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Protein

Solute carrier family 12 member 1

Gene

SLC12A1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Electrically silent transporter system. Mediates sodium and chloride reabsorption. Plays a vital role in the regulation of ionic balance and cell volume.

Enzyme regulationi

Activated by WNK3.1 Publication

GO - Molecular functioni

  • sodium:potassium:chloride symporter activity Source: ProtInc

GO - Biological processi

  • chemical homeostasis Source: Ensembl
  • chloride transmembrane transport Source: GOC
  • chloride transport Source: GOC
  • excretion Source: Ensembl
  • ion transmembrane transport Source: BHF-UCL
  • ion transport Source: Reactome
  • kidney development Source: Ensembl
  • potassium ion transport Source: UniProtKB-KW
  • sodium ion transport Source: UniProtKB-KW
  • transmembrane transport Source: Reactome
  • transport Source: ProtInc
Complete GO annotation...

Keywords - Biological processi

Ion transport, Potassium transport, Sodium transport, Symport, Transport

Keywords - Ligandi

Potassium, Sodium

Enzyme and pathway databases

ReactomeiREACT_19315. Cation-coupled Chloride cotransporters.

Protein family/group databases

TCDBi2.A.30.1.2. the cation-chloride cotransporter (ccc) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Solute carrier family 12 member 1
Alternative name(s):
Bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2
Kidney-specific Na-K-Cl symporter
Gene namesi
Name:SLC12A1
Synonyms:NKCC2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componenti: Chromosome 15

Organism-specific databases

HGNCiHGNC:10910. SLC12A1.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 177177CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei178 – 19821HelicalSequence AnalysisAdd
BLAST
Transmembranei202 – 22221HelicalSequence AnalysisAdd
BLAST
Topological domaini223 – 25937CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei260 – 28021HelicalSequence AnalysisAdd
BLAST
Transmembranei303 – 32321HelicalSequence AnalysisAdd
BLAST
Topological domaini324 – 3274CytoplasmicSequence Analysis
Transmembranei328 – 34821HelicalSequence AnalysisAdd
BLAST
Transmembranei380 – 40021HelicalSequence AnalysisAdd
BLAST
Topological domaini401 – 41717CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei418 – 43821HelicalSequence AnalysisAdd
BLAST
Transmembranei485 – 50521HelicalSequence AnalysisAdd
BLAST
Topological domaini506 – 55045CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei551 – 57121HelicalSequence AnalysisAdd
BLAST
Transmembranei572 – 59221HelicalSequence AnalysisAdd
BLAST
Topological domaini593 – 60917CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei610 – 63021HelicalSequence AnalysisAdd
BLAST
Transmembranei793 – 81321HelicalSequence AnalysisAdd
BLAST
Topological domaini814 – 1099286CytoplasmicSequence AnalysisAdd
BLAST

GO - Cellular componenti

  • apical plasma membrane Source: Ensembl
  • extracellular exosome Source: UniProtKB
  • integral component of membrane Source: UniProtKB-KW
  • membrane Source: ProtInc
  • plasma membrane Source: Reactome
Complete GO annotation...

Keywords - Cellular componenti

Membrane

Pathology & Biotechi

Involvement in diseasei

Bartter syndrome 1 (BS1)1 Publication

The disease is caused by mutations affecting the gene represented in this entry.

Disease descriptionAn autosomal recessive disorder characterized by impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and varying degrees of hypercalciuria. Bartter syndrome type 1 is a life-threatening condition beginning in utero, with marked fetal polyuria that leads to polyhydramnios and premature delivery. Another hallmark is a marked hypercalciuria and, as a secondary consequence, the development of nephrocalcinosis and osteopenia.

See also OMIM:601678
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti272 – 2721V → F in BS1. 1 Publication
VAR_010223
Natural varianti648 – 6481D → N in BS1. 1 Publication
VAR_010224

Keywords - Diseasei

Bartter syndrome, Disease mutation, Neurodegeneration

Organism-specific databases

MIMi601678. phenotype.
Orphaneti93604. Antenatal Bartter syndrome.
PharmGKBiPA320.

Chemistry

DrugBankiDB00887. Bumetanide.
DB00534. Chlormerodrin.
DB00310. Chlorthalidone.
DB00903. Ethacrynic acid.
DB00695. Furosemide.
DB00774. Hydroflumethiazide.
DB00232. Methyclothiazide.
DB00761. Potassium Chloride.
DB01325. Quinethazone.
DB00214. Torasemide.
DB01021. Trichlormethiazide.

Polymorphism and mutation databases

BioMutaiSLC12A1.
DMDMi212276464.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 10991099Solute carrier family 12 member 1PRO_0000178018Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei130 – 1301Phosphoserine; by AMPKBy similarity
Glycosylationi446 – 4461N-linked (GlcNAc...)Sequence Analysis
Glycosylationi456 – 4561N-linked (GlcNAc...)Sequence Analysis

Keywords - PTMi

Glycoprotein, Phosphoprotein

Proteomic databases

PaxDbiQ13621.
PRIDEiQ13621.

PTM databases

PhosphoSiteiQ13621.

Expressioni

Tissue specificityi

Kidney specific.

Gene expression databases

BgeeiQ13621.
CleanExiHS_SLC12A1.
ExpressionAtlasiQ13621. baseline and differential.
GenevisibleiQ13621. HS.

Organism-specific databases

HPAiHPA014967.
HPA018107.

Interactioni

Protein-protein interaction databases

IntActiQ13621. 3 interactions.
STRINGi9606.ENSP00000370381.

Structurei

3D structure databases

ProteinModelPortaliQ13621.
SMRiQ13621. Positions 239-585.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the SLC12A transporter family.Curated

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiCOG0531.
GeneTreeiENSGT00760000119053.
HOGENOMiHOG000062855.
HOVERGENiHBG052851.
InParanoidiQ13621.
KOiK14425.
OMAiADDNTDP.
PhylomeDBiQ13621.
TreeFamiTF313191.

Family and domain databases

InterProiIPR004841. AA-permease/SLC12A_dom.
IPR013612. AA_permease_N.
IPR002443. Na/K/Cl_cotranspt.
IPR004842. Na/K/Cl_cotransptS.
IPR002445. Slc12a1.
[Graphical view]
PANTHERiPTHR11827:SF45. PTHR11827:SF45. 1 hit.
PfamiPF00324. AA_permease. 1 hit.
PF08403. AA_permease_N. 1 hit.
[Graphical view]
PRINTSiPR01207. NAKCLTRNSPRT.
PR01209. NAKCLTRSPRT2.
TIGRFAMsiTIGR00930. 2a30. 1 hit.

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform A (identifier: Q13621-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MSLNNSSNVF LDSVPSNTNR FQVSVINENH ESSAAADDNT DPPHYEETSF
60 70 80 90 100
GDEAQKRLRI SFRPGNQECY DNFLQSGETA KTDASFHAYD SHTNTYYLQT
110 120 130 140 150
FGHNTMDAVP KIEYYRNTGS ISGPKVNRPS LLEIHEQLAK NVAVTPSSAD
160 170 180 190 200
RVANGDGIPG DEQAENKEDD QAGVVKFGWV KGVLVRCMLN IWGVMLFIRL
210 220 230 240 250
SWIVGEAGIG LGVLIILLST MVTSITGLST SAIATNGFVR GGGAYYLISR
260 270 280 290 300
SLGPEFGGSI GLIFAFANAV AVAMYVVGFA ETVVDLLKES DSMMVDPTND
310 320 330 340 350
IRIIGSITVV ILLGISVAGM EWEAKAQVIL LVILLIAIAN FFIGTVIPSN
360 370 380 390 400
NEKKSRGFFN YQASIFAENF GPRFTKGEGF FSVFAIFFPA ATGILAGANI
410 420 430 440 450
SGDLEDPQDA IPRGTMLAIF ITTVAYLGVA ICVGACVVRD ATGNMNDTII
460 470 480 490 500
SGMNCNGSAA CGLGYDFSRC RHEPCQYGLM NNFQVMSMVS GFGPLITAGI
510 520 530 540 550
FSATLSSALA SLVSAPKVFQ ALCKDNIYKA LQFFAKGYGK NNEPLRGYIL
560 570 580 590 600
TFLIAMAFIL IAELNTIAPI ISNFFLASYA LINFSCFHAS YAKSPGWRPA
610 620 630 640 650
YGIYNMWVSL FGAVLCCAVM FVINWWAAVI TYVIEFFLYV YVTCKKPDVN
660 670 680 690 700
WGSSTQALSY VSALDNALEL TTVEDHVKNF RPQCIVLTGG PMTRPALLDI
710 720 730 740 750
THAFTKNSGL CICCEVFVGP RKLCVKEMNS GMAKKQAWLI KNKIKAFYAA
760 770 780 790 800
VAADCFRDGV RSLLQASGLG RMKPNTLVIG YKKNWRKAPL TEIENYVGII
810 820 830 840 850
HDAFDFEIGV VIVRISQGFD ISQVLQVQEE LERLEQERLA LEATIKDNEC
860 870 880 890 900
EEESGGIRGL FKKAGKLNIT KTTPKKDGSI NTSQSMHVGE FNQKLVEAST
910 920 930 940 950
QFKKKQEKGT IDVWWLFDDG GLTLLIPYIL TLRKKWKDCK LRIYVGGKIN
960 970 980 990 1000
RIEEEKIVMA SLLSKFRIKF ADIHIIGDIN IRPNKESWKV FEEMIEPYRL
1010 1020 1030 1040 1050
HESCKDLTTA EKLKRETPWK ITDAELEAVK EKSYRQVRLN ELLQEHSRAA
1060 1070 1080 1090
NLIVLSLPVA RKGSISDLLY MAWLEILTKN LPPVLLVRGN HKNVLTFYS
Length:1,099
Mass (Da):121,450
Last modified:November 4, 2008 - v2
Checksum:iC1C868B7F8B563AC
GO
Isoform B (identifier: Q13621-2)

Sequence is not available
Length:
Mass (Da):
Isoform F (identifier: Q13621-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     214-238: LIILLSTMVTSITGLSTSAIATNGF → IIIGLSVVVTTLTGISMSAICTNGV

Show »
Length:1,099
Mass (Da):121,388
Checksum:i6C8CF44143E5D074
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti75 – 751Q → H in AAB07364 (PubMed:8640224).Curated
Isoform F (identifier: Q13621-3)
Sequence conflicti220 – 2212VV → TI in AAB07364 (PubMed:8640224).
Sequence conflicti225 – 2251L → I in AAB07364 (PubMed:8640224).
Sequence conflicti228 – 2281I → M in AAB07364 (PubMed:8640224).
Sequence conflicti230 – 2301M → T in AAB07364 (PubMed:8640224).
Sequence conflicti234 – 2341C → A in AAB07364 (PubMed:8640224).

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti272 – 2721V → F in BS1. 1 Publication
VAR_010223
Natural varianti648 – 6481D → N in BS1. 1 Publication
VAR_010224
Natural varianti958 – 9581V → A.2 Publications
Corresponds to variant rs1552311 [ dbSNP | Ensembl ].
VAR_047257

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei214 – 23825LIILL…ATNGF → IIIGLSVVVTTLTGISMSAI CTNGV in isoform F. 1 PublicationVSP_035701Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U58130 mRNA. Translation: AAB07364.1.
EF559316 mRNA. Translation: ABU69043.2.
AC023355 Genomic DNA. No translation available.
AC066612 Genomic DNA. No translation available.
CCDSiCCDS10129.2. [Q13621-1]
CCDS53940.1. [Q13621-3]
RefSeqiNP_000329.2. NM_000338.2. [Q13621-1]
NP_001171761.1. NM_001184832.1. [Q13621-3]
UniGeneiHs.123116.
Hs.605373.

Genome annotation databases

EnsembliENST00000380993; ENSP00000370381; ENSG00000074803. [Q13621-1]
ENST00000396577; ENSP00000379822; ENSG00000074803. [Q13621-3]
ENST00000558405; ENSP00000453409; ENSG00000074803. [Q13621-1]
GeneIDi6557.
KEGGihsa:6557.
UCSCiuc001zwn.4. human. [Q13621-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U58130 mRNA. Translation: AAB07364.1.
EF559316 mRNA. Translation: ABU69043.2.
AC023355 Genomic DNA. No translation available.
AC066612 Genomic DNA. No translation available.
CCDSiCCDS10129.2. [Q13621-1]
CCDS53940.1. [Q13621-3]
RefSeqiNP_000329.2. NM_000338.2. [Q13621-1]
NP_001171761.1. NM_001184832.1. [Q13621-3]
UniGeneiHs.123116.
Hs.605373.

3D structure databases

ProteinModelPortaliQ13621.
SMRiQ13621. Positions 239-585.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ13621. 3 interactions.
STRINGi9606.ENSP00000370381.

Chemistry

ChEMBLiCHEMBL1874.
DrugBankiDB00887. Bumetanide.
DB00534. Chlormerodrin.
DB00310. Chlorthalidone.
DB00903. Ethacrynic acid.
DB00695. Furosemide.
DB00774. Hydroflumethiazide.
DB00232. Methyclothiazide.
DB00761. Potassium Chloride.
DB01325. Quinethazone.
DB00214. Torasemide.
DB01021. Trichlormethiazide.
GuidetoPHARMACOLOGYi968.

Protein family/group databases

TCDBi2.A.30.1.2. the cation-chloride cotransporter (ccc) family.

PTM databases

PhosphoSiteiQ13621.

Polymorphism and mutation databases

BioMutaiSLC12A1.
DMDMi212276464.

Proteomic databases

PaxDbiQ13621.
PRIDEiQ13621.

Protocols and materials databases

DNASUi6557.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000380993; ENSP00000370381; ENSG00000074803. [Q13621-1]
ENST00000396577; ENSP00000379822; ENSG00000074803. [Q13621-3]
ENST00000558405; ENSP00000453409; ENSG00000074803. [Q13621-1]
GeneIDi6557.
KEGGihsa:6557.
UCSCiuc001zwn.4. human. [Q13621-1]

Organism-specific databases

CTDi6557.
GeneCardsiGC15P048498.
H-InvDBHIX0026769.
HGNCiHGNC:10910. SLC12A1.
HPAiHPA014967.
HPA018107.
MIMi600839. gene.
601678. phenotype.
neXtProtiNX_Q13621.
Orphaneti93604. Antenatal Bartter syndrome.
PharmGKBiPA320.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiCOG0531.
GeneTreeiENSGT00760000119053.
HOGENOMiHOG000062855.
HOVERGENiHBG052851.
InParanoidiQ13621.
KOiK14425.
OMAiADDNTDP.
PhylomeDBiQ13621.
TreeFamiTF313191.

Enzyme and pathway databases

ReactomeiREACT_19315. Cation-coupled Chloride cotransporters.

Miscellaneous databases

ChiTaRSiSLC12A1. human.
GenomeRNAii6557.
NextBioi25515.
PROiQ13621.
SOURCEiSearch...

Gene expression databases

BgeeiQ13621.
CleanExiHS_SLC12A1.
ExpressionAtlasiQ13621. baseline and differential.
GenevisibleiQ13621. HS.

Family and domain databases

InterProiIPR004841. AA-permease/SLC12A_dom.
IPR013612. AA_permease_N.
IPR002443. Na/K/Cl_cotranspt.
IPR004842. Na/K/Cl_cotransptS.
IPR002445. Slc12a1.
[Graphical view]
PANTHERiPTHR11827:SF45. PTHR11827:SF45. 1 hit.
PfamiPF00324. AA_permease. 1 hit.
PF08403. AA_permease_N. 1 hit.
[Graphical view]
PRINTSiPR01207. NAKCLTRNSPRT.
PR01209. NAKCLTRSPRT2.
TIGRFAMsiTIGR00930. 2a30. 1 hit.
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Bartter's syndrome, hypokalemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2."
    Simon D.B., Karet F.E., Hamdan J.M., Di Pietro A., Sanjad S.A., Lifton R.P.
    Nat. Genet. 13:183-188(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM F), VARIANTS BS1 PHE-272 AND ASN-648, VARIANT ALA-958, ALTERNATIVE SPLICING.
  2. "Molecular cloning and characterization of NKCC2A in non-renal tissues."
    Di Fulvio M., Garzon-Muvdi T., Alvarez-Leefmans F.J.
    Submitted (NOV-2007) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A), VARIANT ALA-958.
    Tissue: Spinal ganglion.
  3. "Analysis of the DNA sequence and duplication history of human chromosome 15."
    Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K., Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N., Abouelleil A.
    , Arachchi H.M., Baradarani L., Birditt B., Bloom S., Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K., DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.
    Nature 440:671-675(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  4. Cited for: ENZYME REGULATION.

Entry informationi

Entry nameiS12A1_HUMAN
AccessioniPrimary (citable) accession number: Q13621
Secondary accession number(s): A8JYA2, E9PDW4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 11, 2001
Last sequence update: November 4, 2008
Last modified: June 24, 2015
This is version 143 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 15
    Human chromosome 15: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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 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.