| Structural highlights
Function
WNK3_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 (PubMed:16275913, PubMed:16275911, PubMed:16357011). Phosphorylates WNK4. Regulates the phosphorylation of SLC12A1 and SLC12A2. Increases Ca(2+) influx mediated by TRPV5 and TRPV6 by enhancing their membrane expression level via a kinase-dependent pathway (PubMed:18768590). Inhibits the activity of KCNJ1 by decreasing its expression at the cell membrane in a non-catalytic manner.[1] [2] [3] [4] [5] [6] [7] Isoform 1, isoform 2, isoform 3 and isoform 4 stimulate the activity of SLC12A1, SLC12A2 and SLC12A3 and inhibit the activity of SLC12A4, SLC12A5, SLC12A6 and SLC12A7. According to PubMed:19470686, isoform 1 inhibits the activity of SLC12A3.[8] [9]
Publication Abstract from PubMed
Osmotic stress and chloride regulate the autophosphorylation and activity of the WNK1 and WNK3 kinase domains. The kinase domain of unphosphorylated WNK1 (uWNK1) is an asymmetric dimer possessing water molecules conserved in multiple uWNK1 crystal structures. Conserved waters are present in two networks, referred to here as conserved water networks 1 and 2 (CWN1 and CWN2). Here, we show that PEG400 applied to crystals of dimeric uWNK1 induces de-dimerization. Both the WNK1 the water networks and the chloride-binding site are disrupted by PEG400. CWN1 is surrounded by a cluster of pan-WNK-conserved charged residues. Here, we mutagenized these charges in WNK3, a highly active WNK isoform kinase domain, and WNK1, the isoform best studied crystallographically. Mutation of E314 in the Activation Loop of WNK3 (WNK3/E314Q and WNK3/E314A, and the homologous WNK1/E388A) enhanced the rate of autophosphorylation, and reduced chloride sensitivity. Other WNK3 mutants reduced the rate of autophosphorylation activity coupled with greater chloride sensitivity than wild-type. The water and chloride regulation thus appear linked. The lower activity of some mutants may reflect effects on catalysis. Crystallography showed that activating mutants introduced conformational changes in similar parts of the structure to those induced by PEG400. WNK activating mutations and crystallography support a role for CWN1 in WNK inhibition consistent with water functioning as an allosteric ligand.
Water and chloride as allosteric inhibitors in WNK kinase osmosensing.,Teixeira LR, Akella R, Humphreys JM, He H, Goldsmith EJ Elife. 2024 Nov 25;12:RP88224. doi: 10.7554/eLife.88224. PMID:39584807[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kahle KT, Rinehart J, de Los Heros P, Louvi A, Meade P, Vazquez N, Hebert SC, Gamba G, Gimenez I, Lifton RP. WNK3 modulates transport of Cl- in and out of cells: implications for control of cell volume and neuronal excitability. Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16783-8. Epub 2005 Nov 7. PMID:16275911 doi:http://dx.doi.org/10.1073/pnas.0508307102
- ↑ Rinehart J, Kahle KT, de Los Heros P, Vazquez N, Meade P, Wilson FH, Hebert SC, Gimenez I, Gamba G, Lifton RP. WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis. Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16777-82. Epub 2005 Nov 7. PMID:16275913 doi:http://dx.doi.org/10.1073/pnas.0508303102
- ↑ Leng Q, Kahle KT, Rinehart J, MacGregor GG, Wilson FH, Canessa CM, Lifton RP, Hebert SC. WNK3, a kinase related to genes mutated in hereditary hypertension with hyperkalaemia, regulates the K+ channel ROMK1 (Kir1.1). J Physiol. 2006 Mar 1;571(Pt 2):275-86. Epub 2005 Dec 15. PMID:16357011 doi:http://dx.doi.org/10.1113/jphysiol.2005.102202
- ↑ Verissimo F, Silva E, Morris JD, Pepperkok R, Jordan P. Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway. Oncogene. 2006 Jul 13;25(30):4172-82. Epub 2006 Feb 27. PMID:16501604 doi:http://dx.doi.org/10.1038/sj.onc.1209449
- ↑ Yang CL, Zhu X, Ellison DH. The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex. J Clin Invest. 2007 Nov;117(11):3403-11. PMID:17975670 doi:10.1172/JCI32033
- ↑ Zhang W, Na T, Peng JB. WNK3 positively regulates epithelial calcium channels TRPV5 and TRPV6 via a kinase-dependent pathway. Am J Physiol Renal Physiol. 2008 Nov;295(5):F1472-84. doi:, 10.1152/ajprenal.90229.2008. Epub 2008 Sep 3. PMID:18768590 doi:http://dx.doi.org/10.1152/ajprenal.90229.2008
- ↑ Heise CJ, Xu BE, Deaton SL, Cha SK, Cheng CJ, Earnest S, Sengupta S, Juang YC, Stippec S, Xu Y, Zhao Y, Huang CL, Cobb MH. Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium channel are regulated by multiple with no lysine (WNK) family members. J Biol Chem. 2010 Aug 13;285(33):25161-7. doi: 10.1074/jbc.M110.103432. Epub 2010, Jun 4. PMID:20525693 doi:10.1074/jbc.M110.103432
- ↑ Glover M, Zuber AM, O'Shaughnessy KM. Renal and brain isoforms of WNK3 have opposite effects on NCCT expression. J Am Soc Nephrol. 2009 Jun;20(6):1314-22. doi: 10.1681/ASN.2008050542. Epub 2009 , May 21. PMID:19470686 doi:http://dx.doi.org/10.1681/ASN.2008050542
- ↑ Cruz-Rangel S, Melo Z, Vazquez N, Meade P, Bobadilla NA, Pasantes-Morales H, Gamba G, Mercado A. Similar effects of all WNK3 variants on SLC12 cotransporters. Am J Physiol Cell Physiol. 2011 Sep;301(3):C601-8. doi:, 10.1152/ajpcell.00070.2011. Epub 2011 May 25. PMID:21613606 doi:http://dx.doi.org/10.1152/ajpcell.00070.2011
- ↑ Teixeira LR, Akella R, Humphreys JM, He H, Goldsmith EJ. Water and chloride as allosteric inhibitors in WNK kinase osmosensing. Elife. 2024 Nov 25;12:RP88224. PMID:39584807 doi:10.7554/eLife.88224
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