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Q80UE6

- WNK4_MOUSE

UniProt

Q80UE6 - WNK4_MOUSE

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Protein

Serine/threonine-protein kinase WNK4

Gene
Wnk4, Prkwnk4
Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

Serine/threonine kinase which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival and proliferation. Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively. Activates SCNN1A, SCNN1B, SCNN1D, SGK1, TRPV5 and TRPV6. Regulates the activity of the thiazide-sensitive Na-Cl cotransporter, SLC12A3, by phosphorylation which appears to prevent membrane trafficking of SLC12A3. Also inhibits the renal K+ channel, KCNJ1, via a kinase-independent mechanism by which it induces clearance of the protein from the cell surface by clathrin-dependent endocytosis. WNK4 appears to act as a molecular switch that can vary the balance between NaCl reabsorption and K+ secretion to maintain integrated homeostasis. Phosphorylates NEDD4L.3 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Magnesium By similarity.By similarity

Enzyme regulationi

Activation requires autophosphorylation of Ser-332. Phosphorylation of Ser-328 also promotes increased activity By similarity.By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei183 – 1831ATP By similarityBy similarity
Active sitei299 – 2991Proton acceptor By similarityBy similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi177 – 1859ATP By similarityBy similarity

GO - Molecular functioni

  1. ATP binding Source: UniProtKB
  2. protein serine/threonine kinase activity Source: UniProtKB

GO - Biological processi

  1. cellular chloride ion homeostasis Source: MGI
  2. chloride transport Source: MGI
  3. distal tubule morphogenesis Source: UniProtKB
  4. intracellular signal transduction Source: UniProtKB
  5. ion homeostasis Source: UniProtKB
  6. ion transport Source: UniProtKB
  7. negative regulation of pancreatic juice secretion Source: MGI
  8. protein localization Source: MGI
  9. protein phosphorylation Source: UniProtKB
  10. regulation of cellular process Source: UniProtKB
  11. renal sodium ion absorption Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiREACT_196640. Stimuli-sensing channels.

Names & Taxonomyi

Protein namesi
Recommended name:
Serine/threonine-protein kinase WNK4 (EC:2.7.11.1)
Alternative name(s):
Protein kinase lysine-deficient 4
Protein kinase with no lysine 4
Gene namesi
Name:Wnk4
Synonyms:Prkwnk4
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 11

Organism-specific databases

MGIiMGI:1917097. Wnk4.

Subcellular locationi

Cell junctiontight junction
Note: Present exclusively in intercellular junctions in the distal convoluted tubule and in both the cytoplasm and intercellular junctions in the cortical collecting duct. WNK4 is part of the tight junction complex.1 Publication

GO - Cellular componenti

  1. cytoplasm Source: MGI
  2. tight junction Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell junction, Tight junction

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi318 – 3181D → A: No effect on inhibition of KCNJ1. 1 Publication
Mutagenesisi559 – 5591E → K: No effect on inhibition of SLC12A3. 1 Publication
Mutagenesisi561 – 5611D → A: Increased protein level, probably due to defects in ubiquitination. No effect on inhibition of SLC12A3. 2 Publications
Mutagenesisi562 – 5621Q → E: Increased protein level, probably due to defects in ubiquitination. Prevents inhibition of SLC12A3. 2 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 12221222Serine/threonine-protein kinase WNK4PRO_0000086825Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Cross-linki154 – 154Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-linki172 – 172Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-linki183 – 183Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-linki223 – 223Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-linki238 – 238Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-linki325 – 325Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Modified residuei328 – 3281Phosphoserine; by autocatalysis By similarityBy similarity
Modified residuei332 – 3321Phosphoserine; by autocatalysis By similarityBy similarity
Cross-linki384 – 384Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-linki390 – 390Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-linki447 – 447Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-linki451 – 451Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-linki990 – 990Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-linki1123 – 1123Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-linki1136 – 1136Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-linki1137 – 1137Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Post-translational modificationi

Phosphorylated by WNK1 and WNK3.1 Publication
Ubiquitinated by the BCR(KLHL3) complex, leading to its degradation and increased expression of KCNJ1 at the cell surface. Ubiquitinated by the BCR(KLHL2) complex By similarity.

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ80UE6.
PRIDEiQ80UE6.

PTM databases

PhosphoSiteiQ80UE6.

Expressioni

Tissue specificityi

Locates to the distal convoluted tubule, the medullary collecting duct and the cortical collecting duct of the kidney.1 Publication

Gene expression databases

ArrayExpressiQ80UE6.
BgeeiQ80UE6.
CleanExiMM_WNK4.
GenevestigatoriQ80UE6.

Interactioni

Subunit structurei

Interacts with the C-terminal region of KCNJ1. Interacts with KLHL3, WNK1 and WNK3.2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Trpv5P697442EBI-295378,EBI-538447

Protein-protein interaction databases

DIPiDIP-33231N.
IntActiQ80UE6. 4 interactions.
MINTiMINT-4980938.

Structurei

3D structure databases

ProteinModelPortaliQ80UE6.
SMRiQ80UE6. Positions 160-520.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini171 – 429259Protein kinaseAdd
BLAST

Sequence similaritiesi

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00550000074385.
HOVERGENiHBG050347.
InParanoidiA2A4J7.
KOiK08867.
OMAiESHLRLP.
OrthoDBiEOG7KDF8Z.
PhylomeDBiQ80UE6.
TreeFamiTF315363.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR024678. Kinase_OSR1/WNK_CCT.
IPR000719. Prot_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF12202. OSR1_C. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 2 hits.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q80UE6-1 [UniParc]FASTAAdd to Basket

« Hide

MLAPRNTETG VPMSQTEADL ALRPSPALTS TGPTRLGPPP RRVRRFSGKA     50
EPRPRSSRPS RRSSVDLGLL SSWSQPASLL PEPPDPPDSA GPTRSPPSSS 100
KEPPEGTWMG AAPVKAVDSA CPELTGSSGG PGSREPPRVP DAAARERRRE 150
QEEKEDTETQ AVATSPDGRY LKFDIEIGRG SFKTVYRGLD TDTTVEVAWC 200
ELQTRKLSRA ERQRFSEEVE MLKGLQHPNI VRFYDSWKSV LRGQVCIVLV 250
TELMTSGTLK TYLRRFREMK PRVLQRWSRQ ILRGLHFLHS RVPPILHRDL 300
KCDNVFITGP SGSVKIGDLG LATLKRASFA KSVIGTPEFM APEMYEEKYD 350
EAVDVYAFGM CMLEMATSEY PYSECQNAAQ IYRKVTSGTK PNSFYKVKMP 400
EVKEIIEGCI RTDKNERFTI QDLLAHAFFR EERGVHVELA EEDDGEKPGL 450
KLWLRMEDAR RGGRPRDNQA IEFLFQLGRD AAEEVAQEMV ALGLVCEADY 500
QPVARAVRER VAAIQRKREK LRKARELEVL PPDSGPPPAT VSLAPGPPSA 550
FPPEPEEPEA DQHQSFLFRH ASYSSTTSDC ETDGYLSSSG FLDASDPALQ 600
PPGGLPSSPA ESHLCLPSGF ALSIPRSGPG SDFSPGDSYA SDAASGLSDM 650
GEGGQMRKNP VKTLRRRPRS RLRVTSVSDQ SDRVVECQLQ THNSKMVTFR 700
FDLDGDSPEE IAAAMVYNEF ILPSERDGFL SRIREIIQRV ETLLKRDAGP 750
PEAAEDALSP QEEPAALPAL PGPPNAEPQR SISPEQRSWA AFSTSPSSPG 800
TPLSPGAPFS PGTPPVFPCP IFPITSPSCY PCPFSQVSSN PYPQAPSSLL 850
PLSSSASQVP LPSSSLPISA PLPFSPSYPQ DPLSPTSLPV CPSPPSLPST 900
TAAPLLSLAS AFSLAVMTVA QSLLSPSPGL LSQSPPAPPG PLPSLPLSLA 950
SCDQESLSAQ TAETENEASR NPAQPLLGDA RLAPISEEGK PQLVGRFQVT 1000
SSKEPAEPPL QPASPTLSRS LKLPSPPLTS ESSDTEDSAA GGPETREALA 1050
ESDRAAEGLG VAVDDEKDEG KEPLLGGSSP ILSHPSPVWM NYSYSSLCLS 1100
SEESESSGED EEFWAELQNL RQKHLSEVEA LQTLQKKEIE DLYSRLGKQP 1150
PPGIVAPAAM LSCRQRRLSK GSFPTSRRNS LQRSDLPGPG IMRRNSLSGS 1200
STGSQEQRAS KGVTFAGDIG RM 1222
Length:1,222
Mass (Da):132,410
Last modified:June 1, 2003 - v1
Checksum:iBE0A193E7D79DCFE
GO

Sequence cautioni

The sequence AAH26679.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.
The sequence AAH43677.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.
The sequence AAO25619.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti179 – 1791R → K in AAO25619. 1 Publication
Sequence conflicti607 – 6071S → F in AAH26679. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AY187027 mRNA. Translation: AAO21955.1.
AY184228 mRNA. Translation: AAO25619.1. Different initiation.
AL590969 Genomic DNA. Translation: CAM19562.1.
BC026591 mRNA. Translation: AAH26591.1.
BC026679 mRNA. Translation: AAH26679.1. Different initiation.
BC043677 mRNA. Translation: AAH43677.1. Different initiation.
BC096453 mRNA. Translation: AAH96453.1.
CCDSiCCDS25459.1.
RefSeqiNP_783569.1. NM_175638.3.
UniGeneiMm.23656.

Genome annotation databases

EnsembliENSMUST00000103108; ENSMUSP00000099397; ENSMUSG00000035112.
GeneIDi69847.
KEGGimmu:69847.
UCSCiuc007loe.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AY187027 mRNA. Translation: AAO21955.1 .
AY184228 mRNA. Translation: AAO25619.1 . Different initiation.
AL590969 Genomic DNA. Translation: CAM19562.1 .
BC026591 mRNA. Translation: AAH26591.1 .
BC026679 mRNA. Translation: AAH26679.1 . Different initiation.
BC043677 mRNA. Translation: AAH43677.1 . Different initiation.
BC096453 mRNA. Translation: AAH96453.1 .
CCDSi CCDS25459.1.
RefSeqi NP_783569.1. NM_175638.3.
UniGenei Mm.23656.

3D structure databases

ProteinModelPortali Q80UE6.
SMRi Q80UE6. Positions 160-520.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

DIPi DIP-33231N.
IntActi Q80UE6. 4 interactions.
MINTi MINT-4980938.

PTM databases

PhosphoSitei Q80UE6.

Proteomic databases

PaxDbi Q80UE6.
PRIDEi Q80UE6.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000103108 ; ENSMUSP00000099397 ; ENSMUSG00000035112 .
GeneIDi 69847.
KEGGi mmu:69847.
UCSCi uc007loe.2. mouse.

Organism-specific databases

CTDi 65266.
MGIi MGI:1917097. Wnk4.

Phylogenomic databases

eggNOGi COG0515.
GeneTreei ENSGT00550000074385.
HOVERGENi HBG050347.
InParanoidi A2A4J7.
KOi K08867.
OMAi ESHLRLP.
OrthoDBi EOG7KDF8Z.
PhylomeDBi Q80UE6.
TreeFami TF315363.

Enzyme and pathway databases

Reactomei REACT_196640. Stimuli-sensing channels.

Miscellaneous databases

NextBioi 330461.
PROi Q80UE6.
SOURCEi Search...

Gene expression databases

ArrayExpressi Q80UE6.
Bgeei Q80UE6.
CleanExi MM_WNK4.
Genevestigatori Q80UE6.

Family and domain databases

InterProi IPR011009. Kinase-like_dom.
IPR024678. Kinase_OSR1/WNK_CCT.
IPR000719. Prot_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view ]
Pfami PF12202. OSR1_C. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view ]
SUPFAMi SSF56112. SSF56112. 2 hits.
PROSITEi PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Molecular pathogenesis of inherited hypertension with hyperkalemia: The Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4."
    Wilson F.H., Kahle K.T., Sabath E., Lalioti M.D., Rapson A.K., Hoover R.S., Hebert S.C., Gamba G., Lifton R.P.
    Proc. Natl. Acad. Sci. U.S.A. 100:680-684(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Strain: C57BL/6.
    Tissue: Kidney.
  2. "WNK kinases regulate thiazide-sensitive Na-Cl cotransport."
    Yang C.-L., Angell J., Mitchell R., Ellison D.H.
    J. Clin. Invest. 111:1039-1045(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, MUTAGENESIS OF GLU-559; ASP-561 AND GLN-562.
    Strain: BALB/c.
  3. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    Strain: C57BL/6J.
  4. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: FVB/N.
    Tissue: Kidney and Mammary carcinoma.
  5. Cited for: SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
  6. Cited for: FUNCTION, INTERACTION WITH KCNJ1, MUTAGENESIS OF ASP-318.
  7. "The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex."
    Yang C.L., Zhu X., Ellison D.H.
    J. Clin. Invest. 117:3403-3411(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH WNK1 AND WNK3, PHOSPHORYLATION BY WNK1 AND WNK3.
  8. Cited for: MUTAGENESIS OF ASP-561.
  9. "Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4."
    Shibata S., Zhang J., Puthumana J., Stone K.L., Lifton R.P.
    Proc. Natl. Acad. Sci. U.S.A. 110:7838-7843(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: MUTAGENESIS OF GLN-562.

Entry informationi

Entry nameiWNK4_MOUSE
AccessioniPrimary (citable) accession number: Q80UE6
Secondary accession number(s): A2A4J7
, Q4VAC1, Q80XB5, Q80XN2, Q8R0N0, Q8R340
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 2, 2004
Last sequence update: June 1, 2003
Last modified: September 3, 2014
This is version 107 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Caution

Cys-200 is present instead of the conserved Lys which is expected to be an active site residue. Lys-183 appears to fulfill the required catalytic function.

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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