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2.A.49 The Chloride Carrier/Channel (ClC) Family

The ClC family is a large family consisting of thousands of sequenced proteins derived from Gram-negative and Gram-positive bacteria, archaea, and all kinds of eukaryotes. These proteins are essentially ubiquitous, although they are not encoded within the genomes of several prokaryotes with small genomes. Sequenced proteins vary in size from 395 amino acyl residues (M. jannaschii) to 988 residues (humans). Many organisms contain multiple ClC family paralogues. For example, E. coli and Synechocystis both have two paralogues; mammals have nine paralogues, and C. elegans has at least five. Of the nine known members in mammals, mutations in three of the corresponding genes cause human diseases (Matulef and Maduke, 2007). MstE (1.A.26.1.2), CLC (2.A.49.6.1) and HlyC/CorC (HCC; 9.A.40.1.2) may all share a hydrophilic domain, and not all members of 9.A.40 have a transmembrane region. ClC family members may be able to transport a variety of anions inclluding nitrate (Kumar et al. 2022). CLCs are involved in cell growth, proliferation, and cell cycle, and they may be involved in prostate cancer (PCa). Silencing CLCN2 or CLCN6 exerts inhibitory effects on energy metabolism in PCa (Luo et al. 2022).

The ClC transport protein family consists of H+-gated Cl- channels, H+/Cl- antiporters and H+/NO3- antiporters. The pore is obstructed at its external opening by a glutamate side-chain which acts as a gate for Cl- passage in channels and as the H+ binding site for H+ exchange. The activity of ClC-2, a genuine Cl- channel, has a biphasic response to extracellular pH with activation by moderate acidification followed by abrupt channel closure at pH values lower than 7. A sensor couples extracellular acidification to closure of the channel, an extracellularly-facing histidine (His5320 at the N-terminus of transmembrane helix Q (Niemeyer et al. 2009).  Neutralization leads to channel closure in a cooperative manner. Acidification-dependent activation of ClC-2 is voltage-dependent and probably mediated by protonation of pore gate glutamate 207. Intracellular Cl- acts as a voltage-independent modulator, regulating the pKa of the protonatable residue. Voltage dependence of ClC-2 occurs by hyperpolarization-dependent penetration of protons from the extracellular side to neutralize the glutamate gate deep within the channel, allowing Cl- efflux. This is reminiscent of a partial exchanger cycle, suggesting that the ClC-2 channel evolved from its transporter counterparts (Niemeyer et al. 2009).

The nine mammalian ClC isoforms differ in tissue distribution and subcellular localization. Some of these are plasma membrane Cl- channels, which play important roles in transepithelial transport and in dampening muscle excitability. Other ClC proteins localize mainly to the endosomal-lysosomal system where they may facilitate luminal acidification or regulate luminal chloride concentration. All vesicular ClCs may be Cl-/H+-exchangers, as shown for the endosomal ClC-4, -5 and -7 proteins. Human diseases include myotonia, renal salt wasting, kidney stones, deafness, blindness, male infertility, leukodystrophy, osteopetrosis, lysosomal storage disease and defective endocytosis (Jentsch, 2008).  CLC channels display two different types of 'gates,' 'protopore' gates that open and close the two pores of a CLC dimer independently of each other, and common gates that act on both pores simultaneously (Ludwig et al. 2013).  The chloride and proton pathways have been identified and proposed, the latter involving a 'water wire' (Han et al. 2013). The CLC superfamily genes in tea plants (Camellia sinensis) have been identifed and examined (Xing et al. 2020).

Two gating mechanisms control the opening and closing of Cl- channels in this family: fast gating, which regulates opening and closing of the individual pores in each subunit of the dimeric transporter, and slow (or common) gating, which simultaneously controls gating of both subunits. Yu et al. 2015 found that intracellularly applied Cd2+ reduces the current of CLC-0 because of its inhibition on the slow gating. They identified CLC-0 residues C229 and H231, located at the intracellular end of the transmembrane domain near the dimer interface, as the Cd2+-coordinating residues. Inhibition of the current of CLC-0 by Cd2+ was enhanced by mutation of I225W and V490W at the dimer interface.

Methanococcus jannaschii and Saccharomyces cerevisiae only have one ClC family member each. With the exception of the large Synechocystis paralogue, bacterial proteins are usually small (395-492 residues) while eukaryotic proteins are usually larger (687-988 residues). These proteins exhibit 12 putative transmembrane α-helical spanners (TMSs) and appear to be present in the membrane as homodimers. A 12 TMS topology with the N- and C-termini in the cytoplasm was suggested.

The structure of the E. coli EriC (TC #2.A.49.5.1) ClC family member has been reported at 3.0 Å resolution (Dutzler et al., 2002; Mindell et al., 2001). Two identical water-filled pores, each within a single subunit of the dimeric channel complex were revealed. Each subunit consists of two roughly repeated halves that span the membrane with 5 TMSs each and opposite orientations in the membrane. This antiparallel architecture defines a selectivity filter in which Cl- is stabilized by electrostatic interactions with α-helix dipoles and chemical coordination with nitrogen and hydroxyl groups in the protein. This protein has been shown to mediate the extreme acid resistance response (Iyer et al., 2002). Thus, E. coli is proposed to use either one of its two ClC channels as electrical shunts for an outwardly directed virtual pump that is linked to amino acid decarboxylation (Iyer et al., 2002). The crystal structure of a eukaryotic CLC transporter defines an intermediate state in the transport cycle (Feng et al., 2010).

The E. coli EriC (also called ClC-ecl) has been studied leading to the conclusion that it is not a simple channel, but instead catalyzes Cl-:H+ antiport with a stoichiometry of 2.1. They can thus function as carriers (Accardi and Miller, 2004). The authors note that the eukaryotic ClC-0, ClC-1 and ClC-2 are unambiguously Cl--selective channels which display proton-dependent gating but show no indication of H+ permeability. Moreover, they note that the 3-D structure published by Dutzler et al. (2002, 2003) does not actually show a transmembrane pore. A conserved glutamate, when mutated in ClC-0 or ClC-1 eliminates the normal pH-dependency of the Cl- flux, while in EriC, this glutamate, E148, may provide the pathway for the proton. E148A or E148Q mutants do not transport H+ but do transport Cl- in an uncoupled process.

Kieseritzky and Knapp (2011) modeled four stable buried waters into both subunits of the wild type E.coli CIC channel (EClC). They form a 'water wire' connecting Glu-203 with the chloride at the central site, which in turn connects to Glu-148, the hypothetical proton exit site. Assuming the transient production of hydrochloride in the central chloride binding site of EClC, the water wire could establish a transmembrane proton transport pathway starting from Glu-203 all the way downstream onto Glu-148. EClC evolves through states involving up to two excess protons and between one and three chlorides, which fulfill the experimentally observed 2:1 stoichiometry. Y445F and E203H mutants of EClC can operate similarly, thus explaining why they exhibit almost WT activity. The proposed mechanism thus involves coupled chloride-proton transport (Kieseritzky and Knapp, 2011).

Mutating a 'gating glutamate' (Glu-224 in ClC-4 and Glu-211 in ClC-5) converted these exchangers into anion conductances, as did the neutralization of another, intracellular 'proton glutamate' in ecClC-1 (Zdebik et al., 2007). Neutralizing the proton glutamate of ClC-4 (Glu-281) and ClC-5 (Glu-268) abolished Cl- and H+ transport although surface expression was unchanged. Uncoupled Cl- transport could be restored in the ClC-4 (E281A) and ClC-5 (E268A) proton glutamate mutants by neutralizing the gating glutamates, suggesting that wild type proteins transport anions only when protons are supplied through a cytoplasmic H+ donor. Each monomeric unit of the dimeric protein is able to carry out Cl-/H+ exchange independently of the activity of the neighboring subunit. NO3- or SCN- transport is partially uncoupled from H+ countertransport but still depends on the proton glutamate. Thus, Cl-/H+ exchange catalyzed by the endosomal ClC-4 and -5 proteins apparently relies on proton delivery from an intracellular titratable residue at position 268 (ClC-5).

Picollo and Pusch (2005) and Scheel et al. (2005) have shown that endosomal ClC4 and ClC5 (both human disease proteins) are electrogenic Cl-/H+ antiporters, probably exhibiting a 2:1 stoichiometry. They showed that mutation of the conserved glutamate, aligning with that in EriC of E. coli abolished proton (but not chloride) transport. They confirmed that ClC-0, ClC-2, ClC-Ka function like channels. Thus, a single residue can convert a channel to a carrier. It seems that point mutations can create ‘broken channels’ out of these carriers. Because Cl-:H+ antiporters function with subunit cross-linking, large quaternary rearrangements, such as those known to occur for 'common gating' in ClC channels, are probably not necessary for the ion transport cycle (Nguitragool and Miller, 2007).

All eukaryotic ClC channels so far examined contain two C-terminal CBS domains, each of 50 residue. CBS domains are found in various globular proteins. The Torpedo ClC-0 and the E. coli YadQ have been reported to have two channels and function by a double barrelled mechanism, one per subunit. Some evidence suggests that for ClC-0, ClC-1 and ClC-2, each subunit bears a single channel, and the association of the subunits of these channel proteins to form homo- or heterodimers does not alter their conductance properties.

The CLC family is formed by two, not so distinct, sub-classes of membrane transport proteins: Cl- channels and H+/Cl- exchangers (Accardi and Picollo, 2010). All CLC's are homodimers with each monomer forming an individual Cl- permeation pathway which appears to be largely unaltered in the two CLC sub-classes. Key residues for ion binding and selectivity are also highly conserved. Most CLC's have large cytosolic carboxy-terminal domains containing two cystathionine beta-synthetase (CBS) domains. The C-termini are critical regulators of protein trafficking and directly modulate Cl- by binding intracellular ATP, H+ or oxidizing compounds.

All functionally characterized members of the ClC family transport chloride, some in a voltage-regulated process. These channels serve a variety physiological functions (cell volume regulation; membrane potential stabilization; signal transduction; transepithelial transport, etc.). Different homologues in humans exhibit differing anion selectivities, i.e., ClC-4 and ClC-5 share a NO3- > Cl- > Br- > I- conductance sequence, while ClC-3 has an I- > Cl- selectivity.

The ClC-4 and ClC-5 channels/carriers and others exhibit outward rectifying currents with currents only at voltages more positive than +20mV. Some but not other ClC channels are permeable to the low conductance blockers, I- and SCN-. ClCα-1 has been studied in detail. ClO4- and SCN- are more permeant than Br-, NO3- or ClO3-, and the hydrophobic anions, benzoate and hexanoates, are more permeable than smaller anions such as BrO3-. It is clear that ClCs are not specific for chloride, but are general anion channels and carriers (Miller, 2006).

A genetic defect of ClC-5 in humans is the cause of Dent's disease. This protein is expressed in endosomes of the proximal tubule. Disruption of the corresponding clcn5 gene in mice causes proteinuria by reducing apical proximal tubular endocytosis. This delays internalization of the apical transporters NaPi-2 and NHE3 (Piwon et al., 2000). It has been suggested that it plays a role in acidification of both endocytic and exocytic vesicles involved in protein trafficking.

Plants need nitrate for growth and store most of it in the central vacuole. Some members of the ClC family, such as the torpedo-fish ClC-0 and mammalian ClC-1, are anion channels, whereas the E. coli EriC and mammalian ClC-4 and ClC-5 are Cl-/H+ exchangers. Some plant members of the ClC family may be anion channels involved in nitrate homeostasis. However, Arabidopsis thaliana ClCa is localized to the tonoplast membrane of the plant vacuole. De Angeli et al. (2006) have demonstrated that ClCa is able to accumulate nitrate in the vacuole and behaves as a NO3-/H+ exchanger.

Feng et al. 2010 have determined the structure of a eukaryotic CLC transporter from the red alga (Rhodophyta) at 2.5 angstrom resolution.  Cytoplasmic cystathionine beta-synthase (CBS) domains are strategically positioned to regulate the ion-transport pathway, and many disease-causing mutations in human CLCs reside on the CBS-transmembrane interface.  Comparison with prokaryotic CLC shows that a gating glutamate residue changes conformation and suggests a basis for 2:1 Cl-/H+ exchange and a simple mechanistic connection between CLC channels and transporters.

Six ClC-type chloride channel genes have been identified in Caenorhabditis elegans, termed clh-1 through clh-6, but clh-2, clh-3, and clh-4 may code for multiple channel variants (Nehrke et al. 2000). CLH-5 is expressed ubiquitously, CLH-6 is expressed mainly in nonneuronal cells, and the remaining isoforms vary from those restricted to a single cell to those expressed in over a dozen cells of the nematode. Both CLH-1 and CLH-3b produced strong, inward-rectifying chloride currents similar to those arising from mammalian ClC2, but which operate over different voltage ranges. 

In eukaryotes, ClC proteins play a role in the stabilization of membrane potential, epithelial ion transport, hippocampal neuroprotection, cardiac pacemaker activity and vesicular acidification. Moreover, mutations in the genes encoding ClC proteins can cause genetic disease in humans (Abeyrathne et al. 2016). In prokaryotes, the Cl-/H+ antiporters, such as ClC-ec1 found in Escherichia coli promote proton expulsion in the extreme acid-resistance response common to enteric bacteria.  Structural features include a complicated transmembrane topology with 18 α-helices in each subunit and an anion-coordinating region in each subunit. Several different approaches such as X-ray crystallography, NMR, biochemical studies, and molecular dynamics simulations have been applied to the study of ClC proteins (Abeyrathne et al. 2016). 

ClC proteins mediate the movement of Cl- across the membrane. In eukaryotes, ClC proteins play roles in membrane potential stabilization, epithelial ion transport, hippocampal neuroprotection, cardiac pacemaker activity and vesicular acidification, and mutations in the genes encoding ClC proteins can cause genetic disease in humans (Abeyrathne et al. 2016). In prokaryotes, the Cl-/H+ antiporters, such as ClC-ec1 found in Escherichia coli promote proton expulsion in the extreme acid-resistance response common to enteric bacteria. Structural and functional studies of the prokaryotic protein have revealed unique structural features, including a complicated transmembrane topology with 18 alpha-helices in each subunit with a central anion-coordinating region. Several different approaches such as X-ray crystallography, NMR, biochemical studies, and molecular dynamics simulations have been applied to the study of ClC proteins.

ClCs are expressed in both plasma and intracellular membranes of cells from almost all eukaryotic organisms. ClC proteins form transmembrane dimers, in which each monomer displays independent ion conductance. Eukaryotic members possess a large cytoplasmic domain containing two CBS domains involved in transport modulation. ClC proteins function as either Cl- channels or Cl-/H+ exchangers, although all ClC proteins probably share the same basic architecture (Poroca et al. 2017). ClC channels have two gating mechanisms: a relatively well-studied fast gating mechanism, and a poorly studied slow gating mechanism. ClCs are involved in a wide range of physiological processes, including regulation of the resting membrane potential in skeletal muscle, facilitation of transepithelial Cl- reabsorption in kidneys, and control of pH and Cl- concentration in intracellular compartments through coupled Cl-/H+ exchange mechanisms. Several inherited diseases result from C1C gene mutations, including myotonia congenita, Bartter's syndrome (types 3 and 4), Dent's disease, osteopetrosis, retinal degeneration, and lysosomal storage diseases (Poroca et al. 2017).

CLC anion transporters are found in all phyla and form a gene family of eight members in mammals. Two CLC proteins, each of which completely contains an ion translocation parthway, assemble to homo- or heteromeric dimers that sometimes require accessory β-subunits for function (Jentsch and Pusch 2018). CLC proteins can be anion channels or anion/proton exchangers. Structures of these two CLC protein classes are surprisingly similar. Extensive structure-function analyses have identified residues involved in ion permeation, anion-proton coupling and gating. In mammals, ClC-1, -2, -Ka/-Kb are plasma membrane Cl- channels, whereas ClC-3 through ClC-7 are 2Cl-/H+-exchangers in endolysosomal membranes. Biological roles of CLCs were mostly studied in mammals, but also in plants and model organisms like yeast and Caenorhabditis elegans. CLC Cl- channels have roles in the control of electrical excitability, extra- and intracellular ion homeostasis, and transepithelial transport, whereas anion/proton exchangers influence vesicular ion composition and impinge on endocytosis and lysosomal function. The surprisingly diverse roles of CLCs are highlighted by human and mouse disorders elicited by mutations in their genes. These pathologies include neurodegeneration, leukodystrophy, mental retardation, deafness, blindness, myotonia, hyperaldosteronism, renal salt loss, proteinuria, kidney stones, male infertility, and osteopetrosis. Jentsch and Pusch 2018 reviewed all aspects of CLC proteins with emphasis on biophysical structure-function analyses and on the cell biological and organismal roles of mammalian CLCs in disease. They can be chloride conducting channels and proton-chloride antiporters. All members in this family consist of two identical protein subunits, and each subunit forms an independent ion-transport pathway, a structural architecture known as 'double barrel.' These CLC proteins serve biological functions ranging from membrane excitability and cell volume regulation to acidification of endosomes (Kwon et al. 2022).

Note: The ClC family was previously given the TC# 1.A.11.

The generalized transport reaction catalyzed by carriers of the ClC family is:

2 Anions (in) + H+ (out) ⇌ 2 Anions (out) + H+ (in).

The generalized transport reaction catalyzed by channels of the ClC family is:

Anion (in) ⇌ Anion (out)

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