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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
 
 
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