S12A6_MOUSE
ID S12A6_MOUSE Reviewed; 1150 AA.
AC Q924N4; A2AGK1; Q924N3;
DT 13-DEC-2002, integrated into UniProtKB/Swiss-Prot.
DT 28-JUN-2011, sequence version 2.
DT 03-AUG-2022, entry version 163.
DE RecName: Full=Solute carrier family 12 member 6;
DE AltName: Full=Electroneutral potassium-chloride cotransporter 3;
DE AltName: Full=K-Cl cotransporter 3;
GN Name=Slc12a6; Synonyms=Kcc3;
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 [MRNA] (ISOFORMS 1 AND 2), AND GLYCOSYLATION.
RC STRAIN=C57BL/6J;
RX PubMed=11246162; DOI=10.1016/s0306-4522(00)00567-4;
RA Pearson M.M., Lu J., Mount D.B., Delpire E.;
RT "Localization of the K(+)-Cl(-) cotransporter, KCC3, in the central and
RT peripheral nervous systems: expression in the choroid plexus, large neurons
RT and white matter tracts.";
RL Neuroscience 103:481-491(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP PROTEIN SEQUENCE OF 601-608; 1054-1061 AND 1103-1113, AND IDENTIFICATION BY
RP MASS SPECTROMETRY.
RC STRAIN=C57BL/6J; TISSUE=Brain;
RA Lubec G., Kang S.U.;
RL Submitted (APR-2007) to UniProtKB.
RN [5]
RP FUNCTION.
RX PubMed=10347194; DOI=10.1074/jbc.274.23.16355;
RA Mount D.B., Mercado A., Song L., Xu J., George A.L. Jr., Delpire E.,
RA Gamba G.;
RT "Cloning and characterization of KCC3 and KCC4, new members of the cation-
RT chloride cotransporter gene family.";
RL J. Biol. Chem. 274:16355-16362(1999).
RN [6]
RP DISEASE.
RX PubMed=12368912; DOI=10.1038/ng1002;
RA Howard H.C., Mount D.B., Rochefort D., Byun N., Dupre N., Lu J., Fan X.,
RA Song L., Riviere J.-B., Prevost C., Horst J., Simonati A., Lemcke B.,
RA Welch R., England R., Zhan F.Q., Mercado A., Siesser W.B., George A.L. Jr.,
RA McDonald M.P., Bouchard J.-P., Mathieu J., Delpire E., Rouleau G.A.;
RT "The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy
RT associated with agenesis of the corpus callosum.";
RL Nat. Genet. 32:384-392(2002).
RN [7]
RP ALTERNATIVE PROMOTER USAGE, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=16048901; DOI=10.1152/ajprenal.00464.2004;
RA Mercado A., Vazquez N., Song L., Cortes R., Enck A.H., Welch R.,
RA Delpire E., Gamba G., Mount D.B.;
RT "NH2-terminal heterogeneity in the KCC3 K+-Cl- cotransporter.";
RL Am. J. Physiol. 289:F1246-1261(2005).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006;
RA Trost M., English L., Lemieux S., Courcelles M., Desjardins M.,
RA Thibault P.;
RT "The phagosomal proteome in interferon-gamma-activated macrophages.";
RL Immunity 30:143-154(2009).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Lung;
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: Mediates electroneutral potassium-chloride cotransport. May
CC be activated by cell swelling. May contribute to cell volume
CC homeostasis in single cells. {ECO:0000269|PubMed:10347194}.
CC -!- ACTIVITY REGULATION: Inhibited by WNK3. {ECO:0000250}.
CC -!- SUBUNIT: Homomultimer and heteromultimer with other K-Cl
CC cotransporters. {ECO:0000250}.
CC -!- INTERACTION:
CC Q924N4-1; Q9Z1W9: Stk39; NbExp=4; IntAct=EBI-620992, EBI-444764;
CC -!- SUBCELLULAR LOCATION: Basolateral cell membrane
CC {ECO:0000269|PubMed:16048901}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:16048901}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative promoter usage; Named isoforms=2;
CC Name=1; Synonyms=KCC3a;
CC IsoId=Q924N4-1; Sequence=Displayed;
CC Name=2; Synonyms=KCC3b;
CC IsoId=Q924N4-2; Sequence=VSP_006117, VSP_006118;
CC -!- TISSUE SPECIFICITY: Isoform 1 is highly expressed throughout the brain
CC and detected at lower levels in kidney. Highly expressed in highly
CC myelinated white matter of the brain, but not in gray matter. Detected
CC in the corpus callosum, in packed cell layers of the hippocampus and in
CC Purkinje neurons within the cerebellum. Highly expressed in white
CC matter in the spinal cord, but not in dorsal root ganglia or sciatic
CC nerve. Colocalizes with the oligodendrocyte marker CNP. Isoform 2 is
CC highly expressed in kidney, but not detected in brain.
CC {ECO:0000269|PubMed:16048901}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:11246162}.
CC -!- DISEASE: Note=Defects in Slc12a6 are a cause of locomotor abnormalities
CC beginning at 2 weeks of age. Slc12a6 deficient mice show
CC hypomyelination, decompaction of myelin, demyelination, axonal swelling
CC and fiber degeneration. {ECO:0000269|PubMed:12368912}.
CC -!- MISCELLANEOUS: [Isoform 2]: Produced by alternative promoter usage.
CC {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the SLC12A transporter family. {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; AF211854; AAK81895.1; -; mRNA.
DR EMBL; AF211855; AAK81896.1; -; mRNA.
DR EMBL; AL683897; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL713853; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466519; EDL27838.1; -; Genomic_DNA.
DR CCDS; CCDS16551.1; -. [Q924N4-1]
DR CCDS; CCDS16552.1; -. [Q924N4-2]
DR RefSeq; NP_598410.2; NM_133649.2. [Q924N4-1]
DR AlphaFoldDB; Q924N4; -.
DR SMR; Q924N4; -.
DR BioGRID; 223518; 1.
DR ELM; Q924N4; -.
DR IntAct; Q924N4; 4.
DR STRING; 10090.ENSMUSP00000028549; -.
DR GlyConnect; 2731; 1 N-Linked glycan (2 sites).
DR GlyGen; Q924N4; 3 sites, 1 N-linked glycan (2 sites).
DR iPTMnet; Q924N4; -.
DR PhosphoSitePlus; Q924N4; -.
DR EPD; Q924N4; -.
DR jPOST; Q924N4; -.
DR MaxQB; Q924N4; -.
DR PaxDb; Q924N4; -.
DR PeptideAtlas; Q924N4; -.
DR PRIDE; Q924N4; -.
DR ProteomicsDB; 255437; -. [Q924N4-1]
DR ProteomicsDB; 255438; -. [Q924N4-2]
DR DNASU; 107723; -.
DR Ensembl; ENSMUST00000028549; ENSMUSP00000028549; ENSMUSG00000027130. [Q924N4-1]
DR Ensembl; ENSMUST00000053666; ENSMUSP00000051490; ENSMUSG00000027130. [Q924N4-2]
DR GeneID; 107723; -.
DR KEGG; mmu:107723; -.
DR UCSC; uc008lou.2; mouse. [Q924N4-1]
DR UCSC; uc008low.2; mouse. [Q924N4-2]
DR CTD; 9990; -.
DR MGI; MGI:2135960; Slc12a6.
DR VEuPathDB; HostDB:ENSMUSG00000027130; -.
DR eggNOG; KOG2082; Eukaryota.
DR GeneTree; ENSGT00940000160238; -.
DR HOGENOM; CLU_001883_1_2_1; -.
DR InParanoid; Q924N4; -.
DR OMA; KNWRPHI; -.
DR PhylomeDB; Q924N4; -.
DR TreeFam; TF313657; -.
DR Reactome; R-MMU-426117; Cation-coupled Chloride cotransporters.
DR BioGRID-ORCS; 107723; 3 hits in 72 CRISPR screens.
DR ChiTaRS; Slc12a6; mouse.
DR PRO; PR:Q924N4; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; Q924N4; protein.
DR Bgee; ENSMUSG00000027130; Expressed in granulocyte and 239 other tissues.
DR ExpressionAtlas; Q924N4; baseline and differential.
DR Genevisible; Q924N4; MM.
DR GO; GO:0030424; C:axon; IDA:MGI.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IEA:InterPro.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0045202; C:synapse; IEA:GOC.
DR GO; GO:0008519; F:ammonium transmembrane transporter activity; ISO:MGI.
DR GO; GO:0015079; F:potassium ion transmembrane transporter activity; ISO:MGI.
DR GO; GO:0015379; F:potassium:chloride symporter activity; ISS:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; IPI:ARUK-UCL.
DR GO; GO:0140157; P:ammonium import across plasma membrane; ISO:MGI.
DR GO; GO:0006884; P:cell volume homeostasis; IBA:GO_Central.
DR GO; GO:0071476; P:cellular hypotonic response; ISO:MGI.
DR GO; GO:0071477; P:cellular hypotonic salinity response; ISS:UniProtKB.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IDA:MGI.
DR GO; GO:0007268; P:chemical synaptic transmission; IBA:GO_Central.
DR GO; GO:0055064; P:chloride ion homeostasis; IBA:GO_Central.
DR GO; GO:1902476; P:chloride transmembrane transport; IBA:GO_Central.
DR GO; GO:0006811; P:ion transport; ISO:MGI.
DR GO; GO:0055075; P:potassium ion homeostasis; IBA:GO_Central.
DR GO; GO:1990573; P:potassium ion import across plasma membrane; ISO:MGI.
DR InterPro; IPR004841; AA-permease/SLC12A_dom.
DR InterPro; IPR030364; KCC3.
DR InterPro; IPR000076; KCL_cotranspt.
DR InterPro; IPR018491; SLC12_C.
DR InterPro; IPR004842; SLC12A_fam.
DR PANTHER; PTHR11827; PTHR11827; 1.
DR PANTHER; PTHR11827:SF66; PTHR11827:SF66; 1.
DR Pfam; PF00324; AA_permease; 2.
DR Pfam; PF03522; SLC12; 2.
DR PRINTS; PR01081; KCLTRNSPORT.
DR TIGRFAMs; TIGR00930; 2a30; 1.
PE 1: Evidence at protein level;
KW Alternative promoter usage; Cell membrane; Chloride;
KW Direct protein sequencing; Glycoprotein; Ion transport; Membrane;
KW Phosphoprotein; Potassium; Potassium transport; Reference proteome;
KW Symport; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..1150
FT /note="Solute carrier family 12 member 6"
FT /id="PRO_0000178038"
FT TOPO_DOM 1..185
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 186..206
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 208..228
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 229..235
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 236..256
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 277..297
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 298..319
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 320..340
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 343..363
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 364..480
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 481..501
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 518..538
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 539..558
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 559..579
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 632..652
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 653..689
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 690..710
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 789..809
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 810..1150
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 1..108
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 161..181
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 30..102
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 163..177
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 32
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UHW9"
FT MOD_RES 120
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UHW9"
FT MOD_RES 148
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UHW9"
FT MOD_RES 1032
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UHW9"
FT CARBOHYD 504
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 1..51
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11246162"
FT /id="VSP_006117"
FT VAR_SEQ 52..90
FT /note="PETSRSEPMSELSGATTSLATVALDPSSDRTSNPQDVTE -> MPHFTVTKV
FT EDPEEGAAGPLSPEPSSAEVKARIQDPQEP (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11246162"
FT /id="VSP_006118"
FT CONFLICT 914
FT /note="W -> R (in Ref. 1; AAK81895/AAK81896)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1150 AA; 127527 MW; 74287FECDBC473BC CRC64;
MHPPEATTKM SSVRFMVTPT KIDDIPGLSD TSPDLSSRSS SRVRFSSRES VPETSRSEPM
SELSGATTSL ATVALDPSSD RTSNPQDVTE DPSQNSITGE HSQLLDDGHK KARNAYLNNS
NYEEGDEYFD KNLALFEEEM DTRPKVSSLL NRMANYTNLT QGAKEHEEAE NITEGKKKPT
KSPQMGTFMG VYLPCLQNIF GVILFLRLTW VVGTAGILQA FAIVLICCCC TMLTAISMSA
IATNGVVPAG GSYFMISRAL GPEFGGAVGL CFYLGTTFAA AMYILGAIEI FLVYIVPRAA
IFRSDDALKE SAAMLNNMRV YGTAFLVLMV LVVFIGVRYV NKFASLFLAC VIVSILAIYA
GAIKSSFAPP HFPVCMLGNR TLSSRHLDIC SKTKEVDNMT VPSKLWGFFC NSSQFFNATC
DEYFVHNNVI SIQGIPGLAS GIITENLWSN YLPKGEIIEK PSAKSSDVLG NLNHEYVLAD
ITTSFTLLVG IFFPSVTGIM AGSNRSGDLK DAQKSIPIGT ILAILTTSFV YLSNVVLFGA
CIEGVVLRDK FGDAVKGNLV VGTLSWPSPW VIVIGSFFST CGAGLQSLTG APRLLQAIAK
DNIIPFLRVF GHSKANGEPT WALLLTAAIA ELGILIASLD LVAPILSMFF LMCYLFVNLA
CALQTLLRTP NWRPRFRYYH WALSFMGMSI CLALMFISSW YYAIVAMVIA GMIYKYIEYQ
GAEKEWGDGI RGLSLSAARF ALLRLEEGPP HTKNWRPQLL VLLKLDEDLH VKHPRLLTFA
SQLKAGKGLT IVGSVIVGNF LENYGDALAA EQTIKHLMEA EKVKGFCQLV VAAKLKEGIS
HLIQSCGLGG MKHNTVVMGW PNGWRQSEDA RAWKTFIGTV RVTTAAHLAL LVAKNVSFFP
SNVEQFSEGN IDVWWIVHDG GMLMLLPFLL KQHKVWRKCS IRIFTVAQLE DNSIQMKKDL
ATFLYHLRIE AEVEVVEMHD SDISAYTYER TLMMEQRSQM LRHMRLSKTE RDREAQLVKD
RNSMLRLTSI GSDEDEETET YQEKVHMTWT KDKYMASRGQ KVKSMEGFQD LLNMRPDQSN
VRRMHTAVKL NEVIVNKSHE AKLVLLNMPG PPRNPEGDEN YMEFLEVLTE GLERVLLVRG
GGSEVITIYS
