Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

Q80UE6 (WNK4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 106. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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 names
Name:Wnk4
Synonyms:Prkwnk4
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length1222 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.2 Ref.6 Ref.7

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium By similarity. UniProtKB Q9H4A3

Enzyme regulation

Activation requires autophosphorylation of Ser-332. Phosphorylation of Ser-328 also promotes increased activity By similarity. UniProtKB Q9JIH7

Subunit structure

Interacts with the C-terminal region of KCNJ1. Interacts with KLHL3, WNK1 and WNK3. Ref.6 Ref.7

Subcellular location

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. Ref.5

Tissue specificity

Locates to the distal convoluted tubule, the medullary collecting duct and the cortical collecting duct of the kidney. Ref.5

Post-translational modification

Phosphorylated by WNK1 and WNK3. Ref.7

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.

Sequence similarities

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. WNK subfamily.

Contains 1 protein kinase domain.

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.

Sequence caution

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.

Ontologies

Keywords
   Cellular componentCell junction
Tight junction
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMIsopeptide bond
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcellular chloride ion homeostasis

Traceable author statement PubMed 14769928. Source: MGI

chloride transport

Inferred from direct assay PubMed 14769928. Source: MGI

distal tubule morphogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

intracellular signal transduction

Inferred from sequence or structural similarity. Source: UniProtKB

ion homeostasis

Inferred from sequence or structural similarity. Source: UniProtKB

ion transport

Inferred from direct assay Ref.6. Source: UniProtKB

negative regulation of pancreatic juice secretion

Inferred from mutant phenotype PubMed 21317537. Source: MGI

protein localization

Inferred from direct assay Ref.1Ref.2. Source: MGI

protein phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of cellular process

Inferred from direct assay Ref.6. Source: UniProtKB

renal sodium ion absorption

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentcytoplasm

Inferred from direct assay PubMed 14769928. Source: MGI

tight junction

Inferred from direct assay Ref.5. Source: UniProtKB

   Molecular_functionATP binding

Inferred from sequence or structural similarity. Source: UniProtKB

protein serine/threonine kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 12221222Serine/threonine-protein kinase WNK4
PRO_0000086825

Regions

Domain171 – 429259Protein kinase
Nucleotide binding177 – 1859ATP By similarity UniProtKB Q8TDX7

Sites

Active site2991Proton acceptor By similarity UniProtKB Q8TDX7
Binding site1831ATP By similarity UniProtKB Q9JIH7

Amino acid modifications

Modified residue3281Phosphoserine; by autocatalysis By similarity UniProtKB Q9JIH7
Modified residue3321Phosphoserine; by autocatalysis By similarity UniProtKB Q9JIH7
Cross-link154Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link172Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link183Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link223Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link238Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link325Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link384Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link390Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link447Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link451Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link990Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link1123Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link1136Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link1137Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Experimental info

Mutagenesis3181D → A: No effect on inhibition of KCNJ1. Ref.6
Mutagenesis5591E → K: No effect on inhibition of SLC12A3. Ref.2
Mutagenesis5611D → A: Increased protein level, probably due to defects in ubiquitination. No effect on inhibition of SLC12A3. Ref.2 Ref.8
Mutagenesis5621Q → E: Increased protein level, probably due to defects in ubiquitination. Prevents inhibition of SLC12A3. Ref.2 Ref.9
Sequence conflict1791R → K in AAO25619. Ref.2
Sequence conflict6071S → F in AAH26679. Ref.4

Sequences

Sequence LengthMass (Da)Tools
Q80UE6 [UniParc].

Last modified June 1, 2003. Version 1.
Checksum: BE0A193E7D79DCFE

FASTA1,222132,410
        10         20         30         40         50         60 
MLAPRNTETG VPMSQTEADL ALRPSPALTS TGPTRLGPPP RRVRRFSGKA EPRPRSSRPS 

        70         80         90        100        110        120 
RRSSVDLGLL SSWSQPASLL PEPPDPPDSA GPTRSPPSSS KEPPEGTWMG AAPVKAVDSA 

       130        140        150        160        170        180 
CPELTGSSGG PGSREPPRVP DAAARERRRE QEEKEDTETQ AVATSPDGRY LKFDIEIGRG 

       190        200        210        220        230        240 
SFKTVYRGLD TDTTVEVAWC ELQTRKLSRA ERQRFSEEVE MLKGLQHPNI VRFYDSWKSV 

       250        260        270        280        290        300 
LRGQVCIVLV TELMTSGTLK TYLRRFREMK PRVLQRWSRQ ILRGLHFLHS RVPPILHRDL 

       310        320        330        340        350        360 
KCDNVFITGP SGSVKIGDLG LATLKRASFA KSVIGTPEFM APEMYEEKYD EAVDVYAFGM 

       370        380        390        400        410        420 
CMLEMATSEY PYSECQNAAQ IYRKVTSGTK PNSFYKVKMP EVKEIIEGCI RTDKNERFTI 

       430        440        450        460        470        480 
QDLLAHAFFR EERGVHVELA EEDDGEKPGL KLWLRMEDAR RGGRPRDNQA IEFLFQLGRD 

       490        500        510        520        530        540 
AAEEVAQEMV ALGLVCEADY QPVARAVRER VAAIQRKREK LRKARELEVL PPDSGPPPAT 

       550        560        570        580        590        600 
VSLAPGPPSA FPPEPEEPEA DQHQSFLFRH ASYSSTTSDC ETDGYLSSSG FLDASDPALQ 

       610        620        630        640        650        660 
PPGGLPSSPA ESHLCLPSGF ALSIPRSGPG SDFSPGDSYA SDAASGLSDM GEGGQMRKNP 

       670        680        690        700        710        720 
VKTLRRRPRS RLRVTSVSDQ SDRVVECQLQ THNSKMVTFR FDLDGDSPEE IAAAMVYNEF 

       730        740        750        760        770        780 
ILPSERDGFL SRIREIIQRV ETLLKRDAGP PEAAEDALSP QEEPAALPAL PGPPNAEPQR 

       790        800        810        820        830        840 
SISPEQRSWA AFSTSPSSPG TPLSPGAPFS PGTPPVFPCP IFPITSPSCY PCPFSQVSSN 

       850        860        870        880        890        900 
PYPQAPSSLL PLSSSASQVP LPSSSLPISA PLPFSPSYPQ DPLSPTSLPV CPSPPSLPST 

       910        920        930        940        950        960 
TAAPLLSLAS AFSLAVMTVA QSLLSPSPGL LSQSPPAPPG PLPSLPLSLA SCDQESLSAQ 

       970        980        990       1000       1010       1020 
TAETENEASR NPAQPLLGDA RLAPISEEGK PQLVGRFQVT SSKEPAEPPL QPASPTLSRS 

      1030       1040       1050       1060       1070       1080 
LKLPSPPLTS ESSDTEDSAA GGPETREALA ESDRAAEGLG VAVDDEKDEG KEPLLGGSSP 

      1090       1100       1110       1120       1130       1140 
ILSHPSPVWM NYSYSSLCLS SEESESSGED EEFWAELQNL RQKHLSEVEA LQTLQKKEIE 

      1150       1160       1170       1180       1190       1200 
DLYSRLGKQP PPGIVAPAAM LSCRQRRLSK GSFPTSRRNS LQRSDLPGPG IMRRNSLSGS 

      1210       1220 
STGSQEQRAS KGVTFAGDIG RM 

« Hide

References

« Hide 'large scale' references
[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]"Lineage-specific biology revealed by a finished genome assembly of the mouse."
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. expand/collapse author list , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
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]"Human hypertension caused by mutations in WNK kinases."
Wilson F.H., Disse-Nicodeme S., Choate K.A., Ishikawa K., Nelson-Williams C., Desitter I., Gunel M., Milford D.V., Lipkin G.W., Achard J.-M., Feely M.P., Dussol B., Berland Y., Unwin R.J., Mayan H., Simon D.B., Farfel Z., Jeunemaitre X., Lifton R.P.
Science 293:1107-1112(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[6]"WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion."
Kahle K.T., Wilson F.H., Leng Q., Lalioti M.D., O'Connell A.D., Dong K., Rapson A.K., MacGregor G.G., Giebisch G., Hebert S.C., Lifton R.P.
Nat. Genet. 35:372-376(2003) [PubMed] [Europe PMC] [Abstract]
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]"Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension."
Wakabayashi M., Mori T., Isobe K., Sohara E., Susa K., Araki Y., Chiga M., Kikuchi E., Nomura N., Mori Y., Matsuo H., Murata T., Nomura S., Asano T., Kawaguchi H., Nonoyama S., Rai T., Sasaki S., Uchida S.
Cell Rep. 3:858-868(2013) [PubMed] [Europe PMC] [Abstract]
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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
CCDSCCDS25459.1.
RefSeqNP_783569.1. NM_175638.3.
UniGeneMm.23656.

3D structure databases

ProteinModelPortalQ80UE6.
SMRQ80UE6. Positions 160-520.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

DIPDIP-33231N.
IntActQ80UE6. 3 interactions.
MINTMINT-4980938.

PTM databases

PhosphoSiteQ80UE6.

Proteomic databases

PaxDbQ80UE6.
PRIDEQ80UE6.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000103108; ENSMUSP00000099397; ENSMUSG00000035112.
GeneID69847.
KEGGmmu:69847.
UCSCuc007loe.2. mouse.

Organism-specific databases

CTD65266.
MGIMGI:1917097. Wnk4.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00550000074385.
HOVERGENHBG050347.
InParanoidA2A4J7.
KOK08867.
OMAESHLRLP.
OrthoDBEOG7KDF8Z.
PhylomeDBQ80UE6.
TreeFamTF315363.

Gene expression databases

ArrayExpressQ80UE6.
BgeeQ80UE6.
CleanExMM_WNK4.
GenevestigatorQ80UE6.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR024678. Kinase_OSR1/WNK_CCT.
IPR000719. Prot_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF12202. OSR1_C. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 2 hits.
PROSITEPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio330461.
PROQ80UE6.
SOURCESearch...

Entry information

Entry nameWNK4_MOUSE
AccessionPrimary (citable) accession number: Q80UE6
Secondary accession number(s): A2A4J7 expand/collapse secondary AC list , Q4VAC1, Q80XB5, Q80XN2, Q8R0N0, Q8R340
Entry history
Integrated into UniProtKB/Swiss-Prot: February 2, 2004
Last sequence update: June 1, 2003
Last modified: July 9, 2014
This is version 106 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot