9d7q
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
| - | '''Unreleased structure''' | ||
| - | + | ==Water and chloride as allosteric inhibitors in WNK kinase osmosensing== | |
| + | <StructureSection load='9d7q' size='340' side='right'caption='[[9d7q]], [[Resolution|resolution]] 3.30Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9d7q]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9D7Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9D7Q FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.301Å</td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9d7q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9d7q OCA], [https://pdbe.org/9d7q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9d7q RCSB], [https://www.ebi.ac.uk/pdbsum/9d7q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9d7q ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/WNK3_HUMAN 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.<ref>PMID:16275911</ref> <ref>PMID:16275913</ref> <ref>PMID:16357011</ref> <ref>PMID:16501604</ref> <ref>PMID:17975670</ref> <ref>PMID:18768590</ref> <ref>PMID:20525693</ref> 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.<ref>PMID:19470686</ref> <ref>PMID:21613606</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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<ref>PMID:39584807</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 9d7q" style="background-color:#fffaf0;"></div> |
| - | [[Category: Akella | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Akella R]] | ||
| + | [[Category: Goldsmith EJ]] | ||
Current revision
Water and chloride as allosteric inhibitors in WNK kinase osmosensing
| |||||||||||
