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| | <StructureSection load='2v3s' size='340' side='right'caption='[[2v3s]], [[Resolution|resolution]] 1.70Å' scene=''> | | <StructureSection load='2v3s' size='340' side='right'caption='[[2v3s]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2v3s]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2V3S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2V3S FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2v3s]] is a 4 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=2V3S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2V3S FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene></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=2v3s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2v3s OCA], [https://pdbe.org/2v3s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2v3s RCSB], [https://www.ebi.ac.uk/pdbsum/2v3s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2v3s ProSAT]</span></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=2v3s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2v3s OCA], [https://pdbe.org/2v3s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2v3s RCSB], [https://www.ebi.ac.uk/pdbsum/2v3s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2v3s ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[https://www.uniprot.org/uniprot/WNK4_HUMAN WNK4_HUMAN]] Defects in WNK4 are a cause of pseudohypoaldosteronism type 2B (PHA2B) [MIM:[https://omim.org/entry/614491 614491]]. PHAII is an autosomal dominant disease characterized by severe hypertension, hyperkalemia, and sensitivity to thiazide diuretics which may result from a chloride shunt in the renal distal nephron.<ref>PMID:11498583</ref> | |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/WNK4_HUMAN WNK4_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, 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>PMID:20525693</ref>
| + | [https://www.uniprot.org/uniprot/OXSR1_HUMAN OXSR1_HUMAN] Regulates downstream kinases in response to environmental stress. May also have a function in regulating the actin cytoskeleton.<ref>PMID:14707132</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Non-specific serine/threonine protein kinase]]
| + | [[Category: Alessi DR]] |
| - | [[Category: Aalten, D M.F van]]
| + | [[Category: Deak M]] |
| - | [[Category: Alessi, D R]] | + | [[Category: Goebel J]] |
| - | [[Category: Deak, M]] | + | [[Category: Rafiqi FH]] |
| - | [[Category: Goebel, J]] | + | [[Category: Thastrup J]] |
| - | [[Category: Rafiqi, F H]] | + | [[Category: Villa F]] |
| - | [[Category: Thastrup, J]] | + | [[Category: Van Aalten DMF]] |
| - | [[Category: Villa, F]] | + | |
| - | [[Category: Atp-binding]] | + | |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Magnesium]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Nucleotide-binding]]
| + | |
| - | [[Category: Phosphorylation]]
| + | |
| - | [[Category: Polymorphism]]
| + | |
| - | [[Category: Serine/threonine-protein kinase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
OXSR1_HUMAN Regulates downstream kinases in response to environmental stress. May also have a function in regulating the actin cytoskeleton.[1]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The oxidative-stress-responsive kinase 1 (OSR1) and the STE20/SPS1-related proline/alanine-rich kinase (SPAK) are key enzymes in a signalling cascade regulating the activity of Na(+)/K(+)/2Cl(-) co-transporters (NKCCs) in response to osmotic stress. Both kinases have a conserved carboxy-terminal (CCT) domain, which recognizes a unique peptide (Arg-Phe-Xaa-Val) motif present in OSR1- and SPAK-activating kinases (with-no-lysine kinase 1 (WNK1) and WNK4) as well as its substrates (NKCC1 and NKCC2). Here, we describe the structural basis of this recognition event as shown by the crystal structure of the CCT domain of OSR1 in complex with a peptide containing this motif, derived from WNK4. The CCT domain forms a novel protein fold that interacts with the Arg-Phe-Xaa-Val motif through a surface-exposed groove. An intricate web of interactions is observed between the CCT domain and an Arg-Phe-Xaa-Val motif-containing peptide derived from WNK4. Mutational analysis shows that these interactions are required for the CCT domain to bind to WNK1 and NKCC1. The CCT domain structure also shows how phosphorylation of a Ser/Thr residue preceding the Arg-Phe-Xaa-Val motif results in a steric clash, promoting its dissociation from the CCT domain. These results provide the first molecular insight into the mechanism by which the SPAK and OSR1 kinases specifically recognize their upstream activators and downstream substrates.
Structural insights into the recognition of substrates and activators by the OSR1 kinase.,Villa F, Goebel J, Rafiqi FH, Deak M, Thastrup J, Alessi DR, van Aalten DM EMBO Rep. 2007 Sep;8(9):839-45. Epub 2007 Aug 17. PMID:17721439[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Chen W, Yazicioglu M, Cobb MH. Characterization of OSR1, a member of the mammalian Ste20p/germinal center kinase subfamily. J Biol Chem. 2004 Mar 19;279(12):11129-36. Epub 2004 Jan 5. PMID:14707132 doi:10.1074/jbc.M313562200
- ↑ Villa F, Goebel J, Rafiqi FH, Deak M, Thastrup J, Alessi DR, van Aalten DM. Structural insights into the recognition of substrates and activators by the OSR1 kinase. EMBO Rep. 2007 Sep;8(9):839-45. Epub 2007 Aug 17. PMID:17721439
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