsp3-nsp4 of murine hepatitis virus |
1.A.120.1.2 | Polyprotein 1a of 4018 aas and ~ 10 TMSs. |
Viruses | Riboviria | PP 1a of Canine coronavirus |
1.A.120.1.3 | ORF1a polyprotein, partial of 4345 aas and ~ 7 TM |
Viruses | Riboviria | ORF1a polyprotein of Severe acute respiratory syndrome coronavirus 2, CoV-2 |
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 | Opisthokonta | APH-1B of Homo sapiens |
1.A.121.1.10 | Uncharacterized protein of 282 aas and 7 TMSs in a 3 + 2 + 2 TMS arrangement. |
Eukaryota | Opisthokonta | UP of Allomyces macrogynus |
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 | Opisthokonta | APH-1A of Homo sapiens |
1.A.121.1.3 | Gamma-secretase subunit APH1-like of208 aas and 7 TMSs in a 3 + 2 + 2 TMS arrangement. |
Eukaryota | Viridiplantae | APH1 of Olea europaea subsp. europaea |
1.A.121.1.4 | Uncharacterized protein of 260 aas and 7 TMSs in a 3 + 4 TMS arrangement. |
Eukaryota | Viridiplantae | UP of Cannabis sativa |
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 | UP of Gonium pectorale |
1.A.121.1.6 | Uncharacterized protein of 259 aas and 7 TMSs in a 3 + 4 TMS arrangement. |
Eukaryota | Sar | UP of Aphanomyces astaci |
1.A.121.1.7 | APH1 of 275 aas and 7 TMSs |
Eukaryota | Viridiplantae | APH1 of Chlorella sorokiniana |
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 | Sar | UP of Nothophytophtyora sp. Chile5 |
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 | Amoebozoa | UP of Polysphondylium violaceum |
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 | Riboviria | Protein 3A of Tremovirus A |
1.A.122.1.2 | Polyprotein of 2134 aas from which protein 3A is derived. |
Viruses | Riboviria | Polyprotein 2134 of Avian encephalomyelitis virus
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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 | EClC of Bos taurus (NP_001070824) |
1.A.13.1.2 | Ca2+-activated Cl- channel-2, CaCC-2 | Eukaryota | Metazoa | CaCC-2 of Homo sapiens |
1.A.13.1.3 | The Ca-activated chloride channel-6 (Lee et al., 2011). |
Eukaryota | Metazoa | Ca-CLC-6 of Xenopus laevis (F7IYU6) |
1.A.13.1.4 | Calcium-activated chloride channel regulator family member 3 (Calcium-activated chloride channel family member 3) (hCLCA3) | Eukaryota | Metazoa | CLCA3P of Homo sapiens |
1.A.13.1.5 | Putative lipoprotein of 1054 aas and 1-3 TMSs. |
Bacteria | Spirochaetes | Putative lipoprotein of Leptospira biflexa |
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). |
Eukaryota | Metazoa | CLCA1 of Homo sapiens |
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 | xCLCA3 of Xenopus laevis (African clawed frog) |
1.A.13.2.1 | Hypothetical protein, HP |
Eukaryota | Viridiplantae | HP of Oryza sativa (B8AFH9) |
1.A.13.2.2 | Sll0103 |
Bacteria | Cyanobacteria | Sll0103 of Synechocystis (Q55874) |
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 | Proteobacteria | YfbK of E. coli (P76481) |
1.A.13.2.4 | Von Willebrand factor type A domain protein of 536 aas and 1 N-terminal TM |
Bacteria | Planctomycetes | Von Willebrand factor of Tuwongella immobilis |
1.A.13.3.1 | Von Willebrand factor type A protein, vWFA. (905 aas; 2 N-terminal and 1 C-terminal TMSs) |
Bacteria | Chloroflexi | vWFA of Chloroflexus aurantiacus (A9WIT9) |
1.A.13.4.1 | Bacterial homologue, BatB, of mammalian Ca-CLC channels (N- and C-terminal TMSs) |
Bacteria | Proteobacteria | BatB of Myxococcus fulvus (F8CM01) |
1.A.13.5.1 | Uncharacterized protein of 252 aas and 2-3 TMSs |
Bacteria | Proteobacteria | UP of E. coli |
1.A.14.1.1 | The Bax Inhibitor-1, BI-1 of 311 aas and 6 TMSs 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). |
Eukaryota | Metazoa | BI-1 or TEGT of Homo sapiens (P55061) |
1.A.14.1.2 | Uncharacterized protein of 304 aas and 7 TMSs. |
Eukaryota | Kinetoplastida | UP of Trypanosoma cruzi marinkellei |
1.A.14.1.3 | Uncharacterized protein of 238 aas and 7 TMSs |
Eukaryota | Apicomplexa | UP of Babesia microti |
1.A.14.1.4 | Uncharacterized protein of 317 aas and 7 TMSs |
Eukaryota | Isochrysidales | UP of Emiliania huxleyi |
1.A.14.1.5 | Growth hormone-inducible membrane protein of 345 aas and 8 putative TMSs |
Eukaryota | Metazoa | GH-inducible membrahe protein of Anas platyrhynchos (Mallard) (Anas boschas) |
1.A.14.1.6 | Putative Bax inhibitor of 213 aas and 7 TMSs |
Eukaryota | Entamoebidae | Putative Bax inhibitor of Entamoeba histolytica |
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 | Proteobacteria | YccA of E. coli (P0AAC6) |
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 | Proteobacteria | YbhL of E. coli (P0AAC4) |
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). |
Bacteria | Firmicutes | YetJ of Bacillus subtilis (O31539) |
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 | Proteobacteria | YbhM of E. coli |
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 | Proteobacteria | Bax1-I protein of E. coli |
1.A.14.2.6 | Uncharacterized protein of 227 aas and 7 TMSs |
Bacteria | Firmicutes | UP of Streptococcus sanguinis |
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 | NMDA receptor glutamate binding chain of Rattus sp. (Q63863) |
1.A.14.3.10 | The Protein Lifeguard 3 (LFG3, RECS1, Tmbim1) of 311 aas and 7 TMSs. LFG3 is a multivesicular bidy regulator that protects agains non-alcoholic fatty liver by targeting the lysosomal degradation of Tlr4 (Zhao et al. 2017). TMBIM1 protects against pathological cardiac hypertrophy through promoting the lysosomal degradation of activated TLR4 (Deng et al. 2018). |
Eukaryota | Metazoa | LFG3 of Homo sapiens |
1.A.14.3.11 | Uncharacterized protein of 638 aas and 7 N-terminal TMSs |
Eukaryota | Metazoa | UP of Drosophila eugracilis |
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 HCMV constitutes a TMBIM-derived viroporin that may contribute to HCMV's overall strategy to counteract apoptosis of infected cells. |
Viruses | Herpesvirales | pUS21 of Human cytomegalovirus (strain Merlin) (HHV-5) (Human herpesvirus 5) |
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).
|
Eukaryota | Viridiplantae | BIL4 of Arabidopsis thaliana |
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 | GRINA of Homo sapiens |
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 | Grinaa of Danio rerio (Zebrafish) (Brachydanio rerio) |
1.A.14.3.16 | Protein lifeguard-2, 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 | |
1.A.14.3.2 | Glutamate Receptor Gr2 |
Eukaryota | Ichthyosporea | Gr2 of Capsaspora owczarzaki (E9CCY6) |
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 | Poxviridae | GAAP of Vaccinia virus, VacV (A2VCJ6) |
1.A.14.3.4 | Ionotropic glutamate receptor; N-methyl-D-aspartate-associated protein 1 (glutamate-binding). |
Eukaryota | Metazoa | Gr1 of Salmo salar (B5X2N0) |
1.A.14.3.5 | The BH3-only protein, Ynl205c (Büttner et al., 2011) |
Eukaryota | Fungi | Ynl305c of Saccharomyces cerevisiae (P48558) |
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). |
Eukaryota | Metazoa | TMBIM4 of Homo sapiens |
1.A.14.3.7 | 7 TMS integral membrane protein |
Bacteria | Planctomycetes | Uncharacterized membrane protein of Rhodopirellula baltica |
1.A.14.3.8 | Uncharacterized protein of 242 aas and 7 TMSs. |
Bacteria | Cyanobacteria | UP of Synechococcus elongatus (Anacystis nidulans R2) |
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 | CG3814 of Drosophila melanogaster (Fruit fly) |
1.A.14.4.1 | Viral protein HWLF3 (342 aas; 7 TMSs) |
Viruses | Herpesvirales | HWLF3 of human cytomegalovirus, HHV-5 (Q03307) |
1.A.14.4.2 | Viral membrane protein US14 of 286 aas and 7 TMSs. |
Viruses | Herpesvirales | US14 of Panine herpesvirus 2 (Chimpanzee cytomegalovirus) |
1.A.14.4.3 | Viral US18 protein of 274 aas and 7 TMSs |
Viruses | Herpesvirales | US18 of Human cytomegalovirus (HHV-5) (Human herpesvirus 5) |
1.A.14.4.4 | Membrane protein US12A of 250 aas and 7 TMSs |
Viruses | Herpesvirales | US12A of Simian cytomegalovirus |
1.A.14.4.5 | Membrane protein US19 of 240 aas and 7 TMSs. |
Viruses | Herpesvirales | US19 of Human cytomegalovirus (HHV-5) (Human herpesvirus 5) |
1.A.15.1.1 | Sec62 of 274 aas and 2, 3 or 4 putative TMSs (Lyman and Schekman 1997). |
Eukaryota | Fungi | Sec62 of Saccharomyces cerevisiae |
1.A.15.1.2 | Sec62 protein of 348 aas and 4 putative TMSs. |
Eukaryota | Intramacronucleata | Sec62 of Paramecium tetraurelia |
1.A.15.1.3 | Translocation protein Sec62 of 276 aas and 3 or 4 putative TMSs. |
Eukaryota | Apicomplexa | Sec62 of Plasmodium vivax |
1.A.15.1.4 | Translocation protein Sec62 of 264 aas and 4 putative TMSs. |
Eukaryota | Viridiplantae | Sec62 of Arabidopsis thaliana (Mouse-ear cress) |
1.A.15.1.5 | Protein translocation protein, Sec62, of 265 aas and 2 - 4 putative TMSs. |
Eukaryota | Viridiplantae | Sec62 of Chlorella variabilis (Green alga) |
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 | NS channel translocation protein-1 or Sec62 of Homo sapiens |
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). |
Bacteria | Proteobacteria | FocA of E. coli (P0AC23) |
1.A.16.1.2 |
Probable formate transporter 2 (Formate channel 2), FocB (Andrews et al. 1997). |
Bacteria | Proteobacteria | FocB of Escherichia coli |
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 | Proteobacteria | FocA of Vibrio cholerae (F9A868) |
1.A.16.2.1 | Formate-specific channel protein, FdhC of 280 aas (Nölling and Reeve 1997). |
Archaea | Euryarchaeota | FdhC of Methanobacterium thermoformicium |
1.A.16.2.2 | Nitrite uptake porter, NitA (Unkles et al., 1991; 2011) |
Eukaryota | Fungi | NitA of Aspergillus (Emericella) nidulans |
1.A.16.2.3 | Probable formate uptake permease (Wood et al., 2003). |
Archaea | Euryarchaeota | FdhC of Methanococcus maripaludis |
1.A.16.2.4 | Nitrite uptake porter of 355 aas, Nar1. |
Eukaryota | Viridiplantae | Nar1 of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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 | Crenarchaeota | NirC of Thermofilum pendens |
1.A.16.2.6 | Nitrite/Nitrate exporter of 476 aas, Nar1 (Cabrera et al. 2014). |
Eukaryota | Fungi | Nar1 of Pichia angusta (Yeast) (Hansenula polymorpha) |
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). |
Eukaryota | Apicomplexa | PfFNT of Plasmodium falciparum |
1.A.16.2.8 | Formate/nitrite (FNT) transporter of 356 aas and 6 TMSs. |
Eukaryota | Entamoebidae | FNT of Entamoeba histolytica |
1.A.16.3.1 | Nitrite uptake/efflux channel (Jia et al. 2009). |
Bacteria | Proteobacteria | NirC of E. coli (P0AC26) |
1.A.16.3.2 | Uncharacterized transporter YwcJ |
Bacteria | Firmicutes | YwcJ of Bacillus subtilis |
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 | Firmicutes | Hsc or Fnt3 HS- channel of Clostridium difficile (Q186B7) |
1.A.16.3.4 | Nitrite transporter, NirC, of 268 aas and 6 TMSs (Park et al. 2008). |
Bacteria | Proteobacteria | NirC of Klebsiella oxytoca |
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 | Firmicutes | FdhC of Bacillus thuringiensis |
1.A.16.4.1 | Inner membrane protein, YfdC (310aas; 6 TMSs). May be involved in surfactant resistance (Nakata et al. 2010). |
Bacteria | Proteobacteria | YfdC of E. coli (P37327) |
1.A.16.4.2 | Putative FNT transporter of 346 aas |
Bacteria | Proteobacteria | FNT transporter of Psychrobacter arcticus |
1.A.16.4.3 | FNT homologue of 313 aas |
Archaea | Euryarchaeota | FNT homologue of Salinarchaeum sp. Harcht-Bsk1 |
1.A.16.5.1 | FNT homologue of 230 aas |
Bacteria | Tenericutes | FNT homologue of Acholeplasma palmae |
1.A.16.5.2 | FNT homologue of 213 aas |
Bacteria | Tenericutes | FNT homologue of Acholeplasma laidlawii |
1.A.17.1.1 | The plasma membrane Ca2 -activated chloride (IClCa) channel, TMEM16A (Anoctamin 1a; ANO1a) (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 asCaMKIIδ (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 posthearing 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). 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). 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). 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). |
Eukaryota | Metazoa | Anoctamin 1a of Homo sapiens (Q5XXA6) |
1.A.17.1.10 | Anoctamin, Anoh-2. Present in mechanoreceptive neurons and spermatheca (Wang et al. 2013). |
Eukaryota | Metazoa | Anoh-2 of Caenorhabditis elegans |
1.A.17.1.11 | Anoctamin-like protein At1g73020 | Eukaryota | Viridiplantae | At1g73020 of Arabidopsis thaliana |
1.A.17.1.12 | Ca-ClC Family homologue |
Eukaryota | Intramacronucleata | Ca-ClC homologue of Paramecium tetraurelia (A0CAP8) |
1.A.17.1.13 | Ciliate CaClC homologue |
Eukaryota | Intramacronucleata | CaClC homologue of Paramecium tetraurelia (A0CIB0) |
1.A.17.1.14 | Water mold Anoctamin-like protein |
Eukaryota | Peronosporales | Anoctamin-like protein of Phytophthora infestans (D0NGF4) |
1.A.17.1.15 | Uncharacterized protein |
Eukaryota | Fungi | Uncharacterized protein of Schizosaccharomyces japonicus |
1.A.17.1.16 | Anoctamin-like protein |
Eukaryota | Intramacronucleata | Anoctamin-like protein of Oxytricha trifallax |
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 | Ist2 of Aspergillus fumigatus (Neosartorya fumigata) |
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). |
Eukaryota | Fungi | TMEM16 of Nectria haematococca (Fusarium solani subsp. pisi) |
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 | Ist2 of Saccharomyces cerevisiae |
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 | Anoctamin 1b of Homo sapiens (Q75UR0) |
1.A.17.1.20 | Anoctamin 3, ANO3 or KCNT1, of 981 aas and 9 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). |
ANO3 or KCNT1 of Homo sapiens |
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1.A.17.1.21 | Ano5 (GDD1, TMEM16E) of 913 aas and 10 TMSs. 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). |
Eukaryota | Metazoa | Ano5 of Homo sapiens |
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 | Subdued of Drosophila melanogaster |
1.A.17.1.23 | ANO-like protein of 921 aas and 9 predicted TMSs. |
Eukaryota | Metazoa | ANO-L family protein of Strongylocentrotus purpuratus (Purple sea urchin) |
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 | Oomycetes | Dupicated anoctamin of Aphanomyces invadans |
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). |
Eukaryota | Metazoa | Ano1 of Mus musculus |
1.A.17.1.26 | Anoctamin-1 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) aggregated, 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). |
Eukaryota | Metazoa | TMEM16K of Homo sapiens |
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).
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Eukaryota | Metazoa | ANO7 of Homo sapiens |
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 | Ano1 of Xenopus laivis |
1.A.17.1.29 | Anoctamin-4, ANO4, TMEM16D, of 955 aas and 10 putative TMSs. 68% identical to ANO4 (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). . |
Eukaryota | Metazoa | ANO4 of Homo sapiens |
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 | TMEM16B of Homo sapiens (Q9NQ90) |
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 |
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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). |
Eukaryota | Metazoa | Anoctamin-6 of Homo sapiens (Q4KMQ2) |
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 | ANO9 of Homo sapiens |
1.A.17.1.6 | Uncharacterized protein |
Eukaryota | Fungi | Uncharacterized protein of Batrachochytrium dendrobatidis |
1.A.17.1.7 | Anoctamin-like protein |
Eukaryota | Choanoflagellida | amoctamin-like protein of Dictyostelium purpureum |
1.A.17.1.8 | Uncharacterized protein |
Eukaryota | Metazoa | unchacterized protein of Aureococcus anophagefferens |
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 | Anoh-1 of Caenorhabditis elegans |
1.A.17.2.1 | DUF590 family protein |
Eukaryota | Dictyosteliida | DUF590 protein of Dicyostelium discoideum (Q54BH1) |
1.A.17.2.2 | TMEM16 homologue of 701 aas. |
Eukaryota | Heterolobosea | TMEM16 homologue of Naegleria gruberi (Amoeba) |
1.A.17.2.3 | Anoctamin homologue of 689 aas |
Eukaryota | Cryptophyta | Anoctamin of Guillardia theta |
1.A.17.2.4 | DUF590 homologue of 487 aas |
Eukaryota | Entamoeba | DUF590 homologue of Entamoeba nuttalli |
1.A.17.2.5 | DUF590 protein of 914 aas |
Eukaryota | Fungi | DUF590 protein of Allomyces macrogynus |
1.A.17.2.6 | Uncharacterized protein of 569 aas and 8 predicted TMSs. |
Eukaryota | Dictyosteliida | UP of Dictyostelium fasciculatum (Slime mold) |
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) |
1.A.17.3.10 | Uncharacterized protein of 1080 aas |
Eukaryota | Viridiplantae | UP of Ostreococcus lucimarinus |
1.A.17.3.11 | Anoctamin homologue of 1265 aas |
Eukaryota | Intramacronucleata | Anoctamin homologue of Tetrahymena thermophila |
1.A.17.3.12 | Uncharacterized protein of 995 aas and 8 TMSs. |
Eukaryota | Intramacronucleata | UP of Tetrahymena thermophila |
1.A.17.3.13 | Uncharacterized protein of 10 TMSs in a 3 + 4 +3 arrangement |
Eukaryota | Intramacronucleata | UP of Paramecium tetraurelia |
1.A.17.3.14 | Uncharacterized protein of 888 aas and 10 TMSs in a 3 + 4 + 3 arrangement |
Eukaryota | Intramacronucleata | UP of Paramecium tetraurelia |
1.A.17.3.15 | Uncharacterized protein of 958 aas and 11 or 12 TMSs in a 3 or 4 + 5 +3 arrangement. |
Eukaryota | Intramacronucleata | UP of Paramecium tetraurelia |
1.A.17.3.2 | Uncharacterized protein of 842 aas and 9 TMSs. |
Eukaryota | Bacillariophyta | UP of Thalassiosira pseudonana (Marine diatom) (Cyclotella nana) |
1.A.17.3.3 | Uncharacterized protein of 835 aas and 9 TMSs. |
Eukaryota | Peronosporales | UP of Phytophthora parasitica (Potato buckeye rot agent) |
1.A.17.3.4 | Uncharacterized protein of 1231 aas and 9 TMSs |
Eukaryota | Pelagophyceae | UP of Aureococcus anophagefferens (Harmful bloom alga) |
1.A.17.3.5 | Uncharacterized protein of 945 aas and 8 TMSs |
Eukaryota | Phaeophyceae | UP of Ectocarpus siliculosus (Brown alga) |
1.A.17.3.6 | Uncharacterized protein of 1437 aas |
Eukaryota | Isochrysidales | UP of Emiliania huxleyi |
1.A.17.3.7 | Uncharacterized protein of 1150 aas |
Eukaryota | Ichthyosporea | UP of Capsaspora owczarzaki |
1.A.17.3.8 | DUF590/putative methyltransferase of 1221 aas and 10 TMSs. |
Eukaryota | Intramacronucleata | DUF490 homologue of Oxytricha trifallax |
1.A.17.3.9 | DUF590 homologue of 1026 aas and 10 TMSs |
Eukaryota | Intramacronucleata | DUF590 homologue of Paramecium tetraurelia (ciliate) |
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 enters neonatal mouse hair cells predominantly through sensorymMechanoelectrical transduction channels, Tmc1 and Tmc2 (Makabe et al. 2020).
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Eukaryota | Metazoa | TMC2 of Mus musculus (Q8R4P4) |
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 | TMC6 of Homo sapiens |
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).
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Eukaryota | Metazoa | TMC8 of Homo sapiens |
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 | Tmc3 of Mus musculus |
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). |
Eukaryota | Metazoa | Tmc1/Tmc2/Pcdh15 complex of Danio rerio (Zebrafish) (Brachydanio rerio) |
1.A.17.4.14 | Tmc4 (MBOAT7) of 712 aas and 10 TMSs (Mancina et al. 2016). Probably transports Ca2+, and other cations. May play a role in nonalcoholic fatty liver disease (NAFLD) (Sookoian et al. 2018). |
Eukaryota | Metazoa | TMC4 of Homo sapiens |
1.A.17.4.15 | Tmc1 of 760 aas and 10 TMSs. 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 mechanoelectrical transduction (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 sensory transduction 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 mechanoelectrical transduction 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). |
Eukaryota | Metazoa | TMC1 of Homo sapiens |
1.A.17.4.16 | TMC5, of 1006 aas and 11 putative TMSs, promotes prostate cancer cell proliferation through cell cycle regulation and could be a target for treatment (Zhang et al. 2019). |
Eukaryota | Metazoa | TMC5 of Homo sapiens |
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 | TMC1 of Amphimedon queenslandica |
1.A.17.4.2 | Transmembrane channel-like protein-B, Tmc8 (EVER2). Occurs in the endoplasmic reticulum where it functions to release Ca2+ and Zn2+ and supresses Cl- currents (Sirianant et al. 2014). |
Eukaryota | Metazoa | Tmc8 of Mus musculus (Q7TN58) |
1.A.17.4.3 | Hypothetical protein, HP |
Eukaryota | Choanoflagellida | HP of Salpingoeca sp. (F2U2C0) |
1.A.17.4.4 | Hypothetical protein, HP |
Eukaryota | Ichthyosporea | HP of Capsaspora owczarzaki (E9C7I1) |
1.A.17.4.5 | Transmembrane channel-like protein 7, TMC7 |
Eukaryota | Metazoa | TMC7 of Acromyrmex echinatior (F4X8H9) |
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). |
Eukaryota | Metazoa | Tmc1 of Mus musculus |
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). |
Eukaryota | Metazoa | TMC-1 of Caenorhabditis elegans |
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). |
Eukaryota | Metazoa | Tmc2 of Caenorhabditis elegans |
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 | Tmc of Drosophila melanogaster |
1.A.17.5.1 | Uncharacterized protein, DUF221, of 703 aas |
Eukaryota | Viridiplantae | UP of Zea mays |
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 | CSC1 of Arabidopsis thaliana |
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 | CSC1 of Saccharomyces cerevisiae |
1.A.17.5.12 | The osmosensitive calcium-permeable cation channel, CSC1 or Tmem63c, of 806 aas. 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).
|
Eukaryota | Metazoa | CSC1 of Homo sapiens |
1.A.17.5.13 | Uncharacterized protein of 901 aas |
Eukaryota | Hexamitidae | UP of Spironucleus salmonicida |
1.A.17.5.14 | Uncharacterized protein of 1267 aas and 12 TMSs |
Eukaryota | Dictyosteliida | UP of Dictyostelium discoideum (Slime mold) |
1.A.17.5.15 | Uncharacterized protein of 1548 aas and 12 TMSs. |
Eukaryota | Bacillariophyta | UP of Thalassiosira pseudonana (Marine diatom) (Cyclotella nana) |
1.A.17.5.16 | Uncharacterized protein of 1172 aas |
Eukaryota | Kinetoplastida | UP of Phytomonas sp. isolate EM1 |
1.A.17.5.17 | Uncharacterized protein of 1258 aas and 11 TMSs. |
Eukaryota | Fungi | UP of Agaricus bisporus (White button mushroom) |
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 | Csc1 homologue of Candida albicans |
1.A.17.5.19 | OSCA1.2 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. |
Eukaryota | Viridiplantae | OSCA1.2 of Arabidopsis thaliana (Mouse-ear cress) |
1.A.17.5.2 | Uncharacterized protein of 816 aas containe a DUF221 domain |
Eukaryota | Metazoa | UP of Danio rerio |
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 | OSCA1.2 of Oryza sativa subsp. japonica (Rice) |
1.A.17.5.3 | Uncharacterized transmembrane protein 63B of 832 aas with a DUF221 domain. |
Eukaryota | Metazoa | UP of Homo sapiens |
1.A.17.5.4 | Uncharacterized transmembrane protein 63B of 832 aas with a DUF221 domain. |
Eukaryota | Longamoebia | UP of Acanthamoeba castellanii |
1.A.17.5.5 | Uncharacterized protein of 853 aas with a DUF221 domain. |
Eukaryota | Fungi | UP of Botryotinia fuckeliana |
1.A.17.5.6 | Phosphate metabolism protein 7, Phm7 |
Eukaryota | Fungi | Phm7 of Saccharomyces cerevisiae |
1.A.17.5.7 | Sporulation-specific protein 75, Spo75 |
Eukaryota | Fungi | Spo75 of Saccharomyce cerevisiae |
1.A.17.5.8 | RSN-1-like protein of 957 aas |
Eukaryota | Fungi | RSN-1-like protein of Saccharomyces kudriavzevii |
1.A.17.5.9 | Early response to dehydrate stress protein, ERD4 of 785 aas |
Eukaryota | Viridiplantae | ERD4 of Arabidopsis thaliana |
1.A.17.6.1 | Uncharacterized protein of 878 aas and 7 putative TMSs. |
Eukaryota | Intramacronucleata | UP of Oxytricha trifallax |
1.A.17.6.10 | Uncharacterized protein of 707 aas and 10 TMSs |
Eukaryota | Plasmodiophoridae | UP of Plasmodiophora brassicae |
1.A.17.6.2 | TMC-like protein 8 of 890 aas and 8 TMSs |
Eukaryota | Intramacronucleata | TMC homologue of Oxytricha trifallax |
1.A.17.6.3 | Uncharacterized protein of 834 aas and 7 TMSs |
Eukaryota | Intramacronucleata | UP of Oxytricha trifallax |
1.A.17.6.4 | Uncharacterized protein of 912 aas and 10 TMSs |
Eukaryota | Peronosporales | UP of Phytophthora parasitica (Potato buckeye rot agent) |
1.A.17.6.5 | Uncharacterized protein of 620 aas and 9 TMSs |
Eukaryota | Phaeophyceae | UP of Ectocarpus siliculosus (Brown alga) |
1.A.17.6.6 | Uncharacterized protein of 865 aas and 10 TMSs |
Eukaryota | Cryptophyta | UP of Guillardia theta |
1.A.17.6.7 | TMC protein of 890 aas and 10 TMSs |
Eukaryota | Intramacronucleata | TMC protein of Tetrahymena thermophila |
1.A.17.6.8 | Uncharacterized protein of 1057 aas and 10 TMSs. |
Eukaryota | Intramacronucleata | UP of Tetrahymena thermophila |
1.A.17.6.9 | Uncharacterized protein of 867 aas and 10 TMSs. |
Eukaryota | Oomycetes | UP of Saprolegnia diclina |
1.A.17.7.1 | Uncharacterized protein of 836 aas and 12 TMSs. |
Eukaryota | Hexamitidae | UP of Giardia intestinalis (Giardia lamblia) |
1.A.17.7.2 | Uncharacterized protein of 637 aas and 8 TMSs. |
Eukaryota | Hexamitidae | UP of Spironucleus salmonicida |
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 | Hexamitidae | Anoctamin homologue of Spironucleus salmonicida |
1.A.17.7.4 | Uncharacterized Anoctamin homologue of 502 aas and 8 putative TMSs |
Eukaryota | Hexamitidae | UP of Spironucleus salmonicida |
1.A.17.7.5 | Uncharacterized anoctamin homologue of 823 aas and 8 predicted TMSs in a 3 + 2 + 3 arrangement. |
Eukaryota | Hexamitidae | UP of Giardia intestinalis (Giardia lamblia) |
1.A.18.1.1 | Protein import-related anion-selective channel, Tic110 | Eukaryota | Viridiplantae | 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 | Bangiophyceae | Tic110 of Cyanidioschyzon merolae (M1V6H9) |
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). |
Viruses | Orthomyxoviridae | M2 of influenza virus type A |
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. |
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 | Orthomyxoviridae | M2 of Influenza A virus (A/swine) |
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. |
Viruses | Orthomyxoviridae |
AM2 of Influenza A virus (A/herring gull/Newfoundland) |
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 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). |
Eukaryota | Metazoa | IRK1 of Homo sapiens (P48048) |
1.A.2.1.10 |
G-protein-activated inward rectifying K+ channel, Kir3.2, KATP2, KCNJ7 or GIRK2 of 423 aas (Inanobe et al., 2011; Yokogawa et al. 2011). Important in regulating heart rate and neuronal excitability. Activated by binding of the βγ-subunit complex to the cytoplasmic pore gate (Yokogawa et al. 2011). Chen et al. 2017 found that the G-protein-gated inwardly rectifying K+ (GIRK) channel is activated by Ivermectin (IVM) directly. 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 is likely to lead 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 the channel domain movements to control gate transitions. Na+ controls the cytosolic gate of the channel through an anti-clockwise rotation, whereas Gbetagamma 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 stabilized the open states of the respective gates (Li et al. 2019). |
Eukaryota | Metazoa | Kir3.2 of Homo sapiens (P48051) |
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. 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). |
Eukaryota | Metazoa | KCNJ16 of Homo sapiens |
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). |
Eukaryota | Metazoa | Kir3.1 (IRK3) of Homo sapiens (P48549) |
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). |
Eukaryota | Metazoa | Kir6.1 of Homo sapiens (Q15842) |
1.A.2.1.14 | Inward rectifying potassium (K+) (IRK) channel of 426 aas and 2 TMSs, AgaP. |
Eukaryota | Metazoa | AgaP of Anopheles gambiae (African malaria mosquito) |
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 | Kir1 of Anopheles gambiae (African malaria mosquito) |
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). |
Eukaryota | Metazoa | Kir4.1 of Homo sapiens |
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). |
Eukaryota | Metazoa | Kir6.2 of Homo sapiens |
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).
|
Eukaryota | Metazoa | KMCJ4 of Homo sapiens |
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 | GIRK3 of Homo sapiens |
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). |
Eukaryota | Metazoa | IRK2 of Homo sapiens (P63252) |
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). 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). |
Eukaryota | Metazoa | IRK5 of Homo sapiens (P48544) |
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 | Kir4.2 of Rattus norvegicus (Q91ZF1) |
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 | Kir2.4 of Rattus norvegicus (O70596) |
1.A.2.1.6 | ATP-sensitive K+ channel, Kir6.3 (Zhang et al., 2005) | Eukaryota | Metazoa | 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 | ROMK of Rattus norvegicus (P70673) |
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. |
Eukaryota | Metazoa | Kir 7.1 or KCNJ13 of Homo sapiens (O60928) |
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). |
Eukaryota | Metazoa | Kir2.2 of Homo sapiens (Q14500) |
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). The 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 a unique 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 initiates 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). |
Bacteria | Proteobacteria | KirBac1.1 OF Burkholderia pseudomallei (IP7BA; gi33357898) |
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). |
Bacteria | Proteobacteria | KirBac3.1 of Magnetospirillum magnetotacticum (D9N164) |
1.A.2.2.3 |
ATP-sensitive inward rectifying Kir K channel (Choi et al. 2010). |
Bacteria | Proteobacteria | Kir K+ channel of Chromobacterium violaceum |
1.A.2.2.4 | Putative K+ channel |
Bacteria | Cyanobacteria | K+ channel of Synechocystis PCC 6803 |
1.A.2.2.5 | Inward rectifier potassium channel |
Bacteria | Proteobacteria | K+ channel of Burkholderia xenovorans |
1.A.20.1.1 | BNip3 channel-forming protein (Bocharov et al., 2007) | Eukaryota | Metazoa | BNip3 of Homo sapiens (Q12983) |
1.A.20.1.2 | NIP3L (NIP3-like protein X; Adenovirus E1B 19kDa-binding protein B5). |
Eukaryota | Metazoa | NIP3L of Homo sapiens (O60238) |
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 | BCL2 of Aquila chrysaetos canadensis |
1.A.20.2.1 | BCL2/Adenovirus E1B interacting protein, NIP3 |
Eukaryota | Metazoa | NIP3 of Caenorhabditis elegans (Q09969) |
1.A.20.2.2 | NIP2-like protein of 195 aas and 1 C-terminal TMS |
Eukaryota | Metazoa | NIP3 of Trichinella spiralis (Trichina worm) |
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). |
Eukaryota | Metazoa | Bcl-X(L) of Homo sapiens |
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). |
Eukaryota | Metazoa | Bcl-2 of Homo sapiens |
1.A.21.1.11 | Apoptosis regulator BAX-like isoform X2, of 198 aas and 2 or 3 TMSs. |
Eukaryota | Metazoa | BAX-like protein of Perca flavescens (yellow perch) |
1.A.21.1.12 | The Cell Death (CED-9) protein (Siskind et al., 2008) | Eukaryota | Metazoa | CED-9 of Caenorhabditis elegans (P41958) |
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). |
Eukaryota | Metazoa | BAX of Homo sapiens (Q07812) |
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). |
Eukaryota | Metazoa | BAK of Homo sapiens (Q16611). |
1.A.21.1.4 | The BH3-only (Mcl-1) protein (mediates apoptosis). (3-d strucure known) |
Eukaryota | Metazoa | BH3-only of Homo sapiens (B4DG83) |
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 | Bcl-w of Homo sapiens |
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 | Bcl-XL of Xenopus laevis (African clawed frog) |
1.A.21.1.7 | Pore-forming Bcl-2-related ovarian killer protein, Bok of 212 aas and 2 or more predicted TMSs. 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).
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Eukaryota | Metazoa | Bok of Homo sapiens |
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 | Death executioner of Locusta migratoria (migratory locust) |
1.A.21.1.9 | Uncharacterized protein of 224 aas and 2 TMSs. |
Eukaryota | Metazoa | UP of Nematostella vectensis (Starlet sea anemone) |
1.A.21.2.1 | BH3-interacting domain death agonist of 199 aas and 2 or 3 putative TMSs. |
Eukaryota | Metazoa | BH3-interacting agonist of Tachysurus fulvidraco (yellow catfish) |
1.A.21.2.2 | BH3-interacting domain death agonist-like isoform X3 of 204 aas and 2 or 3 TM |
Eukaryota | Metazoa | Death agonists of Boleophthalmus pectinirostris (great blue-spotted mudskipper) |
1.A.21.2.3 | Uncharacterized protein of 207 aas and 2 or 3 TMSs. |
Eukaryota | Metazoa | UP of Lepisosteus oculatus (spotted gar) |
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 | BID of Homo sapiens |
1.A.21.2.5 | BH3-interacting domain death agonist isoform X3 of 241 aas and 2 or 3 TM |
Eukaryota | Metazoa | Death agonist of Phocoena sinus |
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). |
Bacteria | Proteobacteria | MscL of E. coli (P0A742) |
1.A.22.1.10 | Osmotic adaptation channel that influences sporulation and secondary metabolite production, Sco3190 (MscL) (Wang et al. 2007). |
Bacteria | Actinobacteria | Sco3190 of Streptomyces coelicolor. |
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). |
Archaea | Euryarchaeota | MscL of Methanosarcina acetivorans |
1.A.22.1.12 | MscL protein of 171 aas and 2 or 3 TMSs. |
Eukaryota | Florideophyceae | MscL of Chondrus crispus (Carrageen Irish moss) (Polymorpha crispa) |
1.A.22.1.13 | Putative large-conductance mechanosensitive channel of 101 aas and 2 TMSs. |
Viruses | MscL channel of Tetraselmis virus 1 |
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1.A.22.1.14 | MscL homologue of 101 aas and 2 TMSs. |
Viruses | Mimiviridae | MscL of Cafeteria roenbergensis virus BV-PW1]. |
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 | Actinobacteria | MscL of Mycobacterium tuberculosis (P0A5K8) |
1.A.22.1.3 | MscL; catalyzes ion and osmolyte release following osmmotic downshift | Bacteria | Firmicutes | 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 | Proteobacteria | MscL of Rhizobium etli (Q2KCQ1) |
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 | Firmicutes | MscL of Staphylococcus aureus (P68805) |
1.A.22.1.6 | MscL; rescues cells form osmotic downshift (Bucarey et al., 2012). |
Bacteria | Actinobacteria | MscL of Micromonospora aurantica (D9T6D3) |
1.A.22.1.7 | Large-conductance mechanosensitive channel, MscL |
Bacteria | Cyanobacteria | MscL of Synechococcus sp. |
1.A.22.1.8 | Bacteria | Firmicutes | MscL of Leuconostoc citreum |
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1.A.22.1.9 | Bacteria | Actinobacteria | 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). 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 | Proteobacteria | KefA (AefA) of E. coli |
1.A.23.1.2 | The putative osmoadaptation receptor, BspA | Bacteria | Proteobacteria | 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 | Proteobacteria | YjeP of E. coli (P39285) |
1.A.23.1.4 | Uncharacterized protein of 571 aas and 6 TMSs. |
Bacteria | Proteobacteria | UP of Bdellovibrio exovorus |
1.A.23.1.5 | Mechanosensitive ion channel, MscS, of 952 aas and 10 TMSs. |
Bacteria | Proteobacteria | MscS of Legionella sp. |
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). |
Bacteria | Proteobacteria | YggB of E. coli (P0C0S1) |
1.A.23.2.2 | MscS protein. The x-ray structure at 4.2 Å is available (Lai et al. 2013). |
Bacteria | Proteobacteria | MscS of Helicobacter pylori |
1.A.23.2.3 | MscS mechanosensitive channel of 462 aas and 5 TMSs. |
Bacteria | Candidatus Peregrinibacteria | MscS channel of Candidatus Peribacter riflensis |
1.A.23.2.4 | Putative small conductance mechanosensetive channel protein of 261 aas and 3 TMSs |
Viruses | Phycodnaviridae | MscS homologue of Aureococcus anophagefferens virus |
1.A.23.3.1 | The YkuT osmolyte efflux channel | Bacteria | Firmicutes | 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 | Proteobacteria | YbiO of E. coli (P75783) |
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 | Actinobacteria | YggB or MscCG of Corynebacterium glutamicum (P42531) |
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 | Actinobacteria | MscCG2 of Corynebacterium glutamicum |
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 | Actinobacteria | Msc1 of Corynebacterium glutamicum |
1.A.23.4.1 | The MscMJ mechanosensitive channel | Archaea | Euryarchaeota | MscMJ of Methanococcus jannaschii |
1.A.23.4.10 | Uncharacterized MscS homologue |
Bacteria | Proteobacteria | MscS homologue of Helicobacter pylori |
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 | MSL1 of Arabidopsis thaliana |
1.A.23.4.12 | Uncharacterized MscS channel of 351 aas and 4 N-terminal TMSs. |
Bacteria | Proteobacteria | UP of Bdellovibrio bacteriovorus |
1.A.23.4.13 | MscS channel of 553 aas and 6 TMSs. |
Eukaryota | Entamoebidae | MscS of Entamoeba histolytica |
1.A.23.4.14 | Mechanosensitive channel-like 10, Msl10 of 734 aas and 5 or more TMSs. Functions in triggering cell death in a process that is independent of its channel activity (Maksaev et al. 2018). |
Eukaryota | Viridiplantae | Mscl10 of Arabidopsis thaliana (Mouse-ear cress) |
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 | MSL4 of Arabidopsis thaliana |
1.A.23.4.2 | The MscMJLR mechanosensitive channel | Archaea | Euryarchaeota | MscMJLR of Methanococcus jannaschii |
1.A.23.4.3 | Mechanosensative cation-selective channel with a conductance of 100 pS, YnaI (344aas; 4TMSs). Protects against hypoosmotic shock (Edwards et al. 2012). The structure has been solved by cryo-electron microscopy to a resolution of 13 A (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. |
Bacteria | Proteobacteria | YnaI of E. coli (P0AEB5) |
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 | Msl2 of Arabidopsis thaliana (Q56X46) |
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 | Proteobacteria | MscM (YbdG) of E. coli (P0AAT4) |
1.A.23.4.6 | Mechanosensitive channel, MscS |
Archaea | Crenarchaeota | MscS of Sulfolobus islandicus (C4KE93) |
1.A.23.4.7 | Mechanosensitive ion channel protein 8 (Mechanosensitive channel of small conductance-like 8) (MscS-Like protein 8) 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). |
Eukaryota | Viridiplantae | MSL8 of Arabidopsis thaliana |
1.A.23.4.8 | Mechanosensitive ion channel protein 5 (Mechanosensitive channel of small conductance-like 5) (MscS-Like protein 5) | Eukaryota | Viridiplantae | MSL5 of Arabidopsis thaliana |
1.A.23.4.9 | Putative small conductance mechanosensitive channel; Calcium channel, MacS |
Eukaryota | Fungi | MacS of Mycosphaerella graminicola (Zymoseptoria tritici) |
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 | Actinobacteria | MscS homologue, MT2508 of Mycobacterium tuberculosis (P71915) |
1.A.23.6.1 | Chloroplast mechanosensitive channel, Msc1 (anions are preferred over cations) (Nakayama et al., 2007). | Eukaryota | Viridiplantae | Msc1 of Chlamydomonas reinhardtii (A3KE12) |
1.A.23.7.1 | MscS homologue |
Bacteria | Actinobacteria | MscS homologue of Streptomyces coelicolor |
1.A.23.7.2 | MscS homologue |
Bacteria | Proteobacteria | MscS of Myxococcus xanthus |
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). |
Bacteria | Proteobacteria | CmpX of Pseudomonas aeruginosa |
1.A.23.8.2 | CmpX protein of 227 aas and 5 TMSs |
Bacteria | Candidatus Wolfebacteria | CmpX of Candidatus Wolfebacteria bacterium |
1.A.23.8.3 | Uncharacterized protein of 439 aas and 9 TMSs in a 5 + 4 arrangement. |
Bacteria | Proteobacteria | UP of Brevundimonas viscosa |
1.A.23.8.4 | Mechanosensitive ion channel protein MscS of 254 aas and 5 TM |
Archaea | Euryarchaeota | MscS of Haloterrigena daqingensis |
1.A.23.8.5 | Uncharacterized protein of 486 aas and 11 TMSs. |
Bacteria | Proteobacteria | UP of Hydrogenophaga taeniospiralis |
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). |
Eukaryota | Metazoa | CX43 of Rattus norvegicus |
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 | Cx31 of Homo sapiens |
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). |
Eukaryota | Metazoa | Cx43 of Danio rerio (Zebrafish) (Brachydanio rerio) |
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 | Cx29 of Mus musculus |
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 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). 31658316 |
Eukaryota | Metazoa | Cx36 of Homo sapiens |
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).
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Eukaryota | Opisthokonta | GJB4 of Homo sapiens |
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 | CX32 of Rattus norvegicus |
1.A.24.1.3 | Heteromeric connexin (Cx)32/Cx26) (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). 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 autosomal recessive sensorineural deafness (Leshinsky-Silver et al. 2005). |
Eukaryota | Metazoa | Cx26/Cx32 of Homo sapiens |
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 | Connexin 35 of Danio rerio (Zebrafish) (Q8JFD6) |
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). |
Eukaryota | Metazoa | Cx46/Cx50 of Homo sapiens: |
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 | Connexin37 of Homo sapiens (P35212) |
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). |
Eukaryota | Metazoa | Cx30.2 of Homo sapiens (Q8NFK1) |
1.A.24.1.8 | Connexin40 (Cx40; Gap Junction Protein δ4; GJδ4) of 370 aas and 4 TM (Kopanic et al. 2015). |
Eukaryota | Metazoa | Cx40 of Homo sapiens |
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 | Gjf1 of Mus musculus |
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. | Eukaryota | Metazoa | Connexin 47 of Mus musculus (Q8BQU6) |
1.A.24.2.2 | Invertebrate cordate Connexin 47 (White et al., 2004). |
Eukaryota | Metazoa | Connexin 47 of Halocynthia pyriformis (Q6U1M0) |
1.A.24.2.3 | Inverebrate cordate Connexin (Hervé et al., 2005). |
Eukaryota | Metazoa | Connexin of Oikopleura dioica (E4YIP4) |
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 | Cx45 of Homo sapiens |
1.A.25.1.1 | Invertebrate innexin, (gap junction protein), INX3 | Eukaryota | Metazoa | INX3 of C. elegans |
1.A.25.1.10 | Leech innexin, Inx2 (Kandarian et al. 2012; Firme et al. 2012) |
Eukaryota | Metazoa | Inx2 of Hirudo verbana |
1.A.25.1.11 | Duplicated innexin of 801 aas and 8 TMSs. |
Eukaryota | Metazoa | Innexin of Ascaris suum |
1.A.25.1.12 | Duplicated innexin protein of 813 aas and 8 TMSs. |
Eukaryota | Metazoa | Duplicated innexin of Trichinella spiralis (Trichina worm) |
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 | Inx2 of Spodoptera litura (Asian cotton leafworm) |
1.A.25.1.2 | Invertebrate innexin, UNC-7 | Eukaryota | Metazoa | UNC-7 of C. elegans |
1.A.25.1.3 | Invertebrate innexin, Ogre | Eukaryota | Metazoa | Ogre of Drosophila melanogaster |
1.A.25.1.4 | Invertebrate innexin, passover protein (shaking B locus) | Eukaryota | Metazoa | 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 | NSY-5 (INX-19) of Caenorhabditis elegans (NP_490983) |
1.A.25.1.6 | Innexin-14 (Protein Opu-14) |
Eukaryota | Metazoa | Inx-14 of Caenorhabditis elegans |
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 | Inx-6 of Caenorhabditis elegans |
1.A.25.1.8 | Innexin Inx4 (Innexin-4) (Protein zero population growth) |
Eukaryota | Metazoa | Zpg of Drosophila melanogaster |
1.A.25.1.9 |
Leech innexin, Inx6 (Kandarian et al. 2012; Firme et al. 2012) |
Eukaryota | Metazoa | Inx6 of Hirudo verbana |
1.A.25.2.1 | Pannexin-1 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. |
Eukaryota | Metazoa | Pannexin-1 of Homo sapiens |
1.A.25.2.2 | Pannexin1 and pannexin2 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). |
Eukaryota | Metazoa | Pannexin-2 of Homo sapiens (Q96RD6) |
1.A.25.2.3 | Pannexin-3 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). |
Eukaryota | Metazoa | Pannexin-3 of Homo sapiens (gi16418453) |
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 | Panx1a of Danio rerio (Zebrafish) (Brachydanio rerio) |
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). 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). |
Eukaryota | Metazoa | The VRAC channel consisting of LRRC8A together with one or two of the subunits, LRRC8B, LRRC8C, LRRC8D and/or LRRC8E of Homo sapiens (Q8IWT6) |
1.A.25.3.2 | The LRRC8B homologue of 480 aas |
Eukaryota | Metazoa | LRRC8B of Ciona intestinalis (Transparent sea squirt) (Ascidia intestinalis) |
1.A.25.3.3 | Uncharacterized protein of 467 aas |
Eukaryota | Metazoa | UP of Branchiostoma floridae (Florida lancelet) (Amphioxus) |
1.A.25.3.4 | Uncharacterized ADP-binding protein of 1311 aas and 2 TMSs. May be involved in defense responses. |
Eukaryota | Viridiplantae | UP of Oryza sativa |
1.A.25.3.5 | Volume-regulated anion channel subunit LRRC8B-likeof 666 aas and 4 TMSs. |
Eukaryota | Metazoa | LRRC8B of Mizuhopecten yessoensis |
1.A.25.3.6 | Uncharacterized protein of 610 aas and 4 TMSs. It is of the Pannexin-like Superfamily. |
Eukaryota | Metazoa | UP of Thelohanellus kitauei |
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 | LRRC59 of Homo sapiens |
1.A.26.1.1 | Mg2+, Co2+ transporter, MgtE (Smith et al. 1995). |
Bacteria | Firmicutes | MgtE of Bacillus firmus (Q45121) |
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 homoldimer with the channel at the interface of the two subunits. There's a plug at the cytoplasmic face. It can bind Mg2+, Mn2+ and Ca2+. |
Bacteria | Deinococcus-Thermus | MgtE of Thermus thermophilus (Q5SMG8) |
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 | Firmicutes | MgtE of Bacillus subtilis |
1.A.26.1.4 | Mg2+, Co2+ transporter, MgtE |
Bacteria | Proteobacteria | MgtE of Providencia stuartii (Q52398) |
1.A.26.1.5 | MgtE homologue (function unknown) |
Archaea | Euryarchaeota | MgtE homologue of Methanobacterium thermoautotrophicum (O26717) |
1.A.26.1.6 | MgtE homologue of 469 AAs and 5 OR 6 TMSs (Pohland and Schneider 2019). |
Bacteria | Cyanobacteria | MgtE of Prochlorococcus marinus |
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 | Proteobacteria | FicI of Shewanella oneidensis |
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. |
Eukaryota | Metazoa | SLC41A1 of Homo sapiens |
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 | SLC41A2 of Homo sapiens |
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 | SLC41A3 of Homo sapiens |
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 | MagT of Caenorhabditis elegans |
1.A.26.3.1 | MgtE of 251 aas and 5 TMSs |
Archaea | Euryarchaeota | MgtE of Natrinema gari |
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 | PLM of Canis familiaris |
1.A.27.1.2 | Cl- conductance inducer protein, Mat-8, of 88 aas and 1 TMS. |
Eukaryota | Metazoa | Mat-8 of Mus musculus |
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). |
Eukaryota | Metazoa | FXYD6 of Homo sapiens (Q9H0Q3) |
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). |
Eukaryota | Metazoa | CHIF of Rattus norvegicus |
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). |
Eukaryota | Metazoa | FXYD3 of Homo sapiens |
1.A.27.1.6 | FXYD4 of 89 aas and 1 TMS. |
Eukaryota | Metazoa | FXYD4 of Homo sapiens |
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 | FXYD7 of Homo sapiens |
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). |
Eukaryota | Metazoa | PLM of Homo sapiens |
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 | FXYD2 channel and γ-subunit of the Na+,K+-ATPase of Homo sapiens |
1.A.27.2.2 | Sodium/potassium-transporting ATPase subunit gamma isoform X1of 82 aas and 1 TMS. |
Eukaryota | Metazoa | γ-subunit of Pseudopodoces humilis |
1.A.27.2.3 | Sodium/potassium-transporting ATPase subunit gamma of 61 aas and 1 TMS. |
Eukaryota | Metazoa | γ-subunit of Xenopus tropicalis (tropical clawed frog) |
1.A.27.2.4 | Sodium/potassium-transporting ATPase subunit gamma isoform X1 |
Eukaryota | Metazoa | Na+, K+-ATPase regulator of Mus pahari (shrew mouse) |
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 | γ-subunit of Sus scrofa (pig) |
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 | FXYD5 of Homo sapiens (178 aas; Q96DB9) |
1.A.27.3.2 | FXYD domain-containing ion transport regulator 5-like isoform X2 of 89 aas and 2 TMSs. |
Eukaryota | Metazoa | FXYD regulator of Ornithorhynchus anatinus (platypus) |
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 | FXYD domain protein of Carassius auratus (goldfish) |
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 | FXYD domain protein of Denticeps clupeoides (denticle herring) |
1.A.27.3.5 | FXYD domain-containing ion transport regulator 5-like isoform X2 of 170aas and 2 TMSs. |
Eukaryota | Metazoa | FXYD domain protein of Rhinatrema bivittatum (two-lined caecilian) |
1.A.28.1.1 | Kidney vasopressin regulated urea transporter, UT-A2 (splice variant of UT-A1) | Eukaryota | Metazoa | 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) |
1.A.28.1.3 | Kidney urea transporter, UT-A1 (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 | UT-A1 of Rattus norvegicus |
1.A.28.1.4 | THe Urea transporter channel protein of 337 aas and 11 TMSs. 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 | Proteobacteria | Urea channel of Desulfovibrio vulgaris (A1VEP3) |
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 | SLC14A1 of Homo sapiens |
1.A.28.1.6 | Urea transporter 2 (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). |
Eukaryota | Metazoa | SLC14A2 of Homo sapiens |
1.A.28.1.7 | Putative urea transporter of 306 aas and 9 TMSs |
Bacteria | Proteobacteria | UT of E. coli |
1.A.28.2.1 | The dimeric urea transporter, Utp (urea flux is saturable, could be inhibited by phloretin, and was not affected by pH; Raunser et al., 2009) | Bacteria | Proteobacteria | Utp of Actinobacillus pleuropneumoniae |
1.A.29.1.1 | Putative amide transporter (AmiS) (Wilson et al., 1995). |
Bacteria | Proteobacteria | AmiS of Pseudomonas aeruginosa |
1.A.29.1.2 | Putative amide transporter (AmiS) | Bacteria | Actinobacteria | 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 | Proteobacteria | UreI of Helicobacter pylori |
1.A.29.1.4 | Urea transporter channel (UreI) (pH-insensitive) | Bacteria | Firmicutes | UreI of Streptococcus salivarius |
1.A.29.1.5 | Urea transporter channel (UreI) (pH-sensitive) | Bacteria | Proteobacteria | 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 | Firmicutes | UreI of Bacillus cereus (Q814I5) |
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). 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). |
Eukaryota | Metazoa | Cardiac muscle RyR-CaC of Homo sapiens |
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 | RyR of Sesamia inferens (pink stem borer) |
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). |
Eukaryota | Metazoa | RyR1 of Homo sapiens (P21817) |
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 | RyRi of Anopheles gambiae (Q7PMK5) |
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 | RyR of Pieris rapae (white cabbage butterfly) |
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 | RyR of Drosophila melanogaster (Fruit fly) |
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 | RyR of Caenorhabditis elegans |
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). |
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 | RyR of Dialeurodes citri (Citrus whitefly) (Aleurodes citri) |
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 | RyR1 of Plutella xylostella (Diamondback moth) (Plutella maculipennis) |
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 | Brain IP3-CaC of Rattus norvegicus |
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 | Intramacronucleata | CRCIII1a of Paramecium tetraurelia |
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 | Intramacronucleata | CRCIV3b of Paramecium tetraurelia |
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 | Intramacronucleata | CRCV4b of Paramecium tetraurelia |
1.A.3.2.13 | Calcium release channel VI-2b, CRCVI2b. Localized to the contractile vacuole (Docampo et al. 2013). |
Eukaryota | Intramacronucleata | CRCVI2b of Paramecium tetraurelia |
1.A.3.2.14 | Endoplasmic reticular inositol triphosphate receptor, IP3R of 3099 aas (Docampo et al. 2013). |
Eukaryota | Kinetoplastida | IP3R of Trypanosoma brucei |
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 | IP3 receptor of Caenorhabditis elegans |
1.A.3.2.17 | IP3R of 3140 aas, RyR1 (Wheeler and Brownlee 2008). |
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 | InsP3l receptor Drosophila melanogaster (P29993) |
1.A.3.2.3 | The cation channel family protein, IsnP3-like protein (2872aas) | Eukaryota | Intramacronucleata | InsP3-like protein of Tetrahymena themophila (Q23K98) |
1.A.3.2.4 | The Inositol 1,4,5- triphosphate (InsP3)-like receptor (3036aas) (Ladenburger et al. 2009; Docampo et al. 2013). |
Eukaryota | Intramacronucleata | InsP3l receptor of Paramecium tetraaurelia (A0CX44) |
1.A.3.2.5 | Inositol 1,4,5-triphosphate receptor type 1 splice variant, IP(3)R1 (Subedi et al., 2012). The human orthologue, IP3R3, is regulated at the ER-mitochondrion interface by BCL-XL (TC# 1.A.21.1.6) (Williams et al. 2016). |
Eukaryota | Metazoa | IP(3)R1 of Rattus norvegicus (Q63269) |
1.A.3.2.6 | Inositol 1,4,5-trisphosphate receptor type 1 (IP3 receptor isoform 1) (IP3R 1) (InsP3R1) (Type 1 inositol 1,4,5-trisphosphate receptor) (Type 1 InsP3 receptor) | Eukaryota | Metazoa | ITPR1 of Homo sapiens |
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 | Intramacronucleata | IP3Rn or CRCII of Paramecium trtraurelia |
1.A.3.2.8 | Putative IP3R calcium-release channel VI-3 of 2021 aas (Docampo et al., 2013). |
Eukaryota | Intramacronucleata | Calcium-release channel VI-3 of Paramecium tetraurelia |
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 | Intramacronucleata | CRCI-1a of Paramecium tetraurelia |
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 | Proteobacteria | MotA and MotB of E. coli |
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). |
Bacteria | Proteobacteria | PomAB/MotXY of Vibrio alginolyticus |
1.A.30.1.3 | The flagellar motor (pmf-dependent) (MotAB) (Ito et al., 2004) |
Bacteria | Firmicutes | MotAB of Bacillus subtilis |
1.A.30.1.4 | The flagellar motor (smf-dependent) (MotPS) (Ito et al., 2004) |
Bacteria | Firmicutes | MotPS (YtxDE) of Bacillus subtilis |
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 | Proteobacteria | The H+-driven flagellar motor complex of Shewanella oneidensis |
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 | Proteobacteria | The Na+-driven flagellar motor complex of Shewanella oneidensis |
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 | Proteobacteria | The TonB system of E. coli |
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 | Cyanobacteria | ExbBD of Synechocystis sp. (strain PCC 6803 / Kazusa) |
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 | Cyanobacteria | ExbB/ExbD/ExbD' of Synechocystis sp. (strain PCC 6803 / Kazusa) |
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). |
Bacteria | Proteobacteria | The TolA system of E. coli |
1.A.30.2.3 |
Putative TolA Energizer, TolQ1/TolR1 |
Bacteria | Proteobacteria | TolQ1/R1 of Myxococcus xanthus |
1.A.30.2.4 |
Putative TolA Energizer, TolQ2/TolR2 |
Bacteria | Proteobacteria | TolQ2/R2 of Myxococcus xanthus |
1.A.30.2.5 |
Putative TolA Energizer, TolQ3/TolR3 |
Bacteria | Proteobacteria | TolQ3/R3 of Myxococcus xanthus |
1.A.30.2.6 |
Putative TolA Energizer, TolQ4/TolR4 |
Bacteria | Proteobacteria | TolQ4/R4 of Myxococcus xanthus |
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 | Proteobacteria | TolQ5/R5 or AglX/AglV of Myxococcus xanthus |
1.A.30.2.8 | The putative ExbBD energizer (H+-channel). |
Bacteria | Spirochaetes | ExbBD of Leptospira interrogans |
1.A.30.2.9 | TolQ/TolR |
Bacteria | Spirochaetes | TolQ/R of Leptospira interrogans |
1.A.30.3.1 | TolQ (DUF2149)/TolR |
Bacteria | Proteobacteria | TolQ/TolR of Geobacter sp. M18 |
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 | Proteobacteria | AglQ/AglR of Myxococcus xanthus |
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 | Proteobacteria | AglRSV of Bdellovibrio bacteriovorus |
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 | Proteobacteria | AglR/S/S' of Bdellovibrio bacteriovorus |
1.A.30.4.1 | SiiAB putative energizer of giant adhesin, SiiE (repetitive 5,559 aa protein) export (Wille et al. 2013). |
Bacteria | Proteobacteria | SiiAB of Salmonella enterica |
1.A.30.4.2 | SiiA/B (MotB/A) homologues of 236 and 362 aas with 1 and 4 putative TMSs, respectively. |
Bacteria | Proteobacteria | SiiA/B of Sulfurimonas denitrificans (Thiomicrospira denitrificans) |
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 | Proteobacteria | SiiA/B homologues of Desulfovibrio salexigens |
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 | Proteobacteria | UP of Bdellovibrio bacteriovorus |
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 | Proteobacteria | ZorAB of Xanthobacter autotrophicus Py2 |
1.A.30.6.2 | ZorA/ZorB (MotAB homologues) of 704 aas with 3 TMSs and 254 aas with 1 N-terminal TMS. |
Bacteria | Proteobacteria | ZorAB of Pseudomonas aeruginosa |
1.A.30.6.3 | ZorA/ZorB components of an anti-phage defense system (Doron et al. 2018). |
Bacteria | Proteobacteria | ZorAB of Acinetobacter baumannii |
1.A.30.6.4 | ZorAB, putative H+ channel proteins, MotAB homologues, functioning in defense against phage attack (Doron et al. 2018). |
Bacteria | Proteobacteria | ZorAB of E. coli PA10 |
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 | Firmicutes | ZorAB of Acidaminococcus fermentans DSM 20731 |
1.A.30.6.6 | ZorA (673 aas amd 3 - 4 TMSs)/ZorB (248 aas and 1 N-terminal TMS) |
Bacteria | Cyanobacteria | ZorAB of Prochlorothrix hollandica PCC 9006 |
1.A.30.6.7 | ZorAB |
Bacteria | Thermotogae | ZorAB of Thermosipho africanus |
1.A.30.6.8 | ZorA (472 aas and 3 TMSs)/ZorB (222 aas and 1 N-terminal TMS. |
Bacteria | Bacteroidetes | ZorAB of Spirosoma linguale |
1.A.31.1.1 | Annexin X | Eukaryota | Metazoa | Annexin X of Drosophila melanogaster |
1.A.31.1.2 | Annexin VI | Eukaryota | Metazoa | Annexin VI of Homo sapiens (673 aas; P08133) |
1.A.31.1.3 | Annexin A1 (McNeil et al., 2006) |
Eukaryota | Metazoa | Annexin A1 of Homo sapiens (346 aas; P04083) |
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). |
Eukaryota | Metazoa | Annexin 2 of Homo sapiens |
1.A.31.1.5 | Non-selective cation channel-forming annexin 1 of 313 aas, Ann1 (Kodavali et al. 2013). |
Eukaryota | Viridiplantae | Ann1 of Medicago truncatula |
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 | Annexin B22 of Schistosoma mansoni |
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 | Annexin A5 of Homo sapiens |
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 | Annexin 1D of Arabidopsis thaliana (Mouse-ear cress) |
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 | Annexin-12 of Hydra vulgaris |
1.A.32.1.1 | NB glycopeptide | Viruses | Orthomyxoviridae | NB of influenza virus type B |
1.A.32.1.2 | Uncharacterized protein of 83 aas and 1 TMS. |
Viruses | Orthomyxoviridae | UP of Influenza B virus (B/Shanghai) |
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 | Riboviria | Neuraminidase of Influenza B virus |
1.A.33.1.1 | Heat shock cognate 70 kDa protein, Hsc70 | Eukaryota | Viridiplantae | 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 | Proteobacteria | DnaK of E. coli |
1.A.33.1.3 | Heat shock protein 70(1B) | Eukaryota | Metazoa | Hsp70(1B) of Homo sapiens (AAH57397) |
1.A.33.1.4 | DnaK of 611 aas |
Bacteria | Firmicutes | DnaK of Bacillus subtiiis |
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). May also play a role in facilitating the assembly of multimeric protein complexes inside the endoplasmic reticulum (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). |
Eukaryota | Metazoa | GRP78 of Homo sapiens |
1.A.33.2.1 | MMAR_0617 MOMP (Hsp70 homologue) (van der Woude et al. 2013). |
Bacteria | Actinobacteria | MMAR_0617 of Mycobcterium marinum |
1.A.33.2.2 | Hsp70 homologue of 581 aas. |
Bacteria | Actinobacteria | Hsp70 homologue of Mycobacterium tuberculosis |
1.A.33.2.3 | Hsp70 homologue of 455 aas |
Bacteria | Actinobacteria | Hsp70 of Nocardia farcinica |
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 | Firmicutes | The SpoIIQ/SpoIIIAH complex of Bacillus subtilis |
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 | Proteobacteria | SpoIIQ homologue of E. coli |
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 | Proteobacteria | UP of E. coli |
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 | Firmicutes | SpoIIQ-SpoIIIAH of Clostridium difficile |
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). |
Bacteria | Proteobacteria | CorA of E. coli (P0ABI4) |
1.A.35.1.2 | Divalent cation (Mg2+, Co2+ and Ni2+) transport system, CorA |
Bacteria | Proteobacteria | CorA of Salmonella typhimurium (P0A2R8) |
1.A.35.1.3 | Magnesium transport protein CorA |
Bacteria | Firmicutes | CorA of Bacillus subtilis |
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 | Al1Rp of Saccharomyces cerevisiae |
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 | MnR2p of Saccharomyces cerevisiae |
1.A.35.2.3 | Eukaryota | Fungi | C27B12.12c of Schizosaccharomyces pombe |
|
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) |
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 | Thermotogae | CorA of Thermotoga maritima |
1.A.35.3.3 | Putative metal ion transporter YfjQ | Bacteria | Firmicutes | YfjQ of Bacillus subtilis |
1.A.35.3.4 | Putative CorA protein of 302 aas |
Bacteria | Firmicutes | CorA of Streptococcus sanguinis |
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 | Actinobacteria | CorA of Mycobacterium tuberculosis |
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 | Kinetoplastida | Mgt1 of Leishmania major |
1.A.35.3.7 | Putative Mg2+ transporter of 322 aas and 2 or 3 TMSs. |
Viruses | Caudovirales | CorA protein of Lactobacillus phage LfeInf |
1.A.35.3.8 | Uncharacterized CorA homologue of 373 aas and 3 TMSs (Pohland and Schneider 2019). |
Bacteria | Cyanobacteria | CorA of Acaryochloris marina |
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 | Proteobacteria | ZntB of Salmonella enterica serovar Typhimurium |
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 | Proteobacteria | ZntB of Vibrio parahaemolyticus (Q87M69) |
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 | Mrs2 of Saccharomyces cerevisiae (Q01926) |
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 | Mrs2-10 of Arabidposis thaliana (Q9SAH0) |
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 | MGT10 of Arabidopsis thaliana |
1.A.35.5.4 | Magnesium transporter MRS2-4 (Magnesium Transporter 6) (AtMGT6) | Eukaryota | Viridiplantae | MRS2-4 of Arabidopsis thaliana |
1.A.35.5.5 | Mitochondrial inner membrane magnesium transporter MFM1; LPE10 (MRS2 function modulating factor 1) |
Eukaryota | Fungi | MFM1 of Saccharomyces cerevisiae |
1.A.35.5.6 | Magnesium transporter MRS2-5 (Magnesium Transporter 3) (AtMGT3) | Eukaryota | Viridiplantae | 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). |
Eukaryota | Metazoa | MRS2 of Homo sapiens |
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 | MCLC of Homo sapiens |
1.A.36.1.2 | CLIC- homologue |
Eukaryota | Metazoa | CLIC homologue of Nematostella vectensis |
1.A.36.1.3 | Clic-like Chloride channel protein 1 |
Eukaryota | Metazoa | Clic-like protein of Acromyrmex echinatior (Panamanian leafcutter ant) (Acromyrmex octospinosus echinatior) |
1.A.36.1.4 | Putative chloride channel |
Viruses | Herpesvirales | Chloride channel of Abalone herpesvirus Victorial |
1.A.36.1.5 | Chloride channel, CLIC-like protein 1 of 508 aas. |
Eukaryota | Metazoa | CLIC of Xenopus laevis (African clawed frog) |
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 | OOC-3 of Caenorhabditis elegans |
1.A.36.2.2 | Uncharacterized protein |
Eukaryota | Metazoa | Uncharacterized protein of Loa loa |
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 and lead to a structural model for complement recruitment. |
Eukaryota | Metazoa | CD20 of Homo sapiens |
1.A.37.1.5 | Uncharacterized protein of 247 aas and 4 TMSs in a 3 + 1 TMS arrangement. |
Eukaryota | Metazoa | UP of Xiphophorus couchianus (Monterrey platyfish) |
1.A.37.2.1 | Membrane-spanning 4 TMS subfamily A member 10 (MS4A superfamily), HTm4 |
Eukaryota | Metazoa | HTm4 of Homo sapiens (Q96PG2) |
1.A.37.3.1 | 4 TMS testes development-related NYD-SP21 protein |
Eukaryota | Metazoa | NYD-SP21 of Homo sapiens (Q96JA4) |
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. |
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 | UP of Cyprinus carpio |
1.A.37.4.1 | Fam189A1 or CD20 family with 539 aas and 4 TMSs. |
Eukaryota | Metazoa | CD20 family protein of Homo sapiens |
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). |
Eukaryota | Metazoa | Sarcospan of Bos taurus |
1.A.37.6.1 | TMem196 of 185 aas and 4 TMSs, Acts as a tumor suppressor (Liu et al. 2015). |
Eukaryota | Metazoa | TMem196 protein of Canis lupus familiaris (Dog) (Canis familiaris) |
1.A.37.7.1 | Transmembrane protein 212, TMEM212, of 194 aas and 4 or 5 TMSs (Brown et al. 2012). |
Eukaryota | Metazoa | TMEM212 of Homo sapiens |
1.A.37.8.1 | TMEM176B 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. The modulation of the cation channel transmembrane protein 176B (TMEM176B) provides one such mechanis, and this protein privides a potential target to unleash inflammasome activation, leading to reinforced anti-tumor immunity and improved efficacy of immune checkpoint blockers (Segovia et al. 2020). |
Eukaryota | Metazoa | TMEM176B of Homo sapiens |
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 | TMEM176A of Homo sapiens |
1.A.37.8.3 | Uncharacterized protein of 244 aas and 5 TMSs in a 4 + 1 TMS arrangement. |
Eukaryota | Metazoa | UP of Carassius auratus |
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 | UP of Branchiostoma floridae (Florida lancelet) (Amphioxus) |
1.A.38.1.1 | The Golgi pH regulator, GPHR, of 455 aas and 9 TMSs in a 5 + 4 TMS arrangement. |
Eukaryota | Metazoa | GPHR of Cricetulus griseus (B2ZXD5) |
1.A.38.1.2 | Uncharacterized protein of 367 aas and 8 TMSs. |
Eukaryota | Entamoebidae | UP of Entamoeba histolytica |
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 | COLD1 of Oryza sativa subsp. indica (Rice) |
1.A.38.2.1 | 10 TMS homologue (826 aas) |
Eukaryota | Kinetoplastida | 10 TMS homologue of Leishmania mexicana (E9AL43) |
1.A.38.3.1 | 4-5 TMS homologue (398 aas) |
Eukaryota | Apicomplexa | 4-5 TMS homologue of Plasmodium yoelii (Q7RQA4) |
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 | Orthomyxoviridae | CM2 of Type C influenza virus |
1.A.39.1.2 | P42 protein of 387 aas and 2 TMSs. |
Viruses | Orthomyxoviridae | P42 of Influenza D virus (D/swine/Oklahoma) |
1.A.39.1.3 | CM2 protein of 105 aas and 2 TMSs. A processed version of 1.A.39.1.1. |
Viruses | Orthomyxoviridae | CM2 of Influenza virus type C |
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). |
Eukaryota | Metazoa | TRP protein of Drosophila melanogaster (P19334) |
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 | Trp-2 of Caenorhabditis elegans |
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). |
Eukaryota | Viridiplantae | TRP channel homologue of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
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 | TrpC4 of Homo sapiens |
1.A.4.1.13 | Transient receptor potential ion channel protein, TRP6, OF 2341 aas and 6 - 9 TMSs. |
Eukaryota | Viridiplantae | TRP6 OF Chlamydomonas reinhardtii (Chlamydomonas smithii) |
1.A.4.1.14 | Flagellar associated calcium channel protein of 1,729 aas, FAP148 (Wheeler and Brownlee 2008). |
Eukaryota | Viridiplantae | FAP148 of Chlamydomonas reinhardtii |
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 | TrpL of Drosophila melanogaster (Fruit fly) |
1.A.4.1.2 | TRP7 receptor-activated capacitative Ca2+ entry channel |
Eukaryota | Metazoa | TRP7 of Mus musculus (Q9WVC5) |
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 | TRPC1 of Homo sapiens (P48995) |
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). |
Eukaryota | Opisthokonta | TRPC3 of Homo sapiens (Q13507) |
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-electron microscopy 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). |
Eukaryota | Metazoa | TRPC6 of Homo sapiens (Q9Y210) |
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 | TRP-3 of Caenorhabditis elegans (AAQ22724) |
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). |
Eukaryota | Metazoa | TrpC5 of Homo sapiens (Q9UL62) |
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). |
Eukaryota | Metazoa | TrpL of Drosophila melanogaster (P48994) |
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 | Trp-1 of Caenorhabditis elegans |
1.A.4.10.1 | TRP cation-slective channel homologue of 1177 aas |
Eukaryota | Viridiplantae | TRP channel homologue of Chlamydomonas reinhardtii (Chlamydomonas smithii) |
1.A.4.10.2 | TRP channel homologue of 962 aas |
Eukaryota | Intramacronucleata | TRP channel homologue of Oxytricha trifallax |
1.A.4.10.3 | TRP channel homologue of 1486 aas |
Eukaryota | Viridiplantae | TRP channel homologue of Volvox carteri |
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). 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). 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). 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). |
Eukaryota | Metazoa | VR1 of Rattus norvegicus |
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). |
Eukaryota | Metazoa | TRPV5 of Homo sapiens (NP_062815) |
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). |
Eukaryota | Metazoa | TRPV6 of Homo sapiens (NP_071858) |
1.A.4.2.12 | Epithelial calcium channel, ECaC (Liao et al., 2007). | Eukaryota | Metazoa | ECaC of Danio rerio (Q6JQN0) |
1.A.4.2.13 | TrpV1 of 839 aas. 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 smallmolecule TRPV1 inhibitors GRT12360V and GRTE16523. The oxidizing reagent copper-o-phenanthroline is an open channel blocker of TRPV1 (Tousova et al. 2004).
|
Eukaryota | Metazoa | TrpV1 of Homo sapiens |
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 | ECaC2 of Takifugu rubripes (Japanese pufferfish) (Fugu rubripes) |
1.A.4.2.2 | Stretch-inhibitable non-selective cation channel, SIC |
Eukaryota | Metazoa | SIC of Rattus norvegicus |
1.A.4.2.3 | Vitamin D-responsive, apical, epithelial Ca2+ channel, ECaC |
Eukaryota | Metazoa | ECaC of Oryctolagus cuniculus |
1.A.4.2.4 | Insulin-like growth factor I-regulated Ca2+ channel |
Eukaryota | Metazoa | IGF-regulated Ca2+ channel of Mus musculus |
1.A.4.2.5 | Vanilloid receptor-related, osmotically activated channel, VR-OAC (also called TRPV4 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). |
Eukaryota | Metazoa | VR-OAC of Rattus norvegicus |
1.A.4.2.6 | Osmosensitive transient receptor potential channel 3, O-TRP3 | Eukaryota | Metazoa | 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 | CaT1 of Rattus norvegicus |
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). |
Eukaryota | Metazoa | TRPV2 of Homo sapiens |
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). |
Eukaryota | Metazoa | TRPV3 of Homo sapiens |
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 | Olfactory channel of Caenorhabditis elegans |
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 | Nan of Drosophila melanogaster (833 aas; Q9VUD5) |
1.A.4.3.3 | TrpV-type Osm-2 (OSM2) chemo-, osmo- and touch sensation receptor channel (Xiao and Xu 2009). |
Eukaryota | Metazoa | Osm-2 of Caenorhabditis elegans |
1.A.4.3.4 | TRP channel homologue of 1240 aas |
Eukaryota | Phaeophyceae | TRP channel homologue of Ectocarpus siliculosus |
1.A.4.3.5 | TRP channel homologue of 1724 aas |
Eukaryota | Phaeophyceae | TRP channel homologue of Ectocarpus siliculosus (Brown alga) |
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). |
Eukaryota | Fungi | YVC1 (Yor088w) of Saccharomyces cerevisiae (Q12324) |
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 | Yvc1 of Kluyveromyces lactis |
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 | TrpY3 of Candida albicans |
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). Transient receptor potential melastatin 7, 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). |
Eukaryota | Metazoa | Channel-kinase-1 (LTRPC7) of Homo sapiens |
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 | Gon-2 of Caenorhabditis elegans |
1.A.4.5.11 | 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 at 4.1 Å resolution (6BPQ_A - D (Yin et al. 2017). |
Eukaryota | Metazoa | TrpM8 of Ficedula albicollis (collared flycatcher) |
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). |
Eukaryota | Metazoa | TRPM4 of Mus musculus |
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). |
Eukaryota | Metazoa | TRP8 of Ficedula albicollis (Collared flycatcher) (Muscicapa albicollis) |
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). |
Eukaryota | Metazoa | Melastatin 1 of Homo sapiens |
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 some of these. Thus, Trpm5-dependent and Trpm5-independent pathways underlie bitter, sweet, and umami tastes (Damak et al. 2006). 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). |
Eukaryota | Metazoa | MTR1 of Homo sapiens |
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 cause progressive symmetric erythrokeratoderma (Wang et al. 2018). Inherited Cardiac Arrhythmia Syndromes |
Eukaryota | Metazoa | TRPM4b of Homo sapiens |
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). |
Eukaryota | Opisthokonta | LTRPC2 of Homo sapiens |
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 | TrpM3 of Homo sapiens (Q9HCF6) |
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 | TRPM8 of Homo sapiens |
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). eviewed 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).
|
Eukaryota | Metazoa | TRPM6 of Homo sapiens (NP_060132) |
1.A.4.5.9 | Transient receptor potential cation channel TrpM |
Eukaryota | Metazoa | T9.a.14.4.12 rpM of Drosophila melanogaster |
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). Also called TRPA1 (Acc #AAS78661) which 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.6.3.1.1) 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). |
Eukaryota | Metazoa | ANKTM1 of Mus musculus (Q8BLA8) |
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). |
Eukaryota | Metazoa | ANKTM1 of Drosophila melanogaster (1197 aas; Q7Z020) |
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). |
Eukaryota | Metazoa | TRPA1 of Homo sapiens (O75762) |
1.A.4.6.4 | The Pyrexia (Pyx) thermal TRP channel allowing increased tolerance to high temperature (Lee et al., 2005) | Eukaryota | Metazoa | 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 | TRPA1 of Caenorhabditis elegans |
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 | WtrW of Drosophila melanogaster |
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 | TRPA1 of Anolis carolinensis (Green anole) (American chameleon) |
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 | 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 | NompC of Drosophila melanogaster (1619 aas; AAF59842) |
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 | Trp-4 of Caenorhabditis elegans (Q9GRV5) |
1.A.4.9.1 | Flavin carrier protein 1 (Bypass of PAM1 protein 1) (FAD transporter 1) (Heme utilization factor 1) (TRP-like ion channel protein FLC1) | Eukaryota | Fungi | FLC1 of Saccharomyces cerevisiae |
1.A.4.9.2 |
TRP-like ion channel PKD2 (Polycystic kidney disease-related ion channel 2). Regulates cytoplasmic calcium ion concentrations (Ma et al. 2011). |
Eukaryota | Fungi | Pkd2 of Schizosaccharomyces pombe |
1.A.4.9.3 | Flavin carrier protein 2, Flc2p. May be responsible for the transport of FAD (and heme) into the endoplasmic reticulum lumen, where FAD may be required for oxidative protein folding involved in disulfide bridge formation (Protchenko et al. 2006). |
Eukaryota | Fungi | Flc2 of Saccharomyces cerevisiae |
1.A.4.9.4 | Trp-like channel protein of 862 aas and 12 TMSs. |
Eukaryota | Fungi | TRP-like channel protein of Schizosaccharomyes pombe (O94543) |
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 | Retroviridae | Vpu of HIV-1 viru |
1.A.40.1.2 | Vpu protein of 81 aas and 1 TMS. |
Viruses | Retroviridae | Vpu of HIV1 |
1.A.40.2.1 | Simian immunodeficiency virus (SIV) Vpu of 79 aas and 1 TMS. |
Viruses | Retroviridae | Vpu of Simian immunodeficiency virus (SIV) |
1.A.40.2.2 | Simian immunodeficiency virus (SIV) Vpu protein of 83 aas and 1 TMS |
Viruses | Retroviridae | Vpu of Simian immunodeficiency virus (SIV) |
1.A.40.2.3 | Simian immunodeficiency virus (SIV) Vpu of 79 aas and 1 TMS. |
Viruses | Retroviridae | Vpu of Simian immunodeficiency virus (SIV) |
1.A.40.2.4 | Vpu of 85 aas and 1 TMS of Human immunodeficiency virus 1 |
Viruses | Retroviridae | Vpu of Human immunodeficiency virus 1 |
1.A.41.1.1 | The avian reovirus p10 protein of 98 aas and 1 TMS. |
Viruses | Reoviridae | p10 of avian reovirus strain S1133 |
1.A.41.1.2 | Duck reovirus protein 10 (p10) of 97 aas and 1 TMS. |
Viruses | Reoviridae | p10 of duck reovirus |
1.A.41.1.3 | p10 protein of 91 aas and 1 TMS. |
Viruses | Nidovirales | p10 of Rousettus bat coronavirus |
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 | Reoviridae | p10 of Nelson Bay Virus |
1.A.41.2.1 | Uncharacterized protein of 103 aas and 1 TMS. |
Eukaryota | Viridiplantae | UP of Capsicum baccatum |
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 | GDU1 of Arabidopsis thaliana (O81775) |
1.A.41.2.3 | GDU1 homologue of 178 aas and 1 TMS. |
Eukaryota | Viridiplantae | GDU1 homologue of Solanum lycopersicum (Tomato) (Lycopersicon esculentum) |
1.A.41.2.4 | Uncharacterized protein of 171 aas and 1 TMS |
Eukaryota | Viridiplantae | UP of Brachypodium distachyon |
1.A.41.2.5 | Uncharacterized homologue of glutamine dumper of 139 aas and 1 TMS. |
Eukaryota | Viridiplantae | UP of Handroanthus impetiginosus |
1.A.41.2.6 | Glutamine dumper 6 of 117 aas and 1 TMS |
Eukaryota | Viridiplantae | GDU1 of Capsella rubella |
1.A.41.2.7 | Uncharacterized protein of 134 aas and 1 TMS |
Eukaryota | Viridiplantae | UP of Rosa chinensis |
1.A.41.2.8 | Uncharacterized protein of 146 aas and 1 TMS |
Eukaryota | Viridiplantae | UP of Cajanus cajan (pigeon pea) |
1.A.42.1.1 | Vpr of HIV | Viruses | Retroviridae | Vpr of HIV type 1 |
1.A.42.1.2 | Vpr of 119 aas and 1 putative TMS |
Viruses | Retroviridae | Vpr of Simian immunodeficiency virus (SIV) |
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 | Proteobacteria | CrcB of E. coli (P37002) |
1.A.43.1.10 | CrcB-like protein of 164 aas and 4 TMSs |
Bacteria | Actinobacteria | CreB of Mobiluncus curtisii (Falcivibrio vaginalis) |
1.A.43.1.11 | Putative fluoride transporter of 122 aas, CrcB |
Bacteria | Proteobacteria | CrcB of Campylobacter jejuni |
1.A.43.1.12 | CreB of 168 aas and 4 TMSs |
Bacteria | Actinobacteria | CreB of Brachybacterium faecium |
1.A.43.1.13 | CreB of 123 aas and 4 TMSs. |
Bacteria | Bacteroidetes/Chlorobi group | CreB of Aequorivita sublithincola |
1.A.43.1.14 | CrcB, putative fluoride channel protein of 124 aas and 4 TMSs |
Bacteria | Firmicutes | CrcB of Lactobacillus kefiranofaciens |
1.A.43.1.15 | CrcB of 133 aas and 4 TMSs. |
Archaea | Euryarchaeota | CrcB of Halorubrum coriense |
1.A.43.1.16 | Fluc homologue of 453 aas and 9 putative TMSs. |
Eukaryota | Longamoebia | Fluc of Acanthamoeba castellanii |
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 | Proteobacteria | Fluc of Bordetella pertussis |
1.A.43.1.2 | Protein CrcB homologue 2 |
Bacteria | Firmicutes | crcB2 of Bacillus subtilis |
1.A.43.1.3 | Putative fluoride-selective channel of 143 aas and 4 TMSs, CrcB. |
Bacteria | Actinobacteria | CreB of Propionibacterium acnes |
1.A.43.1.4 | CreB homologue of 124 aas |
Archaea | Euryarchaeota | CrcB homologue of Methanocaldococcus fervens |
1.A.43.1.5 | CrcB homologue of 172 aas and 4 TMSs |
Bacteria | Proteobacteria | CrcB of Parvularcula bermudensis |
1.A.43.1.6 | Putative fluoride exporter, CrcB. |
Bacteria | Bacteroidetes/Chlorobi group | CrcB of Pelodictyon luteolum (Chlorobium luteolum) |
1.A.43.1.7 | Putative fluoride exporter, CrcB if 114 aas and 4 TMSs. |
Archaea | Euryarchaeota | CrcB of Thermococcus barophilus |
1.A.43.1.8 | Uncharacterized protein of 151 aas and 4 TMSs. |
Bacteria | Actinobacteria | UP of Rothia mucilaginosa (Stomatococcus mucilaginosus) |
1.A.43.1.9 | Putative fluoride exporter, CrcB of 113 aas and 4 TMSs. |
Archaea | Euryarchaeota | UP of Haloquadratum walsbyi |
1.A.43.2.1 | CrcB-like protein of 307 aas and 6 TMSs in an apparent 3 + 3 arrangement. |
Eukaryota | Intramacronucleata | CrcB homologue of Tetrahymena thermophila |
1.A.43.2.2 | Uncharacterized protein of 372 aas and 9 - 10 TMSs |
Eukaryota | Fungi | UP of Kazachstania africana (Kluyveromyces africanus) |
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 | CrcB homologue of Schizosaccharomyces cryophilus |
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 | FEX1 of Saccharomyces cerevisiae |
1.A.43.2.5 | Fluoride exporter, FEX2 of 375 aas and 8 TMSs (Li et al. 2013). |
Eukaryota | Fungi | FEX2 of Saccharomyces cerevisiae |
1.A.43.2.6 | Fluoride exporter, FEX, of 526 aas and 10 putative TMSs (Li et al. 2013). |
Eukaryota | Fungi | FEX of Neurospora crassa |
1.A.43.2.7 | Camphor resistance CrcB protein of 461 aas and 9 putative TMSs. |
Eukaryota | Viridiplantae | CrcB of Arabidopsis thaliana |
1.A.43.2.8 | Uncharacterized protein of 405 aas and 8 putative TMSs. |
Eukaryota | Metazoa | UP of Ciona intestinalis (Transparent sea squirt) (Ascidia intestinalis) |
1.A.43.2.9 | Uncharacterized protein of 460 aas and 9 TMSs/ |
Eukaryota | Oomycetes | UP of Phytophthora parasitica |
1.A.43.3.1 | CreB of 346 aas and 4 TMSs. |
Bacteria | Actinobacteria | CreB of Bifidobacterium longum |
1.A.43.3.2 | Putative fluoride channel, CrcB, of 180 aas and 4 TMSs. |
Bacteria | Actinobacteria | CrcB of Scardovia wiggsiae |
1.A.43.3.3 | Putative fluoride ion channnel, CrcB, of 178 aas and 4 TMSs |
Bacteria | Actinobacteria | CrcB of Bifidobacterium longum |
1.A.43.3.4 | Putative fluoride ion channel, CrcB, with 310 aas and 4 TMSs. |
Bacteria | Actinobacteria | CrcB of Bifidobacterium animalis subsp. lactis |
1.A.44.1.1 | The pore-forming tail tip protein Pb2 | Viruses | Caudovirales | Pb2 of phage T5 (Q7Y5E2) |
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. 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). |
Eukaryota | Metazoa | Bestrophin-1 of Homo sapiens (O76090) |
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 | Bestrophin-2 of Homo sapiens (AAM76995) |
1.A.46.1.3 | Bestrophin family anion channel, YxaK (Protein R13.3) (Sun et al., 2002) | Eukaryota | Metazoa | 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 | Best3 of Mus musculus |
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 | Bestrophin1 of Drosophila melanogaster (B7Z0U6) |
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 | Best1 of Gallus gallus (chicken) |
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 | BEST4 of Homo sapiens |
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 | BEST3 of Homo sapiens |
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 | Best1 of Aspergillus nidulans (Q5BB29) |
1.A.46.2.10 | Bestrophin homologue of 361 aas and 2 - 4 TMSs. |
Eukaryota | Bangiophyceae | Best protein of Galdieria sulphuraria (Red alga) |
1.A.46.2.11 | Bestrophin homologue of 446 aas and ~ 4 TMSs. |
Eukaryota | Viridiplantae | Best protein of Volvox carteri |
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 | Best2 of Aspergillus nidulans (Q5AXS1) |
1.A.46.2.3 | Bestrophin homologue |
Bacteria | Cyanobacteria | Bestrophin homologue of Cyanothece sp. PCC8801 (B7K217) |
1.A.46.2.4 | Bestrophin homologue |
Bacteria | Firmicutes | Bestrophin homologue of Bacillus cereus (C2UY63) |
1.A.46.2.5 | Bestrophin homologue |
Bacteria | Proteobacteria | Bestrophin homologue of Bdellovibrio bacteriovorus (Q6MLK6) |
1.A.46.2.6 | Bestrophin homologue, YneE |
Bacteria | Proteobacteria | YneE of E. coli (B2N0W4) |
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 | Bestrophin homologue of Arabidopsis thaliana (Q9M2D2) |
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 | Proteobacteria | KpBEST of Klebsiella pneumoniae |
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 | UP of Ostreococcus lucimarinus |
1.A.47.1.1 | The nucleotide-sensitive ion channel, ICln, of 237 aas and 0 TMSs, based on hydropathy plots. |
Eukaryota | Metazoa | ICln of Homo sapiens (P54105) |
1.A.47.2.1 | Homologue of ICln | Eukaryota | Fungi | ICln homologue in Schizosaccharomyces pombe (O13777) |
1.A.47.3.1 | Homologuc of ICln | Eukaryota | Apicomplexa | ICln homologue in Plasmodium falciparum (CAD52477) |
1.A.47.4.1 | Homologue of ICln | Eukaryota | Viridiplantae | ICln homologue in Arabidopsis thaliana (BAA97193) |
1.A.48.1.1 | Tweety maxi-Cl- anion channel | Eukaryota | Metazoa | Tweety of Drosophila melanogaster (T08424) |
1.A.48.1.2 | TTYH1 maxi-Cl- anion channel |
Eukaryota | Metazoa | Tweety homologue 1 (TTYH1) of Homo sapiens (Q9H313) |
1.A.48.1.3 | TTYH2 maxi-Cl- anion channel | Eukaryota | Metazoa | Tweety homologue 2 (TTYH2) of Homo sapiens (AAH05168) |
1.A.48.1.4 | TTYH3 maxi-Cl- anion channel | Eukaryota | Metazoa | Tweety homologue 3 (TTYH3) of Homo sapiens (BAD20190) |
1.A.48.1.5 | Protein tweety-2 (Dttyh2) | Eukaryota | Metazoa | CG3638 of Drosophila melanogaster |
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 | Nidovirales | ns12.9 of human coronavirus OC43 |
1.A.49.1.2 | The non-structural protein, ns12.7 viroporin, of 112 aas and 1 putative C-terminal TMS. |
Viruses | Nidovirales | ns12.7 of Murine coronavirus (Murine hepatitis virus) |
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 | Nidovirales | ns5 of β-coronavirus HKU2 |
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). |
Eukaryota | Metazoa | Polycystin 1 of Homo sapiens |
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 | PKD1L3 of Homo sapiens |
1.A.5.1.3 | Heteromeric polycystic kidney disease proteins 1 and 2-like 1 (PKD1L1/PKD2L1) 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).
|
Eukaryota | Metazoa | PKD1L1/PKD2L1 of Homo sapiens |
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 | REJ of Strongylocentrotus purpuratus (Purple sea urchin) |
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 | REJ4 of Strongylocentrotus purpuratus (Purple sea urchin) |
1.A.5.1.6 | PKD-REJ3 of 2681 aas (Gunaratne et al. 2007). |
Eukaryota | Metazoa | REJ3 of Strongylocentrotus purpuratus (Purple sea urchin) |
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 | Polycystin-1L2 of Homo sapiens |
1.A.5.2.1 | Polycystin 2 (PKD2, PC2 or TRPP2) of 968 aas and 8 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). |
Eukaryota | Metazoa | Polycystin 2 of Homo sapiens (Q13563) |
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). |
Eukaryota | Metazoa | TrpP3 of Mus musculus (Q14B55) |
1.A.5.2.3 | PKD2 or PKD-REJ2 of 907 aas (Gunaratne et al. 2007). |
Eukaryota | Metazoa | REJ2 of Strongylocentrotus purpuratus (Purple sea urchin) |
1.A.5.2.4 | Polycystin-2 (CePc2) (Polycystic kidney disease 2 protein homologue) |
Eukaryota | Metazoa | Pkd-2 of Caenorhabditis elegans |
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). |
Eukaryota | Metazoa | TRP-ML1 (Mucolipin-1) of Homo sapiens (Q9GZU1) |
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 | Trp-ML3 of Mus musculus |
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 | TRPML2 of Homo sapiens (Q8IZK6) |
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 | TRPML3 of Homo sapiens |
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 | Kinetoplastida | Mucolipin of Trypanosoma grayi |
1.A.5.3.6 | Uncharacterized protein of 1844 aas and 5 - 6 TMSs. |
Eukaryota | Kinetoplastida | UP of Leishmania major |
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 | Opisthokonta; metazoans | CUP-5 of Caenorhabditis elegans |
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 | 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 | PLB of Homo sapiens (P26678) |
1.A.50.1.2 | Cardiac phospholamban-like protein of 131 aas and 1 TMS. |
Eukaryota | Metazoa | Phospholamban of Scleropages formosus |
1.A.50.1.3 | Cardiac phospholamban of 55 aas and 1 TMS. |
Eukaryota | Metazoa | Phospholamban of Esox lucius (northern pike) |
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). |
Eukaryota | Metazoa | SLN of Homo sapiens (O00631) |
1.A.50.2.2 | sarcolipin-like protein of 32 aas and 1 TMS. |
Eukaryota | Metazoa | Sarcolipin of Esox lucius (northern pike) |
1.A.50.2.3 | Sarcolipin-like protein (SLN) of 31 aas and 1 TMS |
Eukaryota | Metazoa | SLN of Ovis aries (Sheep) |
1.A.50.3.1 | Myoregulin of 46 aas (Anderson et al. 2015). |
Eukaryota | Metazoa | Myoregulin of Homo sapiens |
1.A.50.3.2 | Myoregulin of 43 aas |
Eukaryota | Metazoa | Myoregulin of Echinops telfairi |
1.A.50.3.3 | Myoregulin of 105 aas |
Eukaryota | Metazoa | Myoregulin of Sarcophilus harrisii (Tasmanian devil) (Sarcophilus laniarius) |
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). Homology with the inhibitory peptides has not been established although all of these peptides have about the same size with a single C-terminal TMS. |
Eukaryota | Metazoa | DWORF of Homo sapiens |
1.A.50.4.2 | Sarcoplasmic/endoplasmic reticulum calcium ATPase regulator, DWORF-like protein, of 37 aas and 1 TMS. |
Eukaryota | Metazoa | DWORF of Esox lucius |
1.A.50.4.3 | DWARF open reading frameof 82 aas and 1 C-terminal TMS. |
Eukaryota | Metazoa | DWARF of Oreochromis niloticus |
1.A.50.4.4 | DWARF open reading frame isoform X1 of 99 aas and 1 C-terminal TMS. |
Eukaryota | Metazoa | DWARF of Athene cunicularia |
1.A.50.4.5 | Dwarf homolog, isoform X2, of 123 aas and 1 C-terminal TMS. |
Eukaryota | Metazoa | DWARF of Paramormyrops kingsleyae |
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 | ALN in Homo sapiens |
1.A.50.6.2 | Uncharacterized protein of 93 aas and 1 TMS. |
Eukaryota | Metazoa | UP of Larimichthys crocea (large yellow croaker) |
1.A.50.6.3 | Uncharacterized protein of 104 aas and 1 TMS |
Eukaryota | Metazoa | UP of Xenopus laevis (African clawed frog) |
1.A.50.6.4 | Uncharacterized C4orf3 homologue of 77 aas and 1 TMS |
Eukaryota | Metazoa | UP of Monodelphis domestica (Gray short-tailed opossum) |
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 currents reveal that voltage-sensor (VS) activation and proton-selective aqueous conductance opening are thermodynamically distinct steps in the Hv1 activation pathway and show 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 | mVSOP of Mus musculus (Q9DCE4) |
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). |
Eukaryota | Metazoa | Hv1 of Homo sapiens (Q96D96) |
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).
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Eukaryota | Metazoa | HvCN1 of Ciona intestinalis (Q1JV40) |
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 | Dinophyceae | kHv1 of Karlodinium veneficum (G5CPN9) |
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 | NpHv1 of Nicoletia phytophila |
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).
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Eukaryota | Metazoa | VSP of Ciona intestinalis (Transparent sea squirt) (Ascidia intestinalis) |
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 | VSP2 of Xenopus laevis (African clawed frog) |
1.A.51.2.3 | Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase, TPTE2, isoform gamma of522 aas and 4 TMSs. |
Eukaryota | Metazoa | TPTE2 of Homo sapiens |
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). |
Eukaryota | Metazoa | Orai1/STIM1 complex of Homo sapiens |
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). |
Eukaryota | Metazoa | Orai3 of Homo sapiens (Q9BRQ5) |
1.A.52.1.3 | The CRAC channel Orai2 (DUF 1650) (264 aas) (Gross et al., 2007). |
Eukaryota | Metazoa | Orai2 of Mus musculus (Q8BH10) |
1.A.52.1.4 |
Insect STIM1/Orai1 (Hull et al., 2010). Influences sex pheromone production in moths. |
Eukaryota | Metazoa | Stim1/Orai1A or B of Bombyx mori |
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 | Orai (Olf186-F) of Drosophila melanogaster |
1.A.52.2.1 | Orai homologue (494aas; 4 or 5 TMSs) |
Eukaryota | Viridiplantae | Orai homologue in Ostreococcus tauri (Q012G5) |
1.A.52.3.1 | Orai homologue (244aas; 4 TMSs) |
Eukaryota | Peronosporales | Orai homologue in Phytophthora infestans T30-4 (D0NKP9) |
1.A.53.1.1 | HCV-P7 (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; 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).
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Viruses | Flaviviridae | P7 of hepatitis C virus (63 aas; 2 TMSs; CAH23613) |
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) |
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 |
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 | Flaviviridae | p7 of hepatitis C virus subtype 3a |
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 | Flaviviridae | Polyprotein of hepacivirus AK |
1.A.53.1.4 | Classical Swine Fever Virus (CSFVA) p7 viroporin (70 aas; 2 TMSs). 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 | Flaviviridae | CSFVA P7 viroporin of Classical Swine Fever Virus (Q9YS30) |
1.A.53.1.5 | The borine viral diarrhea virus (BVDV) p7 peptide, viral budding process initiator. |
Viruses | Flaviviridae | p7 of Bovine viral diarrhea virus (AAB47140) polyprotein: Q96662 |
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)] | Viruses | Flaviviridae | POLG_HCVVN of Hepatitis C virus genotype 6d |
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 | Flaviviridae | 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 | Flaviviridae | p7 of Hepatitis C virus strain HCV-J (genotype 1b) |
1.A.53.1.9 | Viroporin of 63 aas and 2 TMSs. |
Viruses | Flaviviridae | Viroporin of Bovine viral diarrhea virus (BVDV) (Mucosal disease virus) |
1.A.54.1.1 | Presenilin-1 (PS-1; STM-1; E5-1; AD) 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 (unpublished observations). 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). |
Eukaryota | Metazoa | Presenilin-1 of Homo sapiens (467 aas; P49768) |
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 | Presenilin-2 of Homo sapiens (448 aas; P49810) |
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) |
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 |
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 | SPP2A of Mus musculus (Q9JJF9) |
1.A.54.3.2 | Signal peptide peptidase like 2A, SPPL2A |
Eukaryota | Metazoa | SPPL2A of Homo sapiens |
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 | Spp of Homo sapiens |
1.A.54.3.4 | Signal peptide peptidase, Spp |
Eukaryota | Metazoa | Spp of Drosophila melanogaster |
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 |
1.A.54.4.2 | Leader peptidase of 342 aas |
Archaea | Euryarchaeota | Leader peptidase of Natrinema pellirubrum |
1.A.54.4.3 | Type IV leader peptidase of 289 aas and 7 TMSs. |
Archaea | Euryarchaeota | peptidase of Methanobrevibacter smithii |
1.A.54.4.4 | Peptidase of 375 aas |
Archaea | Euryarchaeota | Peptidase of Thermococcus sibiricus |
1.A.54.4.5 | Peptidase of 260 aas |
Archaea | Euryarchaeota | Peptidase of Methanosphaerula palustris |
1.A.54.5.1 | Prepilliin peptidase A24 of 167 aas and 6 TMSs. |
Bacteria | Firmicutes | Peptidase of Desulfotomaculum hydrothermale |
1.A.54.5.2 | Peptidase A24 prepilin type IV of 158 aas |
Bacteria | Synergistetes | Peptidase of Aminobacterium colombiense |
1.A.54.5.3 | Peptidase of 286 aas |
Bacteria | Proteobacteria | Peptidase of Acinetobacter pittii |
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 | Proteobacteria | PppA of E. coli |
1.A.54.6.1 | Uncharacterized protein of 229 aas and 6 TMSs. |
Archaea | Euryarchaeota | UP of Thermoplasma volcanium |
1.A.55.1.1 | Mammalian Ca2+ channel, Flower, homologue, isoform a (Yao et al., 2009). |
Eukaryota | Metazoa | Flower of Homo sapiens (Q9UGQ2) |
1.A.55.1.2 | Insect Ca2+ channel, Flower (194 aas; 4 putative TMSs) |
Eukaryota | Metazoa | Flower of Drosophila melanogaster (Q95T12) |
1.A.55.1.3 | Roundworm Flower homologue (166aas) |
Eukaryota | Metazoa | Flower homologue of Caenorhabditis elegans (Q93533) |
1.A.55.2.2 | Flower homologue of 175 aas and 3 putative TMSs |
Eukaryota | Ichthyosporea | Flower homologue of Capsaspora owczarzaki |
1.A.55.2.3 | Flower homologue of 193 aas |
Eukaryota | Choanoflagellida | Fower homologue of Salpingoeca rosetta |
1.A.55.3.1 | Flatworm Flower homologue (195aas) |
Eukaryota | Metazoa | Flower homologue of Schistosoma japonicum (Q5DFV8) |
1.A.55.4.1 | Fungal flower homologue (149aas) |
Eukaryota | Fungi | Flower homologue of Aspergillus flavus (B8N1Q6) |
1.A.55.4.2 | The yeast Tvp18p protein of 102 aas and 2 TMSs. |
Eukaryota | Fungi | Tvp180 of Saccharomyces cerevisiae |
1.A.55.4.3 | Uncharacterized protein of 127 aas and 4 TMSs |
Eukaryota | Blastocystis | UP of Blastocystis hominis |
1.A.55.5.1 | Uncharacterized protein of 151 aas and 3-4 putative TMSs. |
Eukaryota | Phaeophyceae | UP of Ectocarpus siliculosus (Brown alga) |
1.A.55.6.1 | Uncharacterized protein of 176 aas and 3 TMSs |
Eukaryota | Dictyosteliida | UP of Dictyostelium fasciculatum |
1.A.55.6.2 | Uncharacterized protein of 154 aas and 3 TMSs |
Eukaryota | Dictyosteliida | UP of Dictyostelium discoideum |
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). |
Eukaryota | Viridiplantae | CopT1 of Arabidopsis thaliana |
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 | COPT5 of Arabidopsis thaliana |
1.A.56.1.12 | Putative copper transporter 5.2 (OsCOPT5.2) | Eukaryota | Viridiplantae | COPT5.2 of Oryza sativa subsp. japonica |
1.A.56.1.13 | Copper transporter 3 (OsCOPT3) | Eukaryota | Viridiplantae | 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 | COPT6 of Arabidopsis thaliana (Q8GWP3) |
1.A.56.1.15 | Copper transporter, PF14_0369 (Choveaux et al. 2012). Binds Cu+ and is present in both the erythrocyte and parasite plasma membranes (Choveaux et al. 2012). |
Eukaryota | Apicomplexa | Copper transporter of Plasmodium falciparum |
1.A.56.1.16 | Plasma membrane copper uptake channel of 257 aas, CtrC (Park et al. 2014). |
Eukaryota | Fungi | CtrC of Neosartorya fumigata (Aspergillus fumigatus) |
1.A.56.1.17 | Grape vacuolar copper transporter, Ctr1 (Martins et al. 2012). |
Eukaryota | Viridiplantae | Ctr1 of Vitis vinifera |
1.A.56.1.18 | Putative copper uptake transporter of 242 aas, CtrB (Park et al. 2014). |
Eukaryota | Fungi | CtrB of Neosartorya fumigata (Aspergillus fumigatus) |
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). |
Eukaryota | Metazoa | SLC31A1 or Ctr1 of Homo sapiens |
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 | Ctr2p of Saccharomyces cerevisiae |
1.A.56.1.4 | Copper uptake transporter | Eukaryota | Fungi | 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 | Ctr4/Ctr5 of Schizosaccharomyces pombe |
1.A.56.1.6 | Vacuolar, trimeric copper release protein (Beaudoin et al. 2013). |
Eukaryota | Fungi | Ctr6 of Schizosaccharomyces pombe |
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 | CtrlB of Drosophila melanogaster (Q9VHS6) |
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 | 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 | SLC31A2 of Homo sapiens |
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 | Ctr1p of Saccharomyces cerevisiae |
1.A.56.2.2 | High affinity copper transporter, Ctr1p (Marvin et al., 2004) | Eukaryota | Fungi | Ctr1p of Candida albicans (CAB878806) |
1.A.56.3.1 | Ctr1 assimilatory copper transporter (has a Cx2(Mx2)2 (C-x)5 motif) (Page et al. 2009). | Eukaryota | Viridiplantae | Ctr1 of Chlamydomonas reinhardtii (Q4U0V9) |
1.A.56.3.2 | Copper uptake porter, CtrA2 (Park et al. 2014). |
Eukaryota | Fungi | CtrA2 of Neosartorya fumigata (Aspergillus fumigatus) |
1.A.56.3.3 | Uncharacterized protein of 244 aas and 3 TMSs |
Eukaryota | Chromerida | UP of Vitrella brassicaformis |
1.A.57.1.1 | SARS-CoV Viroporin tetrameric ion channel. Protein 3a 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). |
Viruses | Nidovirales | SARS-Caronavirus |
1.A.57.1.2 | Orf3 of 249 aas and 3 putative TMSs |
Viruses | Nidovirales | Orf3 of Zaria bat coronavirus (F1BYM0) |
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 | Nidovirales | NS3 of Bat coronavirus HKU9-5-1 (E0ZN37) |
1.A.57.1.4 | Orf3 of 238aas and 3 putative TMSs |
Viruses | Nidovirales | Orf3 of Eidolon bat coronavirus (F1DAZ2) |
1.A.57.1.5 | Orf 3a of 245 aas |
Viruses | Nidovirales | Orf3a of Bat Hp-betacoronavirus |
1.A.57.1.6 | ORF3a viroporin of 275 aas and 3 TMSs. 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 weree also identified (Bianchi et al. 2020). |
Viruses | Nidovirales | ORF3a of severe acute respiratory syndrome coronavirus 2 |
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).
|
Viruses | Orthomyxoviridae | BM2 influenza virus type B |
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# 2KIK) (Pielak et al. 2011). |
Viruses | Orthomyxoviridae | Chimeric AM2-BM2 35 aa peptide of A- and B-type Influenza viruses |
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 | Orthomyxoviridae | BM2 of Influenza B virus (B/Maryland) |
1.A.58.1.4 | M2 protein of 124 aas and 1 TMS. |
Viruses | Negarnaviricota | M2 of Wuhan spiny eel influenza virus |
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 | Birnaviridae | PP precursor of Pep46 of Infectious Bursal Disease Virus (P61825) |
1.A.59.1.2 | Pore-forming 46 aa peptide with 1 TMS. The NMR structure is known (Galloux et al. 2010). |
Viruses | Birnaviridae | Pep46 of Infectious Bursal Disease Virus (Ibdv) |
1.A.59.1.3 | Pore-forming polyprotein fragment of 103 aas and 1 TMS |
Viruses | Birnaviridae | Polyprotein fragment of Aquabirnavirus genogroup VII |
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). |
Eukaryota | Metazoa | αβγ- or δβγ-ENaC heterotrimeric epithelial Na+ channel of Homo sapiens |
1.A.6.1.10 | Acid-sensing ion channel 1, ACCN2 of 514 aas and 2 TMSs. |
Eukaryota | Metazoa | ACCN2 of Lampetra fluviatilis (European river lamprey) (Petromyzon fluviatilis) |
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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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 |
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 | ASIC5 of Brachionus plicatilis |
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: |
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. |
Eukaryota | Metazoa | αβγENaC of Rattus norvegicus. |
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 | ENaC5 of Rattus norvegicus (Q9R0W5) |
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 | ACD-1 of Caenorhabditis elegans (P91102) |
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). |
Eukaryota | Metazoa | ASIC-1 of Gallus gallus (Q1XA76) |
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 | 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 | ASIC4.2 of Danio rerio (Q708S3) |
1.A.6.1.8 | Amiloride and acid-sensitive cation channels, ASCI2a 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). |
Eukaryota | Metazoa | ASIC1b of Mus musculus |
1.A.6.1.9 | Acid-sensing ion channel 2, ASIC2, of 520 aas and 2 TMSs. |
Eukaryota | Metazoa | ASIC2 of Petromyzon marinus (Sea lamprey) |
1.A.6.2.1 | Degenerin-1 | Eukaryota | Metazoa | 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 | Mec-2, 4, 6, 10 mechanosensitive degenerin channel complex in Caenorhabditis elegans |
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 | UNC-105 of Caenorhabditis elegans (Q09274) |
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 | UNC-8 of Caenorhaditis elegans (Q21974) |
1.A.6.2.5 | Mechanotransduction degenerin, DEL-1 (Bianchi, 2007). |
Eukaryota | Metazoa | DEL-1 of Caenorhabditis elegans (Q19038) |
1.A.6.2.6 | Serum paraoxonase/arylesterase 1, PON 1 (Aromatic esterase 1) (A-esterase 1) (Serum aryldialkylphosphatase 1) |
Eukaryota | Metazoa | PON1 of Homo sapiens |
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 | Ion channel of Pristionchus pacificus |
1.A.6.3.1 | Peptide neurotransmitter-gated ionotropic receptor | Eukaryota | Metazoa | 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). |
Eukaryota | Metazoa | FaNaC of Aplysia kurodai |
1.A.6.3.3 | Uncharacterized protein of 577 aas and 2 TMSs, N- and C-terminal. |
Eukaryota | Metazoa | UP of Taenia asiatica |
1.A.6.3.4 | Uncharacterized protein of 616 aas and 2 TMSs, N- and C-terminal. |
Eukaryota | Metazoa | UP of Hymenolepis diminuta |
1.A.6.3.5 | Uncharacterized protein of 534 aas and 2 TMSs. |
Eukaryota | Metazoa | UP of Helobdella robusta |
1.A.6.4.1 | Ripped pocket (Rpk) fly gonad-specific Na+ channel (amiloride-sensitive) (Adams et al., 1998). |
Eukaryota | Metazoa | Rpk of Drosophila melanogaster |
1.A.6.4.2 | Pickpocket (Adams et al., 1998; Zhong et al., 2010). |
Eukaryota | Metazoa | Pickpocket of Drosophila melanogaster (Q7KT94) |
1.A.6.4.3 | Putative Na+ channel |
Eukaryota | Metazoa | Putative Na+ channel of Drosophila melanogaster (O61365) |
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 | NaCh of Cyphomyrmex costatus |
1.A.6.4.5 | Uncharacterized protein of 509 aas and 2 TMSs, N- and C-terminal. |
Eukaryota | Metazoa | UP of Laodelphax striatellus (small brown planthopper) |
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 | NaCh of Vollenhovia emeryi |
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 | Reoviridae | Mu-1 of mammalian reovirus (P12397) |
1.A.60.1.2 | Outer shell protein of 638 aas and 0 - 8 TMSs, based on a hydropathy plot. |
Viruses | Riboviria | Shell protein of Chinook aquareovirus |
1.A.60.1.3 | Major virion structural protein of 652 aa |
Viruses | Riboviria | Structural protein of Atlantic halibut reovirus |
1.A.61.1.1 | Chain F or gamma-peptide (44aas; 1TMS), membrane active domain (Bong et al., 1999) | Viruses | Nodaviridae | 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.
|
Viruses | Nodaviridae | α-capsid protein, including the C-terminal γ-peptide of Flock House virus (FHV) |
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 | 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 | TRIC-B of Mus musculus (Q9DAV9) |
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. 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). |
Eukaryota | Metazoa | TRIC-B of Homo sapiens |
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 | TRICB1/B2 of Caenorhabditis elegans |
1.A.62.2.1 | Bacterial TRIC family homologue |
Bacteria | Bacteroidetes/Chlorobi group | TRIC homologue of Gramella forsetii (A0M015) |
1.A.62.2.2 | Uncharacterized protein of 204 aas and 7 TMSs. |
Bacteria | Proteobacteria | UP of Yersinia pestis |
1.A.62.2.3 | Uncharacterized protein, YicG, of 205 aas and 7 TMSs. |
Bacteria | Proteobacteria | YicG of E. coli |
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 | Proteobacteria | TRIC channel of Rhodobacter spheroides |
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 | Crenarchaeota | TRIC homologue of Sulfolobus solfataricus (Q981D4) |
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 | Actinobacteria | UPF0126 of Streptomyces coelicolor (Q9RKM3) |
1.A.62.4.1 | Putative TRIC channel protein |
Eukaryota | Bangiophyceae | Putative TRIC channel of Galdieria sulphuraria |
1.A.62.4.2 | Putative TRIC channel protein |
Eukaryota | Blastocystis | Putative TRIC channel of Blastocystis hominis |
1.A.62.4.3 | Putative TRIC channel protein |
Eukaryota | Longamoebia | Putative TRIC channel protein of Acanthamoeba castellanii |
1.A.63.1.1 | The α-helical pore-forming outer membrane nanomeric porin, Imp1227 | Archaea | Crenarchaeota | Imp1227 of Ignicoccus hospitalis (A8ABZ0) |
1.A.63.2.1 | Transmembrane DUF4845 protein with 120 aas and one TMS. |
Bacteria | Proteobacteria | Transmembrane protein of Acidovorax sp. KKS102 |
1.A.63.2.2 | Uncharacterized protein of 129 aas and 1 TMS |
Bacteria | Proteobacteria | UP of Congregibacter litoralis |
1.A.63.2.3 | Uncharacterized protein of 130 aas and 1 TMS/ |
Bacteria | Proteobacteria | UP of Legionella pneumophila |
1.A.64.1.1 | Channel-forming Plasmolipin (Fischer and Sapirstein, 1994) | Eukaryota | Metazoa | Plasmolipin of Rattus norvegicus (P47987) |
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 | MAL/VIP17 of Canis familiaris (Q28296) |
1.A.64.3.1 | Myeloid-associated differentiation marker, MyADM (322 aas; 8 TMSs) |
Eukaryota | Metazoa | MyADM of Homo sapiens (Q96S97) |
1.A.64.4.1 | 4 TMS MARVEL superfamily member |
Eukaryota | Metazoa | 4TMS homologue of Caenorhabditis elegans (P83387) |
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 | CMTM7 of Homo sapiens (Q96FZ5) |
1.A.64.5.2 | Proteolipid protein 2 (Differentiation-dependent protein A4) (Intestinal membrane A4 protein) |
Eukaryota | Metazoa |
A4 protein of Homo sapiens |
1.A.64.5.3 | Uncharacterized protein of 208 aas |
Eukaryota | Metazoa | UP of Caenorhabditis elegans |
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 | CMTM8 of Anas platyrhynchos (Mallard) (Anas boschas) |
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 | CMTM1 of Homo sapiens |
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 | CMTM2A of Mus musculus |
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 | CMTM2B of Mus musculus |
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 | CMTM5 of Homo sapiens |
1.A.64.5.9 | CKLF-like MARVEL transmembrane domain-containing protein 4, CMTM4, of 234 aas and 4 TMSs. It acts as a backup for CMTM6 to regulate plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity (Mezzadra et al. 2017). |
Eukaryota | Opisthokonta | CMTM4 of Homo sapiens |
1.A.64.6.1 | Marvel D3 tight junctionh-associated occludin of 401 aas and 4 TMSs; a determinant of paracellular permeability (Steed et al. 2009). |
Eukaryota | Metazoa | MarvelD3 of Homo sapiens |
1.A.65.1.1 | The envelope (E) viroporin protein of 85 aas and 2 TMSs. |
Viruses | Nidovirales | E protein of Murine Hepatitis Virus (MHV) (83aas; P0C2R0) |
1.A.65.1.2 | The SARS coronavirus pore-forming envelope (E) protein or protein 3a (76 aas; 1 TMS) forms a pentameric pore (Torres et al. 2006) 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) |
1.A.65.1.3 | Envelope small membrane viroporin protein of 82 aas and 1 TMS, protein E or sM. Viroporin inhibitors have been identified (Takano et al. 2015). |
Viruses | Nidovirales | Viroporin of feline infectious peritonitis virus (FIPV) |
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 | Nidovirales | Viroporin of Human Middle East respiratory syndrome coronavirus (MERS CoV) or EMC (HCoV-EMC) |
1.A.65.1.5 | ORF5-E fusion protein of 194 aa |
Viruses | Nidovirales | Orf5-E of Middle East respiratory syndrome-related coronavirus |
1.A.65.1.6 | Envelope protein of 75 aas and 1 TMS. |
Viruses | Nidovirales | Envelope small protein of Alphacoronavirus Bat-CoV/P. kuhlii |
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). The structure and drug binding of the SARS-CoV-2 Envelope (E) protein in phospholipid bilayers has been determined (Hong et al. 2020). In lipid bilayers, 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. 2020). |
Viruses | Nidovirales | E-protein of severe acute respiratory syndrome coronavirus 2 |
1.A.65.1.8 | Protein-E of 78 aas and 2 TMSs. |
Viruses | Nidovirales | E-protein of rodent coronavirus |
1.A.65.1.9 | E-protein of 89 aas and 2 TMSs |
Viruses | Nidovirales | E-protein of rabbit coronavirus |
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 | Pardaxin of Pardachirus marmoratus (P81861) |
1.A.66.1.2 | Uncharacterized protein of 78 aas and 1 N-terminal TMS. |
Archaea | TACK group | UP of Crenarchaeota archaeon |
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 | MMgT1 of Mus musculus (A7UH87) |
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 | MMgT2 of Mus musculus (Q8R3L0) |
1.A.67.1.3 | Uncharacterized protein of 107 aas and 2 TMSs. |
Eukaryota | Fungi | UP of Ustilago hordei (Barley covered smut fungus) |
1.A.67.1.4 | Uncharacterized protein of 487 aas and 2 C-terminal TMSs. |
Eukaryota | Viridiplantae | UP of Brassica rapa (Chinese cabbage) (Brassica pekinensis) |
1.A.67.1.5 | Uncharacterized protein of 137 aas and 2 N-terminal TMSs |
Eukaryota | Fungi | UP of Leptosphaeria maculans (Blackleg fungus) (Phoma lingam) |
1.A.67.1.6 | Uncharacterized protein of 126 aas and 2 N-terminal TMSs. |
Eukaryota | Heterolobosea | UP of Naegleria gruberi (Amoeba) |
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 | Emc5 of Saccharomyces cerevisiae (Baker's yeast) |
1.A.67.1.8 | Membrane magnesium transporter, MmgT, of 112 aas and 2 TMSs. |
Eukaryota | Apicomplexa | MmgT of Toxoplasma gondii |
1.A.67.1.9 | Uncharacterized protein of 103 aas and 2 TMSs |
Eukaryota | Fungi | UP of Piriformospora indica |
1.A.67.2.1 | Uncharacterized protein of 132 aas and 2 TMSs. |
Eukaryota | Kinetoplastida | UP of Leishmania braziliensis |
1.A.67.2.2 | Uncharacterized protein of 143 aas and 2 TMSs. |
Eukaryota | Kinetoplastida | UP of Trypanosoma cruzi |
1.A.67.2.3 | Uncharacterized protein of 133 aas and 2 TMSs |
Eukaryota | Kinetoplastida | UP of Strigomonas culicis |
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). |
Viruses | Mononegavirales | SH protein of human respiratory syncytial virus (P04852) |
1.A.68.1.2 | BSV small hydrophobic (SH) protein of 81 aas (Karger et al. 2001). |
Viruses | Mononegavirales | SH of bovine respiratory syncytial virus |
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 ion channel, playing a role in budding and /or virus entry. 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 | Mononegavirales | Viroporin SH of human respiratory syncytial virus B |
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). |
Eukaryota | Metazoa | Heterometic odorant receptor (OR) of Drosophila melanogaster: |
1.A.69.1.2 | Odorant receptor, OR2 (Carraher et al., 2012). |
Eukaryota | Metazoa | OR2 of Anopheles gambiae (Q8WTE6) |
1.A.69. |