| TCID | Name | Domain | Kingdom/Phylum | Protein(s) |
|---|---|---|---|---|
|
2.A.49.1.1 | Voltage-gated Cl- channel, Gef1 | Eukaryota |
Fungi, Ascomycota | Gef1 of Saccharomyces cerevisiae |
|
2.A.49.1.2 | The vascular wilt fungal CLC-type voltage-gated chloride channel, Clc1 (influences disease progression and stress responses) (Canero and Roncero, 2008). | Eukaryota |
Fungi, Ascomycota | Clc1 of Fusarium oxysporum (A7LKG1) |
|
2.A.49.1.3 | The voltage-gated chloride channel, CLC-A (Zhu and Williamson, 2003) (required for capsule and laccase expression) | Eukaryota |
Fungi, Basidiomycota | CLC-A of Cryptococcus neoformans (Q874K8) |
|
2.A.49.1.4 | Chloride channel protein of 2075 aas and 10 TMSs. | Eukaryota |
Apicomplexa | CLC family member of Toxoplasma gondii |
|
2.A.49.2.1 | Voltage and (possibly) ATP-gated Cl- channel, ClC-1 or CLCN1 (Bennetts et al., 2005; Zifarelli and Pusch, 2008). It may also transport other anions such as thiocyanate, perchlorate, bromide, nitrate, chlorate and iodide. When mutant, it causes dominant and recessive myotonia. Myotonia congenita is a genetic disease characterized by impaired muscle relaxation after forceful contraction (Orsini et al. 2020). It has a large cytoplasmic C-terminal domain bearing two CBS (cystathionine-β-synthase) domains. Alternative splicing is a posttranscriptional mechanism regulating chloride conductance during muscle development (Lueck et al. 2007). ClC-1-like channels are preferentially located at the somata of medium spiny neurons and can modulate neuronal excitability (Yarotskyy et al. 2022). | Eukaryota |
Metazoa, Chordata | ClC1 or CLCN1 of Homo sapiens (P35523) |
|
2.A.49.2.2 | Intracellular (endosomal) outward rectifying kidney Cl-:H (2:1) antiporter ClC5; CLC-5; CLCN5 (nitrate > Cl- = Br- > I- > acetate > gluconate) (Picollo and Pusch, 2005; Scheel et al., 2005); responsible for Dent''s disease in humans, an X-linked disorder characterized by low molecular weight proteinuria, hypercalciuria, and nephrolithiasis (Stechman et al., 2007; Zifarelli and Pusch, 2009; Ashida et al. 2012). Plays a role by facilitating endosomal acidification through neutralization of proton pump currents (Novarino et al., 2010; Rickheit et al., 2010). The carrier is regulated by protons as studied by Picollo et al., (2010). CLC-5 and KIF3B interact to facilitate CLC-5 plasma membrane expression, endocytosis, and microtubular transport (Reed et al., 2010). A point mutations can convert NHE-6 into a nitrate (NO3-):H+ antiporter (Zifarelli and Pusch 2009). | Eukaryota |
Metazoa, Chordata | ClC5 of Sus scrofa (Q9GKE7) |
|
2.A.49.2.3 | The hepatocyte canalicular chloride channel/carrier, CLC-3 or CLCN3 (I- > Br- > Cl-); outward rectifying; inactivated at positive voltages (Shimada et al., 2000). Oxidation induces surface expression of ClC-3 and activation of ClC-3-dependent anion permeability (Kasinathan et al., 2007). It is swell-activated in human neutrophils during a respiratory burst (Ahluwalia, 2008). The ClC-3 Cl-/H+ antiporter becomes uncoupled at low extracellular pH (Matsuda et al., 2010). It transports superoxide, O2- (Hawkins et al. 2007; Fisher 2009). ClC-3 might be involved in modulating vascular remodeling in hypertension and arteriosclerosis (Guan et al. 2006). ClC-3 upregulation may protect against oxidative stress-induced necrosis (Remillard and Yuan 2005). | Eukaryota |
Metazoa, Chordata | CLC3 of Rattus norvegicus (P51792) |
|
2.A.49.2.4 | The kidney medulla voltage-gated dimeric chloride channel, ClC-K1 or CLCNKA. Transports Br-, I- and NO3- as well as Cl-. Regulated by dehydration; functions in the regulation of cell volume, membrane potential stabilization, signal transduction and transepithelial transport. Possibly required for urinary concentration in the kidney (Uchida et al., 1993). The human orthologue when mutated can give rise to salt loss associated with Bartter''s syndrome. In the inner ear, it plays a role in hearing. Activators and inhibitors that may have theraputic benefits are known (Gradogna and Pusch 2010). Regulated by the accessory subunit, Barttin (Wojciechowski et al. 2015). | Eukaryota |
Metazoa, Chordata | ClC-K1 of Rattus norvegicus (Q06393) |
|
2.A.49.2.5 | The kidney thick ascending limb of Henle's loop and collecting duct chloride channel/carrier, ClC-K2 (Br- > I- > Cl- >> cyclamate) (Adachi et al., 1994). Regulated by the accessory subunit, Barttin (Wojciechowski et al. 2015). | Eukaryota |
Metazoa, Chordata | ClC-K2 of Rattus norvegicus (P51802) |
|
2.A.49.2.6 | The ClC-2 or CLCN2 chloride channel is expressed in many tissues (Cl- ≥ Br- > I-) (Thiemann et al., 1992). Regulated in the retina by Cereblon (Q96SW2) (Hohberger and Enz, 2009). A toxin, GaTx2, is a potent and specific inhibitor of ClC-2, binding with a Ki of 20pM (Thompson et al., 2009). ClC-2 channels constitute part of the background conductance and assist chloride extrusion (Rinke et al., 2010). ClC-2 channels regulate neuronal excitability,vision and fertility, but not intracellular chloride levels (Ratté and Prescott, 2011; Sánchez-Rodríguez et al. 2012). Sequential interactions of chloride and proton ions with the fast gate steer voltage-dependent gating (Sánchez-Rodríguez et al. 2012). The detailed mechanism of proton gating of chloride currents has been presented (Niemeyer et al. 2009). | Eukaryota |
Metazoa, Chordata | ClC-2 of Rattus norvegicus (P35525) |
|
2.A.49.2.7 | The ClC-A of the trophozoite plasma membrane (Cl->Br->I->F->NO3- ). Functions as an ion channel, not a Cl:H+ antiporter; regulates cell pH and volume (Salas-Casas et al., 2006) | Eukaryota |
Evosea | ClC-A of Entamoeba histolytica (Q70S43) |
|
2.A.49.2.8 | ClC-4 or CLCN4 (catalyzes 2 Cl-:H+ exchange, but NO3- uniport (Bergsdorf et al., 2009). SCN- uncouples Cl- from H+ transport so anions are transported with high unitary transport rates. Voltage then influences transport as is observed for the gating of ion channels (Orhan et al., 2011). Also transports bromide and iodide. | Eukaryota |
Metazoa, Chordata | ClC-4 of Homo sapiens (P51793) |
|
2.A.49.2.9 | The CIC carrier (stoichiometry H+:Cl- = 2:1). 3D structure known to 3.5 Å resolution (PDB# 3ORG; Feng et al., 2010). | Eukaryota |
Rhodophyta | CIC carrier of Cyanidioschyzon melolae (PDB 3ORG_A) |
|
2.A.49.2.10 | Chloride transporter/chloride channel (ClC) family protein of 1604 aas (Docampo et al. 2013). | Eukaryota |
Apicomplexa | CLC family member of Toxoplasma gondii |
|
2.A.49.2.11 | The voltage-gated torpedo chloride channel, CLC-0, of 810 aas. This channel is thought to ensure the high conductance of the non-innervated membrane of the electrocyte necessary for efficient current generation caused by sodium influx through the acetylcholine receptor at the innervated membrane. ClC-0 is a homodimer with separate pores in each subunit. Each protopore can be opened and closed independently from the other pore by a "fast gate". A common, slow gate acts on both pores simultaneously. The opening of the fast gate is controlled by a critical glutamate (E166), whose protonation state determines the fast gate's pH dependence (Zifarelli and Pusch 2010). Extracellular protons likely arrive directly at E166, but protonation of E166 from the inside may be mediated by the dissociation of an intrapore water molecule. The OH- anion resulting from dissociation of water is stabilized in one of the anion binding sites of the channel, competing with intracellular Cl-. Proton translocation drives irreversible gating transitions associated with the slow gate (Zifarelli and Pusch 2010). The structure of the cytoplasmic domain has been solved (Meyer and Dutzler 2006). It contains a folded core of two tightly interacting cystathionine beta-synthetase (CBS) subdomains which are connected by a 96 residue mobile linker. The domains form dimers, thereby extending the 2-fold symmetry of the transmembrane pore.
| Eukaryota |
Metazoa, Chordata | CLC-0 of Torpedo californica (Pacific electric ray) |
|
2.A.49.2.12 | Chloride (bromide; iodide) channel-2, CLC-2, CLC2, CLCN2; 94% identical to the rat orthologue, 2.A.49.2.6. Hyperpolarization activates CLC-2 mainly by driving intracellular anions into the channel pores. Protonation by extracellular H+ plays a minor role in dislodging the glutamate gate (De Jesús-Pérez et al. 2016). The absence of ClC-2 results in less differentiated colonic crypts and increased tumorigenicity associated with colitis via dysregulation (Jin et al. 2018). Biallelic CLCN2 mutations cause retinal degeneration by impairing retinal pigment epithelium phagocytosis and chloride channel function (Xu et al. 2023). | Eukaryota |
Metazoa, Chordata | CLC-2 of Homo sapiens |
|
2.A.49.2.13 | Clh-3; Clc-3, Clh3, Clc3 of 1001 aas and 11 TMSs. Isoform a: Voltage-gated chloride channel (Rutledge et al. 2002; Denton et al. 2005). Insensitive to depolarizing voltages; requires low voltages for activation; insensitive to chloride levels but has a mild sensitivity to low pH. Channel gating properties are conferred by the cytoplasmic C-terminus (He et al. 2006). Plays a role in egg laying by modulating hermaphrodite-specific neuron excitability and the ovulatory contractions of gap-junction-coupled gonadal sheath cells (Branicky et al. 2014). When active, may prevent tubular formation of the excretory canals (Hisamoto et al. 2008). Activated during oocyte meiotic maturation and by membrane hyperpolarization and cell swelling (Denton et al. 2004). Inhibited by Zn2+ and to a lesser extent by Cd2+(Rutledge et al. 2001). Isoform b: Voltage-gated chloride channel sensitive to depolarizing conditioning voltages; requires stronger voltages for activation and activation is slower, is inhibited by low concentrations of chloride and is activated by low pH. Channel gating properties are conferred by the cytoplasmic C-terminus (He et al. 2006). | Eukaryota |
Metazoa, Nematoda | Clh3 of Caenorhabditis elegans |
|
2.A.49.2.14 | The voltage-gated chloride channel, CLCNKB, CLCCK or CLC-Kb of 687 aas and 10 TMSs in a 2 + 2 + 2 + 2 + 2 arrangement. These anion channels have several functions including the regulation of cell volume; membrane potential stabilization, signal transduction and transepithelial transport. It may also be important in urinary concentrating mechanisms (Estévez et al. 2001). Inactivated variants in the CLCNKB gene, encoding the basolateral chloride channel ClC-Kb cause classic Bartter syndrome, characterized by hypokalemic metabolic alkalosis and hyperreninemic hyperaldosteronism (Wang et al. 2018). | Bacteria |
Pseudomonadota | CLCNKb of Pseudomonas sp. UK4 |
|
2.A.49.2.15 | Chloride channel protein, CLCNKB or ClC-Kb or CLCKB of 687 aas and 10 TMSs in a 2 + 2 + 2 + 2 + 2 TMS arrangement. Voltage-gated chloride channel. Chloride channels have several functions including the regulation of cell volume; membrane potential stabilization, signal transduction and transepithelial transport. May be important in urinary concentrating mechanisms (Estévez et al. 2001). CLCNKB Complex Heterozygous Mutations play a role in Adult-Onset Type III Bartter Syndrome (Chen and Hong 2024). | Eukaryota |
Metazoa, Chordata | CLCNKB of Homo sapiens |
|
2.A.49.2.16 | H+/Cl- exchange transporter 5, ClC-5 (CLCN5; CLCK2) of 816 aas and 12 TMSs in a 1 + 1 + 2 + 2 + 2 + 2 + 2 TMS arrangement. It functions as antiport system and exchanges chloride ions against protons (Neagoe et al. 2010). ClC-5 is expressed in the apical membrane of cyst epithelia and is a likely candidate mediating Cl- secretion into the kidney cyst lumen in the tuberous sclerosis complex (TSC) (Barone et al. 2022). Dent disease (DD) is a hereditary renal disorder characterized by low molecular weight (LMW) proteinuria and progressive renal failure. Inactivating mutations of the CLCN5 gene encoding the 2Cl-/H+exchanger ClC-5 have been identified in patients with DD type 1. ClC-5 is essentially expressed in proximal tubules (PT) where it is thought to play a role in maintaining an efficient endocytosis of LMW proteins (Sakhi et al. 2024). | Eukaryota |
Metazoa, Chordata | CLC5 of Homo sapiens |
|
2.A.49.2.17 | ClC-c of 893 aas and 11 TMSs. Drosophila ClC-c is a homolog of human CLC-5 and a new model for Dent Disease type 1 (Reynolds et al. 2024). | Eukaryota |
Metazoa, Arthropoda | ClC-c of Drosophila melanogaster |
|
2.A.49.3.1 | NO3-:H+ (or less efficiently, Cl-:H+) antiporter, ClC-A or CLCa (De Angeli et al., 2006; Bergsdorf et al., 2009). Responsible for nitrate uptake into vacuoles (Zifarelli and Pusch, 2009b). It is up-regulated under salt stress conditions (Yang et al. 2018) and may play a role in nitrate and Cd2+ resistance (Liao et al. 2019). The cryoEM structure has been solved at 2.8 Å resolution. An almost identical sequence has Uniprot acc # P92941 and differs from the one included in TCDB between residues 380 and 430, possibly due to sequencing errors. The central nitrate is shifted by approximately 1.4 Å from chloride, which is likely caused by a weaker interaction between the anion and Pro160; the side chains of aromatic residues around the central binding site are rearranged to accommodate the larger nitrate (He et al. 2022). The regulatory mechanisms of AtCLCa by nucleotides and phospholipids have been proposed (Yang et al. 2018) and may play a role in nitrate and Cd2+ resistance (Liao et al. 2019). The cryoEM structure has been solved at 2.8 Å resolution. An almost identical sequence has Uniprot acc # P92941 and differs from the one included in TCDB between residues 380 and 430, possibly due to sequencing errors. The central nitrate is shifted by approximately 1.4 Å from chloride, which is likely caused by a weaker interaction between the anion and Pro160; the side chains of aromatic residues around the central binding site are rearranged to accommodate the larger nitrate (He et al. 2022). The regulatory mechanisms of AtCLCa by nucleotides and phospholipids have been proposed (Yang et al. 2023). | Eukaryota |
Viridiplantae, Streptophyta | ClC-A of Arabidopsis thaliana (Q96325) |
|
2.A.49.3.2 | Mitochondrial inner membrane anion channel (IMAC). Fatty acids induce chloride permeation in rat liver mitochondria probably by activation of the inner membrane anion channel (IMAC) (Schönfeld et al. 2004). | Eukaryota |
Viridiplantae, Streptophyta | ClC-Nt2 (ClC-1) of Nicotiana tabacum (Q9XF71) |
|
2.A.49.3.3 | CLC-7, CLC7 or Clcn7 Cl-:H+ antiporter; provides the primary Cl- permeation pathway in the lysosome (Graves et al., 2008). Cl- provides the counter ion for acidification of the lysosomal lumen via the V-type ATPase (Mindell, 2012). It is a slowly voltage-gated 2Cl-/1H+-exchanger and requires Ostm1 for transport activity (Leisle et al., 2011). Common gating (involving both of the two subunits) underlies the slow voltage activation dependent on the C-terminal CBS domain (Ludwig et al. 2013). Lethal CLCN7-related osteopetrosis has been described (Rössler et al. 2021). ClC-7 drives intraphagosomal chloride accumulation to support hydrolase activity and phagosome resolution (Wu et al. 2023). CLCN7 is a pathogenesis protein in osteopetrosis (Ma et al. 2023).
| Eukaryota |
Metazoa, Chordata | CLC-7 of Homo sapiens (P51798) |
|
2.A.49.3.4 | CLC-6 or CLCN6, Cl-:H+ late endosomal/lysosomal antiporter (43% identical to CLC-7) and 99% identical to the human ortholog (P51797). Cl- > I-; mutating the gating glutamate yielded ohmic anion conductance (Neagoe et al., 2010). A recurrent gain-of-function mutation in CLCN6, encoding the ClC-6 Cl-/H+-exchanger, causes early-onset neurodegeneration (Polovitskaya et al. 2020). Loss of ClC-6 function reduces Golgi calcium stores, which may play a role in vascular contraction and relaxation signaling in vascular smooth muscle cells. Thus, ClC-6 may modulate blood pressure by regulating Golgi calcium reserves, which in turn contribute to vascular smooth muscle function (Klemens et al. 2021). Ocular manifestations of a gain-of-function mutation in CLCN6, a newly diagnosed disease gene (Kimera et al. 2023). Mutations in CLCN6 are a genetic cause of neuronal ceroid lipofuscinosis in a mice (He et al. 2024). | Eukaryota |
Metazoa, Chordata | CLC-6 of Mus musculus (O35454) |
|
2.A.49.3.5 | Anion transporter with specificity for nitrate (NO3-) and chloride (Cl-), CLCa1, of 811 aas and probably 12 TMSs in a 4 + 4 + 4 TMS arrangement (Nedelyaeva et al. 2019). It is expressed in the roots, and induced with nitrate depletion. | Eukaryota |
Viridiplantae, Streptophyta | CLCa1 of Suaeda altissima |
|
2.A.49.4.1 | Putative Cl- channel, MJ0305 | Archaea |
Euryarchaeota | MJ0305 of Methanococcus jannaschii (Q57753) |
|
2.A.49.5.1 | Cl-:H+ (2:1) antiporter, EriC or ClcA (ClC-ecl) (Accardi and Miller, 2004). The x-ray structure has been determined (PDB 1OTS) Dutzler et al., 2002, 2003). The exchange mechanism involves a conformational cycle of alternating exposure of Cl- and H+ binding sites of both ClC pores to the two sides of the membrane (Miloshevsky et al., 2010). Specific aspects of these conformational changes have been proposed (Wang et al. 2018). Although the protein is present as a homodimer, a single ClC subunit alone is the basic functional unit for transport, and cross-subunit interaction is not required for Cl-/H+ exchange in ClC transporters (Robertson et al., 2010). Glu202 is essential for H+ symport and is on the H+ pathway (Lim et al. 2012). CLC exchangers have two gates that are coupled through conformational rearrangements outside the ion pathway (Basilio et al. 2014). The rotation of E148 plays a critical role in defining the Cl-/H+ coupling (Lee et al. 2016). The channel shows conserved re-entrant helix-coil-helix domains (Tsirigos et al. 2017). Proton transport is intrinsically coupled to protein cavity hydration changes and is influenced by the protein environment (Wang et al. 2018). EriC also transports fluoride (F-) (Baker et al. 2012). Non-polar membrane embedded side-chains in CLC-ec1 play a role in defining dimer stability, but the stoichiometry is contextual to the solvent environment, and L194 is a molecular hot-spot for defining dimerization (Mersch et al. 2021). | Bacteria |
Pseudomonadota | EriC of Escherichia coli (P37019) |
|
2.A.49.5.2 | Slow CLC Cl-:H+ antiporter. 3-d structures known at 3.1 Å resolution (3Q17A) (turnover rate: 20/sec; Cl-:H+ stoichiometry = 2:1). The turnover rate of the E. coli EriC is ~2000/sec. (Jayaram et al., 2011). | Bacteria |
Cyanobacteriota | Slow CLC of Synechocystis sp. PCC6803 (Q55858) |
|
2.A.49.5.3 | Voltage-gated ClC-type chloride channel ClcB or MriT of 418 aas. | Bacteria |
Pseudomonadota | ClcB of Escherichia coli O6:H1 |
|
2.A.49.5.4 | Voltage-gated ClC-type Cl- channel, ClcB (Phillips et al. 2012). | Bacteria |
Pseudomonadota | ClcB of Citrorbacter koseri |
|
2.A.49.5.5 | H+/Cl- antiporter, ClcA (stoichiometry 1:2) (Phillips et al. 2012). | Bacteria |
Pseudomonadota | ClcA of Citrobacter koseri |
|
2.A.49.6.1 | Putative Cl- channel | Bacteria |
Cyanobacteriota | Putative Cl- channel of Synechocystis (P74477) |
|
2.A.49.6.2 | Voltage-gated Cl- channel, ClC chloride channel core, CCC | Bacteria |
Pseudomonadota | CCC of Variovorax paradoxus (C5D215) |
|
2.A.49.6.3 | Chloride channel protein CLC-e (AtCLC-e) (CBS domain-containing protein CBSCLC3). Present in the thylacoid membrane of the chloroplast. Initially proposed to function in photosynthesis, and later in nitrate assimilation (Herdean et al. 2016). | Eukaryota |
Viridiplantae, Streptophyta | CLC-E of Arabidopsis thaliana |
|
2.A.49.6.4 | Putative chloride:H+ antiporter, voltage gated, of 792 aas and 15 TMSs with an N-terminal 4 TMS domain of unknown function found only in a few archaea and a C-terminal CBS domain.
| Archaea |
Euryarchaeota | CLC protein of Halobacterium salinarum (Halobacterium halobium) |
|
2.A.49.6.5 | Uncharacterized membrane protein of 481 aas and 10 - 13 TMSs. This protein was probably incorrectly assigned the function as the membrane constituent of an ABC Zn2+ uptake transporter (Mandal et al. 2019). However, this is unlikely; it is probably a Cl- transporter in agreement with its assignment to TC family 2.A.49. | Bacteria |
Deinococcota | UP of Thermus thermophilus |
|
2.A.49.7.1 | Voltage-gated Cl- channel, ClC (YfeO) | Bacteria |
Pseudomonadota | YfeO of E. coli (H5KWQ5) |
|
2.A.49.7.2 | Voltage-gated Cl- channel, ClC (EriC) | Bacteria |
Actinomycetota | EriC of Saccharomonospora azurea (H8G8F4) |
|
2.A.49.7.3 | Voltage-gated Cl- channel, ClC SCO5964 | Bacteria |
Actinomycetota | SCO5964 of Streptomyces coelicolor (O54193) |
|
2.A.49.8.1 | EriC-like protein | Archaea |
Euryarchaeota | EriC of Methanoculleus marisnigri (A3CXC7) |
|
2.A.49.8.2 | Putative chloride channel of 469 aas and 11 putative TMSs | Eukaryota |
Rhodophyta | Chloride channel of Galdieria sulphuraria |
|
2.A.49.9.1 | Fluoride:proton antiporter of 459 aas and 10 TMSs, CLCF, with high selectivity for fluoride over chloride (Brammer et al. 2014). These proteins normally exist as dimers, but the monomers are fully active (Last and Miller 2015). | Bacteria |
Planctomycetota | CLCF of Pirellula staleyi |
|
2.A.49.9.2 | Fluoride:proton antiporter, CLCF, of 426 aas and 10 TMSs, with specificity for fluoride over other anions (Brammer et al. 2014). | Pseudomonadota | CLCF of Ralstonia pickettii | |
|
2.A.49.9.3 | Fluoride:proton antiporter of 406 aas and 10 TMSs, CLCF (Brammer et al. 2014). | Bacteria |
Bacillota | CLCF of Enterococcus casseliflavus |
|
2.A.49.9.4 | Putative fluoride:proton antiporter of 403 aas and 10 TMSs (Brammer et al. 2014). | Bacteria |
Bacillota | CLCF of Lactococcus lactis subsp. cremoris (Streptococcus cremoris) |
|
2.A.49.9.5 | Anion transporter, EriC, of 452 aas and 10 TMSs. Transports Cl- and F-, and probably other anions (Baker et al. 2012). | Bacteria |
Pseudomonadota | EriC of Pseudomonas syringae |