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148  structures 6027  species 0  interactions 20585  sequences 185  architectures

Family: Voltage_CLC (PF00654)

Summary: Voltage gated chloride channel

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This is the Wikipedia entry entitled "Chloride channel". More...

Chloride channel Edit Wikipedia article

Voltage gated chloride channel
1ots opm.png
Clc chloride channel (PDB: 1OTS​)
OPM superfamily10
OPM protein1ots

Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration in vivo is much higher than other anions.[1] Several families of voltage-gated channels and ligand-gated channels (e.g., the CaCC families) have been characterized in humans.

Voltage-gated chloride channels display a variety of important physiological and cellular roles that include regulation of pH, volume homeostasis, organic solute transport, cell migration, cell proliferation and differentiation. Based on sequence homology the chloride channels can be subdivided into a number of groups.

General functions

Voltage-gated chloride channels are important for setting cell resting membrane potential and maintaining proper cell volume. These channels conduct Cl− or other anions such as HCO−
, I−, SCN−, and NO−
. The structure of these channels are not like other known channels. The chloride channel subunits contain between 1 and 12 transmembrane segments. Some chloride channels are activated only by voltage (i.e., voltage-gated), while others are activated by Ca2+, other extracellular ligands, or pH.[2]

CLC family

The CLC family of chloride channels contains 10 or 12 transmembrane helices. Each protein forms a single pore. It has been shown that some members of this family form homodimers. In terms of primary structure, they are unrelated to known cation channels or other types of anion channels. Three CLC subfamilies are found in animals. CLCN1 is involved in setting and restoring the resting membrane potential of skeletal muscle, while other channels play important parts in solute concentration mechanisms in the kidney.[3] These proteins contain two CBS domains. Chloride channels are also important for maintaining safe ion concentrations within plant cells.[4]

Structure and mechanism

The CLC channel structure has not yet been resolved, however the structure of the CLC exchangers has been resolved by x-ray crystallography. Because the primary structure of the channels and exchangers are so similar, most assumptions about the structure of the channels are based on the structure established for the bacterial exchangers.[5]

A cartoon representation of a CLC chloride channel. The arrows indicate the orientation of each half of the individual subunit. Each CLC channel is formed from two monomers, each monomer containing the antiparallel transmembrane domain. Each monomer has its own pore through which chloride and other anions may be conducted.

Each channel or exchanger is composed of two similar subunits—a dimer—each subunit containing one pore. The proteins are formed from two copies of the same protein—a homodimer—though scientists have artificially combined subunits from different channels to form heterodimers. Each subunit binds ions independently of the other, meaning conduction or exchange occur independently in each subunit.[3]

A cartoon representation of a CLC channel monomer. Two of these subunits come together to form the CLC channel. Each monomer has three binding sites for anions, Sext, Scen, and Sint. The two CBS domains bind adenosine nucleotides to alter channel function

Each subunit consists of two related halves oriented in opposite directions, forming an ‘antiparallel’ structure. These halves come together to form the anion pore.[5] The pore has a filter through which chloride and other anions can pass, but lets little else through. These water-filled pores filter anions via three binding sites—Sint, Scen, and Sext—which bind chloride and other anions. The names of these binding sites correspond to their positions within the membrane. Sint is exposed to intracellular fluid, Scen lies inside the membrane or in the center of the filter, and Sext is exposed to extracellular fluid.[4] Each binding site binds different chloride anions simultaneously. In the exchangers, these chloride ions do not interact strongly with one another, due to compensating interactions with the protein. In the channels, the protein does not shield chloride ions at one binding site from the neighboring negatively charged chlorides.[6] Each negative charge exerts a repulsive force on the negative charges next to it. Researchers have suggested that this mutual repulsion contributes to the high rate of conduction through the pore.[5]

CLC transporters shuttle H+ across the membrane. The H+ pathway in CLC transporters utilizes two glutamate residues—one on the extracellular side, Gluex, and one on the intracellular side, Gluin. Gluex also serves to regulate chloride exchange between the protein and extracellular solution. This means that the chloride and the proton share a common pathway on the extracellular side, but diverge on the intracellular side.[6]

CLC channels also have dependence on H+, but for gating rather than Cl− exchange. Instead of utilizing gradients to exchange two Cl− for one H+, the CLC channels transport one H+ while simultaneously transporting millions of anions.[6] This corresponds with one cycle of the slow gate.

Eukaryotic CLC channels also contain cytoplasmic domains. These domains have a pair of CBS motifs, whose function is not fully characterized yet.[5] Though the precise function of these domains is not fully characterized, their importance is illustrated by the pathologies resulting from their mutation. Thomsen's disease, Dent's disease, infantile malignant osteopetrosis, and Bartter's syndrome are all genetic disorders due to such mutations.

At least one role of the cytoplasmic CBS domains regards regulation via adenosine nucleotides. Particular CLC transporters and proteins have modulated activity when bound with ATP, ADP, AMP, or adenosine at the CBS domains. The specific effect is unique to each protein, but the implication is that certain CLC transporters and proteins are sensitive to the metabolic state of the cell.[6]


The Scen acts as the primary selectivity filter for most CLC proteins, allowing the following anions to pass through, from most selected to least: SCN−, Cl−, Br−, NO−
, I−. Altering a serine residue at the selectivity filter, labeled Sercen, to a different amino acid alters the selectivity.[6]

Gating and kinetics

Gating occurs through two mechanisms: protopore or fast gating and common or slow gating. Common gating involves both protein subunits closing their pores at the same time (cooperation), while protopore gating involves independent opening and closing of each pore.[5] As the names imply, fast gating occur at a much faster rate than slow gating. Precise molecular mechanisms for gating are still being studied.

For the channels, when the slow gate is closed, no ions permeate through the pore. When the slow gate is open, the fast gates open spontaneously and independently of one another. Thus, the protein could have both gates open, or both gates closed, or just one of the two gates open. Single-channel patch-clamp studies demonstrated this biophysical property even before the dual-pore structure of CLC channels had been resolved. Each fast gate opens independently of the other and the ion conductance measured during these studies reflects a binomial distribution.[3]

H+ transport promotes opening of the common gate in CLC channels. For every opening and closing of the common gate, one H+ is transported across the membrane. The common gate is also affected by the bonding of adenosine nucleotides to the intracellular CBS domains. Inhibition or activation of the protein by these domains is specific to each protein.[6]


The CLC channels allow chloride to flow down its electrochemical gradient, when open. These channels are expressed on the cell membrane. CLC channels contribute to the excitability of these membranes as well as transport ions across the membrane.[3]

The CLC exchangers are localized to intracellular components like endosomes or lysosomes and help regulate the pH of their compartments.[3]


Bartter's syndrome, which is associated with renal salt wasting and hypokalemic alkalosis, is due to the defective transport of chloride ions and associated ions in the thick ascending loop of Henle. CLCNKB has been implicated.[7]

Another inherited disease that affects the kidney organs is Dent's Disease, characterised by low molecular weight proteinuria and hypercalciuria where mutations in CLCN5 are implicated.[7]

Thomsen disease is associated with dominant mutations and Becker disease with recessive mutations in CLCN1.[7]


E-ClC family

CLCA, N-terminal

Members of Epithelial Chloride Channel (E-ClC) Family (TC# 1.A.13) catalyze bidirectional transport of chloride ions. Mammals have multiple isoforms (at least 6 different gene products plus splice variants) of epithelial chloride channel proteins, catalogued into the Chloride channel accessory (CLCA) family.[8] The first member of this family to be characterized was a respiratory epithelium, Ca2+-regulated, chloride channel protein isolated from bovine tracheal apical membranes.[9] It was biochemically characterized as a 140 kDa complex. The bovine EClC protein has 903 amino acids and four putative transmembrane segments. The purified complex, when reconstituted in a planar lipid bilayer, behaved as an anion-selective channel.[10] It was regulated by Ca2+ via a calmodulin kinase II-dependent mechanism. Distant homologues may be present in plants, ciliates and bacteria, Synechocystis and Escherichia coli, so at least some domains within E-ClC family proteins have an ancient origin.


CLIC family

Chloride intracellular ion channel

The Chloride Intracellular Ion Channel (CLIC) Family (TC# 1.A.12) consists of six conserved proteins in humans (CLIC1, CLIC2, CLIC3, CLIC4, CLIC5, CLIC6). Members exist as both monomeric soluble proteins and integral membrane proteins where they function as chloride-selective ion channels. These proteins are thought to function in the regulation of the membrane potential and in transepithelial ion absorption and secretion in the kidney.[11] They are a member of the glutathione S-transferase (GST) superfamily.


They possess one or two putative transmembrane α-helical segments (TMSs). The bovine p64 protein is 437 amino acyl residues in length and has the two putative TMSs at positions 223-239 and 367-385. The N- and C-termini are cytoplasmic, and the large central luminal loop may be glycosylated. The human nuclear protein (CLIC1 or NCC27) is much smaller (241 residues) and has only one putative TMS at positions 30-36. It is homologous to the second half of p64.

Structural studies showed that in the soluble form, CLIC proteins adopt a GST fold with an active site exhibiting a conserved glutaredoxin monothiol motif, similar to the omega class GSTs. Al Khamici et al. demonstrated that CLIC proteins have glutaredoxin-like glutathione-dependent oxidoreductase enzymatic activity.[12] CLICs 1, 2 and 4 demonstrate typical glutaredoxin-like activity using 2-hydroxyethyl disulfide as a substrate. This activity may regulate CLIC ion channel function.[12]

Transport reaction

The generalized transport reaction believed to be catalyzed chloride channels is:

Cl− (cytoplasm) → Cl− (intraorganellar space)


CFTR is a chloride channel belonging to the superfamily of ABC transporters. Each channel has two transmembrane domains and two nucleotide binding domains. ATP binding to both nucleotide binding domains causes changes these domains to associate, further causing changes that open up the ion pore. When ATP is hydrolyzed, the nucleotide binding domains dissociate again and the pore closes.[13]


Cystic fibrosis is caused by mutations in the CFTR gene on chromosome 7, the most common mutation being deltaF508 (a deletion of a codon coding for phenylalanine, which occupies the 508th amino acid position in the normal CFTR polypeptide). Any of these mutations can prevent the proper folding of the protein and induce its subsequent degradation, resulting in decreased numbers of chloride channels in the body.[citation needed] This causes the buildup of mucus in the body and chronic infections.[13]

Other chloride channels and families


  1. ^ Jentsch TJ, Stein V, Weinreich F, Zdebik AA (April 2002). "Molecular structure and physiological function of chloride channels". Physiological Reviews. 82 (2): 503–68. doi:10.1152/physrev.00029.2001. PMID 11917096.
  2. ^ Suzuki M, Morita T, Iwamoto T (January 2006). "Diversity of Cl(-) channels". Cellular and Molecular Life Sciences. 63 (1): 12–24. doi:10.1007/s00018-005-5336-4. PMC 2792346. PMID 16314923.
  3. ^ a b c d e Stölting G, Fischer M, Fahlke C (January 2014). "CLC channel function and dysfunction in health and disease". Frontiers in Physiology. 5: 378. doi:10.3389/fphys.2014.00378. PMC 4188032. PMID 25339907.
  4. ^ Li WY, Wong FL, Tsai SN, Phang TH, Shao G, Lam HM (June 2006). "Tonoplast-located GmCLC1 and GmNHX1 from soybean enhance NaCl tolerance in transgenic bright yellow (BY)-2 cells". Plant, Cell & Environment. 29 (6): 1122–37. doi:10.1111/j.1365-3040.2005.01487.x. PMID 17080938.
  5. ^ a b c d e Dutzler R (June 2007). "A structural perspective on ClC channel and transporter function". FEBS Letters. 581 (15): 2839–44. doi:10.1016/j.febslet.2007.04.016. PMID 17452037.
  6. ^ a b c d e f Accardi A, Picollo A (August 2010). "CLC channels and transporters: proteins with borderline personalities". Biochimica et Biophysica Acta. 1798 (8): 1457–64. doi:10.1016/j.bbamem.2010.02.022. PMC 2885512. PMID 20188062.
  7. ^ a b c Planells-Cases R, Jentsch TJ (March 2009). "Chloride channelopathies" (PDF). Biochimica et Biophysica Acta. 1792 (3): 173–89. doi:10.1016/j.bbadis.2009.02.002. PMID 19708126.
  8. ^ Evans SR, Thoreson WB, Beck CL (October 2004). "Molecular and functional analyses of two new calcium-activated chloride channel family members from mouse eye and intestine". The Journal of Biological Chemistry. 279 (40): 41792–800. doi:10.1074/jbc.M408354200. PMC 1383427. PMID 15284223.
  9. ^ Agnel M, Vermat T, Culouscou JM (July 1999). "Identification of three novel members of the calcium-dependent chloride channel (CaCC) family predominantly expressed in the digestive tract and trachea". FEBS Letters. 455 (3): 295–301. doi:10.1016/s0014-5793(99)00891-1. PMID 10437792.
  10. ^ Brunetti E, Filice C (June 1996). "Percutaneous aspiration in the treatment of hydatid liver cysts". Gut. 38 (6): 936. doi:10.1136/gut.38.6.936. PMC 1383206. PMID 8984037.
  11. ^ Singh H, Ashley RH (2007-02-01). "CLIC4 (p64H1) and its putative transmembrane domain form poorly selective, redox-regulated ion channels". Molecular Membrane Biology. 24 (1): 41–52. doi:10.1080/09687860600927907. PMID 17453412.
  12. ^ a b Al Khamici H, Brown LJ, Hossain KR, Hudson AL, Sinclair-Burton AA, Ng JP, Daniel EL, Hare JE, Cornell BA, Curmi PM, Davey MW, Valenzuela SM (2015-01-01). "Members of the chloride intracellular ion channel protein family demonstrate glutaredoxin-like enzymatic activity". PLOS One. 10 (1): e115699. doi:10.1371/journal.pone.0115699. PMC 4291220. PMID 25581026.
  13. ^ a b Gadsby DC, Vergani P, Csanády L (March 2006). "The ABC protein turned chloride channel whose failure causes cystic fibrosis". Nature. 440 (7083): 477–83. doi:10.1038/nature04712. PMC 2720541. PMID 16554808.

Further reading

External links

As of this edit, this article uses content from "1.A.13 The Epithelial Chloride Channel (E-ClC) Family", which is licensed in a way that permits reuse under the Creative Commons Attribution-ShareAlike 3.0 Unported License, but not under the GFDL. All relevant terms must be followed. As of this edit, this article uses content from "1.A.12 The Intracellular Chloride Channel (CLIC) Family", which is licensed in a way that permits reuse under the Creative Commons Attribution-ShareAlike 3.0 Unported License, but not under the GFDL. All relevant terms must be followed.

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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Voltage gated chloride channel Provide feedback

This family of ion channels contains 10 or 12 transmembrane helices. Each protein forms a single pore. It has been shown that some members of this family form homodimers. In terms of primary structure, they are unrelated to known cation channels or other types of anion channels. Three ClC subfamilies are found in animals. ClC-1 (P35523) is involved in setting and restoring the resting membrane potential of skeletal muscle, while other channels play important parts in solute concentration mechanisms in the kidney [3]. These proteins contain two PF00571 domains.

Literature references

  1. Schmidt-Rose T, Jentsch TJ; , J Biol Chem 1997;272:20515-20521.: Reconstitution of functional voltage-gated chloride channels from complementary fragments of CLC-1. PUBMED:9252364 EPMC:9252364

  2. Zhang J, George AL Jr, Griggs RC, Fouad GT, Roberts J, Kwiecinski H, Connolly AM, Ptacek LJ; , Neurology 1996;47:993-998.: Mutations in the human skeletal muscle chloride channel gene (CLCN1) associated with dominant and recessive myotonia congenita. PUBMED:8857733 EPMC:8857733

  3. Mindell JA, Maduke M; , Genome Biol 2001;2:REVIEWS3003.: ClC chloride channels. PUBMED:11182894 EPMC:11182894

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001807

Chloride channels (CLCs) constitute an evolutionarily well-conserved family of voltage-gated channels that are structurally unrelated to the other known voltage-gated channels. They are found in organisms ranging from bacteria to yeasts and plants, and also to animals. Their functions in higher animals likely include the regulation of cell volume, control of electrical excitability and trans-epithelial transport [ PUBMED:9046241 ].

The first member of the family (CLC-0) was expression-cloned from the electric organ of Torpedo marmorata [ PUBMED:2174129 ], and subsequently nine CLC-like proteins have been cloned from mammals. They are thought to function as multimers of two or more identical or homologous subunits, and they have varying tissue distributions and functional properties. To date, CLC-0, CLC-1, CLC-2, CLC-4 and CLC-5 have been demonstrated to form functional Cl- channels; whether the remaining isoforms do so is either contested or unproven. One possible explanation for the difficulty in expressing activatable Cl- channels is that some of the isoforms may function as Cl- channels of intracellular compartments, rather than of the plasma membrane. However, they are all thought to have a similar transmembrane (TM) topology, initial hydropathy analysis suggesting 13 hydrophobic stretches long enough to form putative TM domains [ PUBMED:2174129 ]. Recently, the postulated TM topology has been revised, and it now seems likely that the CLCs have 10 (or possibly 12) TM domains, with both N- and C-termini residing in the cytoplasm [ PUBMED:9207144 ].

A number of human disease-causing mutations have been identified in the genes encoding CLCs. Mutations in CLCN1, the gene encoding CLC-1, the major skeletal muscle Cl- channel, lead to both recessively and dominantly-inherited forms of muscle stiffness or myotonia [ PUBMED:7581380 ]. Similarly, mutations in CLCN5, which encodes CLC-5, a renal Cl- channel, lead to several forms of inherited kidney stone disease [ PUBMED:8559248 ]. These mutations have been demonstrated to reduce or abolish CLC function.

Gene Ontology

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Domain organisation

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Curation and family details

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Seed source: wublastp P37020/1-588
Previous IDs: voltage_CLC;
Type: Family
Sequence Ontology: SO:0100021
Author: Bateman A
Number in seed: 105
Number in full: 20585
Average length of the domain: 342.40 aa
Average identity of full alignment: 25 %
Average coverage of the sequence by the domain: 53.59 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 24.8 24.8
Trusted cut-off 24.8 24.8
Noise cut-off 24.6 24.7
Model length: 348
Family (HMM) version: 23
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Species distribution

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Archea Archea Eukaryota Eukaryota
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Voltage_CLC domain has been found. There are 148 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A098DN12 View 3D Structure Click here
A0A0P0VB46 View 3D Structure Click here
A0A0R0ETR9 View 3D Structure Click here
A0A0R0FWE1 View 3D Structure Click here
A0A0R0JZI4 View 3D Structure Click here
A0A0R0KI21 View 3D Structure Click here
A0A140LGR0 View 3D Structure Click here
A0A1D6DWJ1 View 3D Structure Click here
A0A1D6H395 View 3D Structure Click here
A0A1D6H396 View 3D Structure Click here
A0A1D6HAT6 View 3D Structure Click here
A0A1D6HII7 View 3D Structure Click here
A0A1D6I4U3 View 3D Structure Click here
A0A1D6I5B0 View 3D Structure Click here
A0A1D6KI77 View 3D Structure Click here
A0A1D6L0A3 View 3D Structure Click here
A0A1D6ML80 View 3D Structure Click here
A0A1D6N5S1 View 3D Structure Click here
A0A1D6NEI7 View 3D Structure Click here
A0A1D6Q4M6 View 3D Structure Click here
A0A1D6Q4Y6 View 3D Structure Click here
A0A1D6QKE5 View 3D Structure Click here
A0A1D8PJZ9 View 3D Structure Click here
A0A1D8PQF0 View 3D Structure Click here
A0A1D8PS75 View 3D Structure Click here
A4HRD9 View 3D Structure Click here
A4HS98 View 3D Structure Click here
A4I8X1 View 3D Structure Click here
C7IWJ0 View 3D Structure Click here
D4A3H5 View 3D Structure Click here
E7F798 View 3D Structure Click here
E7FCE2 View 3D Structure Click here
E7FFG9 View 3D Structure Click here
E9AHM3 View 3D Structure Click here
F1Q5F4 View 3D Structure Click here
F1Q5M3 View 3D Structure Click here
F1Q927 View 3D Structure Click here
F1QAS1 View 3D Structure Click here
F1QNV1 View 3D Structure Click here
F1QXH5 View 3D Structure Click here