CLCN3_HUMAN
ID CLCN3_HUMAN Reviewed; 818 AA.
AC P51790; B7Z932; B9EGJ9; D3DP34; E9PB97; O14918; Q86Z21;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 14-APR-2009, sequence version 2.
DT 03-AUG-2022, entry version 196.
DE RecName: Full=H(+)/Cl(-) exchange transporter 3;
DE AltName: Full=Chloride channel protein 3;
DE Short=ClC-3;
DE AltName: Full=Chloride transporter ClC-3;
GN Name=CLCN3;
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).
RC TISSUE=Retina;
RX PubMed=7665160; DOI=10.1006/geno.1995.1015;
RA Borsani G., Rugarli E.I., Taglialatela M., Wong C., Ballabio A.;
RT "Characterization of a human and murine gene (CLCN3) sharing similarities
RT to voltage-gated chloride channels and to a yeast integral membrane
RT protein.";
RL Genomics 27:131-141(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Lens epithelium;
RX PubMed=9678416; DOI=10.1080/02713689808951247;
RA Shepard A.R., Rae J.L.;
RT "Ion transporters and receptors in cDNA libraries from lens and cornea
RT epithelia.";
RL Curr. Eye Res. 17:708-719(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, GLYCOSYLATION,
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF GLY-280.
RC TISSUE=Colon tumor;
RX PubMed=11274166; DOI=10.1074/jbc.m009376200;
RA Huang P., Liu J., Di A., Robinson N.C., Musch M.W., Kaetzel M.A.,
RA Nelson D.J.;
RT "Regulation of human CLC-3 channels by multifunctional Ca2+/calmodulin-
RT dependent protein kinase.";
RL J. Biol. Chem. 276:20093-20100(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), TISSUE SPECIFICITY, INTERACTION
RP WITH SLC9A3R1 (ISOFORM 2), DOMAIN (ISOFORM 2), FUNCTION (ISOFORM 2), AND
RP SUBCELLULAR LOCATION (ISOFORM 2).
RX PubMed=11967229; DOI=10.1096/fj.01-0845fje;
RA Ogura T., Furukawa T., Toyozaki T., Yamada K., Zheng Y.-J., Katayama Y.,
RA Nakaya H., Inagaki N.;
RT "ClC-3B, a novel ClC-3 splicing variant that interacts with EBP50 and
RT facilitates expression of CFTR-regulated ORCC.";
RL FASEB J. 16:863-865(2002).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon endothelium;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Trachea;
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=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Testis;
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, Fetal lung, 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 INTERACTION WITH GOPC; PDZK1 AND SLC9A3R1 (ISOFORM 2), GLYCOSYLATION,
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION (ISOFORMS 1 AND 2).
RX PubMed=12471024; DOI=10.1074/jbc.m211050200;
RA Gentzsch M., Cui L., Mengos A., Chang X.-B., Chen J.-H., Riordan J.R.;
RT "The PDZ-binding chloride channel ClC-3B localizes to the Golgi and
RT associates with cystic fibrosis transmembrane conductance regulator-
RT interacting PDZ proteins.";
RL J. Biol. Chem. 278:6440-6449(2003).
RN [12]
RP REVIEW.
RX PubMed=29845874; DOI=10.1152/physrev.00047.2017;
RA Jentsch T.J., Pusch M.;
RT "CLC Chloride Channels and Transporters: Structure, Function, Physiology,
RT and Disease.";
RL Physiol. Rev. 98:1493-1590(2018).
RN [13]
RP INVOLVEMENT IN NEDHYBA, INVOLVEMENT IN NEDSBA, AND VARIANTS NEDHYBA CYS-85;
RP THR-252; ALA-324; VAL-413; ARG-453; ILE-570; THR-607 AND ALA-772.
RX PubMed=34186028; DOI=10.1016/j.ajhg.2021.06.003;
RG CAUSES Study;
RA Duncan A.R., Polovitskaya M.M., Gaitan-Penas H., Bertelli S., VanNoy G.E.,
RA Grant P.E., O'Donnell-Luria A., Valivullah Z., Lovgren A.K., England E.M.,
RA Agolini E., Madden J.A., Schmitz-Abe K., Kritzer A., Hawley P., Novelli A.,
RA Alfieri P., Colafati G.S., Wieczorek D., Platzer K., Luppe J.,
RA Koch-Hogrebe M., Abou Jamra R., Neira-Fresneda J., Lehman A.,
RA Boerkoel C.F., Seath K., Clarke L., van Ierland Y., Argilli E., Sherr E.H.,
RA Maiorana A., Diel T., Hempel M., Bierhals T., Estevez R., Jentsch T.J.,
RA Pusch M., Agrawal P.B.;
RT "Unique variants in CLCN3, encoding an endosomal anion/proton exchanger,
RT underlie a spectrum of neurodevelopmental disorders.";
RL Am. J. Hum. Genet. 108:1450-1465(2021).
CC -!- FUNCTION: [Isoform 1]: Strongly outwardly rectifying, electrogenic
CC H(+)/Cl(-)exchanger which mediates the exchange of chloride ions
CC against protons (By similarity). The CLC channel family contains both
CC chloride channels and proton-coupled anion transporters that exchange
CC chloride or another anion for protons (PubMed:29845874). The presence
CC of conserved gating glutamate residues is typical for family members
CC that function as antiporters (PubMed:29845874).
CC {ECO:0000250|UniProtKB:P51791, ECO:0000303|PubMed:29845874}.
CC -!- FUNCTION: [Isoform 2]: Strongly outwardly rectifying, electrogenic
CC H(+)/Cl(-)exchanger which mediates the exchange of chloride ions
CC against protons. {ECO:0000269|PubMed:11967229}.
CC -!- SUBUNIT: [Isoform 1]: Monomer and homodimer (By similarity). Forms
CC heterodimers with CLCN4 (By similarity).
CC {ECO:0000250|UniProtKB:P51791}.
CC -!- SUBUNIT: [Isoform 2]: Interacts with GOPC, PDZK1 and SLC9A3R1/EBP50.
CC {ECO:0000269|PubMed:11967229, ECO:0000269|PubMed:12471024}.
CC -!- INTERACTION:
CC P51790-2; P13569: CFTR; NbExp=2; IntAct=EBI-25495635, EBI-349854;
CC P51790-2; P51790-1: CLCN3; NbExp=2; IntAct=EBI-25495635, EBI-25495642;
CC P51790-2; Q5T2W1: PDZK1; NbExp=2; IntAct=EBI-25495635, EBI-349819;
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Early endosome membrane
CC {ECO:0000269|PubMed:12471024}; Multi-pass membrane protein
CC {ECO:0000255}. Late endosome membrane {ECO:0000269|PubMed:12471024};
CC Multi-pass membrane protein {ECO:0000255}. Lysosome membrane
CC {ECO:0000250|UniProtKB:P51791}; Multi-pass membrane protein
CC {ECO:0000255}. Cell membrane {ECO:0000250|UniProtKB:P51792}; Multi-pass
CC membrane protein {ECO:0000255}. Note=Isoform 1 is localized mainly in
CC late endosomes. {ECO:0000269|PubMed:12471024}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Golgi apparatus membrane
CC {ECO:0000269|PubMed:12471024}; Multi-pass membrane protein
CC {ECO:0000255}. Cell projection, ruffle membrane
CC {ECO:0000269|PubMed:11967229}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:11967229}. Note=Isoform 2 is mainly enriched in the
CC Golgi (PubMed:12471024). Colocalizes with SLC9A3R1/EBP50 in membrane
CC ruffles (PubMed:11967229). {ECO:0000269|PubMed:11967229,
CC ECO:0000269|PubMed:12471024}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=ClC-3A;
CC IsoId=P51790-1; Sequence=Displayed;
CC Name=2; Synonyms=ClC-3B;
CC IsoId=P51790-2; Sequence=VSP_016073;
CC Name=3;
CC IsoId=P51790-4; Sequence=VSP_045105;
CC Name=4;
CC IsoId=P51790-5; Sequence=VSP_054415;
CC -!- TISSUE SPECIFICITY: Expressed primarily in tissues derived from
CC neuroectoderm. Within the brain, its expression is particularly evident
CC in the hippocampus, olfactory cortex, and olfactory bulb. Highly
CC expressed in aortic and coronary vascular smooth muscle cells, and
CC aortic endothelial cells. Also expressed in tracheal and alveolar
CC epithelial cells, and intima and media of the pulmonary vessels.
CC Expressed in bronchus and colon (at protein level).
CC {ECO:0000269|PubMed:10198195, ECO:0000269|PubMed:11967229,
CC ECO:0000269|PubMed:12471024}.
CC -!- DOMAIN: Isoform 2 contains a C-terminal PDZ-binding motif mediating the
CC interaction with GOPC. {ECO:0000269|PubMed:11967229}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:11274166,
CC ECO:0000269|PubMed:12471024}.
CC -!- DISEASE: Neurodevelopmental disorder with hypotonia and brain
CC abnormalities (NEDHYBA) [MIM:619512]: An autosomal dominant disorder
CC characterized by onset in infancy or early childhood, global
CC developmental delay, hypotonia, impaired intellectual development, and
CC poor or absent speech. Additional variable manifestations may be
CC present, including feeding difficulties, seizures, behavioral
CC abnormalities, and non-specific dysmorphic facial features. Brain
CC imaging shows variable abnormalities, including corpus callosum and
CC cerebellar defects, and decreased white matter volume.
CC {ECO:0000269|PubMed:34186028}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Neurodevelopmental disorder with seizures and brain
CC abnormalities (NEDSBA) [MIM:619517]: An autosomal recessive neurologic
CC disorder characterized by global developmental delay and onset of
CC seizures in the first months of life, and structural brain defects on
CC brain imaging. Additional features may include pigmentary retinopathy
CC with poor visual fixation and spasticity.
CC {ECO:0000269|PubMed:34186028}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the chloride channel (TC 2.A.49) family. ClC-
CC 3/CLCN3 subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC54560.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=CAA55281.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; X78520; CAA55280.1; -; mRNA.
DR EMBL; X78520; CAA55281.1; ALT_INIT; mRNA.
DR EMBL; AF029346; AAB95161.1; -; mRNA.
DR EMBL; AF172729; AAD51034.1; -; mRNA.
DR EMBL; AB019542; BAC54560.1; ALT_INIT; mRNA.
DR EMBL; AK304362; BAH14168.1; -; mRNA.
DR EMBL; BX647119; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC084724; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC106878; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471056; EAX04782.1; -; Genomic_DNA.
DR EMBL; CH471056; EAX04786.1; -; Genomic_DNA.
DR EMBL; BC136510; AAI36511.1; -; mRNA.
DR CCDS; CCDS34100.1; -. [P51790-2]
DR CCDS; CCDS34101.1; -. [P51790-1]
DR CCDS; CCDS58932.1; -. [P51790-4]
DR PIR; I37240; I37240.
DR RefSeq; NP_001230301.1; NM_001243372.1. [P51790-4]
DR RefSeq; NP_001230303.1; NM_001243374.1.
DR RefSeq; NP_001820.2; NM_001829.3. [P51790-1]
DR RefSeq; NP_776297.2; NM_173872.3. [P51790-2]
DR AlphaFoldDB; P51790; -.
DR SMR; P51790; -.
DR BioGRID; 107596; 69.
DR IntAct; P51790; 15.
DR STRING; 9606.ENSP00000261514; -.
DR ChEMBL; CHEMBL2401603; -.
DR GuidetoPHARMACOLOGY; 702; -.
DR GlyGen; P51790; 4 sites.
DR iPTMnet; P51790; -.
DR PhosphoSitePlus; P51790; -.
DR SwissPalm; P51790; -.
DR BioMuta; CLCN3; -.
DR DMDM; 226693513; -.
DR EPD; P51790; -.
DR jPOST; P51790; -.
DR MassIVE; P51790; -.
DR MaxQB; P51790; -.
DR PaxDb; P51790; -.
DR PeptideAtlas; P51790; -.
DR PRIDE; P51790; -.
DR ProteomicsDB; 56388; -. [P51790-1]
DR ProteomicsDB; 56389; -. [P51790-2]
DR ProteomicsDB; 7526; -.
DR ABCD; P51790; 1 sequenced antibody.
DR Antibodypedia; 28481; 257 antibodies from 22 providers.
DR DNASU; 1182; -.
DR Ensembl; ENST00000347613.8; ENSP00000261514.5; ENSG00000109572.15. [P51790-2]
DR Ensembl; ENST00000360642.7; ENSP00000353857.3; ENSG00000109572.15. [P51790-4]
DR Ensembl; ENST00000513761.6; ENSP00000424603.1; ENSG00000109572.15. [P51790-1]
DR GeneID; 1182; -.
DR KEGG; hsa:1182; -.
DR MANE-Select; ENST00000513761.6; ENSP00000424603.1; NM_001829.4; NP_001820.2.
DR UCSC; uc003ish.4; human. [P51790-1]
DR CTD; 1182; -.
DR DisGeNET; 1182; -.
DR GeneCards; CLCN3; -.
DR HGNC; HGNC:2021; CLCN3.
DR HPA; ENSG00000109572; Low tissue specificity.
DR MIM; 600580; gene.
DR MIM; 619512; phenotype.
DR MIM; 619517; phenotype.
DR neXtProt; NX_P51790; -.
DR OpenTargets; ENSG00000109572; -.
DR Orphanet; 528084; Non-specific syndromic intellectual disability.
DR PharmGKB; PA26548; -.
DR VEuPathDB; HostDB:ENSG00000109572; -.
DR eggNOG; KOG0475; Eukaryota.
DR GeneTree; ENSGT00940000153763; -.
DR HOGENOM; CLU_003181_2_1_1; -.
DR InParanoid; P51790; -.
DR OMA; IMHLTIS; -.
DR OrthoDB; 271925at2759; -.
DR PhylomeDB; P51790; -.
DR TreeFam; TF313867; -.
DR PathwayCommons; P51790; -.
DR Reactome; R-HSA-2672351; Stimuli-sensing channels.
DR SignaLink; P51790; -.
DR SIGNOR; P51790; -.
DR BioGRID-ORCS; 1182; 13 hits in 1077 CRISPR screens.
DR ChiTaRS; CLCN3; human.
DR GeneWiki; CLCN3; -.
DR GenomeRNAi; 1182; -.
DR Pharos; P51790; Tchem.
DR PRO; PR:P51790; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; P51790; protein.
DR Bgee; ENSG00000109572; Expressed in mucosa of sigmoid colon and 207 other tissues.
DR ExpressionAtlas; P51790; baseline and differential.
DR Genevisible; P51790; HS.
DR GO; GO:0016324; C:apical plasma membrane; IEA:Ensembl.
DR GO; GO:0043679; C:axon terminus; IEA:Ensembl.
DR GO; GO:0009986; C:cell surface; NAS:UniProtKB.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:GO_Central.
DR GO; GO:0005769; C:early endosome; IDA:UniProtKB.
DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0010008; C:endosome membrane; ISS:UniProtKB.
DR GO; GO:0009897; C:external side of plasma membrane; IDA:GO_Central.
DR GO; GO:0098982; C:GABA-ergic synapse; IDA:SynGO.
DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0060077; C:inhibitory synapse; IEA:Ensembl.
DR GO; GO:0016021; C:integral component of membrane; TAS:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0099055; C:integral component of postsynaptic membrane; IEA:Ensembl.
DR GO; GO:0030285; C:integral component of synaptic vesicle membrane; IDA:SynGO.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0005770; C:late endosome; IDA:UniProtKB.
DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005765; C:lysosomal membrane; ISS:UniProtKB.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0045335; C:phagocytic vesicle; IDA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:GO_Central.
DR GO; GO:0055037; C:recycling endosome; ISS:UniProtKB.
DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030141; C:secretory granule; IDA:GO_Central.
DR GO; GO:0042581; C:specific granule; IDA:GO_Central.
DR GO; GO:0008021; C:synaptic vesicle; IDA:GO_Central.
DR GO; GO:0012506; C:vesicle membrane; IDA:UniProtKB.
DR GO; GO:0015297; F:antiporter activity; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005254; F:chloride channel activity; IDA:GO_Central.
DR GO; GO:0030165; F:PDZ domain binding; IDA:UniProtKB.
DR GO; GO:0015299; F:solute:proton antiporter activity; IBA:GO_Central.
DR GO; GO:0005247; F:voltage-gated chloride channel activity; IBA:GO_Central.
DR GO; GO:0072320; F:volume-sensitive chloride channel activity; IMP:GO_Central.
DR GO; GO:0008344; P:adult locomotory behavior; IEA:Ensembl.
DR GO; GO:1902476; P:chloride transmembrane transport; IDA:GO_Central.
DR GO; GO:0048388; P:endosomal lumen acidification; TAS:UniProtKB.
DR GO; GO:0045794; P:negative regulation of cell volume; IMP:GO_Central.
DR GO; GO:0006911; P:phagocytosis, engulfment; IEA:Ensembl.
DR GO; GO:0045494; P:photoreceptor cell maintenance; IEA:Ensembl.
DR GO; GO:1903428; P:positive regulation of reactive oxygen species biosynthetic process; IEA:Ensembl.
DR GO; GO:0006885; P:regulation of pH; TAS:UniProtKB.
DR GO; GO:0051932; P:synaptic transmission, GABAergic; IEA:Ensembl.
DR GO; GO:0035249; P:synaptic transmission, glutamatergic; IEA:Ensembl.
DR GO; GO:0097401; P:synaptic vesicle lumen acidification; IEA:Ensembl.
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; IPR002245; Cl_channel-3.
DR Pfam; PF00571; CBS; 2.
DR Pfam; PF00654; Voltage_CLC; 1.
DR PRINTS; PR00762; CLCHANNEL.
DR PRINTS; PR01114; CLCHANNEL3.
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; Cell membrane;
KW Cell projection; Chloride; Disease variant; Endosome; Epilepsy;
KW Glycoprotein; Golgi apparatus; Intellectual disability; Ion transport;
KW Lysosome; Membrane; Nucleotide-binding; Reference proteome; Repeat;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..818
FT /note="H(+)/Cl(-) exchange transporter 3"
FT /id="PRO_0000094438"
FT TOPO_DOM 1..125
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 126..163
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 209..232
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT INTRAMEM 241..248
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 258..276
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 282..301
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT INTRAMEM 313..325
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT INTRAMEM 329..337
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 349..367
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 391..416
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 423..443
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 500..520
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 525..544
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT INTRAMEM 572..586
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT INTRAMEM 590..601
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT INTRAMEM 602..605
FT /note="Note=Loop between two helices"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TRANSMEM 606..624
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT TOPO_DOM 625..818
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P35523"
FT DOMAIN 658..722
FT /note="CBS 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00703"
FT DOMAIN 755..812
FT /note="CBS 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00703"
FT MOTIF 28..29
FT /note="Di-leucine internalization motif; mediates targeting
FT to late endosome and lysosome membranes"
FT /evidence="ECO:0000250|UniProtKB:P51791"
FT MOTIF 46..47
FT /note="Di-leucine internalization motif; mediates targeting
FT to late endosome and lysosome membranes"
FT /evidence="ECO:0000250|UniProtKB:P51791"
FT MOTIF 71..75
FT /note="Di-leucine internalization motif; mediates targeting
FT to late endosome and lysosome membranes"
FT /evidence="ECO:0000250|UniProtKB:P51791"
FT MOTIF 238..242
FT /note="Selectivity filter part_1"
FT /evidence="ECO:0000250"
FT MOTIF 280..284
FT /note="Selectivity filter part_2"
FT /evidence="ECO:0000250"
FT MOTIF 525..529
FT /note="Selectivity filter part_3"
FT /evidence="ECO:0000250"
FT BINDING 239
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT BINDING 527
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT BINDING 630
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT BINDING 689..691
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 796..799
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT SITE 282
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 339
FT /note="Mediates proton transfer from the protein to the
FT inner aqueous phase"
FT /evidence="ECO:0000250"
FT CARBOHYD 177
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 451
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 479
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 1..53
FT /note="MESEQLFHRGYYRNSYNSITSASSDEELLDGAGVIMDFQTSEDDNLLDGDTA
FT V -> MVTLQLGESHYVVQAGLQLLGSSNPPALASQVAEIT (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_054415"
FT VAR_SEQ 312..338
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_045105"
FT VAR_SEQ 790..818
FT /note="RLLGIITKKDILRHMAQTANQDPASIMFN -> IVLGIITKKNILEHLEQLK
FT QHVEPLAPPWHYNKKRYPPAYGPDGKPRPRFNNVQLNLTDEEREETEEEVYLLNSTTL
FT (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11967229"
FT /id="VSP_016073"
FT VARIANT 85
FT /note="Y -> C (in NEDHYBA)"
FT /evidence="ECO:0000269|PubMed:34186028"
FT /id="VAR_086219"
FT VARIANT 252
FT /note="I -> T (in NEDHYBA)"
FT /evidence="ECO:0000269|PubMed:34186028"
FT /id="VAR_086220"
FT VARIANT 324
FT /note="V -> A (in NEDHYBA)"
FT /evidence="ECO:0000269|PubMed:34186028"
FT /id="VAR_086221"
FT VARIANT 413
FT /note="A -> V (in NEDHYBA; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:34186028"
FT /id="VAR_086222"
FT VARIANT 453
FT /note="S -> R (in NEDHYBA)"
FT /evidence="ECO:0000269|PubMed:34186028"
FT /id="VAR_086223"
FT VARIANT 570
FT /note="T -> I (in NEDHYBA)"
FT /evidence="ECO:0000269|PubMed:34186028"
FT /id="VAR_086224"
FT VARIANT 607
FT /note="I -> T (in NEDHYBA)"
FT /evidence="ECO:0000269|PubMed:34186028"
FT /id="VAR_086225"
FT VARIANT 772
FT /note="V -> A (in NEDHYBA)"
FT /evidence="ECO:0000269|PubMed:34186028"
FT /id="VAR_086226"
FT MUTAGEN 280
FT /note="G->E: Changes channel selectivity from I(-)>Cl(-) to
FT Cl(-)>I(-)."
FT /evidence="ECO:0000269|PubMed:11274166"
FT CONFLICT 209
FT /note="M -> T (in Ref. 5; BX647119)"
FT /evidence="ECO:0000305"
FT CONFLICT 551
FT /note="Y -> C (in Ref. 5; BX647119)"
FT /evidence="ECO:0000305"
FT CONFLICT 570
FT /note="T -> A (in Ref. 5; BX647119)"
FT /evidence="ECO:0000305"
FT CONFLICT 646
FT /note="E -> EEF (in Ref. 1; CAA55280/CAA55281 and 4;
FT BAC54560)"
FT /evidence="ECO:0000305"
FT CONFLICT 723
FT /note="Q -> R (in Ref. 5; BX647119)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 818 AA; 90966 MW; 30FF0A6A2D6EF3B8 CRC64;
MESEQLFHRG YYRNSYNSIT SASSDEELLD GAGVIMDFQT SEDDNLLDGD TAVGTHYTMT
NGGSINSSTH LLDLLDEPIP GVGTYDDFHT IDWVREKCKD RERHRRINSK KKESAWEMTK
SLYDAWSGWL VVTLTGLASG ALAGLIDIAA DWMTDLKEGI CLSALWYNHE QCCWGSNETT
FEERDKCPQW KTWAELIIGQ AEGPGSYIMN YIMYIFWALS FAFLAVSLVK VFAPYACGSG
IPEIKTILSG FIIRGYLGKW TLMIKTITLV LAVASGLSLG KEGPLVHVAC CCGNIFSYLF
PKYSTNEAKK REVLSAASAA GVSVAFGAPI GGVLFSLEEV SYYFPLKTLW RSFFAALVAA
FVLRSINPFG NSRLVLFYVE YHTPWYLFEL FPFILLGVFG GLWGAFFIRA NIAWCRRRKS
TKFGKYPVLE VIIVAAITAV IAFPNPYTRL NTSELIKELF TDCGPLESSS LCDYRNDMNA
SKIVDDIPDR PAGIGVYSAI WQLCLALIFK IIMTVFTFGI KVPSGLFIPS MAIGAIAGRI
VGIAVEQLAY YHHDWFIFKE WCEVGADCIT PGLYAMVGAA ACLGGVTRMT VSLVVIVFEL
TGGLEYIVPL MAAVMTSKWV GDAFGREGIY EAHIRLNGYP FLDAKEEFTH TTLAADVMRP
RRNDPPLAVL TQDNMTVDDI ENMINETSYN GFPVIMSKES QRLVGFALRR DLTIAIESAR
KKQEGIVGSS RVCFAQHTPS LPAESPRPLK LRSILDMSPF TVTDHTPMEI VVDIFRKLGL
RQCLVTHNGR LLGIITKKDI LRHMAQTANQ DPASIMFN
