Q13621 (S12A1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	SLC12A1
Synonyms:	NKCC2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1099 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Electrically silent transporter system. Mediates sodium and chloride reabsorption. Plays a vital role in the regulation of ionic balance and cell volume.
Enzyme regulation	Activated by WNK3. Ref.4
Subcellular location	Membrane; Multi-pass membrane protein.
Tissue specificity	Kidney specific.
Involvement in disease	Bartter syndrome 1 (BS1) [MIM:601678]: An 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. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1
Sequence similarities	Belongs to the SLC12A transporter family.

Ontologies

Keywords
Biological process	Ion transport Potassium transport Sodium transport Symport Transport
Cellular component	Membrane
Coding sequence diversity	Alternative splicing
Disease	Bartter syndrome Disease mutation
Domain	Transmembrane Transmembrane helix
Ligand	Potassium Sodium
PTM	Glycoprotein Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	potassium ion transport Inferred from electronic annotation. Source: UniProtKB-KW sodium ion transport Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW plasma membrane Traceable author statement. Source: Reactome
Molecular_function	sodium:potassium:chloride symporter activity Traceable author statement Ref.1. Source: ProtInc
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform A (identifier: Q13621-1)

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.

Isoform B (identifier: Q13621-2)

The sequence of this isoform is not available.

Isoform F (identifier: Q13621-3)

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

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1099	1099	Solute carrier family 12 member 1		PRO_0000178018
Regions
	Topological domain	1 – 177	177	Cytoplasmic Potential
	Transmembrane	178 – 198	21	Helical; Potential
	Transmembrane	202 – 222	21	Helical; Potential
	Topological domain	223 – 259	37	Cytoplasmic Potential
	Transmembrane	260 – 280	21	Helical; Potential
	Transmembrane	303 – 323	21	Helical; Potential
	Topological domain	324 – 327	4	Cytoplasmic Potential
	Transmembrane	328 – 348	21	Helical; Potential
	Transmembrane	380 – 400	21	Helical; Potential
	Topological domain	401 – 417	17	Cytoplasmic Potential
	Transmembrane	418 – 438	21	Helical; Potential
	Transmembrane	485 – 505	21	Helical; Potential
	Topological domain	506 – 550	45	Cytoplasmic Potential
	Transmembrane	551 – 571	21	Helical; Potential
	Transmembrane	572 – 592	21	Helical; Potential
	Topological domain	593 – 609	17	Cytoplasmic Potential
	Transmembrane	610 – 630	21	Helical; Potential
	Transmembrane	793 – 813	21	Helical; Potential
	Topological domain	814 – 1099	286	Cytoplasmic Potential
Amino acid modifications
	Modified residue	130	1	Phosphoserine; by AMPK By similarity
	Glycosylation	446	1	N-linked (GlcNAc...) Potential
	Glycosylation	456	1	N-linked (GlcNAc...) Potential
Natural variations
	Alternative sequence	214 – 238	25	LIILL…ATNGF → IIIGLSTIVTTITGMSTSAI ATNGV in isoform F.		VSP_035701
	Natural variant	272	1	V → F in BS1. Ref.1		VAR_010223
	Natural variant	648	1	D → N in BS1. Ref.1		VAR_010224
	Natural variant	958	1	V → A. Ref.1 Ref.2 Corresponds to variant rs1552311 [ dbSNP | Ensembl ].		VAR_047257
Experimental info
	Sequence conflict	75	1	Q → H in AAB07364. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform A [UniParc]. Last modified November 4, 2008. Version 2. Checksum: C1C868B7F8B563AC	FASTA	1,099	121,450
	10 20 30 40 50 60 MSLNNSSNVF LDSVPSNTNR FQVSVINENH ESSAAADDNT DPPHYEETSF GDEAQKRLRI 70 80 90 100 110 120 SFRPGNQECY DNFLQSGETA KTDASFHAYD SHTNTYYLQT FGHNTMDAVP KIEYYRNTGS 130 140 150 160 170 180 ISGPKVNRPS LLEIHEQLAK NVAVTPSSAD RVANGDGIPG DEQAENKEDD QAGVVKFGWV 190 200 210 220 230 240 KGVLVRCMLN IWGVMLFIRL SWIVGEAGIG LGVLIILLST MVTSITGLST SAIATNGFVR 250 260 270 280 290 300 GGGAYYLISR SLGPEFGGSI GLIFAFANAV AVAMYVVGFA ETVVDLLKES DSMMVDPTND 310 320 330 340 350 360 IRIIGSITVV ILLGISVAGM EWEAKAQVIL LVILLIAIAN FFIGTVIPSN NEKKSRGFFN 370 380 390 400 410 420 YQASIFAENF GPRFTKGEGF FSVFAIFFPA ATGILAGANI SGDLEDPQDA IPRGTMLAIF 430 440 450 460 470 480 ITTVAYLGVA ICVGACVVRD ATGNMNDTII SGMNCNGSAA CGLGYDFSRC RHEPCQYGLM 490 500 510 520 530 540 NNFQVMSMVS GFGPLITAGI FSATLSSALA SLVSAPKVFQ ALCKDNIYKA LQFFAKGYGK 550 560 570 580 590 600 NNEPLRGYIL TFLIAMAFIL IAELNTIAPI ISNFFLASYA LINFSCFHAS YAKSPGWRPA 610 620 630 640 650 660 YGIYNMWVSL FGAVLCCAVM FVINWWAAVI TYVIEFFLYV YVTCKKPDVN WGSSTQALSY 670 680 690 700 710 720 VSALDNALEL TTVEDHVKNF RPQCIVLTGG PMTRPALLDI THAFTKNSGL CICCEVFVGP 730 740 750 760 770 780 RKLCVKEMNS GMAKKQAWLI KNKIKAFYAA VAADCFRDGV RSLLQASGLG RMKPNTLVIG 790 800 810 820 830 840 YKKNWRKAPL TEIENYVGII HDAFDFEIGV VIVRISQGFD ISQVLQVQEE LERLEQERLA 850 860 870 880 890 900 LEATIKDNEC EEESGGIRGL FKKAGKLNIT KTTPKKDGSI NTSQSMHVGE FNQKLVEAST 910 920 930 940 950 960 QFKKKQEKGT IDVWWLFDDG GLTLLIPYIL TLRKKWKDCK LRIYVGGKIN RIEEEKIVMA 970 980 990 1000 1010 1020 SLLSKFRIKF ADIHIIGDIN IRPNKESWKV FEEMIEPYRL HESCKDLTTA EKLKRETPWK 1030 1040 1050 1060 1070 1080 ITDAELEAVK EKSYRQVRLN ELLQEHSRAA NLIVLSLPVA RKGSISDLLY MAWLEILTKN 1090 LPPVLLVRGN HKNVLTFYS
	Isoform B (Sequence not available).		–	–
	Isoform F [UniParc]. Checksum: 268149350AA5955E	FASTA	1,099	121,360
	10 20 30 40 50 60 MSLNNSSNVF LDSVPSNTNR FQVSVINENH ESSAAADDNT DPPHYEETSF GDEAQKRLRI 70 80 90 100 110 120 SFRPGNQECY DNFLQSGETA KTDASFHAYD SHTNTYYLQT FGHNTMDAVP KIEYYRNTGS 130 140 150 160 170 180 ISGPKVNRPS LLEIHEQLAK NVAVTPSSAD RVANGDGIPG DEQAENKEDD QAGVVKFGWV 190 200 210 220 230 240 KGVLVRCMLN IWGVMLFIRL SWIVGEAGIG LGVIIIGLST IVTTITGMST SAIATNGVVR 250 260 270 280 290 300 GGGAYYLISR SLGPEFGGSI GLIFAFANAV AVAMYVVGFA ETVVDLLKES DSMMVDPTND 310 320 330 340 350 360 IRIIGSITVV ILLGISVAGM EWEAKAQVIL LVILLIAIAN FFIGTVIPSN NEKKSRGFFN 370 380 390 400 410 420 YQASIFAENF GPRFTKGEGF FSVFAIFFPA ATGILAGANI SGDLEDPQDA IPRGTMLAIF 430 440 450 460 470 480 ITTVAYLGVA ICVGACVVRD ATGNMNDTII SGMNCNGSAA CGLGYDFSRC RHEPCQYGLM 490 500 510 520 530 540 NNFQVMSMVS GFGPLITAGI FSATLSSALA SLVSAPKVFQ ALCKDNIYKA LQFFAKGYGK 550 560 570 580 590 600 NNEPLRGYIL TFLIAMAFIL IAELNTIAPI ISNFFLASYA LINFSCFHAS YAKSPGWRPA 610 620 630 640 650 660 YGIYNMWVSL FGAVLCCAVM FVINWWAAVI TYVIEFFLYV YVTCKKPDVN WGSSTQALSY 670 680 690 700 710 720 VSALDNALEL TTVEDHVKNF RPQCIVLTGG PMTRPALLDI THAFTKNSGL CICCEVFVGP 730 740 750 760 770 780 RKLCVKEMNS GMAKKQAWLI KNKIKAFYAA VAADCFRDGV RSLLQASGLG RMKPNTLVIG 790 800 810 820 830 840 YKKNWRKAPL TEIENYVGII HDAFDFEIGV VIVRISQGFD ISQVLQVQEE LERLEQERLA 850 860 870 880 890 900 LEATIKDNEC EEESGGIRGL FKKAGKLNIT KTTPKKDGSI NTSQSMHVGE FNQKLVEAST 910 920 930 940 950 960 QFKKKQEKGT IDVWWLFDDG GLTLLIPYIL TLRKKWKDCK LRIYVGGKIN RIEEEKIVMA 970 980 990 1000 1010 1020 SLLSKFRIKF ADIHIIGDIN IRPNKESWKV FEEMIEPYRL HESCKDLTTA EKLKRETPWK 1030 1040 1050 1060 1070 1080 ITDAELEAVK EKSYRQVRLN ELLQEHSRAA NLIVLSLPVA RKGSISDLLY MAWLEILTKN 1090 LPPVLLVRGN HKNVLTFYS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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]	"Similar Effects of all WNK3 Variants upon SLC12 Cotransporters." Cruz-Rangel S., Melo Z., Vazquez N., Meade P., Bobadilla N.A., Pasantes-Morales H., Gamba G., Mercado A. Am. J. Physiol. 301:C601-C608(2011) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U58130 mRNA. Translation: AAB07364.1. EF559316 mRNA. Translation: ABU69043.2. AC023355 Genomic DNA. No translation available. AC066612 Genomic DNA. No translation available.
IPI	IPI00443898. IPI00914893.
RefSeq	NP_000329.2. NM_000338.2. NP_001171761.1. NM_001184832.1.
UniGene	Hs.123116.
3D structure databases
ProteinModelPortal	Q13621.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q13621. 3 interactions.
STRING	9606.ENSP00000370381.
PTM databases
PhosphoSite	Q13621.
Polymorphism databases
DMDM	212276464.
Proteomic databases
PaxDb	Q13621.
PRIDE	Q13621.
Protocols and materials databases
DNASU	6557.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000380993; ENSP00000370381; ENSG00000074803. ENST00000558405; ENSP00000453409; ENSG00000074803.
GeneID	6557.
KEGG	hsa:6557.
UCSC	uc001zwn.4. human.
Organism-specific databases
CTD	6557.
GeneCards	GC15P048498.
H-InvDB	HIX0026769.
HGNC	HGNC:10910. SLC12A1.
HPA	HPA014967. HPA018107.
MIM	600839. gene. 601678. phenotype.
neXtProt	NX_Q13621.
Orphanet	93604. Antenatal Bartter syndrome.
PharmGKB	PA320.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0531.
HOGENOM	HOG000062855.
HOVERGEN	HBG052851.
InParanoid	Q13621.
KO	K14425.
Enzyme and pathway databases
Reactome	REACT_15518. Transmembrane transport of small molecules.
Gene expression databases
ArrayExpress	Q13621.
Bgee	Q13621.
CleanEx	HS_SLC12A1.
Genevestigator	Q13621.
GermOnline	ENSG00000074803. Homo sapiens.
Family and domain databases
InterPro	IPR004841. AA-permease_dom. IPR013612. AA_permease_N. IPR002443. Na/K/Cl_cotranspt. IPR002445. Na/K/Cl_cotranspt2. IPR004842. Na/K/Cl_cotransptS. [Graphical view]
Pfam	PF00324. AA_permease. 1 hit. PF08403. AA_permease_N. 1 hit. [Graphical view]
PRINTS	PR01207. NAKCLTRNSPRT. PR01209. NAKCLTRSPRT2.
TIGRFAMs	TIGR00930. 2a30. 1 hit.
ProtoNet	Search...
Other
ChEMBL	CHEMBL1874.
ChiTaRS	SLC12A1. human.
DrugBank	DB00887. Bumetanide. DB00534. Chlormerodrin. DB00310. Chlorthalidone. DB00903. Ethacrynic acid. DB00695. Furosemide. DB00774. Hydroflumethiazide. DB00232. Methyclothiazide. DB00524. Metolazone. DB00761. Potassium Chloride. DB00214. Torasemide. DB01021. Trichlormethiazide.
GenomeRNAi	6557.
NextBio	25515.
SOURCE	Search...

Entry information

Entry name

S12A1_HUMAN

Accession

Primary (citable) accession number: Q13621
Secondary accession number(s): A8JYA2

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 11, 2001
Last sequence update:	November 4, 2008
Last modified:	May 1, 2013
This is version 123 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.