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Q80UE6

- WNK4_MOUSE

UniProt

Q80UE6 - WNK4_MOUSE

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Protein

Serine/threonine-protein kinase WNK4

Gene

Wnk4

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

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 – 1831ATPBy similarityPROSITE-ProRule annotation
Active sitei299 – 2991Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi177 – 1859ATPBy similarityPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: UniProtKB
  2. chloride channel inhibitor activity Source: Ensembl
  3. 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)Imported
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 11

Organism-specific databases

MGIiMGI:1917097. Wnk4.

Subcellular locationi

Cell junctiontight junction 1 Publication
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.

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 autocatalysisBy similarity
Modified residuei332 – 3321Phosphoserine; by autocatalysisBy 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).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

BgeeiQ80UE6.
CleanExiMM_WNK4.
ExpressionAtlasiQ80UE6. baseline and differential.
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 97-520.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini171 – 429259Protein kinasePROSITE-ProRule annotationAdd
BLAST

Sequence similaritiesi

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. WNK subfamily.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00550000074385.
HOVERGENiHBG050347.
InParanoidiQ80UE6.
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

        10         20         30         40         50
MLAPRNTETG VPMSQTEADL ALRPSPALTS TGPTRLGPPP RRVRRFSGKA
60 70 80 90 100
EPRPRSSRPS RRSSVDLGLL SSWSQPASLL PEPPDPPDSA GPTRSPPSSS
110 120 130 140 150
KEPPEGTWMG AAPVKAVDSA CPELTGSSGG PGSREPPRVP DAAARERRRE
160 170 180 190 200
QEEKEDTETQ AVATSPDGRY LKFDIEIGRG SFKTVYRGLD TDTTVEVAWC
210 220 230 240 250
ELQTRKLSRA ERQRFSEEVE MLKGLQHPNI VRFYDSWKSV LRGQVCIVLV
260 270 280 290 300
TELMTSGTLK TYLRRFREMK PRVLQRWSRQ ILRGLHFLHS RVPPILHRDL
310 320 330 340 350
KCDNVFITGP SGSVKIGDLG LATLKRASFA KSVIGTPEFM APEMYEEKYD
360 370 380 390 400
EAVDVYAFGM CMLEMATSEY PYSECQNAAQ IYRKVTSGTK PNSFYKVKMP
410 420 430 440 450
EVKEIIEGCI RTDKNERFTI QDLLAHAFFR EERGVHVELA EEDDGEKPGL
460 470 480 490 500
KLWLRMEDAR RGGRPRDNQA IEFLFQLGRD AAEEVAQEMV ALGLVCEADY
510 520 530 540 550
QPVARAVRER VAAIQRKREK LRKARELEVL PPDSGPPPAT VSLAPGPPSA
560 570 580 590 600
FPPEPEEPEA DQHQSFLFRH ASYSSTTSDC ETDGYLSSSG FLDASDPALQ
610 620 630 640 650
PPGGLPSSPA ESHLCLPSGF ALSIPRSGPG SDFSPGDSYA SDAASGLSDM
660 670 680 690 700
GEGGQMRKNP VKTLRRRPRS RLRVTSVSDQ SDRVVECQLQ THNSKMVTFR
710 720 730 740 750
FDLDGDSPEE IAAAMVYNEF ILPSERDGFL SRIREIIQRV ETLLKRDAGP
760 770 780 790 800
PEAAEDALSP QEEPAALPAL PGPPNAEPQR SISPEQRSWA AFSTSPSSPG
810 820 830 840 850
TPLSPGAPFS PGTPPVFPCP IFPITSPSCY PCPFSQVSSN PYPQAPSSLL
860 870 880 890 900
PLSSSASQVP LPSSSLPISA PLPFSPSYPQ DPLSPTSLPV CPSPPSLPST
910 920 930 940 950
TAAPLLSLAS AFSLAVMTVA QSLLSPSPGL LSQSPPAPPG PLPSLPLSLA
960 970 980 990 1000
SCDQESLSAQ TAETENEASR NPAQPLLGDA RLAPISEEGK PQLVGRFQVT
1010 1020 1030 1040 1050
SSKEPAEPPL QPASPTLSRS LKLPSPPLTS ESSDTEDSAA GGPETREALA
1060 1070 1080 1090 1100
ESDRAAEGLG VAVDDEKDEG KEPLLGGSSP ILSHPSPVWM NYSYSSLCLS
1110 1120 1130 1140 1150
SEESESSGED EEFWAELQNL RQKHLSEVEA LQTLQKKEIE DLYSRLGKQP
1160 1170 1180 1190 1200
PPGIVAPAAM LSCRQRRLSK GSFPTSRRNS LQRSDLPGPG IMRRNSLSGS
1210 1220
STGSQEQRAS KGVTFAGDIG RM
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.

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti179 – 1791R → K in AAO25619. (PubMed:12671053)Curated
Sequence conflicti607 – 6071S → F in AAH26679. (PubMed:15489334)Curated

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 97-520.
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 Q80UE6.
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

Bgeei Q80UE6.
CleanExi MM_WNK4.
ExpressionAtlasi Q80UE6. baseline and differential.
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/6Imported.
    Tissue: KidneyImported.
  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/cImported.
  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/NImported.
    Tissue: Kidney1 Publication 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: October 29, 2014
This is version 109 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.Curated

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