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| | ==Crystal structure of the human KLHL3 Kelch domain in complex with a WNK3 peptide== | | ==Crystal structure of the human KLHL3 Kelch domain in complex with a WNK3 peptide== |
| - | <StructureSection load='5nkp' size='340' side='right' caption='[[5nkp]], [[Resolution|resolution]] 2.80Å' scene=''> | + | <StructureSection load='5nkp' size='340' side='right'caption='[[5nkp]], [[Resolution|resolution]] 2.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5nkp]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NKP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NKP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5nkp]] 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=5NKP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NKP FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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]] 2.8Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ch9|4ch9]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=5nkp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nkp OCA], [https://pdbe.org/5nkp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5nkp RCSB], [https://www.ebi.ac.uk/pdbsum/5nkp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5nkp ProSAT]</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=5nkp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nkp OCA], [http://pdbe.org/5nkp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nkp RCSB], [http://www.ebi.ac.uk/pdbsum/5nkp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nkp ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/KLHL3_HUMAN KLHL3_HUMAN]] Pseudohypoaldosteronism type 2D. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/KLHL3_HUMAN KLHL3_HUMAN] Pseudohypoaldosteronism type 2D. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/KLHL3_HUMAN KLHL3_HUMAN]] Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of ion transport in the distal nephron. The BCR(KLHL3) complex acts by mediating ubiquitination of WNK4, an inhibitor of potassium channel KCNJ1, leading to WNK4 degradation.<ref>PMID:14528312</ref> <ref>PMID:23387299</ref> <ref>PMID:23453970</ref> <ref>PMID:23665031</ref> <ref>PMID:23576762</ref> <ref>PMID:22406640</ref> [[http://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> | + | [https://www.uniprot.org/uniprot/KLHL3_HUMAN KLHL3_HUMAN] Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of ion transport in the distal nephron. The BCR(KLHL3) complex acts by mediating ubiquitination of WNK4, an inhibitor of potassium channel KCNJ1, leading to WNK4 degradation.<ref>PMID:14528312</ref> <ref>PMID:23387299</ref> <ref>PMID:23453970</ref> <ref>PMID:23665031</ref> <ref>PMID:23576762</ref> <ref>PMID:22406640</ref> |
| | + | |
| | + | ==See Also== |
| | + | *[[Kelch-like protein 3D structures|Kelch-like protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Non-specific serine/threonine protein kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Arrowsmith, C H]] | + | [[Category: Large Structures]] |
| - | [[Category: Bountra, C]] | + | [[Category: Arrowsmith CH]] |
| - | [[Category: Bullock, A]] | + | [[Category: Bountra C]] |
| - | [[Category: Burgess-Brown, N]] | + | [[Category: Bullock A]] |
| - | [[Category: Chen, Z]] | + | [[Category: Burgess-Brown N]] |
| - | [[Category: Delft, F von]]
| + | [[Category: Chen Z]] |
| - | [[Category: Edwards, A M]] | + | [[Category: Edwards AM]] |
| - | [[Category: Goubin, S]] | + | [[Category: Goubin S]] |
| - | [[Category: Mathea, S]] | + | [[Category: Mathea S]] |
| - | [[Category: Pinkas, D M]] | + | [[Category: Pinkas DM]] |
| - | [[Category: Sorrell, F J]] | + | [[Category: Sorrell FJ]] |
| - | [[Category: Williams, E]] | + | [[Category: Williams E]] |
| - | [[Category: Kelch domain]] | + | [[Category: Von Delft F]] |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Disease
KLHL3_HUMAN Pseudohypoaldosteronism type 2D. The disease is caused by mutations affecting the gene represented in this entry.
Function
KLHL3_HUMAN Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of ion transport in the distal nephron. The BCR(KLHL3) complex acts by mediating ubiquitination of WNK4, an inhibitor of potassium channel KCNJ1, leading to WNK4 degradation.[1] [2] [3] [4] [5] [6]
See Also
References
- ↑ Furukawa M, He YJ, Borchers C, Xiong Y. Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin ligases. Nat Cell Biol. 2003 Nov;5(11):1001-7. Epub 2003 Oct 5. PMID:14528312 doi:10.1038/ncb1056
- ↑ Ohta A, Schumacher FR, Mehellou Y, Johnson C, Knebel A, Macartney TJ, Wood NT, Alessi DR, Kurz T. The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction. Biochem J. 2013 Apr 1;451(1):111-22. doi: 10.1042/BJ20121903. PMID:23387299 doi:http://dx.doi.org/10.1042/BJ20121903
- ↑ Wakabayashi M, Mori T, Isobe K, Sohara E, Susa K, Araki Y, Chiga M, Kikuchi E, Nomura N, Mori Y, Matsuo H, Murata T, Nomura S, Asano T, Kawaguchi H, Nonoyama S, Rai T, Sasaki S, Uchida S. Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension. Cell Rep. 2013 Mar 28;3(3):858-68. doi: 10.1016/j.celrep.2013.02.024. Epub 2013, Feb 28. PMID:23453970 doi:http://dx.doi.org/10.1016/j.celrep.2013.02.024
- ↑ Wu G, Peng JB. Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation. FEBS Lett. 2013 Jun 19;587(12):1717-22. doi: 10.1016/j.febslet.2013.04.032. Epub , 2013 May 9. PMID:23665031 doi:http://dx.doi.org/10.1016/j.febslet.2013.04.032
- ↑ Shibata S, Zhang J, Puthumana J, Stone KL, Lifton RP. Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7838-43. doi:, 10.1073/pnas.1304592110. Epub 2013 Apr 1. PMID:23576762 doi:http://dx.doi.org/10.1073/pnas.1304592110
- ↑ Louis-Dit-Picard H, Barc J, Trujillano D, Miserey-Lenkei S, Bouatia-Naji N, Pylypenko O, Beaurain G, Bonnefond A, Sand O, Simian C, Vidal-Petiot E, Soukaseum C, Mandet C, Broux F, Chabre O, Delahousse M, Esnault V, Fiquet B, Houillier P, Bagnis CI, Koenig J, Konrad M, Landais P, Mourani C, Niaudet P, Probst V, Thauvin C, Unwin RJ, Soroka SD, Ehret G, Ossowski S, Caulfield M, Bruneval P, Estivill X, Froguel P, Hadchouel J, Schott JJ, Jeunemaitre X. KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nat Genet. 2012 Mar 11;44(4):456-60, S1-3. doi: 10.1038/ng.2218. PMID:22406640 doi:http://dx.doi.org/10.1038/ng.2218
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