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Protein

Solute carrier family 12 member 4

Gene

SLC12A4

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

Functioni

Mediates electroneutral potassium-chloride cotransport when activated by cell swelling. May contribute to cell volume homeostasis in single cells. May be involved in the regulation of basolateral Cl- exit in NaCl absorbing epithelia (By similarity). Isoform 4 has no transport activity.By similarity

Enzyme regulationi

Inhibited by WNK3.1 Publication

GO - Molecular functioni

  • potassium:chloride symporter activity Source: GO_Central
  • protein kinase binding Source: ParkinsonsUK-UCL

GO - Biological processi

  • cell volume homeostasis Source: ProtInc
  • chemical synaptic transmission Source: GO_Central
  • ion transport Source: Reactome

Keywordsi

Biological processIon transport, Potassium transport, Symport, Transport
LigandChloride, Potassium

Enzyme and pathway databases

ReactomeiR-HSA-426117 Cation-coupled Chloride cotransporters

Protein family/group databases

TCDBi2.A.30.1.17 the cation-chloride cotransporter (ccc) family

Names & Taxonomyi

Protein namesi
Recommended name:
Solute carrier family 12 member 4
Alternative name(s):
Electroneutral potassium-chloride cotransporter 1
Erythroid K-Cl cotransporter 1
Short name:
hKCC1
Gene namesi
Name:SLC12A4
Synonyms:KCC1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 16

Organism-specific databases

EuPathDBiHostDB:ENSG00000124067.16
HGNCiHGNC:10913 SLC12A4
MIMi604119 gene
neXtProtiNX_Q9UP95

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 118CytoplasmicSequence analysisAdd BLAST118
Transmembranei119 – 139HelicalSequence analysisAdd BLAST21
Transmembranei149 – 169HelicalSequence analysisAdd BLAST21
Topological domaini170 – 214CytoplasmicSequence analysisAdd BLAST45
Transmembranei215 – 235HelicalSequence analysisAdd BLAST21
Transmembranei253 – 273HelicalSequence analysisAdd BLAST21
Topological domaini274 – 275CytoplasmicSequence analysis2
Transmembranei276 – 296HelicalSequence analysisAdd BLAST21
Transmembranei356 – 376HelicalSequence analysisAdd BLAST21
Topological domaini377 – 407CytoplasmicSequence analysisAdd BLAST31
Transmembranei408 – 428HelicalSequence analysisAdd BLAST21
Transmembranei453 – 473HelicalSequence analysisAdd BLAST21
Topological domaini474 – 493CytoplasmicSequence analysisAdd BLAST20
Transmembranei494 – 514HelicalSequence analysisAdd BLAST21
Transmembranei567 – 587HelicalSequence analysisAdd BLAST21
Topological domaini588 – 627CytoplasmicSequence analysisAdd BLAST40
Transmembranei628 – 648HelicalSequence analysisAdd BLAST21
Transmembranei845 – 865HelicalSequence analysisAdd BLAST21
Topological domaini866 – 1085CytoplasmicSequence analysisAdd BLAST220

Keywords - Cellular componenti

Membrane

Pathology & Biotechi

Organism-specific databases

DisGeNETi6560
OpenTargetsiENSG00000124067
PharmGKBiPA35807

Chemistry databases

DrugBankiDB00887 Bumetanide
DB00761 Potassium Chloride

Polymorphism and mutation databases

BioMutaiSLC12A4
DMDMi27151691

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001780301 – 1085Solute carrier family 12 member 4Add BLAST1085

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei24PhosphoserineCombined sources1
Modified residuei47PhosphoserineBy similarity1
Modified residuei51PhosphoserineCombined sources1
Modified residuei81PhosphoserineBy similarity1
Modified residuei88PhosphoserineCombined sources1
Glycosylationi245N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi312N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi331N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi347N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi439N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei967PhosphoserineCombined sources1
Modified residuei983PhosphothreonineCombined sources1

Post-translational modificationi

N-glycosylated.

Keywords - PTMi

Glycoprotein, Phosphoprotein

Proteomic databases

EPDiQ9UP95
PaxDbiQ9UP95
PeptideAtlasiQ9UP95
PRIDEiQ9UP95
ProteomicsDBi85360
85361 [Q9UP95-2]
85362 [Q9UP95-3]
85363 [Q9UP95-4]

PTM databases

iPTMnetiQ9UP95
PhosphoSitePlusiQ9UP95

Expressioni

Tissue specificityi

Ubiquitous. Levels are much higher in erythrocytes from patients with Hb SC and Hb SS compared to normal AA erythrocytes. This may contribute to red blood cell dehydration and to the manifestation of sickle cell disease by increasing the intracellular concentration of HbS. Isoform 1 was not detected in circulating reticulocytes.

Gene expression databases

BgeeiENSG00000124067
CleanExiHS_SLC12A4
ExpressionAtlasiQ9UP95 baseline and differential
GenevisibleiQ9UP95 HS

Organism-specific databases

HPAiHPA041138

Interactioni

Subunit structurei

Homomultimer and heteromultimer with other K-Cl cotransporters.1 Publication

Binary interactionsi

Show more details

GO - Molecular functioni

  • protein kinase binding Source: ParkinsonsUK-UCL

Protein-protein interaction databases

BioGridi112449, 34 interactors
IntActiQ9UP95, 14 interactors
MINTiQ9UP95
STRINGi9606.ENSP00000395983

Structurei

3D structure databases

ProteinModelPortaliQ9UP95
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi160 – 163Poly-Cys4

Sequence similaritiesi

Belongs to the SLC12A transporter family.Curated

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2082 Eukaryota
COG0531 LUCA
GeneTreeiENSGT00760000119053
HOGENOMiHOG000092644
HOVERGENiHBG052852
InParanoidiQ9UP95
KOiK14427
OMAiDICAKTA
OrthoDBiEOG091G0WB4
PhylomeDBiQ9UP95
TreeFamiTF313657

Family and domain databases

InterProiView protein in InterPro
IPR004841 AA-permease/SLC12A_dom
IPR000622 KCC1
IPR000076 KCL_cotranspt
IPR018491 SLC12_C
IPR004842 SLC12A_fam
PANTHERiPTHR11827:SF46 PTHR11827:SF46, 1 hit
PfamiView protein in Pfam
PF00324 AA_permease, 2 hits
PF03522 SLC12, 2 hits
PRINTSiPR01081 KCLTRNSPORT
PR01082 KCLTRNSPORT1
TIGRFAMsiTIGR00930 2a30, 1 hit

Sequences (7)i

Sequence statusi: Complete.

This entry describes 7 isoformsi produced by alternative splicing. AlignAdd to basket

Note: Experimental confirmation may be lacking for some isoforms.
Isoform 1 (identifier: Q9UP95-1) [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
MPHFTVVPVD GPRRGDYDNL EGLSWVDYGE RAELDDSDGH GNHRESSPFL
60 70 80 90 100
SPLEASRGID YYDRNLALFE EELDIRPKVS SLLGKLVSYT NLTQGAKEHE
110 120 130 140 150
EAESGEGTRR RAAEAPSMGT LMGVYLPCLQ NIFGVILFLR LTWMVGTAGV
160 170 180 190 200
LQALLIVLIC CCCTLLTAIS MSAIATNGVV PAGGSYFMIS RSLGPEFGGA
210 220 230 240 250
VGLCFYLGTT FAAAMYILGA IEILLTYIAP PAAIFYPSGA HDTSNATLNN
260 270 280 290 300
MRVYGTIFLT FMTLVVFVGV KYVNKFASLF LACVIISILS IYAGGIKSIF
310 320 330 340 350
DPPVFPVCML GNRTLSRDQF DICAKTAVVD NETVATQLWS FFCHSPNLTT
360 370 380 390 400
DSCDPYFMLN NVTEIPGIPG AAAGVLQENL WSAYLEKGDI VEKHGLPSAD
410 420 430 440 450
APSLKESLPL YVVADIATSF TVLVGIFFPS VTGIMAGSNR SGDLRDAQKS
460 470 480 490 500
IPVGTILAII TTSLVYFSSV VLFGACIEGV VLRDKYGDGV SRNLVVGTLA
510 520 530 540 550
WPSPWVIVIG SFFSTCGAGL QSLTGAPRLL QAIAKDNIIP FLRVFGHGKV
560 570 580 590 600
NGEPTWALLL TALIAELGIL IASLDMVAPI LSMFFLMCYL FVNLACAVQT
610 620 630 640 650
LLRTPNWRPR FKYYHWALSF LGMSLCLALM FVSSWYYALV AMLIAGMIYK
660 670 680 690 700
YIEYQGAEKE WGDGIRGLSL SAARYALLRL EEGPPHTKNW RPQLLVLLKL
710 720 730 740 750
DEDLHVKYPR LLTFASQLKA GKGLTIVGSV IQGSFLESYG EAQAAEQTIK
760 770 780 790 800
NMMEIEKVKG FCQVVVASKV REGLAHLIQS CGLGGMRHNS VVLGWPYGWR
810 820 830 840 850
QSEDPRAWKT FIDTVRCTTA AHLALLVPKN IAFYPSNHER YLEGHIDVWW
860 870 880 890 900
IVHDGGMLML LPFLLRQHKV WRKCRMRIFT VAQMDDNSIQ MKKDLAVFLY
910 920 930 940 950
HLRLEAEVEV VEMHNSDISA YTYERTLMME QRSQMLRQMR LTKTEREREA
960 970 980 990 1000
QLVKDRHSAL RLESLYSDEE DESAVGADKI QMTWTRDKYM TETWDPSHAP
1010 1020 1030 1040 1050
DNFRELVHIK PDQSNVRRMH TAVKLNEVIV TRSHDARLVL LNMPGPPRNS
1060 1070 1080
EGDENYMEFL EVLTEGLERV LLVRGGGREV ITIYS
Length:1,085
Mass (Da):120,650
Last modified:December 13, 2002 - v2
Checksum:i42B590EC3D94EA4D
GO
Isoform 2 (identifier: Q9UP95-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1056-1068: YMEFLEVLTEGLE → CIPLWRGRQLGGG
     1069-1085: Missing.

Show »
Length:1,068
Mass (Da):118,620
Checksum:i7A1FB4FD47252C88
GO
Isoform 3 (identifier: Q9UP95-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1012-1085: Missing.

Show »
Length:1,011
Mass (Da):112,275
Checksum:i33860CBEC1BE578B
GO
Isoform 4 (identifier: Q9UP95-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     749-955: Missing.
     956-958: RHS → PCA
     963-987: ESLYSDEEDESAVGADKIQMTWTRD → PTWPCSCPRTSPSTPATTSATWRAT
     988-1085: Missing.

Show »
Length:780
Mass (Da):84,701
Checksum:i63DD249B6CA8689C
GO
Isoform 5 (identifier: Q9UP95-5) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-38: MPHFTVVPVDGPRRGDYDNLEGLSWVDYGERAELDDSD → MGDTLSP

Note: No experimental confirmation available.
Show »
Length:1,054
Mass (Da):117,046
Checksum:i328721D9B50DF738
GO
Isoform 6 (identifier: Q9UP95-6) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-38: MPHFTVVPVDGPRRGDYDNLEGLSWVDYGERAELDDSD → MAAEGAVCGFVYLEGTAWAVPEDTEPLASCTL

Note: No experimental confirmation available.Curated
Show »
Length:1,079
Mass (Da):119,629
Checksum:iEC9A4E5C31C90A87
GO
Isoform 7 (identifier: Q9UP95-7) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-70: MPHFTVVPVD...YYDRNLALFE → MRAGGACRPG...GSAPSWMTRT

Note: No experimental confirmation available.
Show »
Length:1,087
Mass (Da):119,745
Checksum:i701F57E7F5732CBD
GO

Sequence cautioni

The sequence AAC35282 differs from that shown. Reason: Frameshift at position 454.Curated
The sequence BAG57330 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti42N → D in BAG61116 (PubMed:14702039).Curated1
Sequence conflicti211F → L in BAG63994 (PubMed:14702039).Curated1
Sequence conflicti288I → N in BAG63994 (PubMed:14702039).Curated1
Sequence conflicti370G → R in BAG57330 (PubMed:14702039).Curated1
Sequence conflicti697L → P in BAG63994 (PubMed:14702039).Curated1
Sequence conflicti1016V → A in BAG57330 (PubMed:14702039).Curated1
Sequence conflicti1055N → D in BAG57330 (PubMed:14702039).Curated1
Isoform 6 (identifier: Q9UP95-6)
Sequence conflicti4E → G in BAH14786 (PubMed:14702039).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0463691 – 70MPHFT…LALFE → MRAGGACRPGAAGTAAGTAA GGWDGGCGGAEPARCLTSPW CQWTGRGAATMTTSRGSVGW TTGSAPSWMTRT in isoform 7. 1 PublicationAdd BLAST70
Alternative sequenceiVSP_0445961 – 38MPHFT…LDDSD → MGDTLSP in isoform 5. 1 PublicationAdd BLAST38
Alternative sequenceiVSP_0461461 – 38MPHFT…LDDSD → MAAEGAVCGFVYLEGTAWAV PEDTEPLASCTL in isoform 6. 1 PublicationAdd BLAST38
Alternative sequenceiVSP_006108749 – 955Missing in isoform 4. 1 PublicationAdd BLAST207
Alternative sequenceiVSP_006109956 – 958RHS → PCA in isoform 4. 1 Publication3
Alternative sequenceiVSP_006110963 – 987ESLYS…TWTRD → PTWPCSCPRTSPSTPATTSA TWRAT in isoform 4. 1 PublicationAdd BLAST25
Alternative sequenceiVSP_006111988 – 1085Missing in isoform 4. 1 PublicationAdd BLAST98
Alternative sequenceiVSP_0061121012 – 1085Missing in isoform 3. 1 PublicationAdd BLAST74
Alternative sequenceiVSP_0061131056 – 1068YMEFL…TEGLE → CIPLWRGRQLGGG in isoform 2. 1 PublicationAdd BLAST13
Alternative sequenceiVSP_0061141069 – 1085Missing in isoform 2. 1 PublicationAdd BLAST17

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U55054 mRNA Translation: AAC50563.1
AF047338 mRNA Translation: AAC32815.1
AF054505 mRNA Translation: AAC39684.1
AF054506 mRNA Translation: AAC39685.1
AK293956 mRNA Translation: BAG57330.1 Different initiation.
AK299042 mRNA Translation: BAG61116.1
AK302790 mRNA Translation: BAG63994.1
AK316415 mRNA Translation: BAH14786.1
AC040162 Genomic DNA No translation available.
BC021193 mRNA Translation: AAH21193.1
AF053402 mRNA Translation: AAC35282.1 Frameshift.
AY026038 mRNA Translation: AAK01946.1
CCDSiCCDS10855.1 [Q9UP95-1]
CCDS54030.1 [Q9UP95-6]
CCDS54031.1 [Q9UP95-5]
CCDS54032.1 [Q9UP95-7]
RefSeqiNP_001139433.1, NM_001145961.1
NP_001139434.1, NM_001145962.1 [Q9UP95-7]
NP_001139435.1, NM_001145963.1 [Q9UP95-6]
NP_001139436.1, NM_001145964.1 [Q9UP95-5]
NP_005063.1, NM_005072.4 [Q9UP95-1]
UniGeneiHs.10094

Genome annotation databases

EnsembliENST00000316341; ENSP00000318557; ENSG00000124067 [Q9UP95-1]
ENST00000422611; ENSP00000395983; ENSG00000124067 [Q9UP95-7]
ENST00000537830; ENSP00000445962; ENSG00000124067 [Q9UP95-6]
ENST00000541864; ENSP00000438334; ENSG00000124067 [Q9UP95-5]
ENST00000576616; ENSP00000458902; ENSG00000124067 [Q9UP95-2]
GeneIDi6560
KEGGihsa:6560
UCSCiuc002euz.2 human [Q9UP95-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiS12A4_HUMAN
AccessioniPrimary (citable) accession number: Q9UP95
Secondary accession number(s): B4DF69
, B4DR04, B4DZ82, B7ZAV0, F5H066, F5H0S9, F5H3C0, O60632, O75893, Q13953, Q96LD5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 13, 2002
Last sequence update: December 13, 2002
Last modified: June 20, 2018
This is version 166 of the entry and version 2 of the sequence. See 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

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