ID S12A4_MOUSE Reviewed; 1085 AA.
AC Q9JIS8; O55069; Q9ET57;
DT 13-DEC-2002, integrated into UniProtKB/Swiss-Prot.
DT 13-DEC-2002, sequence version 2.
DT 24-JAN-2024, entry version 164.
DE RecName: Full=Solute carrier family 12 member 4;
DE AltName: Full=Electroneutral potassium-chloride cotransporter 1;
DE AltName: Full=Erythroid K-Cl cotransporter 1;
DE Short=mKCC1;
GN Name=Slc12a4; Synonyms=Kcc1;
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], TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RC STRAIN=DBA; TISSUE=Erythroleukemia;
RX PubMed=9516379; DOI=10.1006/bcmd.1998.0168;
RA Pellegrino C.M., Rybicki A.C., Musto S., Nagel R.L., Schwartz R.S.;
RT "Molecular identification and expression of erythroid K:Cl cotransporter in
RT human and mouse erythroleukemic cells.";
RL Blood Cells Mol. Dis. 24:31-40(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RC STRAIN=CD-1; TISSUE=Brain, and Spleen;
RX PubMed=10564083; DOI=10.1152/ajpcell.1999.277.5.c899;
RA Su W., Shmukler B.E., Chernova M.N., Stuart-Tilley A.K., de Franceschi L.,
RA Brugnara C., Alper S.L.;
RT "Mouse K-Cl cotransporter KCC1: cloning, mapping, pathological expression,
RT and functional regulation.";
RL Am. J. Physiol. 277:C899-C912(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=11004507; DOI=10.1016/s0167-4781(00)00118-4;
RA Shmukler B.E., Brugnara C., Alper S.L.;
RT "Structure and genetic polymorphism of the mouse KCC1 gene.";
RL Biochim. Biophys. Acta 1492:353-361(2000).
RN [4]
RP FUNCTION, TRANSPORTER ACTIVITY, AND SUBUNIT.
RX PubMed=11551954; DOI=10.1074/jbc.m107155200;
RA Casula S., Shmukler B.E., Wilhelm S., Stuart-Tilley A.K., Su W.,
RA Chernova M.N., Brugnara C., Alper S.L.;
RT "A dominant negative mutant of the KCC1 K-Cl cotransporter: both N- and C-
RT terminal cytoplasmic domains are required for K-Cl cotransport activity.";
RL J. Biol. Chem. 276:41870-41878(2001).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-47, AND IDENTIFICATION BY
RP 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 [7]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-331.
RC TISSUE=Myoblast;
RX PubMed=19656770; DOI=10.1074/mcp.m900195-mcp200;
RA Gundry R.L., Raginski K., Tarasova Y., Tchernyshyov I., Bausch-Fluck D.,
RA Elliott S.T., Boheler K.R., Van Eyk J.E., Wollscheid B.;
RT "The mouse C2C12 myoblast cell surface N-linked glycoproteome:
RT identification, glycosite occupancy, and membrane orientation.";
RL Mol. Cell. Proteomics 8:2555-2569(2009).
RN [8]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-331.
RX PubMed=19349973; DOI=10.1038/nbt.1532;
RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M.,
RA Schiess R., Aebersold R., Watts J.D.;
RT "Mass-spectrometric identification and relative quantification of N-linked
RT cell surface glycoproteins.";
RL Nat. Biotechnol. 27:378-386(2009).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-24 AND SER-967, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Spleen, and
RC Testis;
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 when
CC activated by cell swelling (PubMed:10564083, PubMed:11551954). May
CC contribute to cell volume homeostasis in single cells. May be involved
CC in the regulation of basolateral Cl(-) exit in NaCl absorbing epithelia
CC (Probable). {ECO:0000269|PubMed:10564083, ECO:0000269|PubMed:11551954,
CC ECO:0000305}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=chloride(in) + K(+)(in) = chloride(out) + K(+)(out);
CC Xref=Rhea:RHEA:72427, ChEBI:CHEBI:17996, ChEBI:CHEBI:29103;
CC Evidence={ECO:0000269|PubMed:11551954};
CC -!- ACTIVITY REGULATION: Inhibited by WNK3. {ECO:0000250|UniProtKB:Q9UP95}.
CC -!- SUBUNIT: Homodimer (By similarity). Heteromultimer with other K-Cl
CC cotransporters (PubMed:11551954). {ECO:0000250|UniProtKB:Q9UP95,
CC ECO:0000269|PubMed:11551954}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q28677};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Detected in embryo, adult heart, erythrocytes,
CC brain, kidney, stomach, ovary, testis and liver.
CC {ECO:0000269|PubMed:9516379}.
CC -!- DEVELOPMENTAL STAGE: Expression levels remained constant upon induction
CC of erythroid differentiation of embryonic stem cells (PubMed:9516379).
CC Not detected in reticulocytes, but present during differentiation of
CC erythroleukemia cells to erythroblasts (PubMed:9516379).
CC {ECO:0000269|PubMed:9516379}.
CC -!- PTM: Phosphorylated, phosphorylation may regulate transporter activity.
CC {ECO:0000250|UniProtKB:Q9UP95}.
CC -!- MISCELLANEOUS: Activated by N-ethylmaleimide (NEM). Inhibited by DIOA.
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; AF047339; AAC32816.1; -; mRNA.
DR EMBL; AF121118; AAF02444.1; -; mRNA.
DR EMBL; AF191023; AAF91094.1; -; Genomic_DNA.
DR EMBL; AH009673; AAF91090.1; -; Genomic_DNA.
DR CCDS; CCDS22623.1; -.
DR RefSeq; NP_033221.1; NM_009195.3.
DR AlphaFoldDB; Q9JIS8; -.
DR SMR; Q9JIS8; -.
DR BioGRID; 203279; 3.
DR IntAct; Q9JIS8; 5.
DR MINT; Q9JIS8; -.
DR STRING; 10090.ENSMUSP00000034370; -.
DR GlyCosmos; Q9JIS8; 4 sites, No reported glycans.
DR GlyGen; Q9JIS8; 4 sites.
DR iPTMnet; Q9JIS8; -.
DR PhosphoSitePlus; Q9JIS8; -.
DR EPD; Q9JIS8; -.
DR jPOST; Q9JIS8; -.
DR MaxQB; Q9JIS8; -.
DR PaxDb; 10090-ENSMUSP00000112130; -.
DR ProteomicsDB; 256859; -.
DR Pumba; Q9JIS8; -.
DR Antibodypedia; 29685; 199 antibodies from 31 providers.
DR DNASU; 20498; -.
DR Ensembl; ENSMUST00000116429.9; ENSMUSP00000112130.3; ENSMUSG00000017765.18.
DR GeneID; 20498; -.
DR KEGG; mmu:20498; -.
DR UCSC; uc009ner.2; mouse.
DR AGR; MGI:1309465; -.
DR CTD; 6560; -.
DR MGI; MGI:1309465; Slc12a4.
DR VEuPathDB; HostDB:ENSMUSG00000017765; -.
DR eggNOG; KOG2082; Eukaryota.
DR GeneTree; ENSGT00940000157672; -.
DR HOGENOM; CLU_001883_1_2_1; -.
DR InParanoid; Q9JIS8; -.
DR OMA; TGQDCPD; -.
DR OrthoDB; 5490251at2759; -.
DR PhylomeDB; Q9JIS8; -.
DR TreeFam; TF313657; -.
DR Reactome; R-MMU-426117; Cation-coupled Chloride cotransporters.
DR BioGRID-ORCS; 20498; 1 hit in 78 CRISPR screens.
DR ChiTaRS; Slc12a4; mouse.
DR PRO; PR:Q9JIS8; -.
DR Proteomes; UP000000589; Chromosome 8.
DR RNAct; Q9JIS8; Protein.
DR Bgee; ENSMUSG00000017765; Expressed in choroid plexus of fourth ventricle and 210 other cell types or tissues.
DR ExpressionAtlas; Q9JIS8; baseline and differential.
DR Genevisible; Q9JIS8; MM.
DR GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0045202; C:synapse; IEA:GOC.
DR GO; GO:0005524; F:ATP binding; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0015379; F:potassium:chloride symporter activity; IDA:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; ISO:MGI.
DR GO; GO:0006884; P:cell volume homeostasis; IBA:GO_Central.
DR GO; GO:0007268; P:chemical synaptic transmission; IBA:GO_Central.
DR GO; GO:0055064; P:chloride ion homeostasis; ISS:UniProtKB.
DR GO; GO:1902476; P:chloride transmembrane transport; IBA:GO_Central.
DR GO; GO:0055075; P:potassium ion homeostasis; ISS:UniProtKB.
DR GO; GO:1990573; P:potassium ion import across plasma membrane; IBA:GO_Central.
DR GO; GO:0071805; P:potassium ion transmembrane transport; IDA:UniProtKB.
DR Gene3D; 1.20.1740.10; Amino acid/polyamine transporter I; 1.
DR InterPro; IPR004841; AA-permease/SLC12A_dom.
DR InterPro; IPR000622; KCC1.
DR InterPro; IPR000076; KCL_cotranspt.
DR InterPro; IPR018491; SLC12_C.
DR InterPro; IPR004842; SLC12A_fam.
DR NCBIfam; TIGR00930; 2a30; 1.
DR PANTHER; PTHR11827:SF46; SOLUTE CARRIER FAMILY 12 MEMBER 4; 1.
DR PANTHER; PTHR11827; SOLUTE CARRIER FAMILY 12, CATION COTRANSPORTERS; 1.
DR Pfam; PF00324; AA_permease; 2.
DR Pfam; PF03522; SLC12; 2.
DR PRINTS; PR01081; KCLTRNSPORT.
DR PRINTS; PR01082; KCLTRNSPORT1.
PE 1: Evidence at protein level;
KW ATP-binding; Cell membrane; Chloride; Disulfide bond; Glycoprotein;
KW Ion transport; Membrane; Metal-binding; Nucleotide-binding; Phosphoprotein;
KW Potassium; Potassium transport; Reference proteome; Symport; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..1085
FT /note="Solute carrier family 12 member 4"
FT /id="PRO_0000178031"
FT TOPO_DOM 1..119
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TRANSMEM 120..141
FT /note="Discontinuously helical"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TOPO_DOM 142..149
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TRANSMEM 150..172
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TOPO_DOM 173..196
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TRANSMEM 197..225
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TOPO_DOM 226..248
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TRANSMEM 249..271
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TRANSMEM 272..297
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TOPO_DOM 298..419
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TRANSMEM 420..440
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TOPO_DOM 441..450
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TRANSMEM 451..473
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TOPO_DOM 474..504
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TRANSMEM 505..531
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TOPO_DOM 532..554
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TRANSMEM 555..575
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TRANSMEM 576..598
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TOPO_DOM 599..612
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TRANSMEM 613..635
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TRANSMEM 636..651
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT TOPO_DOM 652..1085
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 131
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 132
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 216
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 429
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 432
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 433
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 434
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 435
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 589
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 589
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 697
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 699
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 707
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 708
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 730
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 794
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 795
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT BINDING 797
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT MOD_RES 24
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 47
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19144319"
FT MOD_RES 81
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UHW9"
FT MOD_RES 88
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT MOD_RES 734
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT MOD_RES 967
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 983
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT MOD_RES 1050
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT CARBOHYD 312
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 331
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973,
FT ECO:0000269|PubMed:19656770"
FT CARBOHYD 347
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 308..323
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
FT DISULFID 343..353
FT /evidence="ECO:0000250|UniProtKB:Q9UP95"
SQ SEQUENCE 1085 AA; 120624 MW; 9094931060972E03 CRC64;
MPHFTVVPVD GPRRGDYDNL EGLSWVDYGE RAEREDSDGQ GNHRENSPFL CPLDASRGND
YYDRNLALFE EELDIRPKVS SLLGKLVSYT NLTQGAKEHE EAESGEGGRR RAAKAPSMGT
LMGVYLPCLQ NIFGVILFLR LTWMVGTAGV LQALLIVLIC CCCTLLTAIS MSAIATNGVV
PAGGSYFMIS RSLGPEFGGA VGLCFYLGTT FAAAMYILGA IEILLTYIAP PAAIFYPSGT
HDMSSATLNN MRVYGTIFLT LMTLVVFVGV KYVNKFASLF LACVIISILS IYAGGIKSIF
DPPVFPVCML GNRTLSRDQF DICAKTVVVD NETVATRLWT FFCHSPNLTA DSCDPYFLLN
NVTEIPGIPG AAAGVLQENL WSAYLEKGEV VEKHGLPSTD TLGLKESLSL YVVADIATSF
TVLVGIFFPS VTGIMAGSNR SGDLRDAQKS IPVGTILAIV TTSLVYFSSV ILFGACIEGV
VLRDKYGDGV SRNLVVGTLA WPSPWVIVVG SFFSTCGAGL QSLTGAPRLL QAIAKDNIIP
FLRVFGHGKA NGEPTWALLL TALIAELGIL IASLDMVAPI LSMFFLMCYL FVNLACAVQT
LLRTPNWRPR FKYYHWTLSF LGMSLCLALM FVSSWYYALV AMLIAGMIYK YIEYQGAEKE
WGDGIRGLSL SAARYALLRL EEGPPHTKNW RPQLLVLLKL DEDLHVKYPR LLTFASQLKA
GKGLTIVGSV IQGSFLESYG EAQAAEQTIK NMMDIEKVKG FCQVVVASKV REGLAHLIQS
CGLGGMRHNS VVLGWPYGWR QSEDPRAWKT FIDTVRCTTA AHLALLVPKN IAFYPSNHER
YLDGHIDVWW IVHDGGMLML LPFLLRQHKV WKKCRMRIFT VAQMDDNSIQ MKKDLAIFLY
HLRLEAEVEV VEMHNSDISA YTYERTLMME QRSQMLRQMR LTKTERDREA QLVKDRHSAL
RLESLYSDEE EESVAGADKI QMTWTRDKYM AEPWDPSHAP DNFRELVHIK PDQSNVRRMH
TAVKLNEVIV TRSHDARLVL LNMPGPPKNS EGDENYMEFL EVLTEGLERV LLVRGGGREV
ITIYS
//
