Q96J92 (WNK4_HUMAN) Reviewed, UniProtKB/Swiss-Prot
Last modified
May 29, 2013.
Version 116.
History...
Names·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order
Names·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize orderNames and origin
| Protein names | 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 names |
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| Organism | Homo sapiens (Human) [Reference proteome] | ||||
| Taxonomic identifier | 9606 [NCBI] | ||||
| Taxonomic lineage | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo![]() |
Protein attributes
| Sequence length | 1243 AA. |
| Sequence status | Complete. |
| Protein existence | Evidence 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.5 |
| Catalytic activity | ATP + a protein = ADP + a phosphoprotein. |
| Cofactor | Magnesium By similarity. UniProtKB Q9H4A3 |
| Enzyme regulation | Activation requires autophosphorylation of Ser-335. Phosphorylation of Ser-331 also promotes increased activity By similarity. UniProtKB Q9JIH7 |
| Subunit structure | Interacts with the C-terminal region of KCNJ1 By similarity. Interacts with WNK1 and WNK3 By similarity. UniProtKB Q80UE6 |
| Subcellular location | Cell junction › tight junction By similarity. 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 By similarity. |
| Tissue specificity | Expressed in kidney, colon and skin. Ref.4 |
| Post-translational modification | Phosphorylated by WNK1 and WNK3 By similarity. |
| Involvement in disease | Pseudohypoaldosteronism 2B (PHA2B) [MIM:614491]: An autosomal dominant disorder characterized by hypertension, hyperkalemia, hyperchloremia, mild hyperchloremic metabolic acidosis, and correction of physiologic abnormalities by thiazide diuretics. |
| Sequence similarities | Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. WNK subfamily. Contains 1 protein kinase domain. |
| Caution | Cys-203 is present instead of the conserved Lys which is expected to be an active site residue. Lys-186 appears to fulfill the required catalytic function. UniProtKB Q9JIH7 |
| Sequence caution | The sequence BAC04669.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended. The sequence CAC48387.1 differs from that shown. Reason: Frameshift at position 4. |
Ontologies
Alternative products
| This entry describes 3 isoforms produced by alternative splicing. [Align] [Select] | ||||||
| Isoform 1 Ref.1 (identifier: Q96J92-1) This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. | ||||||
| Isoform 2 (identifier: Q96J92-2) The sequence of this isoform differs from the canonical sequence as follows: 1-228: Missing. 229-264: QHPNIVRFYDSWKSVLRGQVCIVLVTELMTSGTLKT → MRRRQQGAAGGNFPVGGSFPEDVSPHQDSGYAPSPR 828-1210: Missing. 1233-1243: GVTFAGDVGRM → EAGQRPGKLWLRATVQLRVWGLELRRKEMMGRNPKLGAAPNP | ||||||
| Note: No experimental confirmation available. | ||||||
| Isoform 3 (identifier: Q96J92-3) The sequence of this isoform differs from the canonical sequence as follows: 1145-1165: HLSEVETLQTLQKKEIEDLYS → PFHALRASSGTCQRWKHYRHY 1166-1243: Missing. | ||||||
| Note: No experimental confirmation available. Incomplete sequence. |
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | ||||
Molecule processing | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Chain | 1 – 1243 | 1243 | Serine/threonine-protein kinase WNK4 | PRO_0000086824 | |||||
Regions | |||||||||
| Domain | 174 – 432 | 259 | Protein kinase | ||||||
| Nucleotide binding | 180 – 188 | 9 | ATP By similarity UniProtKB Q8TDX7 | ||||||
Sites | |||||||||
| Active site | 302 | 1 | Proton acceptor By similarity UniProtKB Q8TDX7 | ||||||
| Binding site | 186 | 1 | ATP By similarity UniProtKB Q9JIH7 | ||||||
Amino acid modifications | |||||||||
| Modified residue | 331 | 1 | Phosphoserine; by autocatalysis By similarity UniProtKB Q9JIH7 | ||||||
| Modified residue | 335 | 1 | Phosphoserine; by autocatalysis By similarity UniProtKB Q9JIH7 | ||||||
Natural variations | |||||||||
| Alternative sequence | 1 – 228 | 228 | Missing in isoform 2. | VSP_050648 | |||||
| Alternative sequence | 229 – 264 | 36 | QHPNI…GTLKT → MRRRQQGAAGGNFPVGGSFP EDVSPHQDSGYAPSPR in isoform 2. | VSP_050649 | |||||
| Alternative sequence | 828 – 1210 | 383 | Missing in isoform 2. | VSP_050650 | |||||
| Alternative sequence | 1145 – 1165 | 21 | HLSEV…EDLYS → PFHALRASSGTCQRWKHYRH Y in isoform 3. | VSP_050652 | |||||
| Alternative sequence | 1166 – 1243 | 78 | Missing in isoform 3. | VSP_050653 | |||||
| Alternative sequence | 1233 – 1243 | 11 | GVTFAGDVGRM → EAGQRPGKLWLRATVQLRVW GLELRRKEMMGRNPKLGAAP NP in isoform 2. | VSP_050651 | |||||
| Natural variant | 434 | 1 | E → D in an ovarian mucinous carcinoma sample; somatic mutation. Ref.6 | VAR_041330 | |||||
| Natural variant | 562 | 1 | E → K in PHA2B. Ref.1 | VAR_017588 | |||||
| Natural variant | 564 | 1 | D → A in PHA2B. Ref.1 | VAR_017589 | |||||
| Natural variant | 565 | 1 | Q → E in PHA2B. Ref.1 | VAR_017590 | |||||
| Natural variant | 601 | 1 | A → S. Corresponds to variant rs55781437 [ dbSNP | Ensembl ]. | VAR_061748 | |||||
| Natural variant | 677 | 1 | R → W. Corresponds to variant rs9896991 [ dbSNP | Ensembl ]. | VAR_051685 | |||||
| Natural variant | 813 | 1 | P → L. Ref.6 | VAR_041331 | |||||
| Natural variant | 961 | 1 | P → S. Corresponds to variant rs2290041 [ dbSNP | Ensembl ]. | VAR_051686 | |||||
| Natural variant | 992 | 1 | P → S in a metastatic melanoma sample; somatic mutation. Ref.6 | VAR_041332 | |||||
| Natural variant | 1013 | 1 | L → P. Ref.6 | VAR_041333 | |||||
| Natural variant | 1185 | 1 | R → C in PHA2B. Ref.1 | VAR_017591 | |||||
Experimental info | |||||||||
| Sequence conflict | 525 | 1 | R → C in BAC04688. Ref.3 | ||||||
Sequences
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References
| « Hide 'large scale' references | |
| [1] | "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: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), DISEASE, VARIANTS PHA2B LYS-562; ALA-564; GLU-565 AND CYS-1185. Tissue: Kidney. |
| [2] | Chistiakov D.A. Thesis (2001), College de France / Paris, France Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Kidney. |
| [3] | "Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. Sugano S.Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 504-1165 (ISOFORM 3). Tissue: Kidney. |
| [4] | "WNK kinases, a novel protein kinase subfamily in multi-cellular organisms." Verissimo F., Jordan P. Oncogene 20:5562-5569(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 207-418 (ISOFORMS 1/3), TISSUE SPECIFICITY, CHROMOSOMAL LOCATION. Tissue: Colon. |
| [5] | "Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium channel are regulated by multiple with no lysine (WNK) family members." Heise C.J., Xu B.E., Deaton S.L., Cha S.K., Cheng C.J., Earnest S., Sengupta S., Juang Y.C., Stippec S., Xu Y., Zhao Y., Huang C.L., Cobb M.H. J. Biol. Chem. 285:25161-25167(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION. |
| [6] | "Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. Stratton M.R.Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] ASP-434; LEU-813; SER-992 AND PRO-1013. |
| + | Additional computationally mapped references. |
Web resources
Cross-references
Sequence databases | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| EMBL GenBank DDBJ | AF390018 mRNA. Translation: AAK91995.1. AJ316534 mRNA. Translation: CAC48387.1. Frameshift. AK096003 mRNA. Translation: BAC04669.1. Different initiation. AK096052 mRNA. Translation: BAC04688.1. AJ309861 mRNA. Translation: CAC32991.1. | ||||||||||||
| IPI | IPI00151141. IPI00398442. IPI00398443. | ||||||||||||
| RefSeq | NP_115763.2. NM_032387.4. | ||||||||||||
| UniGene | Hs.105448. | ||||||||||||
3D structure databases | |||||||||||||
| PDBe RCSB PDB PDBj |
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| ProteinModelPortal | Q96J92. | ||||||||||||
| ModBase | Search... | ||||||||||||
Protein-protein interaction databases | |||||||||||||
| IntAct | Q96J92. 3 interactions. | ||||||||||||
| MINT | MINT-5207492. | ||||||||||||
| STRING | 9606.ENSP00000246914. | ||||||||||||
PTM databases | |||||||||||||
| PhosphoSite | Q96J92. | ||||||||||||
Polymorphism databases | |||||||||||||
| DMDM | 41688789. | ||||||||||||
Proteomic databases | |||||||||||||
| PaxDb | Q96J92. | ||||||||||||
| PRIDE | Q96J92. | ||||||||||||
Protocols and materials databases | |||||||||||||
| StructuralBiologyKnowledgebase | Search... | ||||||||||||
Genome annotation databases | |||||||||||||
| Ensembl | ENST00000246914; ENSP00000246914; ENSG00000126562. | ||||||||||||
| GeneID | 65266. | ||||||||||||
| KEGG | hsa:65266. | ||||||||||||
| UCSC | uc002ibj.3. human. | ||||||||||||
Organism-specific databases | |||||||||||||
| CTD | 65266. | ||||||||||||
| GeneCards | GC17P040932. | ||||||||||||
| HGNC | HGNC:14544. WNK4. | ||||||||||||
| HPA | HPA016500. | ||||||||||||
| MIM | 601844. gene. 614491. phenotype. | ||||||||||||
| neXtProt | NX_Q96J92. | ||||||||||||
| Orphanet | 88939. Pseudohypoaldosteronism type 2B. | ||||||||||||
| PharmGKB | PA134875400. | ||||||||||||
| GenAtlas | Search... | ||||||||||||
Phylogenomic databases | |||||||||||||
| eggNOG | COG0515. | ||||||||||||
| HOGENOM | HOG000230962. | ||||||||||||
| HOVERGEN | HBG050347. | ||||||||||||
| InParanoid | Q96J92. | ||||||||||||
| KO | K08867. | ||||||||||||
| OMA | WAELQNL. | ||||||||||||
| OrthoDB | EOG4DFPN4. | ||||||||||||
| PhylomeDB | Q96J92. | ||||||||||||
Enzyme and pathway databases | |||||||||||||
| SignaLink | Q96J92. | ||||||||||||
Gene expression databases | |||||||||||||
| ArrayExpress | Q96J92. | ||||||||||||
| Bgee | Q96J92. | ||||||||||||
| CleanEx | HS_WNK4. | ||||||||||||
| Genevestigator | Q96J92. | ||||||||||||
| GermOnline | ENSG00000126562. Homo sapiens. | ||||||||||||
Family and domain databases | |||||||||||||
| InterPro | IPR011009. Kinase-like_dom. IPR024678. Kinase_OSR1/WNK_CCT. IPR000719. Prot_kinase_cat_dom. IPR008271. Ser/Thr_kinase_AS. [Graphical view] | ||||||||||||
| Pfam | PF12202. OSR1_C. 1 hit. PF00069. Pkinase. 1 hit. [Graphical view] | ||||||||||||
| SUPFAM | SSF56112. Kinase_like. 1 hit. | ||||||||||||
| PROSITE | PS00107. PROTEIN_KINASE_ATP. False negative. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view] | ||||||||||||
| ProtoNet | Search... | ||||||||||||
Other | |||||||||||||
| ChEMBL | CHEMBL1795196. | ||||||||||||
| ChiTaRS | WNK4. human. | ||||||||||||
| EvolutionaryTrace | Q96J92. | ||||||||||||
| GenomeRNAi | 65266. | ||||||||||||
| NextBio | 67398. | ||||||||||||
| SOURCE | Search... | ||||||||||||
Entry information
| Entry name | WNK4_HUMAN | ||||||||
| Accession | Primary (citable) accession number: Q96J92 Secondary accession number(s): Q8N8X3 Q9BYS5 | ||||||||
| Entry history |
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| Entry status | Reviewed (UniProtKB/Swiss-Prot) | ||||||||
| Annotation program | Chordata Protein Annotation Program | ||||||||
| Disclaimer | Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. | ||||||||
Relevant documents
| Human and mouse protein kinases Human and mouse protein kinases: classification and index |
| Human chromosome 17 Human chromosome 17: entries, gene names and cross-references to MIM |
| Human entries with polymorphisms or disease mutations List of human entries with polymorphisms or disease mutations |
| Human polymorphisms and disease mutations Index of human polymorphisms and disease mutations |
| MIM cross-references Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot |
| PDB cross-references Index of Protein Data Bank (PDB) cross-references |
| SIMILARITY comments Index of protein domains and families |

Clusters with
