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Protein

Solute carrier family 12 member 3

Gene

Slc12a3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Electroneutral sodium and chloride ion cotransporter. In kidney distal convoluted tubules, key mediator of sodium and chloride reabsorption (By similarity). Receptor for the proinflammatory cytokine IL18. Contributes to IL18-induced cytokine production, including IFNG, IL6, IL18 and CCL2. May act either independently of IL18R1, or in a complex with IL18R1 (PubMed:26099046).By similarity1 Publication

Enzyme regulationi

Activated by WNK3.By similarity

GO - Molecular functioni

  • sodium:chloride symporter activity Source: Ensembl
  • transporter activity Source: UniProtKB

GO - Biological processi

  • sodium ion transport Source: UniProtKB
Complete GO annotation...

Keywords - Biological processi

Ion transport, Sodium transport, Symport, Transport

Keywords - Ligandi

Sodium

Enzyme and pathway databases

ReactomeiR-MMU-426117. Cation-coupled Chloride cotransporters.

Names & Taxonomyi

Protein namesi
Recommended name:
Solute carrier family 12 member 3
Alternative name(s):
Na-Cl symporter
Thiazide-sensitive sodium-chloride cotransporter
Gene namesi
Name:Slc12a3
Synonyms:Ncc, Tsc
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 8

Organism-specific databases

MGIiMGI:108114. Slc12a3.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 133133CytoplasmicSequence analysisAdd
BLAST
Transmembranei134 – 15421HelicalSequence analysisAdd
BLAST
Transmembranei165 – 18521HelicalSequence analysisAdd
BLAST
Topological domaini186 – 21631CytoplasmicSequence analysisAdd
BLAST
Transmembranei217 – 23721HelicalSequence analysisAdd
BLAST
Transmembranei260 – 28021HelicalSequence analysisAdd
BLAST
Topological domaini281 – 2844CytoplasmicSequence analysis
Transmembranei285 – 30521HelicalSequence analysisAdd
BLAST
Transmembranei338 – 35821HelicalSequence analysisAdd
BLAST
Topological domaini359 – 37517CytoplasmicSequence analysisAdd
BLAST
Transmembranei376 – 39621HelicalSequence analysisAdd
BLAST
Transmembranei451 – 47121HelicalSequence analysisAdd
BLAST
Topological domaini472 – 50938CytoplasmicSequence analysisAdd
BLAST
Transmembranei510 – 53021HelicalSequence analysisAdd
BLAST
Transmembranei576 – 59621HelicalSequence analysisAdd
BLAST
Topological domaini597 – 65862CytoplasmicSequence analysisAdd
BLAST
Transmembranei659 – 67921HelicalSequence analysisAdd
BLAST
Transmembranei811 – 83121HelicalSequence analysisAdd
BLAST
Topological domaini832 – 1002171CytoplasmicSequence analysisAdd
BLAST

GO - Cellular componenti

  • apical plasma membrane Source: UniProtKB
  • cytosol Source: UniProtKB
  • extracellular exosome Source: MGI
  • integral component of membrane Source: UniProtKB-KW
  • plasma membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Disruption phenotypei

Simultaneous knockout of APOE and SLC12A3 results lower plasma Mg2+ compared to plasma levels in wild-type and APOE knockout animals. Simultaneous knockdown of APOE and SLC12A3 shows no significant differences in aortic root atherosclerotic lesion intima area and thoracic-abdominal aorta lipid deposition as compared to APOE and double APOE and IL18R1 knockout animals. In contrast, simultaneous knockdown of APOE, SLC12A3 and IL18R1 results in significantly smaller aortic root intimal size and decreased thoracic-abdominal aorta lipid deposition. The triple knockout mice exhibit lower plasma K+ and Mg2+ compared to plasma levels in wild-type animals. The effect on atherosclerosis is due to IL18 activation of bone marrow-derived leukocytes, and possibly vascular cells, rather than to kidney tubular disorders or electrolyte disturbances.1 Publication

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi53 – 531T → A: Substantial reduction in MAPK1/3 (ERK1/2) phosphorylation in response to IL18, with or without IL12. 1 Publication
Mutagenesisi58 – 581T → A: No effect on MAPK1/3 (ERK1/2) phosphorylation in response to IL18, with or without IL12. Substantial reduction in MAPK1/3 (ERK1/2) phosphorylation in response to IL18, with or without IL12; when associated with A-53 and A-71. 1 Publication
Mutagenesisi71 – 711S → A: No effect on MAPK1/3 (ERK1/2) phosphorylation in response to IL18, with or without IL12. Substantial reduction in MAPK1/3 (ERK1/2) phosphorylation in response to IL18, with or without IL12; when associated with A-53 and A-58. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 10021002Solute carrier family 12 member 3PRO_0000178027Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei41 – 411PhosphoserineCombined sources
Modified residuei47 – 471PhosphoserineCombined sources
Modified residuei48 – 481PhosphothreonineCombined sources
Modified residuei53 – 531PhosphothreonineCombined sources
Modified residuei58 – 581PhosphothreonineCombined sources
Modified residuei71 – 711PhosphoserineCombined sources
Modified residuei89 – 891PhosphoserineBy similarity
Modified residuei122 – 1221PhosphothreonineCombined sources
Modified residuei124 – 1241PhosphoserineCombined sources
Glycosylationi404 – 4041N-linked (GlcNAc...)Sequence analysis
Glycosylationi424 – 4241N-linked (GlcNAc...)Sequence analysis
Glycosylationi542 – 5421N-linked (GlcNAc...)Sequence analysis
Glycosylationi779 – 7791N-linked (GlcNAc...)Sequence analysis

Post-translational modificationi

Ubiquitinated; ubiquitination is essential for regulation of endocytosis.1 Publication
Phosphorylated in response to IL18.1 Publication

Keywords - PTMi

Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiP59158.
PeptideAtlasiP59158.
PRIDEiP59158.

PTM databases

iPTMnetiP59158.
PhosphoSiteiP59158.

Expressioni

Tissue specificityi

Expressed predominantly in kidney, including in distal tubules (at protein level). Detected at low levels in heart, lung and liver. Not detected in normal aorta, but abundantly expressed in fatty streaks and advanced atherosclerotic lesions. In atherosclerotic lesions, expressed in macrophages, smooth muscle cells and endothelial cells (at protein level).1 Publication

Inductioni

In macrophages and T-lymphocytes, up-regulated by IL18. In endothelial cells and smooth muscle cells, up-regulated by IL1B, IL18 and TNF (at protein level).1 Publication

Gene expression databases

BgeeiENSMUSG00000031766.
CleanExiMM_SLC12A3.
ExpressionAtlasiP59158. baseline and differential.
GenevisibleiP59158. MM.

Interactioni

Subunit structurei

Interacts with KLHL3 (By similarity). Interacts with IL18R1 in peritoneal macrophages; this interaction is increased by IL18 treatment (PubMed:26099046).By similarity1 Publication

Protein-protein interaction databases

BioGridi203278. 2 interactions.
IntActiP59158. 1 interaction.
MINTiMINT-4133700.
STRINGi10090.ENSMUSP00000034218.

Structurei

3D structure databases

ProteinModelPortaliP59158.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the SLC12A transporter family.Curated

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2083. Eukaryota.
COG0531. LUCA.
HOGENOMiHOG000062855.
HOVERGENiHBG052851.
InParanoidiP59158.
KOiK14426.
OMAiNKEATAN.
OrthoDBiEOG091G04G2.
PhylomeDBiP59158.
TreeFamiTF313191.

Family and domain databases

InterProiIPR004841. AA-permease/SLC12A_dom.
IPR013612. AA_permease_N.
IPR018491. SLC12_C.
IPR002948. SLC12A3.
IPR004842. SLC12A_fam.
[Graphical view]
PANTHERiPTHR11827:SF9. PTHR11827:SF9. 2 hits.
PfamiPF00324. AA_permease. 1 hit.
PF08403. AA_permease_N. 1 hit.
PF03522. SLC12. 2 hits.
[Graphical view]
PRINTSiPR01230. NACLTRNSPORT.
TIGRFAMsiTIGR00930. 2a30. 1 hit.

Sequencei

Sequence statusi: Complete.

P59158-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAELPVTELP GDALCSGRFT ISTLMGGDEP PPAACDSSQP SHLTHGSTLY
60 70 80 90 100
MRTFGYNTID VVPAYEHYAN SALPGEPRKV RPTLADLHSF LKQEGSHLHA
110 120 130 140 150
LAFDGRQGRE LTDGLVEDET GTNSEKSPGE PVRFGWVKGV MIRCMLNIWG
160 170 180 190 200
VILYLRLPWI TAQAGIVLTW LIILLSVMVT SITGLSISAI STNGKVKSGG
210 220 230 240 250
TYFLISRSLG PELGGSIGLI FAFANAVGVA MHTVGFAETV RDLLQEYGTP
260 270 280 290 300
IVDPINDIRI IGVVTVTVLL AISLAGMEWE SKAQVLFFLV IMVSFANYLV
310 320 330 340 350
GTLIPASEDK ASKGFYSYHG DIFVQNLVPD WRGIDGSFFG MFSIFFPSAT
360 370 380 390 400
GILAGANISG DLKDPAVAIP KGTLMAIFWT TISYLAISAT IGSCVVRDAS
410 420 430 440 450
GDVNDTMTPG PGPCEGLACG YGWNFTECSQ QRSCRYGLIN YYQTMSMVSA
460 470 480 490 500
FAPLITAGIF GATLSSALAC LVSAAKVFQC LCEDQLYPLI GFFGKGYGKN
510 520 530 540 550
REPVRGYLLA YAIAVAFIII AELNTIAPII SNFFLCSYAL INFSCFHASI
560 570 580 590 600
TNSPGWRPSF RYYSKWAALF GAVISVVIMF LLTWWAALIA IGVVLFLLLY
610 620 630 640 650
VIYKKPEVNW GSSVQAGSYN LALSYSVGLN EVEDHIKNYR PQCLVLTGPP
660 670 680 690 700
NFRPALVDFV STFTQNLSLM ICGHVLIGPG KQRVPELRLI ASGHTKWLNK
710 720 730 740 750
RKIKAFYSDV IAEDLRSGVQ ILMQASGLGR MKPNILVVGF KRNWQSAHPA
760 770 780 790 800
TVEDYIGVLH DAFDFNYGVC VMRMREGLNV SEALQTHTTP EALIQEEQAS
810 820 830 840 850
TIFQSEQGKK TIDIYWLFDD GGLTLLIPYL LHRKKRWGKC KIRVFVGGQI
860 870 880 890 900
NRMDEERKAI ISLLSKFRLG FHEVHVLPDI NQKPQAEHTK RFEDMIAPFR
910 920 930 940 950
LNDGFKDEAT VTEMRRDCPW KISDEEINKN RIKSLRQVRL SEILLDYSRD
960 970 980 990 1000
AALIILTLPI GRKGKCPSSL YMAWLETLSQ DLRPPVLLIR GNQENVLTFY

CQ
Length:1,002
Mass (Da):110,694
Last modified:December 13, 2002 - v1
Checksum:i61CB02500C9093B9
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC038612 mRNA. Translation: AAH38612.1.
CCDSiCCDS57632.1.
RefSeqiNP_001192240.1. NM_001205311.1.
UniGeneiMm.25804.

Genome annotation databases

EnsembliENSMUST00000034218; ENSMUSP00000034218; ENSMUSG00000031766.
GeneIDi20497.
KEGGimmu:20497.
UCSCiuc009mwc.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC038612 mRNA. Translation: AAH38612.1.
CCDSiCCDS57632.1.
RefSeqiNP_001192240.1. NM_001205311.1.
UniGeneiMm.25804.

3D structure databases

ProteinModelPortaliP59158.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi203278. 2 interactions.
IntActiP59158. 1 interaction.
MINTiMINT-4133700.
STRINGi10090.ENSMUSP00000034218.

PTM databases

iPTMnetiP59158.
PhosphoSiteiP59158.

Proteomic databases

PaxDbiP59158.
PeptideAtlasiP59158.
PRIDEiP59158.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000034218; ENSMUSP00000034218; ENSMUSG00000031766.
GeneIDi20497.
KEGGimmu:20497.
UCSCiuc009mwc.2. mouse.

Organism-specific databases

CTDi6559.
MGIiMGI:108114. Slc12a3.

Phylogenomic databases

eggNOGiKOG2083. Eukaryota.
COG0531. LUCA.
HOGENOMiHOG000062855.
HOVERGENiHBG052851.
InParanoidiP59158.
KOiK14426.
OMAiNKEATAN.
OrthoDBiEOG091G04G2.
PhylomeDBiP59158.
TreeFamiTF313191.

Enzyme and pathway databases

ReactomeiR-MMU-426117. Cation-coupled Chloride cotransporters.

Miscellaneous databases

ChiTaRSiSlc12a3. mouse.
PROiP59158.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000031766.
CleanExiMM_SLC12A3.
ExpressionAtlasiP59158. baseline and differential.
GenevisibleiP59158. MM.

Family and domain databases

InterProiIPR004841. AA-permease/SLC12A_dom.
IPR013612. AA_permease_N.
IPR018491. SLC12_C.
IPR002948. SLC12A3.
IPR004842. SLC12A_fam.
[Graphical view]
PANTHERiPTHR11827:SF9. PTHR11827:SF9. 2 hits.
PfamiPF00324. AA_permease. 1 hit.
PF08403. AA_permease_N. 1 hit.
PF03522. SLC12. 2 hits.
[Graphical view]
PRINTSiPR01230. NACLTRNSPORT.
TIGRFAMsiTIGR00930. 2a30. 1 hit.
ProtoNetiSearch...

Entry informationi

Entry nameiS12A3_MOUSE
AccessioniPrimary (citable) accession number: P59158
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 13, 2002
Last sequence update: December 13, 2002
Last modified: September 7, 2016
This is version 111 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.