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Protein

Serine/threonine-protein kinase WNK4

Gene

Wnk4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -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

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

Catalytic activityi

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

Cofactori

Mg2+By similarity

Activity 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

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 Expressed in 204 organ(s), highest expression level in stria vascularis of cochlear duct
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

Protein-protein interaction databases

DIPiDIP-33231N
ELMiQ80UE6
IntActiQ80UE6, 6 interactors
MINTiQ80UE6
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
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, 1 hit
PROSITEiView protein in PROSITE
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 4 potential isoforms that are computationally mapped.Show allAlign All

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

Computationally mapped potential isoform sequencesi

There are 4 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
F6X7K7F6X7K7_MOUSE
Serine/threonine-protein kinase WNK...
Wnk4
153Annotation score:
E9PZ38E9PZ38_MOUSE
Serine/threonine-protein kinase WNK...
Wnk4
413Annotation score:
E9Q470E9Q470_MOUSE
Serine/threonine-protein kinase WNK...
Wnk4
285Annotation score:
F6Z709F6Z709_MOUSE
Serine/threonine-protein kinase WNK...
Wnk4
30Annotation score:

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 No translation available.
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

Cross-referencesi

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 No translation available.
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

3D structure databases

ProteinModelPortaliQ80UE6
SMRiQ80UE6
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-33231N
ELMiQ80UE6
IntActiQ80UE6, 6 interactors
MINTiQ80UE6
STRINGi10090.ENSMUSP00000099397

PTM databases

iPTMnetiQ80UE6
PhosphoSitePlusiQ80UE6

Proteomic databases

MaxQBiQ80UE6
PaxDbiQ80UE6
PRIDEiQ80UE6

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi65266
MGIiMGI:1917097 Wnk4

Phylogenomic databases

eggNOGiKOG0584 Eukaryota
ENOG410XQWZ LUCA
GeneTreeiENSGT00800000124049
HOVERGENiHBG050347
InParanoidiQ80UE6
KOiK08867
OrthoDBiEOG091G06LL
PhylomeDBiQ80UE6
TreeFamiTF315363

Enzyme and pathway databases

ReactomeiR-MMU-2672351 Stimuli-sensing channels

Miscellaneous databases

PROiPR:Q80UE6
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000035112 Expressed in 204 organ(s), highest expression level in stria vascularis of cochlear duct
CleanExiMM_WNK4
ExpressionAtlasiQ80UE6 baseline and differential
GenevisibleiQ80UE6 MM

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, 1 hit
PROSITEiView protein in PROSITE
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit
ProtoNetiSearch...

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 7, 2018
This is version 140 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

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

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