| Structural highlights
4pwn is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: |
| | Related: | 3fpq, 4q2a |
| Activity: | Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Disease
[WNK1_HUMAN] Hereditary sensory and autonomic neuropathy type 2;Pseudohypoaldosteronism type 2C. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
Function
[WNK1_HUMAN] 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 and SGK1. Controls sodium and chloride ion transport by inhibiting the activity of WNK4, by either phosphorylating the kinase or via an interaction between WNK4 and the autoinhibitory domain of WNK1. WNK4 regulates the activity of the thiazide-sensitive Na-Cl cotransporter, SLC12A3, by phosphorylation. WNK1 may also play a role in actin cytoskeletal reorganization. Phosphorylates NEDD4L.[1] [2]
Publication Abstract from PubMed
WNK1 [with no lysine (K)] is a serine-threonine kinase associated with a form of familial hypertension. WNK1 is at the top of a kinase cascade, leading to phosphorylation of several cotransporters, in particular those transporting sodium, potassium, and chloride (NKCC), sodium and chloride (NCC), and potassium and chloride (KCC). The responsiveness of NKCC, NCC, and KCC to changes in extracellular chloride parallels their phosphorylation state, provoking the proposal that these transporters are controlled by a chloride-sensitive protein kinase. We found that chloride stabilizes the inactive conformation of WNK1, preventing kinase autophosphorylation and activation. Crystallographic studies of inactive WNK1 in the presence of chloride revealed that chloride binds directly to the catalytic site, providing a basis for the unique position of the catalytic lysine. Mutagenesis of the chloride-binding site rendered the kinase less sensitive to inhibition of autophosphorylation by chloride, validating the binding site. Thus, these data suggest that WNK1 functions as a chloride sensor through direct binding of a regulatory chloride ion to the active site, which inhibits autophosphorylation.
Chloride Sensing by WNK1 Involves Inhibition of Autophosphorylation.,Piala AT, Moon TM, Akella R, He H, Cobb MH, Goldsmith EJ Sci Signal. 2014 May 6;7(324):ra41. doi: 10.1126/scisignal.2005050. PMID:24803536[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Moore TM, Garg R, Johnson C, Coptcoat MJ, Ridley AJ, Morris JD. PSK, a novel STE20-like kinase derived from prostatic carcinoma that activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and regulates actin cytoskeletal organization. J Biol Chem. 2000 Feb 11;275(6):4311-22. PMID:10660600
- ↑ Lafreniere RG, MacDonald ML, Dube MP, MacFarlane J, O'Driscoll M, Brais B, Meilleur S, Brinkman RR, Dadivas O, Pape T, Platon C, Radomski C, Risler J, Thompson J, Guerra-Escobio AM, Davar G, Breakefield XO, Pimstone SN, Green R, Pryse-Phillips W, Goldberg YP, Younghusband HB, Hayden MR, Sherrington R, Rouleau GA, Samuels ME. Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates. Am J Hum Genet. 2004 May;74(5):1064-73. Epub 2004 Apr 1. PMID:15060842 doi:http://dx.doi.org/10.1086/420795
- ↑ Piala AT, Moon TM, Akella R, He H, Cobb MH, Goldsmith EJ. Chloride Sensing by WNK1 Involves Inhibition of Autophosphorylation. Sci Signal. 2014 May 6;7(324):ra41. doi: 10.1126/scisignal.2005050. PMID:24803536 doi:http://dx.doi.org/10.1126/scisignal.2005050
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