CLCN6_MOUSE
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 03-AUG-2022, entry version 165.
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}.
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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.ENSMUSP00000121751; -.
DR ChEMBL; CHEMBL2176794; -.
DR TCDB; 2.A.49.3.4; the chloride carrier/channel (clc) family.
DR GlyGen; O35454; 3 sites.
DR iPTMnet; O35454; -.
DR PhosphoSitePlus; O35454; -.
DR SwissPalm; O35454; -.
DR PaxDb; O35454; -.
DR PRIDE; O35454; -.
DR ProteomicsDB; 283377; -. [O35454-1]
DR Antibodypedia; 28262; 99 antibodies from 21 providers.
DR DNASU; 26372; -.
DR Ensembl; ENSMUST00000030879; ENSMUSP00000030879; ENSMUSG00000029016. [O35454-1]
DR GeneID; 26372; -.
DR KEGG; mmu:26372; -.
DR UCSC; uc008vtr.1; mouse. [O35454-1]
DR CTD; 1185; -.
DR MGI; MGI:1347049; Clcn6.
DR VEuPathDB; HostDB:ENSMUSG00000029016; -.
DR eggNOG; KOG0474; Eukaryota.
DR GeneTree; ENSGT00940000159291; -.
DR InParanoid; O35454; -.
DR OMA; FMHEHIS; -.
DR Reactome; R-MMU-2672351; Stimuli-sensing channels.
DR BioGRID-ORCS; 26372; 3 hits in 71 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 222 other tissues.
DR ExpressionAtlas; O35454; baseline and differential.
DR Genevisible; O35454; MM.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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 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 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
