TCDB is operated by the Saier Lab Bioinformatics Group
TCIDNameDomainKingdom/PhylumProtein(s)
*2.A.49.1.1









Voltage-gated Cl- channel, Gef1
Eukaryota
Fungi
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
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
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). When mutant, it causes dominant and recessive myotonia. 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).

Eukaryota
Metazoa
ClC1 or CLCN1 of Homo sapiens (P35523)
*2.A.49.2.2









Intracellular (endosomal) outward rectifying kidney Cl-:H (2:1) antiporter ClC5 (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
ClC5 of Sus scrofa (Q9GKE7)
*2.A.49.2.3









The hepatocyte canalicular chloride channel/carrier, CLC-3 (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).  Transport superoxide, O2- (Hawkins et al. 2007; Fisher 2009).

Eukaryota
Metazoa
CLC3 of Rattus norvegicus (P51792)
*2.A.49.2.4









The kidney medulla voltage-gated dimeric chloride channel, ClC-K1 or CLCNKA.  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
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
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
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
Entamoeba
ClC-A of Entamoeba histolytica (Q70S43)
*2.A.49.2.8









ClC-4 (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).

Eukaryota
Metazoa
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
Bangiophyceae
CIC carrier of Cyanidioschyzon melolae (PDB 3ORG_A)
*2.A.49.2.10









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).

 

Eukaryota
Metazoa
CLC-0 of Torpedo californica (Pacific electric ray)
*2.A.49.2.12









Chloride 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).

Eukaryota
Metazoa
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
Clh3 of Caenorhabditis elegans
*2.A.49.3.1









NO3-:H+ (or less efficiently, Cl-:H+) antiporter, ClC-A (De Angeli et al., 2006; Bergsdorf et al., 2009). Responsible for nitrate uptake into vacuoles (Zifarelli and Pusch, 2009b).

Eukaryota
Viridiplantae
ClC-A of Arabidopsis thaliana (Q96325)
*2.A.49.3.2









Mitochondrial inner membrane anion channel (IMAC)
Eukaryota
Viridiplantae
ClC-Nt2 (ClC-1) of Nicotiana tabacum (Q9XF71)
*2.A.49.3.3









CLC-7 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).

Eukaryota
Metazoa
CLC-7 of Homo sapiens (P51798)
*2.A.49.3.4









CLC-6 Cl-:H+ late endosomal/lysosomal antiporter (43% identical to CLC-7). Cl->I-; mutating the gating glutamate yielded ohmic anion conductance (Neagoe et al., 2010).

Eukaryota
Metazoa
CLC-6 of Mus musculus (O35454)
*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; 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). 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).

Bacteria
Proteobacteria
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
Cyanobacteria
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
Proteobacteria
ClcB of Escherichia coli O6:H1
*2.A.49.5.4









Voltage-gated ClC-type Cl- channel, ClcB (Phillips et al. 2012).

Bacteria
Proteobacteria
ClcB of Citrorbacter koseri
*2.A.49.5.5









H+/Cl- antiporter, ClcA (stoichiometry 1:2) (Phillips et al. 2012).

Bacteria
Proteobacteria
ClcA of Citrobacter koseri
*2.A.49.6.1









Putative Cl- channel
Bacteria
Cyanobacteria
Putative Cl- channel of Synechocystis (P74477)
*2.A.49.6.2









Voltage-gated Cl- channel, ClC chloride channel core, CCC

Bacteria
Proteobacteria
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
CLC-E of Arabidopsis thaliana
*2.A.49.6.4









Putative chloride:H+ antiporter 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.49.7.1









Voltage-gated Cl- channel, ClC (YfeO)

Bacteria
Proteobacteria
YfeO of E. coli (H5KWQ5)
*2.A.49.7.2









Voltage-gated Cl- channel, ClC (EriC)

Bacteria
Actinobacteria
EriC of Saccharomonospora azurea (H8G8F4)
*2.A.49.7.3









Voltage-gated Cl- channel, ClC SCO5964

Bacteria
Actinobacteria
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
Bangiophyceae
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
Planctomycetes
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).

CLCF of Ralstonia pickettii
*2.A.49.9.3









Fluoride:proton antiporter of 406 aas and 10 TMSs, CLCF (Brammer et al. 2014).

Bacteria
Firmicutes
CLCF of Enterococcus casseliflavus
*2.A.49.9.4









Putative fluoride:proton antiporter of 403 aas and 10 TMSs (Brammer et al. 2014).

Bacteria
Firmicutes
CLCF of Lactococcus lactis subsp. cremoris (Streptococcus cremoris)