CLCN6_HUMAN
ID CLCN6_HUMAN Reviewed; 869 AA.
AC P51797; A8K1T4; B4DGT7; F8W9R3; O60818; O60819; O60820; O60821; P78520;
AC P78521; Q17R81; Q5SNW2; Q5SNW3; Q5SNX1; Q5SNX2; Q5SNX3; Q99427; Q99428;
AC Q99429;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 02-NOV-2010, sequence version 2.
DT 03-AUG-2022, entry version 196.
DE RecName: Full=H(+)/Cl(-) exchange transporter 6 {ECO:0000305};
DE AltName: Full=Chloride channel protein 6;
DE Short=ClC-6;
DE AltName: Full=Chloride transport protein 6 {ECO:0000305};
GN Name=CLCN6 {ECO:0000312|HGNC:HGNC:2024}; Synonyms=KIAA0046;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND VARIANT
RP GLY-198.
RC TISSUE=Brain;
RX PubMed=8543009; DOI=10.1016/0014-5793(95)01298-2;
RA Brandt S., Jentsch T.J.;
RT "ClC-6 and ClC-7 are two novel broadly expressed members of the CLC
RT chloride channel family.";
RL FEBS Lett. 377:15-20(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 2; 3 AND 4), NUCLEOTIDE
RP SEQUENCE [MRNA] OF 1-409 (ISOFORM 1), TISSUE SPECIFICITY, AND VARIANT
RP GLY-198.
RC TISSUE=Chronic myeloid leukemia cell;
RX PubMed=9224655; DOI=10.1042/bj3250269;
RA Eggermont J., Buyse G., Voets T., Tytgat J., De Smedt H., Droogmans G.,
RA Nilius B.;
RT "Alternative splicing of ClC-6 (a member of the ClC chloride-channel
RT family) transcripts generates three truncated isoforms one of which, ClC-
RT 6c, is kidney-specific.";
RL Biochem. J. 325:269-276(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1), AND VARIANT GLY-198.
RX PubMed=10500249; DOI=10.1016/s0167-4781(99)00128-1;
RA Kornak U., Boesl M.R., Kubisch C.;
RT "Complete genomic structure of the CLCN6 and CLCN7 putative chloride
RT channel genes.";
RL Biochim. Biophys. Acta 1447:100-106(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT GLY-198.
RC TISSUE=Bone marrow;
RX PubMed=7584044; DOI=10.1093/dnares/1.5.223;
RA Nomura N., Nagase T., Miyajima N., Sazuka T., Tanaka A., Sato S., Seki N.,
RA Kawarabayasi Y., Ishikawa K., Tabata S.;
RT "Prediction of the coding sequences of unidentified human genes. II. The
RT coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of
RT cDNA clones from human cell line KG-1.";
RL DNA Res. 1:223-229(1994).
RN [5]
RP SEQUENCE REVISION.
RX PubMed=12168954; DOI=10.1093/dnares/9.3.99;
RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.;
RT "Construction of expression-ready cDNA clones for KIAA genes: manual
RT curation of 330 KIAA cDNA clones.";
RL DNA Res. 9:99-106(2002).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 6), AND VARIANT
RP GLY-198.
RC TISSUE=Brain, and Hippocampus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT GLY-198.
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT GLY-198.
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP TISSUE SPECIFICITY.
RC TISSUE=Aortic endothelium, and Vascular smooth muscle;
RX PubMed=10198195; DOI=10.1006/jmcc.1998.0901;
RA Lamb F.S., Clayton G.H., Liu B.-X., Smith R.L., Barna T.J., Schutte B.C.;
RT "Expression of CLCN voltage-gated chloride channel genes in human blood
RT vessels.";
RL J. Mol. Cell. Cardiol. 31:657-666(1999).
RN [11]
RP SUBCELLULAR LOCATION, GLYCOSYLATION, AND MUTAGENESIS OF ASN-410; ASN-422
RP AND ASN-432.
RX PubMed=17534424; DOI=10.1371/journal.pone.0000474;
RA Ignoul S., Simaels J., Hermans D., Annaert W., Eggermont J.;
RT "Human ClC-6 is a late endosomal glycoprotein that associates with
RT detergent-resistant lipid domains.";
RL PLoS ONE 2:E474-E474(2007).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF SER-157; GLU-200; GLU-267
RP AND TYR-576.
RX PubMed=20466723; DOI=10.1074/jbc.m110.125971;
RA Neagoe I., Stauber T., Fidzinski P., Bergsdorf E.Y., Jentsch T.J.;
RT "The late endosomal ClC-6 mediates proton/chloride countertransport in
RT heterologous plasma membrane expression.";
RL J. Biol. Chem. 285:21689-21697(2010).
RN [13]
RP VARIANT CONRIBA CYS-553, CHARACTERIZATION OF VARIANT CONRIBA CYS-553,
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=33217309; DOI=10.1016/j.ajhg.2020.11.004;
RA Polovitskaya M.M., Barbini C., Martinelli D., Harms F.L., Cole F.S.,
RA Calligari P., Bocchinfuso G., Stella L., Ciolfi A., Niceta M., Rizza T.,
RA Shinawi M., Sisco K., Johannsen J., Denecke J., Carrozzo R., Wegner D.J.,
RA Kutsche K., Tartaglia M., Jentsch T.J.;
RT "A Recurrent Gain-of-Function Mutation in CLCN6, Encoding the ClC-6 Cl-/H+-
RT Exchanger, Causes Early-Onset Neurodegeneration.";
RL Am. J. Hum. Genet. 107:1062-1077(2020).
CC -!- FUNCTION: Voltage-gated channel mediating the exchange of chloride ions
CC against protons. Functions as antiporter and contributes to the
CC acidification of the late endosome lumen. The CLC channel family
CC contains both chloride channels and proton-coupled anion transporters
CC that exchange chloride or another anion for protons. The presence of
CC conserved gating glutamate residues is typical for family members that
CC function as antiporters. {ECO:0000269|PubMed:20466723}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 chloride(in) + H(+)(out) = 2 chloride(out) + H(+)(in);
CC Xref=Rhea:RHEA:29567, ChEBI:CHEBI:15378, ChEBI:CHEBI:17996;
CC Evidence={ECO:0000269|PubMed:20466723, ECO:0000269|PubMed:33217309};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:29568;
CC Evidence={ECO:0000269|PubMed:20466723, ECO:0000269|PubMed:33217309};
CC -!- SUBCELLULAR LOCATION: Late endosome membrane
CC {ECO:0000269|PubMed:17534424, ECO:0000269|PubMed:33217309}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:17534424}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1; Synonyms=A, Clc-6a;
CC IsoId=P51797-1; Sequence=Displayed;
CC Name=2; Synonyms=B, ClC-6b, D2-A1;
CC IsoId=P51797-2; Sequence=VSP_001043, VSP_001044;
CC Name=3; Synonyms=C, ClC-6c, D1-A1;
CC IsoId=P51797-3; Sequence=VSP_001045, VSP_001046;
CC Name=4; Synonyms=D, ClC-6d, D1-A2;
CC IsoId=P51797-4; Sequence=VSP_001047, VSP_001048;
CC Name=5;
CC IsoId=P51797-5; Sequence=VSP_017188;
CC Name=6;
CC IsoId=P51797-6; Sequence=VSP_047169;
CC -!- TISSUE SPECIFICITY: Testis, ovary, small intestine, brain and skeletal
CC muscle. Low level expression in aortic and coronary vascular smooth
CC muscle cells, and aortic endothelial cells. Isoform 3 is only detected
CC in kidney. {ECO:0000269|PubMed:10198195, ECO:0000269|PubMed:8543009,
CC ECO:0000269|PubMed:9224655}.
CC -!- PTM: N-glycosylated on several asparagine residues.
CC {ECO:0000269|PubMed:17534424}.
CC -!- DISEASE: Neurodegeneration, childhood-onset, with hypotonia,
CC respiratory insufficiency, and brain imaging abnormalities (CONRIBA)
CC [MIM:619173]: An autosomal dominant, progressive, neurodegenerative
CC disorder characterized by severe global developmental delay, impaired
CC intellectual development, poor or absent speech, hypotonia, impaired
CC motor development, respiratory insufficiency, and feeding difficulties.
CC Most patients have visual defects, including cortical visual blindness,
CC nystagmus, and esotropia. Brain imaging shows abnormalities affecting
CC the brainstem, cerebellum, and corticospinal tracts. Disease onset is
CC in infancy or early childhood. {ECO:0000269|PubMed:33217309}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the chloride channel (TC 2.A.49) family. ClC-
CC 6/CLCN6 subfamily. {ECO:0000305}.
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DR EMBL; X83378; CAA58292.1; -; mRNA.
DR EMBL; X96391; CAA65255.1; -; mRNA.
DR EMBL; X99472; CAA67835.1; -; Genomic_DNA.
DR EMBL; X99473; CAA67836.1; -; mRNA.
DR EMBL; X99474; CAA67837.1; -; mRNA.
DR EMBL; X99475; CAA67838.1; -; mRNA.
DR EMBL; AF009257; AAB69287.1; -; Genomic_DNA.
DR EMBL; AF009247; AAB69287.1; JOINED; Genomic_DNA.
DR EMBL; AF009248; AAB69287.1; JOINED; Genomic_DNA.
DR EMBL; AF009249; AAB69287.1; JOINED; Genomic_DNA.
DR EMBL; AF009250; AAB69287.1; JOINED; Genomic_DNA.
DR EMBL; AF009251; AAB69287.1; JOINED; Genomic_DNA.
DR EMBL; AF009252; AAB69287.1; JOINED; Genomic_DNA.
DR EMBL; AF009253; AAB69287.1; JOINED; Genomic_DNA.
DR EMBL; AF009254; AAB69287.1; JOINED; Genomic_DNA.
DR EMBL; AF009255; AAB69287.1; JOINED; Genomic_DNA.
DR EMBL; AF009256; AAB69287.1; JOINED; Genomic_DNA.
DR EMBL; D28475; BAA05836.4; -; mRNA.
DR EMBL; AK289999; BAF82688.1; -; mRNA.
DR EMBL; AK294764; BAG57898.1; -; mRNA.
DR EMBL; AL021155; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL953897; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471130; EAW71715.1; -; Genomic_DNA.
DR EMBL; BC117420; AAI17421.1; -; mRNA.
DR EMBL; BC117424; AAI17425.1; -; mRNA.
DR CCDS; CCDS138.1; -. [P51797-1]
DR CCDS; CCDS57972.1; -. [P51797-6]
DR PIR; S68428; S68428.
DR RefSeq; NP_001243888.1; NM_001256959.1. [P51797-6]
DR RefSeq; NP_001277.1; NM_001286.3. [P51797-1]
DR AlphaFoldDB; P51797; -.
DR SMR; P51797; -.
DR BioGRID; 107599; 6.
DR IntAct; P51797; 2.
DR MINT; P51797; -.
DR STRING; 9606.ENSP00000234488; -.
DR GuidetoPHARMACOLOGY; 705; -.
DR GlyGen; P51797; 3 sites.
DR iPTMnet; P51797; -.
DR PhosphoSitePlus; P51797; -.
DR SwissPalm; P51797; -.
DR BioMuta; CLCN6; -.
DR DMDM; 311033364; -.
DR EPD; P51797; -.
DR jPOST; P51797; -.
DR MassIVE; P51797; -.
DR MaxQB; P51797; -.
DR PaxDb; P51797; -.
DR PeptideAtlas; P51797; -.
DR PRIDE; P51797; -.
DR ProteomicsDB; 30368; -.
DR ProteomicsDB; 56393; -. [P51797-1]
DR ProteomicsDB; 56394; -. [P51797-2]
DR ProteomicsDB; 56395; -. [P51797-3]
DR ProteomicsDB; 56396; -. [P51797-4]
DR ProteomicsDB; 56397; -. [P51797-5]
DR Antibodypedia; 28262; 99 antibodies from 21 providers.
DR DNASU; 1185; -.
DR Ensembl; ENST00000312413.10; ENSP00000308367.7; ENSG00000011021.23. [P51797-6]
DR Ensembl; ENST00000346436.11; ENSP00000234488.9; ENSG00000011021.23. [P51797-1]
DR Ensembl; ENST00000376496.4; ENSP00000365679.3; ENSG00000011021.23. [P51797-5]
DR GeneID; 1185; -.
DR KEGG; hsa:1185; -.
DR MANE-Select; ENST00000346436.11; ENSP00000234488.9; NM_001286.5; NP_001277.2.
DR UCSC; uc001ate.6; human. [P51797-1]
DR CTD; 1185; -.
DR DisGeNET; 1185; -.
DR GeneCards; CLCN6; -.
DR HGNC; HGNC:2024; CLCN6.
DR HPA; ENSG00000011021; Low tissue specificity.
DR MalaCards; CLCN6; -.
DR MIM; 602726; gene.
DR MIM; 619173; phenotype.
DR neXtProt; NX_P51797; -.
DR OpenTargets; ENSG00000011021; -.
DR Orphanet; 610573; CLCN6-related childhood-onset progressive neurodegeneration-peripheral neuropathy syndrome.
DR PharmGKB; PA26551; -.
DR VEuPathDB; HostDB:ENSG00000011021; -.
DR eggNOG; KOG0474; Eukaryota.
DR GeneTree; ENSGT00940000159291; -.
DR HOGENOM; CLU_003181_4_1_1; -.
DR InParanoid; P51797; -.
DR OMA; FMHEHIS; -.
DR OrthoDB; 410280at2759; -.
DR PhylomeDB; P51797; -.
DR TreeFam; TF313867; -.
DR PathwayCommons; P51797; -.
DR Reactome; R-HSA-2672351; Stimuli-sensing channels.
DR Reactome; R-HSA-6802952; Signaling by BRAF and RAF1 fusions.
DR SignaLink; P51797; -.
DR BioGRID-ORCS; 1185; 17 hits in 1076 CRISPR screens.
DR ChiTaRS; CLCN6; human.
DR GeneWiki; CLCN6; -.
DR GenomeRNAi; 1185; -.
DR Pharos; P51797; Tchem.
DR PRO; PR:P51797; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; P51797; protein.
DR Bgee; ENSG00000011021; Expressed in right testis and 154 other tissues.
DR ExpressionAtlas; P51797; baseline and differential.
DR Genevisible; P51797; HS.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral component of membrane; NAS:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005765; C:lysosomal membrane; HDA:UniProtKB.
DR GO; GO:0015297; F:antiporter activity; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0015108; F:chloride transmembrane transporter activity; IBA:GO_Central.
DR GO; GO:0005247; F:voltage-gated chloride channel activity; IDA:UniProtKB.
DR GO; GO:0006884; P:cell volume homeostasis; NAS:UniProtKB.
DR GO; GO:0006821; P:chloride transport; IDA:UniProtKB.
DR GO; GO:0034220; P:ion transmembrane transport; TAS:Reactome.
DR GO; GO:0009612; P:response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; NAS:UniProtKB.
DR Gene3D; 3.10.580.10; -; 1.
DR InterPro; IPR000644; CBS_dom.
DR InterPro; IPR046342; CBS_dom_sf.
DR InterPro; IPR014743; Cl-channel_core.
DR InterPro; IPR001807; Cl-channel_volt-gated.
DR InterPro; IPR002248; Cl_channel-6.
DR Pfam; PF00571; CBS; 2.
DR Pfam; PF00654; Voltage_CLC; 1.
DR PRINTS; PR00762; CLCHANNEL.
DR PRINTS; PR01117; CLCHANNEL6.
DR SMART; SM00116; CBS; 2.
DR SUPFAM; SSF54631; SSF54631; 1.
DR SUPFAM; SSF81340; SSF81340; 1.
DR PROSITE; PS51371; CBS; 2.
PE 1: Evidence at protein level;
KW Alternative splicing; Antiport; ATP-binding; CBS domain; Chloride;
KW Disease variant; Endosome; Glycoprotein; Ion transport; Membrane;
KW Neurodegeneration; Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Repeat; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..869
FT /note="H(+)/Cl(-) exchange transporter 6"
FT /id="PRO_0000094449"
FT TOPO_DOM 1..80
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 81..113
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 128..150
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 159..166
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 176..194
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 200..217
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 241..253
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 257..265
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 277..294
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 335..364
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 371..392
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 462..481
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 487..511
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 519..533
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 534..536
FT /note="Note=Loop between two helices"
FT /evidence="ECO:0000250"
FT INTRAMEM 537..548
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 549..552
FT /note="Note=Loop between two helices"
FT /evidence="ECO:0000250"
FT TRANSMEM 553..571
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TOPO_DOM 572..869
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT DOMAIN 605..662
FT /note="CBS 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00703"
FT DOMAIN 807..868
FT /note="CBS 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00703"
FT MOTIF 156..160
FT /note="Selectivity filter part_1"
FT /evidence="ECO:0000250"
FT MOTIF 198..202
FT /note="Selectivity filter part_2"
FT /evidence="ECO:0000250"
FT MOTIF 487..491
FT /note="Selectivity filter part_3"
FT /evidence="ECO:0000250"
FT BINDING 157
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT BINDING 489
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT BINDING 576
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT BINDING 630..632
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 849..852
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT SITE 200
FT /note="Mediates proton transfer from the outer aqueous
FT phase to the interior of the protein; involved in linking
FT H(+) and Cl(-) transport"
FT /evidence="ECO:0000250"
FT SITE 267
FT /note="Mediates proton transfer from the protein to the
FT inner aqueous phase"
FT /evidence="ECO:0000250"
FT MOD_RES 773
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O35454"
FT CARBOHYD 410
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:17534424"
FT CARBOHYD 422
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:17534424"
FT CARBOHYD 432
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:17534424"
FT VAR_SEQ 50..71
FT /note="Missing (in isoform 6)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_047169"
FT VAR_SEQ 237..320
FT /note="DKRDFVSAGAAAGVAAAFGAPIGGTLFSLEEGSSFWNQGLTWKVLFCSMSAT
FT FTLNFFRSGIQFGSWGSFQLPGLLNFGEFKCS -> YGKRQERLCISRSGCWSCCSFRG
FT ANRGYLVQSRGGFVLLEPRAHVESALLFHVCHLHPQLLPFWDSVWKLGFLPAPWIAELW
FT RV (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:9224655"
FT /id="VSP_001043"
FT VAR_SEQ 237..308
FT /note="DKRDFVSAGAAAGVAAAFGAPIGGTLFSLEEGSSFWNQGLTWKVLFCSMSAT
FT FTLNFFRSGIQFGSWGSFQL -> SGCWSCCSFRGANRGYLVQSRGGFVLLEPRAHVES
FT ALLFHVCHLHPQLLPFWDSVWKLGFLPAPWIAELWRV (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:9224655"
FT /id="VSP_001047"
FT VAR_SEQ 309..869
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:9224655"
FT /id="VSP_001048"
FT VAR_SEQ 319..353
FT /note="CSDSDKKCHLWTAMDLGFFVVMGVIGGLLGATFNC -> SLREPPCVSGNHR
FT GGVCGLDGVRRMPTDVLFESNR (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:9224655"
FT /id="VSP_001045"
FT VAR_SEQ 321..869
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:9224655"
FT /id="VSP_001044"
FT VAR_SEQ 354..869
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:9224655"
FT /id="VSP_001046"
FT VAR_SEQ 844..869
FT /note="IVGIITRHNLTYEFLQARLRQHYQTI -> VSEAPALPPPLREDPLARCCLC
FT TQASHQKRRHPTRRGECGPTLALNPARLPCTRDPFPCLPADGTSVPLAVLSSQSRASTR
FT LCLPPEMLLFTPYHWCSLVLHLRRDLRIR (in isoform 5)"
FT /evidence="ECO:0000305"
FT /id="VSP_017188"
FT VARIANT 198
FT /note="E -> G (in dbSNP:rs198400)"
FT /evidence="ECO:0000269|PubMed:10500249,
FT ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:7584044, ECO:0000269|PubMed:8543009,
FT ECO:0000269|PubMed:9224655, ECO:0000269|Ref.8"
FT /id="VAR_023051"
FT VARIANT 553
FT /note="Y -> C (in CONRIBA; strongly slowed gating and
FT increased current amplitudes)"
FT /evidence="ECO:0000269|PubMed:33217309"
FT /id="VAR_085384"
FT MUTAGEN 157
FT /note="S->P: Increases the nitrate/chloride conductance
FT ratio."
FT /evidence="ECO:0000269|PubMed:20466723"
FT MUTAGEN 200
FT /note="E->A: Abolishes proton transport, but not chloride
FT transport. Strongly increases anion current; when
FT associated with S-576."
FT /evidence="ECO:0000269|PubMed:20466723"
FT MUTAGEN 267
FT /note="E->A: Loss of proton and chloride transport."
FT /evidence="ECO:0000269|PubMed:20466723"
FT MUTAGEN 410
FT /note="N->A: Abolishes N-glycosylation; when associated
FT with A-422 and A-432."
FT /evidence="ECO:0000269|PubMed:17534424"
FT MUTAGEN 422
FT /note="N->A: Abolishes N-glycosylation; when associated
FT with A-410 and A-432."
FT /evidence="ECO:0000269|PubMed:17534424"
FT MUTAGEN 432
FT /note="N->A: Abolishes N-glycosylation; when associated
FT with A-410 and A-422."
FT /evidence="ECO:0000269|PubMed:17534424"
FT MUTAGEN 576
FT /note="Y->S: Strongly increases anion current; when
FT associated with A-200."
FT /evidence="ECO:0000269|PubMed:20466723"
FT CONFLICT 19
FT /note="G -> S (in Ref. 6; BAG57898)"
FT /evidence="ECO:0000305"
FT CONFLICT 92
FT /note="G -> D (in Ref. 6; BAG57898)"
FT /evidence="ECO:0000305"
FT CONFLICT 442
FT /note="F -> S (in Ref. 6; BAG57898)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 869 AA; 97289 MW; D625F0C2189EB6F7 CRC64;
MAGCRGSLCC CCRWCCCCGE RETRTPEELT ILGETQEEED EILPRKDYES LDYDRCINDP
YLEVLETMDN KKGRRYEAVK WMVVFAIGVC TGLVGLFVDF FVRLFTQLKF GVVQTSVEEC
SQKGCLALSL LELLGFNLTF VFLASLLVLI EPVAAGSGIP EVKCYLNGVK VPGIVRLRTL
LCKVLGVLFS VAGGLFVEKE GPMIHSGSVV GAGLPQFQSI SLRKIQFNFP YFRSDRDKRD
FVSAGAAAGV AAAFGAPIGG TLFSLEEGSS FWNQGLTWKV LFCSMSATFT LNFFRSGIQF
GSWGSFQLPG LLNFGEFKCS DSDKKCHLWT AMDLGFFVVM GVIGGLLGAT FNCLNKRLAK
YRMRNVHPKP KLVRVLESLL VSLVTTVVVF VASMVLGECR QMSSSSQIGN DSFQLQVTED
VNSSIKTFFC PNDTYNDMAT LFFNPQESAI LQLFHQDGTF SPVTLALFFV LYFLLACWTY
GISVPSGLFV PSLLCGAAFG RLVANVLKSY IGLGHIYSGT FALIGAAAFL GGVVRMTISL
TVILIESTNE ITYGLPIMVT LMVAKWTGDF FNKGIYDIHV GLRGVPLLEW ETEVEMDKLR
ASDIMEPNLT YVYPHTRIQS LVSILRTTVH HAFPVVTENR GNEKEFMKGN QLISNNIKFK
KSSILTRAGE QRKRSQSMKS YPSSELRNMC DEHIASEEPA EKEDLLQQML ERRYTPYPNL
YPDQSPSEDW TMEERFRPLT FHGLILRSQL VTLLVRGVCY SESQSSASQP RLSYAEMAED
YPRYPDIHDL DLTLLNPRMI VDVTPYMNPS PFTVSPNTHV SQVFNLFRTM GLRHLPVVNA
VGEIVGIITR HNLTYEFLQA RLRQHYQTI
