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Protein

Serine/threonine-protein kinase WNK4

Gene

Wnk4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: 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. Acts as a scaffold to inhibit SLC4A4 as well as CFTR activities and surface expression, recruits STK39 which mediates the inhibition (PubMed:21317537).4 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.By similarity

Cofactori

Mg2+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)DescriptionActionsGraphical viewLength
Binding sitei181ATP; via amide nitrogenBy similarity1
Binding sitei301ATPBy similarity1
Active sitei318Proton acceptorBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi251 – 254ATPBy similarity4

GO - Molecular functioni

GO - Biological processi

  • cellular chloride ion homeostasis Source: MGI
  • chloride transport Source: MGI
  • distal tubule morphogenesis Source: UniProtKB
  • intracellular signal transduction Source: UniProtKB
  • ion homeostasis Source: UniProtKB
  • ion transport Source: UniProtKB
  • negative regulation of pancreatic juice secretion Source: MGI
  • negative regulation of sodium ion transport Source: UniProtKB
  • protein localization Source: MGI
  • protein phosphorylation Source: UniProtKB
  • regulation of cellular process Source: UniProtKB
  • renal sodium ion absorption Source: UniProtKB

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-MMU-2672351. Stimuli-sensing channels.

Names & Taxonomyi

Protein namesi
Recommended name:
Serine/threonine-protein kinase WNK4Curated (EC:2.7.11.1By similarity)
Alternative name(s):
Protein kinase lysine-deficient 4Imported
Protein kinase with no lysine 41 Publication
Gene namesi
Name:Wnk4Imported
Synonyms:Prkwnk4Imported
OrganismiMus musculus (Mouse)Imported
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 11

Organism-specific databases

MGIiMGI:1917097. Wnk4.

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

Keywords - Cellular componenti

Cell junction, Tight junction

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi318D → A: No effect on inhibition of KCNJ1. 1 Publication1
Mutagenesisi318D → E: No effect on inhibition of SLC4A4. 1 Publication1
Mutagenesisi559E → K: No effect on inhibition of SLC12A3. 1 Publication1
Mutagenesisi561D → A: Increased protein level, probably due to defects in ubiquitination. No effect on inhibition of SLC12A3. 2 Publications1
Mutagenesisi562Q → E: Increased protein level, probably due to defects in ubiquitination. Prevents inhibition of SLC12A3. 2 Publications1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000868251 – 1222Serine/threonine-protein kinase WNK4Add BLAST1222

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei95PhosphoserineBy similarity1
Cross-linki154Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki172Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki183Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki223Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki238Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki325Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei328Phosphoserine; by autocatalysisBy similarity1
Modified residuei332Phosphoserine; by autocatalysisBy similarity1
Cross-linki384Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki390Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki447Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki451Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki990Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei1014PhosphoserineBy similarity1
Cross-linki1123Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki1136Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki1137Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei1196PhosphoserineCombined sources1

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

MaxQBiQ80UE6.
PaxDbiQ80UE6.
PRIDEiQ80UE6.

PTM databases

iPTMnetiQ80UE6.
PhosphoSitePlusiQ80UE6.

Expressioni

Tissue specificityi

Locates to the distal convoluted tubule, the medullary collecting duct and the cortical collecting duct of the kidney (PubMed:11498583). Expressed in pancreatic duct (PubMed:21317537).2 Publications

Gene expression databases

BgeeiENSMUSG00000035112.
CleanExiMM_WNK4.
ExpressionAtlasiQ80UE6. baseline and differential.
GenevisibleiQ80UE6. MM.

Interactioni

Subunit structurei

Interacts with the C-terminal region of KCNJ1 (PubMed:14608358). Interacts with WNK1 and WNK3 (PubMed:17975670). Interacts with KLHL3 (By similarity).By similarity2 Publications

Binary interactionsi

Show more details

Protein-protein interaction databases

DIPiDIP-33231N.
ELMiQ80UE6.
IntActiQ80UE6. 6 interactors.
MINTiMINT-4980938.
STRINGi10090.ENSMUSP00000099397.

Structurei

3D structure databases

ProteinModelPortaliQ80UE6.
SMRiQ80UE6.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini171 – 429Protein kinasePROSITE-ProRule annotationAdd BLAST259

Sequence similaritiesi

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

Phylogenomic databases

eggNOGiKOG0584. Eukaryota.
ENOG410XQWZ. LUCA.
GeneTreeiENSGT00800000124049.
HOVERGENiHBG050347.
InParanoidiQ80UE6.
KOiK08867.
OMAiWAELQNL.
OrthoDBiEOG091G06LL.
PhylomeDBiQ80UE6.
TreeFamiTF315363.

Family and domain databases

InterProiView protein in InterPro
IPR011009. Kinase-like_dom_sf.
IPR024678. Kinase_OSR1/WNK_CCT.
IPR000719. Prot_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
PfamiView protein in Pfam
PF12202. OSR1_C. 1 hit.
PF00069. Pkinase. 1 hit.
SMARTiView protein in SMART
SM00220. S_TKc. 1 hit.
SUPFAMiSSF56112. SSF56112. 2 hits.
PROSITEiView protein in PROSITE
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.

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

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti179R → K in AAO25619 (PubMed:12671053).Curated1
Sequence conflicti607S → F in AAH26679 (PubMed:15489334).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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.

Similar proteinsi

Entry informationi

Entry nameiWNK4_MOUSE
AccessioniPrimary (citable) accession number: Q80UE6
Secondary accession number(s): A2A4J7
, Q4VAC1, Q80XB5, Q80XN2, Q8R0N0, Q8R340
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 2, 2004
Last sequence update: June 1, 2003
Last modified: November 22, 2017
This is version 135 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Caution

Was named WNK/'with no lysine(K)' because key residues for catalysis, including the lysine involved in ATP binding, are either not conserved or differ compared to the residues described in other kinase family proteins.By similarity

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