ID   CLCN6_MOUSE             Reviewed;         870 AA.
AC   O35454;
DT   15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT   01-JAN-1998, sequence version 1.
DT   27-MAR-2024, entry version 174.
DE   RecName: Full=H(+)/Cl(-) exchange transporter 6;
DE   AltName: Full=Chloride channel protein 6;
DE            Short=ClC-6;
DE   AltName: Full=Chloride transport protein 6;
GN   Name=Clcn6 {ECO:0000312|MGI:MGI:1347049}; Synonyms=Clc6;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA   Kornak U., Boesl M.R., Jentsch T.J.;
RL   Submitted (OCT-1997) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   TISSUE SPECIFICITY, AND ALTERNATIVE SPLICING.
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   FUNCTION, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, AND TISSUE
RP   SPECIFICITY.
RX   PubMed=16950870; DOI=10.1073/pnas.0606137103;
RA   Poet M., Kornak U., Schweizer M., Zdebik A.A., Scheel O., Hoelter S.,
RA   Wurst W., Schmitt A., Fuhrmann J.C., Planells-Cases R., Mole S.E.,
RA   Huebner C.A., Jentsch T.J.;
RT   "Lysosomal storage disease upon disruption of the neuronal chloride
RT   transport protein ClC-6.";
RL   Proc. Natl. Acad. Sci. U.S.A. 103:13854-13859(2006).
RN   [4]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-774, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Brain;
RX   PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA   Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA   Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT   "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL   Cell 143:1174-1189(2010).
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:16950870}.
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:0000250|UniProtKB:P51797};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:29568;
CC         Evidence={ECO:0000250|UniProtKB:P51797};
CC   -!- SUBCELLULAR LOCATION: Late endosome membrane
CC       {ECO:0000269|PubMed:16950870}; Multi-pass membrane protein
CC       {ECO:0000269|PubMed:16950870}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=ClC-6a;
CC         IsoId=O35454-1; Sequence=Displayed;
CC       Name=ClC-6c;
CC         IsoId=O35454-2; Sequence=Not described;
CC   -!- TISSUE SPECIFICITY: Detected in whole brain and in hippocampus neurons
CC       (at protein level). Detected in brain, trigeminus, dorsal root
CC       ganglion, spinal cord, eye, kidney, testis, skeletal muscle, thymus and
CC       pancreas. Isoform ClC-6c is expressed only in kidney.
CC       {ECO:0000269|PubMed:16950870, ECO:0000269|PubMed:9224655}.
CC   -!- PTM: N-glycosylated on several asparagine residues.
CC       {ECO:0000250|UniProtKB:P51797}.
CC   -!- DISRUPTION PHENOTYPE: Reduced pain sensitivity and moderate behavioral
CC       abnormalities, but have normal fertility and are generally not very
CC       different from wild-type. {ECO:0000269|PubMed:16950870}.
CC   -!- SIMILARITY: Belongs to the chloride channel (TC 2.A.49) family. ClC-
CC       6/CLCN6 subfamily. {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; AF030106; AAC17702.1; -; Genomic_DNA.
DR   EMBL; AF030101; AAC17702.1; JOINED; Genomic_DNA.
DR   EMBL; AF030102; AAC17702.1; JOINED; Genomic_DNA.
DR   EMBL; AF030103; AAC17702.1; JOINED; Genomic_DNA.
DR   EMBL; AF030104; AAC17702.1; JOINED; Genomic_DNA.
DR   EMBL; AF030105; AAC17702.1; JOINED; Genomic_DNA.
DR   CCDS; CCDS18928.1; -. [O35454-1]
DR   RefSeq; NP_036059.1; NM_011929.3. [O35454-1]
DR   AlphaFoldDB; O35454; -.
DR   SMR; O35454; -.
DR   BioGRID; 204932; 10.
DR   STRING; 10090.ENSMUSP00000030879; -.
DR   ChEMBL; CHEMBL2176794; -.
DR   TCDB; 2.A.49.3.4; the chloride carrier/channel (clc) family.
DR   GlyCosmos; O35454; 3 sites, No reported glycans.
DR   GlyGen; O35454; 3 sites.
DR   iPTMnet; O35454; -.
DR   PhosphoSitePlus; O35454; -.
DR   SwissPalm; O35454; -.
DR   PaxDb; 10090-ENSMUSP00000121751; -.
DR   ProteomicsDB; 283377; -. [O35454-1]
DR   Pumba; O35454; -.
DR   Antibodypedia; 28262; 114 antibodies from 21 providers.
DR   DNASU; 26372; -.
DR   Ensembl; ENSMUST00000030879.12; ENSMUSP00000030879.6; ENSMUSG00000029016.14. [O35454-1]
DR   GeneID; 26372; -.
DR   KEGG; mmu:26372; -.
DR   UCSC; uc008vtr.1; mouse. [O35454-1]
DR   AGR; MGI:1347049; -.
DR   CTD; 1185; -.
DR   MGI; MGI:1347049; Clcn6.
DR   VEuPathDB; HostDB:ENSMUSG00000029016; -.
DR   eggNOG; KOG0474; Eukaryota.
DR   GeneTree; ENSGT00940000159291; -.
DR   InParanoid; O35454; -.
DR   OMA; FARIDHG; -.
DR   OrthoDB; 1089019at2759; -.
DR   Reactome; R-MMU-2672351; Stimuli-sensing channels.
DR   BioGRID-ORCS; 26372; 3 hits in 76 CRISPR screens.
DR   ChiTaRS; Clcn6; mouse.
DR   PRO; PR:O35454; -.
DR   Proteomes; UP000000589; Chromosome 4.
DR   RNAct; O35454; Protein.
DR   Bgee; ENSMUSG00000029016; Expressed in substantia nigra and 224 other cell types or tissues.
DR   ExpressionAtlas; O35454; baseline and differential.
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:0015297; F:antiporter activity; IEA:UniProtKB-KW.
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; ISS:UniProtKB.
DR   GO; GO:0006821; P:chloride transport; ISS:UniProtKB.
DR   GO; GO:0009612; P:response to mechanical stimulus; ISO:MGI.
DR   CDD; cd04591; CBS_pair_voltage-gated_CLC_euk_bac; 1.
DR   CDD; cd03685; ClC_6_like; 1.
DR   Gene3D; 3.10.580.10; CBS-domain; 1.
DR   Gene3D; 1.10.3080.10; Clc chloride channel; 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   PANTHER; PTHR11689; CHLORIDE CHANNEL PROTEIN CLC FAMILY MEMBER; 1.
DR   PANTHER; PTHR11689:SF136; H(+)_CL(-) EXCHANGE TRANSPORTER 6; 1.
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; CBS-domain pair; 1.
DR   SUPFAM; SSF81340; Clc chloride channel; 1.
DR   PROSITE; PS51371; CBS; 2.
DR   Genevisible; O35454; MM.
PE   1: Evidence at protein level;
KW   Alternative splicing; Antiport; ATP-binding; CBS domain; Chloride;
KW   Endosome; Glycoprotein; Ion transport; Membrane; Nucleotide-binding;
KW   Phosphoprotein; Reference proteome; Repeat; Transmembrane;
KW   Transmembrane helix; Transport.
FT   CHAIN           1..870
FT                   /note="H(+)/Cl(-) exchange transporter 6"
FT                   /id="PRO_0000094450"
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        463..482
FT                   /note="Helical"
FT                   /evidence="ECO:0000250"
FT   TRANSMEM        488..512
FT                   /note="Helical"
FT                   /evidence="ECO:0000250"
FT   INTRAMEM        520..534
FT                   /note="Helical"
FT                   /evidence="ECO:0000250"
FT   INTRAMEM        535..537
FT                   /note="Note=Loop between two helices"
FT                   /evidence="ECO:0000250"
FT   INTRAMEM        538..549
FT                   /note="Helical"
FT                   /evidence="ECO:0000250"
FT   INTRAMEM        550..553
FT                   /note="Note=Loop between two helices"
FT                   /evidence="ECO:0000250"
FT   TRANSMEM        554..572
FT                   /note="Helical"
FT                   /evidence="ECO:0000250"
FT   TOPO_DOM        573..870
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250"
FT   DOMAIN          606..663
FT                   /note="CBS 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00703"
FT   DOMAIN          808..869
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           488..492
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         490
FT                   /ligand="chloride"
FT                   /ligand_id="ChEBI:CHEBI:17996"
FT                   /evidence="ECO:0000250"
FT   BINDING         577
FT                   /ligand="chloride"
FT                   /ligand_id="ChEBI:CHEBI:17996"
FT                   /evidence="ECO:0000250"
FT   BINDING         631..633
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000250"
FT   BINDING         850..853
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         774
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   CARBOHYD        410
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        423
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        433
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
SQ   SEQUENCE   870 AA;  96980 MW;  872C090069188749 CRC64;
     MAGCRGSVCC CCRWCCCCGE RESRTPEELT ILGETQEEED EILPRKDYES LDYDRCINDP
     YLEVLETMDN KKGRRYEAVK WMVVFAIGVC TGLVGLFVDF SVRLFTQLKF GVVQTSVEEC
     SQKGCLALSL LELLGFNLTF VFLASLLVLI EPVAAGSGIP EIKCYLNGVK VPGIVRLRTL
     LCKVFGVLFS VSGGLFVGKE GPMIHSGAVV GAGLPQFQSI SLRKIQFNFP YFRSDRDKRD
     FVSAGAAAGV AAAFGAPIGG TLFSLEEGSS FWNQGLTWKV LFCSMSATFT LNFFRSGIQF
     GSWGSFQLPG LLNFGEFKCS DSDKKCHLWT AMDLGFFVVM GVIGGLLGAT FNCLNKRLAK
     YRMRNVHPKP KLVRVLESLL VSLVTTVVVF VASMVLGECR QMSSTSQTGN GSFQLQVTSE
     DVNSTIKAFF CPNDTYNDMA TLFFNSQESA ILQLFHQDGT FSPVTLALFF ILYFLLACWT
     FGTSVPSGLF VPSLLCGAAF GRLVANVLKS YIGLGHLYSG TFALIGAAAF LGGVVRMTIS
     LTVILIESTN EITYGLPIMV TLMVAKWTGD LFNKGIYDVH IGLRGVPLLE WETDVEMDKL
     RASDIMEPNL TYVYPHTRIQ SLVSILRTTV HHAFPVVTEN RGNEKEFMKG NQLISNNIKF
     KKSSILTRAG EQRKRGQSMK SYPSSELRNV CDEHVASEEP AEKEDLLQQM LERRYTPYPN
     LYPDQSPSED WTMEERFRPL TFHGLVLRSQ LVTLLVRGVC YSESQSSASQ PRLSYAEMAE
     DYPRYPDIHD LDLTLLNPRM IVDVTPYMNP SPFTVSPNTH VSQVFNLFRT MGLRHLPVVN
     AVGEIVGIIT RHNLTNEFLQ ARLRQHYQTL
//