WNK4_RAT
ID WNK4_RAT Reviewed; 1222 AA.
AC Q7TPK6; Q810H4; Q811R5;
DT 02-FEB-2004, integrated into UniProtKB/Swiss-Prot.
DT 30-AUG-2005, sequence version 3.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=Serine/threonine-protein kinase WNK4 {ECO:0000305};
DE EC=2.7.11.1 {ECO:0000250|UniProtKB:Q9H4A3};
DE AltName: Full=Protein kinase lysine-deficient 4 {ECO:0000312|RGD:631401};
DE AltName: Full=Protein kinase with no lysine 4 {ECO:0000305};
GN Name=Wnk4 {ECO:0000312|RGD:631401};
GN Synonyms=Prkwnk4 {ECO:0000303|PubMed:14608358};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Wistar Kyoto {ECO:0000269|PubMed:12642508};
RC TISSUE=Kidney {ECO:0000312|EMBL:AAO18238.1};
RX PubMed=12642508; DOI=10.1161/01.hyp.0000063147.92433.7d;
RA Monti J., Zimdahl H., Schulz H., Plehm R., Ganten D., Hubner N.;
RT "The role of Wnk4 in polygenic hypertension: a candidate gene analysis on
RT rat chromosome 10.";
RL Hypertension 41:938-942(2003).
RN [2] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Wistar Kyoto {ECO:0000269|PubMed:14608358};
RC TISSUE=Kidney {ECO:0000312|EMBL:AAO38858.1};
RX PubMed=14608358; DOI=10.1038/ng1271;
RA Kahle K.T., Wilson F.H., Leng Q., Lalioti M.D., O'Connell A.D., Dong K.,
RA Rapson A.K., MacGregor G.G., Giebisch G., Hebert S.C., Lifton R.P.;
RT "WNK4 regulates the balance between renal NaCl reabsorption and K+
RT secretion.";
RL Nat. Genet. 35:372-376(2003).
RN [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1014, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Serine/threonine kinase which plays an important role in the
CC regulation of electrolyte homeostasis, cell signaling, survival and
CC proliferation. Acts as an activator and inhibitor of sodium-coupled
CC chloride cotransporters and potassium-coupled chloride cotransporters
CC respectively. Activates SCNN1A, SCNN1B, SCNN1D, SGK1, TRPV5 and TRPV6.
CC Regulates the activity of the thiazide-sensitive Na-Cl cotransporter,
CC SLC12A3, by phosphorylation which appears to prevent membrane
CC trafficking of SLC12A3. Also inhibits the renal K(+) channel, KCNJ1,
CC via a kinase-independent mechanism by which it induces clearance of the
CC protein from the cell surface by clathrin-dependent endocytosis. WNK4
CC appears to act as a molecular switch that can vary the balance between
CC NaCl reabsorption and K(+) secretion to maintain integrated
CC homeostasis. Acts as a scaffold to inhibit SLC4A4 as well as CFTR
CC activities and surface expression, recruits STK39 which mediates the
CC inhibition. Phosphorylates NEDD4L (By similarity).
CC {ECO:0000250|UniProtKB:Q80UE6, ECO:0000250|UniProtKB:Q96J92}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC Evidence={ECO:0000250|UniProtKB:Q9H4A3};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1; Evidence={ECO:0000250|UniProtKB:Q9H4A3};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q9H4A3};
CC -!- ACTIVITY REGULATION: Activation requires autophosphorylation of Ser-
CC 332. Phosphorylation of Ser-328 also promotes increased activity (By
CC similarity). {ECO:0000250|UniProtKB:Q9JIH7}.
CC -!- SUBUNIT: Interacts with the C-terminal region of KCNJ1. Interacts with
CC WNK1 and WNK3. Interacts with KLHL3. {ECO:0000250|UniProtKB:Q96J92}.
CC -!- SUBCELLULAR LOCATION: Cell junction, tight junction
CC {ECO:0000250|UniProtKB:Q80UE6}. Note=Present exclusively in
CC intercellular junctions in the distal convoluted tubule and in both the
CC cytoplasm and intercellular junctions in the cortical collecting duct.
CC WNK4 is part of the tight junction complex.
CC {ECO:0000250|UniProtKB:Q80UE6}.
CC -!- PTM: Phosphorylated by WNK1 and WNK3. {ECO:0000250|UniProtKB:Q80UE6}.
CC -!- PTM: Ubiquitinated by the BCR(KLHL3) complex, leading to its
CC degradation and increased expression of KCNJ1 at the cell surface.
CC Ubiquitinated by the BCR(KLHL2) complex (By similarity).
CC {ECO:0000250|UniProtKB:Q96J92}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC kinase family. WNK subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC -!- CAUTION: Was named WNK/'with no lysine(K)' because key residues for
CC catalysis, including the lysine involved in ATP binding, are either not
CC conserved or differ compared to the residues described in other kinase
CC family proteins. {ECO:0000250|UniProtKB:Q9H4A3}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAO18238.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AY187039; AAO18238.1; ALT_FRAME; mRNA.
DR EMBL; AY192567; AAO38858.1; -; mRNA.
DR RefSeq; NP_783169.2; NM_175579.3.
DR AlphaFoldDB; Q7TPK6; -.
DR SMR; Q7TPK6; -.
DR DIP; DIP-59689N; -.
DR IntAct; Q7TPK6; 1.
DR STRING; 10116.ENSRNOP00000027770; -.
DR iPTMnet; Q7TPK6; -.
DR PhosphoSitePlus; Q7TPK6; -.
DR jPOST; Q7TPK6; -.
DR PaxDb; Q7TPK6; -.
DR PRIDE; Q7TPK6; -.
DR Ensembl; ENSRNOT00000027770; ENSRNOP00000027770; ENSRNOG00000020441.
DR GeneID; 287715; -.
DR KEGG; rno:287715; -.
DR UCSC; RGD:631401; rat.
DR CTD; 65266; -.
DR RGD; 631401; Wnk4.
DR eggNOG; KOG0584; Eukaryota.
DR GeneTree; ENSGT00940000159871; -.
DR InParanoid; Q7TPK6; -.
DR OMA; AMVHNEF; -.
DR OrthoDB; 27514at2759; -.
DR PhylomeDB; Q7TPK6; -.
DR TreeFam; TF315363; -.
DR Reactome; R-RNO-2672351; Stimuli-sensing channels.
DR PRO; PR:Q7TPK6; -.
DR Proteomes; UP000002494; Chromosome 10.
DR Bgee; ENSRNOG00000020441; Expressed in kidney and 19 other tissues.
DR ExpressionAtlas; Q7TPK6; baseline and differential.
DR Genevisible; Q7TPK6; RN.
DR GO; GO:0005923; C:bicellular tight junction; ISS:UniProtKB.
DR GO; GO:0044297; C:cell body; ISO:RGD.
DR GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR GO; GO:0005829; C:cytosol; IDA:ParkinsonsUK-UCL.
DR GO; GO:0016020; C:membrane; IDA:ParkinsonsUK-UCL.
DR GO; GO:0032991; C:protein-containing complex; ISO:RGD.
DR GO; GO:0005524; F:ATP binding; ISS:UniProtKB.
DR GO; GO:0019869; F:chloride channel inhibitor activity; ISO:RGD.
DR GO; GO:0019870; F:potassium channel inhibitor activity; IBA:GO_Central.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:RGD.
DR GO; GO:0055074; P:calcium ion homeostasis; ISO:RGD.
DR GO; GO:0030003; P:cellular cation homeostasis; ISS:UniProtKB.
DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; ISO:RGD.
DR GO; GO:0006821; P:chloride transport; ISO:RGD.
DR GO; GO:0072156; P:distal tubule morphogenesis; ISS:UniProtKB.
DR GO; GO:0010467; P:gene expression; ISO:RGD.
DR GO; GO:0006954; P:inflammatory response; ISO:RGD.
DR GO; GO:0035556; P:intracellular signal transduction; ISS:UniProtKB.
DR GO; GO:0050801; P:ion homeostasis; ISS:UniProtKB.
DR GO; GO:0006811; P:ion transport; ISS:UniProtKB.
DR GO; GO:0042116; P:macrophage activation; ISO:RGD.
DR GO; GO:0090188; P:negative regulation of pancreatic juice secretion; ISO:RGD.
DR GO; GO:0010766; P:negative regulation of sodium ion transport; IDA:UniProtKB.
DR GO; GO:1903288; P:positive regulation of potassium ion import across plasma membrane; IBA:GO_Central.
DR GO; GO:2000651; P:positive regulation of sodium ion transmembrane transporter activity; IBA:GO_Central.
DR GO; GO:0008104; P:protein localization; ISO:RGD.
DR GO; GO:0006468; P:protein phosphorylation; IDA:RGD.
DR GO; GO:0070294; P:renal sodium ion absorption; ISS:UniProtKB.
DR GO; GO:0035725; P:sodium ion transmembrane transport; ISO:RGD.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR024678; Kinase_OSR1/WNK_CCT.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF12202; OSR1_C; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cell junction; Isopeptide bond; Kinase; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Tight junction; Transferase; Ubl conjugation.
FT CHAIN 1..1222
FT /note="Serine/threonine-protein kinase WNK4"
FT /id="PRO_0000086826"
FT DOMAIN 171..429
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..163
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 527..562
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 591..612
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 626..679
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 747..809
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 836..873
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 927..1087
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1169..1222
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..32
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 44..60
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 61..78
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 79..93
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 139..160
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 531..555
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 779..800
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 836..863
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 931..946
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 951..971
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 995..1039
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1047..1073
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1169..1183
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1194..1211
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 318
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:Q9JIH7"
FT BINDING 181
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9H4A3"
FT BINDING 251..254
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9H4A3"
FT BINDING 301
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q9H4A3"
FT MOD_RES 95
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96J92"
FT MOD_RES 328
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q9JIH7"
FT MOD_RES 332
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q9JIH7"
FT MOD_RES 1014
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 1196
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q80UE6"
FT CROSSLNK 154
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q96J92"
FT CROSSLNK 172
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q96J92"
FT CROSSLNK 183
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q96J92"
FT CROSSLNK 223
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q96J92"
FT CROSSLNK 238
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q96J92"
FT CROSSLNK 325
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q96J92"
FT CROSSLNK 384
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q96J92"
FT CROSSLNK 390
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q96J92"
FT CROSSLNK 447
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q96J92"
FT CROSSLNK 451
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q96J92"
FT CROSSLNK 990
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q96J92"
FT CROSSLNK 1123
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q96J92"
FT CROSSLNK 1136
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q96J92"
FT CROSSLNK 1137
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q96J92"
FT CONFLICT 9
FT /note="T -> R (in Ref. 1; AAO18238)"
FT /evidence="ECO:0000305"
FT CONFLICT 204
FT /note="T -> A (in Ref. 1; AAO18238)"
FT /evidence="ECO:0000305"
FT CONFLICT 764
FT /note="P -> A (in Ref. 1; AAO18238)"
FT /evidence="ECO:0000305"
FT CONFLICT 776
FT /note="A -> E (in Ref. 1; AAO18238)"
FT /evidence="ECO:0000305"
FT CONFLICT 1194
FT /note="R -> K (in Ref. 1; AAO18238)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1222 AA; 132833 MW; E7E53DAC9D1FA446 CRC64;
MLAPRNTETG VHMSQTEADL ALRPSPSLTS MGPTRLGPPP RRVRRFSGKA EPRPRSSRPS
RRSSVDLGLL SSWSQPASLL PEPPDPPDSA GPMRSPPSNS KEHPEGTWTG AAPVKAADSA
CPELTVSSGG PGSREPPRVP DAAARERRRE QEEKEDTETQ AVATSPDGRY LKFDIEIGRG
SFKTVYRGLD TDTTVEVAWC ELQTRKLSRA ERQRFSEEVE MLKGLQHPNI VRFYDSWKSV
LRGQVCIVLV TELMTSGTLK TYLRRFREMK PRVLQRWSRQ ILRGLHFLHS RVPPILHRDL
KCDNVFITGP SGSVKIGDLG LATLKRASFA KSVIGTPEFM APEMYEEKYD EAVDVYAFGM
CMLEMATSEY PYSECQNAAQ IYRKVTSGTK PNSFYKVKMP EVKEIIEGCI RTDKNERFTI
QDLLTHAFFR EERGVHVELA EEDDGEKPGL KLWLRMEDAR RGGRPRDNQA IEFLFQLGRD
AAEEVAQEMV ALGLVCEADY QPVARAVRER VAAIQRKREK LRKARELEVL PPDSGPPPAT
VSMTPGPPSA FPPEPEEPEA DQHQSFLFRH ASYSSTTSDC ETDGYLSSSG FLDASDPALQ
PPGGMPSSPA EPHLCLPSGF ALSIPRSGPG SDFSPGDSYA SDAASGLSDM GEGGQMRKNP
VKTLRRRPRS RLRVTSVSDQ SDRVVECQLQ THNSKMVTFR FDLDGDSPEE IAAAMVYNEF
ILPSERDGFL SRIREIIQRV ETLLKRDAGP SEATEDALSP QEEPAAMPAL PGPSDAELQR
SISPEQRSWA AFSTSPSSPG TPLSPGTPFS PGTPPVFPCP IFPITSPSCH PYPFSQVSSN
PCPQAPSSLL PSSSGASQVP FPSPSLPTSS PLPFSPSYPQ VPLHPASLPT CPSPPPLPST
TAAPLLSLAS AFSLAVMTVA QSLLSPSPGL LSQSPPAPPG PLPSMPLPLA SCDQESLSAQ
TAETENEASR NPAQPLLGDA RLAPISEEGK PQLVGRFQVT SSKEPAEPPL QPASPTLSRS
LKLPTPQLTS ESSDTEDSAA GGPETREALA ESDRAAEGLG VAIDEEKDEG KEPQIGGSSP
ILSQPSPVWM NYSYSSLCLS SEESESSGED EEFWAELQNL RQKHLSEVEA LQTLQKKEIE
DLYSRLGKQP PPGIVAPAAM LSCRQRRLSK GSFPTSRRNS LQRSDLPGPG IMRRNSLSGS
STGSQEQRAS KGVTFAGDVG RM
