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4chb

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Revision as of 17:45, 7 September 2022

Crystal structure of the human KLHL2 Kelch domain in complex with a WNK4 peptide

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 <StructureSection load='4chb' size='340' side='right'caption='[[4chb]], [[Resolution|resolution]] 1.56&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4chb]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CHB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CHB FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4chb]] 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=4CHB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CHB FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=12P:DODECAETHYLENE+GLYCOL'>12P</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=12P:DODECAETHYLENE+GLYCOL'>12P</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ch9|4ch9]]</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=4chb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4chb OCA], [https://pdbe.org/4chb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4chb RCSB], [https://www.ebi.ac.uk/pdbsum/4chb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4chb ProSAT]</span></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4chb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4chb OCA], [http://pdbe.org/4chb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4chb RCSB], [http://www.ebi.ac.uk/pdbsum/4chb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4chb ProSAT]</span></td></tr>
 </table>
-== Disease ==
-[[http://www.uniprot.org/uniprot/WNK4_HUMAN WNK4_HUMAN]] Defects in WNK4 are a cause of pseudohypoaldosteronism type 2B (PHA2B) [MIM:[http://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 ==
-[[http://www.uniprot.org/uniprot/KLHL2_HUMAN KLHL2_HUMAN]] May play a role in organizing the actin cytoskeleton of the brain cells. [[http://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/KLHL2_HUMAN KLHL2_HUMAN]] May play a role in organizing the actin cytoskeleton of the brain cells.
-<div style="background-color:#fffaf0;">
-== Publication Abstract from PubMed ==
-WNK1 [with no lysine (K)] and WNK4 regulate blood pressure by controlling the activity of ion co-transporters in the kidney. Groundbreaking work has revealed that the ubiquitylation and hence levels of WNK isoforms are controlled by a Cullin-RING E3 ubiquitin ligase complex (CRL3KLHL3) that utilizes CUL3 (Cullin3) and its substrate adaptor, KLHL3 (Kelch-like protein 3). Loss-of-function mutations in either CUL3 or KLHL3 cause the hereditary high blood pressure disease Gordon's syndrome by stabilizing WNK isoforms. KLHL3 binds to a highly conserved degron motif located within the C-terminal non-catalytic domain of WNK isoforms. This interaction is essential for ubiquitylation by CRL3KLHL3 and disease-causing mutations in WNK4 and KLHL3 exert their effects on blood pressure by disrupting this interaction. In the present study, we report on the crystal structure of the KLHL3 Kelch domain in complex with the WNK4 degron motif. This reveals an intricate web of interactions between conserved residues on the surface of the Kelch domain beta-propeller and the WNK4 degron motif. Importantly, many of the disease-causing mutations inhibit binding by disrupting critical interface contacts. We also present the structure of the WNK4 degron motif in complex with KLHL2 that has also been reported to bind WNK4. This confirms that KLHL2 interacts with WNK kinases in a similar manner to KLHL3, but strikingly different to how another KLHL protein, KEAP1 (Kelch-like enoyl-CoA hydratase-associated protein 1), binds to its substrate NRF2 (nuclear factor-erythroid 2-related factor 2). The present study provides further insights into how Kelch-like adaptor proteins recognize their substrates and provides a structural basis for how mutations in WNK4 and KLHL3 lead to hypertension.
-Structural and biochemical characterization of the KLHL3-WNK kinase interaction important in blood pressure regulation.,Schumacher FR, Sorrell FJ, Alessi DR, Bullock AN, Kurz T Biochem J. 2014 Jun 1;460(2):237-46. doi: 10.1042/BJ20140153. PMID:24641320<ref>PMID:24641320</ref>
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 4chb" style="background-color:#fffaf0;"></div>
 ==See Also==
-*[[Kelch-like protein|Kelch-like protein]]
+*[[Kelch-like protein 3D structures|Kelch-like protein 3D structures]]
-== References ==
-<references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Alessi DR]]
-[[Category: Alessi, D R]]
+[[Category: Arrowsmith CH]]
-[[Category: Arrowsmith, C H]]
+[[Category: Bountra C]]
-[[Category: Bountra, C]]
+[[Category: Bullock A]]
-[[Category: Bullock, A]]
+[[Category: Canning P]]
-[[Category: Canning, P]]
+[[Category: Cooper CDO]]
-[[Category: Cooper, C D.O]]
+[[Category: Edwards AM]]
-[[Category: Delft, F von]]
+[[Category: Kopec J]]
-[[Category: Edwards, A M]]
+[[Category: Krojer T]]
-[[Category: Kopec, J]]
+[[Category: Kurz T]]
-[[Category: Krojer, T]]
+[[Category: Newman J]]
-[[Category: Kurz, T]]
+[[Category: Schumacher FR]]
-[[Category: Newman, J]]
+[[Category: Sorrell FJ]]
-[[Category: Schumacher, F R]]
+[[Category: Williams E]]
-[[Category: Sorrell, F J]]
+[[Category: Von Delft F]]
-[[Category: Williams, E]]
-[[Category: Adaptor protein]]
-[[Category: Kelch repeat]]
-[[Category: Klhl3]]
-[[Category: Protein-binding]]
-[[Category: Signaling protein-transferase complex]]
-[[Category: Ubiquitin]]
-[[Category: Wnk signalling pathway]]

4chb

From Proteopedia

Revision as of 17:45, 7 September 2022

Crystal structure of the human KLHL2 Kelch domain in complex with a WNK4 peptide

Structural highlights

Function

See Also

Contents

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