S12A1_MOUSE
ID S12A1_MOUSE Reviewed; 1095 AA.
AC P55014; O35938; Q91W55; Q9Z1E0;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 13-DEC-2002, sequence version 2.
DT 25-MAY-2022, entry version 170.
DE RecName: Full=Solute carrier family 12 member 1;
DE AltName: Full=BSC1;
DE AltName: Full=Bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2;
DE AltName: Full=Kidney-specific Na-K-Cl symporter;
GN Name=Slc12a1; Synonyms=Nkcc2;
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 A; B AND F), AND TISSUE SPECIFICITY
RP (ISOFORMS A; B AND F).
RC TISSUE=Kidney;
RX PubMed=7573490; DOI=10.1152/ajprenal.1995.269.3.f405;
RA Igarashi P., Vanden Heuvel G.B., Payne J.A., Forbush B. III;
RT "Cloning, embryonic expression, and alternative splicing of a murine
RT kidney-specific Na-K-Cl cotransporter.";
RL Am. J. Physiol. 269:F405-F418(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A4 AND F).
RC STRAIN=CD-1;
RX PubMed=10070158; DOI=10.1152/ajprenal.1999.276.3.f347;
RA Mount D.B., Baekgaard A., Hall A.E., Plata C., Xu J., Beier D.R., Gamba G.,
RA Hebert S.C.;
RT "Isoforms of the Na-K-2Cl cotransporter in murine TAL I. Molecular
RT characterization and intrarenal localization.";
RL Am. J. Physiol. 276:F347-F358(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A).
RC TISSUE=Kidney;
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 [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-57; THR-96 AND THR-101, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Kidney;
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).
RN [5]
RP TISSUE SPECIFICITY.
RX PubMed=20385770; DOI=10.1128/mcb.01560-09;
RA Reiche J., Theilig F., Rafiqi F.H., Carlo A.S., Militz D., Mutig K.,
RA Todiras M., Christensen E.I., Ellison D.H., Bader M., Nykjaer A.,
RA Bachmann S., Alessi D., Willnow T.E.;
RT "SORLA/SORL1 functionally interacts with SPAK to control renal activation
RT of Na(+)-K(+)-Cl(-) cotransporter 2.";
RL Mol. Cell. Biol. 30:3027-3037(2010).
RN [6]
RP FUNCTION, AND PHOSPHORYLATION AT THR-96 AND THR-101.
RX PubMed=25967121; DOI=10.1681/asn.2014070728;
RA Borschewski A., Himmerkus N., Boldt C., Blankenstein K.I., McCormick J.A.,
RA Lazelle R., Willnow T.E., Jankowski V., Plain A., Bleich M., Ellison D.H.,
RA Bachmann S., Mutig K.;
RT "Calcineurin and sorting-related receptor with A-type repeats interact to
RT regulate the renal Na(+)-K(+)-2Cl(-) cotransporter.";
RL J. Am. Soc. Nephrol. 27:107-119(2016).
RN [7]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=29993276; DOI=10.1152/ajprenal.00539.2017;
RA Frische S., Chambrey R., Trepiccione F., Zamani R., Marcussen N.,
RA Alexander R.T., Skjoedt K., Svenningsen P., Dimke H.;
RT "H+-ATPase B1 subunit localizes to thick ascending limb and distal
RT convoluted tubule of rodent and human kidney.";
RL Am. J. Physiol. 315:F429-F444(2018).
CC -!- FUNCTION: Renal sodium, potassium and chloride ion cotransporter that
CC mediates the transepithelial NaCl reabsorption in the thick ascending
CC limb and plays an essential role in the urinary concentration and
CC volume regulation. Electrically silent transporter system.
CC {ECO:0000305|PubMed:25967121}.
CC -!- ACTIVITY REGULATION: Activated by WNK3. {ECO:0000250}.
CC -!- SUBUNIT: When phosphorylated, interacts with PPP3CB.
CC {ECO:0000250|UniProtKB:P55016}.
CC -!- SUBCELLULAR LOCATION: Apical cell membrane
CC {ECO:0000269|PubMed:29993276}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=A;
CC IsoId=P55014-1; Sequence=Displayed;
CC Name=A4;
CC IsoId=P55014-2; Sequence=VSP_006101, VSP_006102;
CC Name=B;
CC IsoId=P55014-3; Sequence=VSP_006099;
CC Name=F; Synonyms=C9;
CC IsoId=P55014-4; Sequence=VSP_006100;
CC -!- TISSUE SPECIFICITY: Predominantly expressed in kidney (at protein
CC level). {ECO:0000269|PubMed:20385770, ECO:0000269|PubMed:29993276}.
CC -!- TISSUE SPECIFICITY: [Isoform F]: Kidney-specific; most highly expressed
CC in the inner stripe of outer medulla (at protein level).
CC {ECO:0000269|PubMed:7573490}.
CC -!- TISSUE SPECIFICITY: [Isoform A]: Kidney-specific; most highly expressed
CC in the outer stripe of outer medulla (at protein level).
CC {ECO:0000269|PubMed:7573490}.
CC -!- TISSUE SPECIFICITY: [Isoform B]: Kidney-specific; most highly expressed
CC in the cortical thick ascending limb (at protein level).
CC {ECO:0000269|PubMed:7573490}.
CC -!- PTM: Short-term cyclosporine administration increases SLC12A1
CC phosphorylation in kidney thick ascending limb, possibly through the
CC inhibition of PPP3CB/calcineurin A beta phosphatase.
CC {ECO:0000269|PubMed:25967121}.
CC -!- SIMILARITY: Belongs to the SLC12A transporter family. {ECO:0000305}.
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DR EMBL; U20973; AAC52632.1; -; mRNA.
DR EMBL; U20974; AAB03495.1; -; mRNA.
DR EMBL; U20975; AAC52633.1; -; mRNA.
DR EMBL; U94518; AAB65150.1; -; mRNA.
DR EMBL; U61381; AAD00091.1; -; mRNA.
DR EMBL; BC016888; AAH16888.1; -; mRNA.
DR PIR; I49268; I49268.
DR PIR; I49269; I49269.
DR PIR; I49270; I49270.
DR RefSeq; NP_001073158.1; NM_001079690.1.
DR RefSeq; NP_899197.2; NM_183354.2.
DR AlphaFoldDB; P55014; -.
DR SMR; P55014; -.
DR BioGRID; 203276; 2.
DR ELM; P55014; -.
DR IntAct; P55014; 1.
DR STRING; 10090.ENSMUSP00000106120; -.
DR GlyGen; P55014; 2 sites.
DR iPTMnet; P55014; -.
DR PhosphoSitePlus; P55014; -.
DR jPOST; P55014; -.
DR MaxQB; P55014; -.
DR PaxDb; P55014; -.
DR PeptideAtlas; P55014; -.
DR PRIDE; P55014; -.
DR ProteomicsDB; 253333; -. [P55014-1]
DR ProteomicsDB; 253334; -. [P55014-2]
DR ProteomicsDB; 253335; -. [P55014-3]
DR ProteomicsDB; 253336; -. [P55014-4]
DR DNASU; 20495; -.
DR GeneID; 20495; -.
DR KEGG; mmu:20495; -.
DR UCSC; uc008mcg.1; mouse. [P55014-1]
DR UCSC; uc008mch.1; mouse. [P55014-4]
DR UCSC; uc008mci.1; mouse. [P55014-2]
DR CTD; 6557; -.
DR MGI; MGI:103150; Slc12a1.
DR eggNOG; KOG2083; Eukaryota.
DR InParanoid; P55014; -.
DR OrthoDB; 254933at2759; -.
DR PhylomeDB; P55014; -.
DR Reactome; R-MMU-426117; Cation-coupled Chloride cotransporters.
DR BioGRID-ORCS; 20495; 1 hit in 72 CRISPR screens.
DR ChiTaRS; Slc12a1; mouse.
DR PRO; PR:P55014; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; P55014; protein.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0009986; C:cell surface; ISO:MGI.
DR GO; GO:0070062; C:extracellular exosome; ISO:MGI.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0015379; F:potassium:chloride symporter activity; IBA:GO_Central.
DR GO; GO:0008511; F:sodium:potassium:chloride symporter activity; ISO:MGI.
DR GO; GO:0006884; P:cell volume homeostasis; 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:0006821; P:chloride transport; ISO:MGI.
DR GO; GO:0034220; P:ion transmembrane transport; ISO:MGI.
DR GO; GO:0001822; P:kidney development; IMP:MGI.
DR GO; GO:0055075; P:potassium ion homeostasis; IBA:GO_Central.
DR GO; GO:1990573; P:potassium ion import across plasma membrane; IBA:GO_Central.
DR GO; GO:0006813; P:potassium ion transport; ISO:MGI.
DR GO; GO:0032978; P:protein insertion into membrane from inner side; ISO:MGI.
DR GO; GO:0055078; P:sodium ion homeostasis; IBA:GO_Central.
DR GO; GO:0035725; P:sodium ion transmembrane transport; IBA:GO_Central.
DR GO; GO:0006814; P:sodium ion transport; ISO:MGI.
DR GO; GO:0071918; P:urea transmembrane transport; IMP:MGI.
DR InterPro; IPR004841; AA-permease/SLC12A_dom.
DR InterPro; IPR013612; AA_permease_N.
DR InterPro; IPR018491; SLC12_C.
DR InterPro; IPR002445; Slc12a1.
DR InterPro; IPR002443; SLC12A1/SLC12A2.
DR InterPro; IPR004842; SLC12A_fam.
DR PANTHER; PTHR11827; PTHR11827; 1.
DR Pfam; PF00324; AA_permease; 1.
DR Pfam; PF08403; AA_permease_N; 1.
DR Pfam; PF03522; SLC12; 1.
DR PRINTS; PR01207; NAKCLTRNSPRT.
DR PRINTS; PR01209; NAKCLTRSPRT2.
DR TIGRFAMs; TIGR00930; 2a30; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Chloride; Glycoprotein; Ion transport;
KW Membrane; Phosphoprotein; Potassium; Potassium transport;
KW Reference proteome; Sodium; Sodium transport; Symport; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..1095
FT /note="Solute carrier family 12 member 1"
FT /id="PRO_0000178019"
FT TOPO_DOM 1..173
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 174..194
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 198..218
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 219..255
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 256..276
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 299..319
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 320..323
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 324..344
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 376..396
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 397..413
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 414..434
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 481..501
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 502..546
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 547..567
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 568..588
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 589..605
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 606..626
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 789..809
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 810..1095
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 29..49
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 57
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 96
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:25967121,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 101
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:25967121,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 114
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P55016"
FT MOD_RES 116
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P55016"
FT MOD_RES 126
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000250|UniProtKB:P55016"
FT MOD_RES 144
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P55016"
FT CARBOHYD 442
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 452
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 210..234
FT /note="LIILLSTMVTSITGLSTSAIATNGF -> IIIGLAVTVTAITGLSTSAIATN
FT GY (in isoform B)"
FT /evidence="ECO:0000303|PubMed:7573490"
FT /id="VSP_006099"
FT VAR_SEQ 210..234
FT /note="LIILLSTMVTSITGLSTSAIATNGF -> IIIGLSVVVTTLTGISMSAICTN
FT GV (in isoform F)"
FT /evidence="ECO:0000303|PubMed:10070158,
FT ECO:0000303|PubMed:7573490"
FT /id="VSP_006100"
FT VAR_SEQ 715..1059
FT /note="Missing (in isoform A4)"
FT /evidence="ECO:0000303|PubMed:10070158"
FT /id="VSP_006101"
FT VAR_SEQ 1060..1095
FT /note="SISDLLYMAWLEILTKNLPPVLLVRGNHKNVLTFYS -> VRATSSGSSAFS
FT LCSQWVMLGGTEDTHGNRKEKKRLGQEFTSLKKQTNKQCNRGCK (in isoform
FT A4)"
FT /evidence="ECO:0000303|PubMed:10070158"
FT /id="VSP_006102"
FT CONFLICT 30
FT /note="A -> S (in Ref. 1; AAC52632/AAB03495/AAC52633)"
FT /evidence="ECO:0000305"
FT CONFLICT 48
FT /note="D -> G (in Ref. 1; AAC52632/AAB03495/AAC52633)"
FT /evidence="ECO:0000305"
FT CONFLICT 599
FT /note="I -> T (in Ref. 1; AAC52632/AAB03495/AAC52633)"
FT /evidence="ECO:0000305"
FT CONFLICT 773
FT /note="L -> P (in Ref. 1; AAC52632/AAB03495/AAC52633)"
FT /evidence="ECO:0000305"
FT CONFLICT 873
FT /note="D -> G (in Ref. 2; AAB65150)"
FT /evidence="ECO:0000305"
FT CONFLICT 946
FT /note="T -> N (in Ref. 2; AAB65150 and 3; AAH16888)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1095 AA; 120355 MW; E3E134016ECCE3B0 CRC64;
MSVSIPSNSV PSSASRFQVH VINEGHGSAA AVGDSADPPH YEETSFGDEA QNRLRISFRP
GNQECYDNFL QTGETAKTDT TFHAYDSHTN TYYLQTFGHN TMDAVPKIEY YRNTGSVSGP
KVNRPSLLEI HEQLAKNVTV APGSADRVAN GDGMPGDEQA ENKEEDMTGV VKFGWVKGVL
VRCMLNIWGV MLFIRLSWIV GEAGIGLGVL IILLSTMVTS ITGLSTSAIA TNGFVRGGGA
YYLISRSLGP EFGGSIGLIF AFANAVAVAM YVVGFAETVV DLLKESDSMM VDPTNDIRII
GSITVVILLG ISVAGMEWEA KAQVILLVIL LIAIANFFIG TVIPSNNEKK SRGFFNYQAS
IFAENFGPSF TKGEGFFSVF AIFFPAATGI LAGANISGDL EDPQDAIPRG TMLAIFITTV
AYIGVAICVA ACVVRDATGS MNDTIVSGMN CNGSAACGLG YDFSRCQHEP CQYGLMNNFQ
VMSMVSGFGP LITAGIFSAT LSSALASLVS APKVFQALCK DNIFKGLQFF AKGYGKNNEP
LRGYFLTFVI AMAFILIAEL NVIAPIISNF FLASYALINF SCFHASYAKS PGWRPAYGIY
NMWVSLFGAI LCCAVMFVIN WWAAVITYVI ELFLYIYVTY KKPDVNWGSS TQALSYVSAL
DNALELTTVE DHVKNFRPQC IVLTGGPMTR PALLDITHAF TKNSGLCICC EVFVGPRKLC
VKEMNSGMAK KQAWLIKNKI KAFYAAVAAD CFRDGVRSLL QASGLGRMKP NTLVIGYKKN
WRKAPLSELE NYVGIIHDAF DFEIGVVIVR ISQGFDISPV LQVQDELEKL EQERLALEAA
IKDNECEEGK GGIRGLFKKA GKLNITKPAP KKDGNISSIQ SMHVGEFNQK LVEASAQFKK
KQGKGTIDVW WLFDDGGLTL LIPYILTLRK KWKDCKLRIY VGGKITRIEE EKISMASLLS
KFRIKFADIH IIGDINIKPN KESWKVFEEM IEPYRLHESH KDLTTAEKLK RESPWKITDA
ELEAVKEKSY RQVRLNELLQ EHSRAANLIV LSLPVARKGS ISDLLYMAWL EILTKNLPPV
LLVRGNHKNV LTFYS
