S12A3_MOUSE
ID S12A3_MOUSE Reviewed; 1002 AA.
AC P59158;
DT 13-DEC-2002, integrated into UniProtKB/Swiss-Prot.
DT 13-DEC-2002, sequence version 1.
DT 03-AUG-2022, entry version 142.
DE RecName: Full=Solute carrier family 12 member 3;
DE AltName: Full=Na-Cl symporter;
DE AltName: Full=Thiazide-sensitive sodium-chloride cotransporter;
GN Name=Slc12a3; Synonyms=Ncc, Tsc;
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 [LARGE SCALE MRNA].
RC STRAIN=FVB/N; 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 [2]
RP UBIQUITINATION.
RX PubMed=20392800; DOI=10.1152/ajprenal.00441.2009;
RA Ko B., Kamsteeg E.J., Cooke L.L., Moddes L.N., Deen P.M., Hoover R.S.;
RT "RasGRP1 stimulation enhances ubiquitination and endocytosis of the sodium-
RT chloride cotransporter.";
RL Am. J. Physiol. 299:F300-F309(2010).
RN [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-41; SER-47; THR-48; THR-53;
RP THR-58; SER-71; THR-122 AND SER-124, AND IDENTIFICATION BY MASS
RP 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 [4]
RP FUNCTION, INTERACTION WITH IL18R1, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, INDUCTION BY IL1B; IL18 AND TNF, DISRUPTION PHENOTYPE,
RP PHOSPHORYLATION, AND MUTAGENESIS OF THR-53; THR-58 AND SER-71.
RX PubMed=26099046; DOI=10.1038/nm.3890;
RA Wang J., Sun C., Gerdes N., Liu C., Liao M., Liu J., Shi M.A., He A.,
RA Zhou Y., Sukhova G.K., Chen H., Cheng X.W., Kuzuya M., Murohara T.,
RA Zhang J., Cheng X., Jiang M., Shull G.E., Rogers S., Yang C.L., Ke Q.,
RA Jelen S., Bindels R., Ellison D.H., Jarolim P., Libby P., Shi G.P.;
RT "Interleukin 18 function in atherosclerosis is mediated by the interleukin
RT 18 receptor and the Na-Cl co-transporter.";
RL Nat. Med. 21:820-826(2015).
RN [5]
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: Electroneutral sodium and chloride ion cotransporter. In
CC kidney distal convoluted tubules, key mediator of sodium and chloride
CC reabsorption (By similarity). Receptor for the pro-inflammatory
CC cytokine IL18. Contributes to IL18-induced cytokine production,
CC including IFNG, IL6, IL18 and CCL2. May act either independently of
CC IL18R1, or in a complex with IL18R1 (PubMed:26099046).
CC {ECO:0000250|UniProtKB:P55017, ECO:0000269|PubMed:26099046}.
CC -!- ACTIVITY REGULATION: Activated by WNK3. {ECO:0000250|UniProtKB:P55017}.
CC -!- SUBUNIT: Interacts with KLHL3 (By similarity). Interacts with IL18R1 in
CC peritoneal macrophages; this interaction is increased by IL18 treatment
CC (PubMed:26099046). {ECO:0000250|UniProtKB:P55017,
CC ECO:0000269|PubMed:26099046}.
CC -!- INTERACTION:
CC P59158; Q61098: Il18r1; NbExp=5; IntAct=EBI-8366645, EBI-13612516;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:26099046};
CC Multi-pass membrane protein {ECO:0000255}. Apical cell membrane
CC {ECO:0000269|PubMed:29993276}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Expressed predominantly in kidney, including in
CC distal tubules (at protein level). Detected at low levels in heart,
CC lung and liver. Not detected in normal aorta, but abundantly expressed
CC in fatty streaks and advanced atherosclerotic lesions. In
CC atherosclerotic lesions, expressed in macrophages, smooth muscle cells
CC and endothelial cells (at protein level). {ECO:0000269|PubMed:26099046,
CC ECO:0000269|PubMed:29993276}.
CC -!- INDUCTION: In macrophages and T-lymphocytes, up-regulated by IL18. In
CC endothelial cells and smooth muscle cells, up-regulated by IL1B, IL18
CC and TNF (at protein level). {ECO:0000269|PubMed:26099046}.
CC -!- PTM: Ubiquitinated; ubiquitination is essential for regulation of
CC endocytosis. {ECO:0000269|PubMed:20392800}.
CC -!- PTM: Phosphorylated in response to IL18. {ECO:0000269|PubMed:26099046}.
CC -!- DISRUPTION PHENOTYPE: Simultaneous knockout of APOE and SLC12A3 results
CC lower plasma Mg(2+) compared to plasma levels in wild-type and APOE
CC knockout animals. Simultaneous knockdown of APOE and SLC12A3 shows no
CC significant differences in aortic root atherosclerotic lesion intima
CC area and thoracic-abdominal aorta lipid deposition as compared to APOE
CC and double APOE and IL18R1 knockout animals. In contrast, simultaneous
CC knockdown of APOE, SLC12A3 and IL18R1 results in significantly smaller
CC aortic root intimal size and decreased thoracic-abdominal aorta lipid
CC deposition. The triple knockout mice exhibit lower plasma K(+) and
CC Mg(2+) compared to plasma levels in wild-type animals. The effect on
CC atherosclerosis is due to IL18 activation of bone marrow-derived
CC leukocytes, and possibly vascular cells, rather than to kidney tubular
CC disorders or electrolyte disturbances. {ECO:0000269|PubMed:26099046}.
CC -!- SIMILARITY: Belongs to the SLC12A transporter family. {ECO:0000305}.
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DR EMBL; BC038612; AAH38612.1; -; mRNA.
DR CCDS; CCDS57632.1; -.
DR RefSeq; NP_001192240.1; NM_001205311.1.
DR AlphaFoldDB; P59158; -.
DR SMR; P59158; -.
DR BioGRID; 203278; 2.
DR IntAct; P59158; 1.
DR STRING; 10090.ENSMUSP00000034218; -.
DR GlyGen; P59158; 4 sites.
DR iPTMnet; P59158; -.
DR PhosphoSitePlus; P59158; -.
DR jPOST; P59158; -.
DR PaxDb; P59158; -.
DR PeptideAtlas; P59158; -.
DR PRIDE; P59158; -.
DR ProteomicsDB; 253338; -.
DR Antibodypedia; 28680; 259 antibodies from 22 providers.
DR DNASU; 20497; -.
DR Ensembl; ENSMUST00000034218; ENSMUSP00000034218; ENSMUSG00000031766.
DR GeneID; 20497; -.
DR KEGG; mmu:20497; -.
DR UCSC; uc009mwc.2; mouse.
DR CTD; 6559; -.
DR MGI; MGI:108114; Slc12a3.
DR VEuPathDB; HostDB:ENSMUSG00000031766; -.
DR eggNOG; KOG2083; Eukaryota.
DR GeneTree; ENSGT00940000155044; -.
DR HOGENOM; CLU_001883_0_0_1; -.
DR InParanoid; P59158; -.
DR OMA; WNFTDCA; -.
DR OrthoDB; 254933at2759; -.
DR PhylomeDB; P59158; -.
DR TreeFam; TF313191; -.
DR Reactome; R-MMU-426117; Cation-coupled Chloride cotransporters.
DR BioGRID-ORCS; 20497; 2 hits in 73 CRISPR screens.
DR ChiTaRS; Slc12a3; mouse.
DR PRO; PR:P59158; -.
DR Proteomes; UP000000589; Chromosome 8.
DR RNAct; P59158; protein.
DR Bgee; ENSMUSG00000031766; Expressed in right kidney and 30 other tissues.
DR ExpressionAtlas; P59158; baseline and differential.
DR Genevisible; P59158; MM.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
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; IDA:UniProtKB.
DR GO; GO:0031982; C:vesicle; ISO:MGI.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR GO; GO:0015379; F:potassium:chloride symporter activity; IBA:GO_Central.
DR GO; GO:0015081; F:sodium ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0015378; F:sodium:chloride symporter activity; ISO:MGI.
DR GO; GO:0008511; F:sodium:potassium:chloride symporter activity; IBA:GO_Central.
DR GO; GO:0006884; P:cell volume homeostasis; IBA:GO_Central.
DR GO; GO:0071241; P:cellular response to inorganic substance; IDA:MGI.
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: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:0006468; P:protein phosphorylation; IDA:MGI.
DR GO; GO:1904044; P:response to aldosterone; IDA:MGI.
DR GO; GO:0002021; P:response to dietary excess; IDA:MGI.
DR GO; GO:0007165; P:signal transduction; IMP:MGI.
DR GO; GO:0055078; P:sodium ion homeostasis; IBA:GO_Central.
DR GO; GO:0035725; P:sodium ion transmembrane transport; IDA:MGI.
DR GO; GO:0006814; P:sodium ion transport; IMP:UniProtKB.
DR InterPro; IPR004841; AA-permease/SLC12A_dom.
DR InterPro; IPR013612; AA_permease_N.
DR InterPro; IPR018491; SLC12_C.
DR InterPro; IPR002948; SLC12A3.
DR InterPro; IPR004842; SLC12A_fam.
DR PANTHER; PTHR11827; PTHR11827; 1.
DR PANTHER; PTHR11827:SF9; PTHR11827:SF9; 1.
DR Pfam; PF00324; AA_permease; 1.
DR Pfam; PF08403; AA_permease_N; 1.
DR Pfam; PF03522; SLC12; 2.
DR PRINTS; PR01230; NACLTRNSPORT.
DR TIGRFAMs; TIGR00930; 2a30; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Chloride; Glycoprotein; Ion transport; Membrane;
KW Phosphoprotein; Reference proteome; Sodium; Sodium transport; Symport;
KW Transmembrane; Transmembrane helix; Transport; Ubl conjugation.
FT CHAIN 1..1002
FT /note="Solute carrier family 12 member 3"
FT /id="PRO_0000178027"
FT TOPO_DOM 1..133
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 134..154
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 165..185
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 186..216
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 217..237
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 260..280
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 281..284
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 285..305
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 338..358
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 359..375
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 376..396
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 451..471
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 472..509
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 510..530
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 576..596
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 597..658
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 659..679
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 811..831
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 832..1002
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT MOD_RES 41
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 47
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 48
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 53
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 58
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 71
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 89
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P55017"
FT MOD_RES 122
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 124
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT CARBOHYD 404
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 424
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 542
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 779
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT MUTAGEN 53
FT /note="T->A: Substantial reduction in MAPK1/3 (ERK1/2)
FT phosphorylation in response to IL18, with or without IL12."
FT /evidence="ECO:0000269|PubMed:26099046"
FT MUTAGEN 58
FT /note="T->A: No effect on MAPK1/3 (ERK1/2) phosphorylation
FT in response to IL18, with or without IL12. Substantial
FT reduction in MAPK1/3 (ERK1/2) phosphorylation in response
FT to IL18, with or without IL12; when associated with A-53
FT and A-71."
FT /evidence="ECO:0000269|PubMed:26099046"
FT MUTAGEN 71
FT /note="S->A: No effect on MAPK1/3 (ERK1/2) phosphorylation
FT in response to IL18, with or without IL12. Substantial
FT reduction in MAPK1/3 (ERK1/2) phosphorylation in response
FT to IL18, with or without IL12; when associated with A-53
FT and A-58."
FT /evidence="ECO:0000269|PubMed:26099046"
SQ SEQUENCE 1002 AA; 110694 MW; 61CB02500C9093B9 CRC64;
MAELPVTELP GDALCSGRFT ISTLMGGDEP PPAACDSSQP SHLTHGSTLY MRTFGYNTID
VVPAYEHYAN SALPGEPRKV RPTLADLHSF LKQEGSHLHA LAFDGRQGRE LTDGLVEDET
GTNSEKSPGE PVRFGWVKGV MIRCMLNIWG VILYLRLPWI TAQAGIVLTW LIILLSVMVT
SITGLSISAI STNGKVKSGG TYFLISRSLG PELGGSIGLI FAFANAVGVA MHTVGFAETV
RDLLQEYGTP IVDPINDIRI IGVVTVTVLL AISLAGMEWE SKAQVLFFLV IMVSFANYLV
GTLIPASEDK ASKGFYSYHG DIFVQNLVPD WRGIDGSFFG MFSIFFPSAT GILAGANISG
DLKDPAVAIP KGTLMAIFWT TISYLAISAT IGSCVVRDAS GDVNDTMTPG PGPCEGLACG
YGWNFTECSQ QRSCRYGLIN YYQTMSMVSA FAPLITAGIF GATLSSALAC LVSAAKVFQC
LCEDQLYPLI GFFGKGYGKN REPVRGYLLA YAIAVAFIII AELNTIAPII SNFFLCSYAL
INFSCFHASI TNSPGWRPSF RYYSKWAALF GAVISVVIMF LLTWWAALIA IGVVLFLLLY
VIYKKPEVNW GSSVQAGSYN LALSYSVGLN EVEDHIKNYR PQCLVLTGPP NFRPALVDFV
STFTQNLSLM ICGHVLIGPG KQRVPELRLI ASGHTKWLNK RKIKAFYSDV IAEDLRSGVQ
ILMQASGLGR MKPNILVVGF KRNWQSAHPA TVEDYIGVLH DAFDFNYGVC VMRMREGLNV
SEALQTHTTP EALIQEEQAS TIFQSEQGKK TIDIYWLFDD GGLTLLIPYL LHRKKRWGKC
KIRVFVGGQI NRMDEERKAI ISLLSKFRLG FHEVHVLPDI NQKPQAEHTK RFEDMIAPFR
LNDGFKDEAT VTEMRRDCPW KISDEEINKN RIKSLRQVRL SEILLDYSRD AALIILTLPI
GRKGKCPSSL YMAWLETLSQ DLRPPVLLIR GNQENVLTFY CQ
