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Q80UE6

- WNK4_MOUSE

UniProt

Q80UE6 - WNK4_MOUSE

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
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    • History
      Entry version 108 (01 Oct 2014)
      Sequence version 1 (01 Jun 2003)
      Previous versions | rss
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    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. protein binding Source: IntAct
    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

    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

    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

    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.
    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.
    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

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    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.

    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 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

    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 1, 2014
    This is version 108 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