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| | <StructureSection load='7k1w' size='340' side='right'caption='[[7k1w]], [[Resolution|resolution]] 5.10Å' scene=''> | | <StructureSection load='7k1w' size='340' side='right'caption='[[7k1w]], [[Resolution|resolution]] 5.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7k1w]] is a 1 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=7K1W OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7K1W FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7k1w]] is a 1 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=7K1W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7K1W FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7k1w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k1w OCA], [http://pdbe.org/7k1w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7k1w RCSB], [http://www.ebi.ac.uk/pdbsum/7k1w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7k1w ProSAT]</span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 5.1Å</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=7k1w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k1w OCA], [https://pdbe.org/7k1w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7k1w RCSB], [https://www.ebi.ac.uk/pdbsum/7k1w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7k1w ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | <div style="background-color:#fffaf0;">
| + | == Disease == |
| - | == Publication Abstract from PubMed == | + | [https://www.uniprot.org/uniprot/FIG4_HUMAN FIG4_HUMAN] Amyotrophic lateral sclerosis;Bilateral parasagittal parieto-occipital polymicrogyria;Charcot-Marie-Tooth disease type 4J;Yunis-Varon syndrome. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. |
| - | The phosphoinositide PI(3,5)P2, generated exclusively by the PIKfyve lipid kinase complex, is key for lysosomal biology. Here, we explore how PI(3,5)P2 levels within cells are regulated. We find the PIKfyve complex comprises five copies of the scaffolding protein Vac14 and one copy each of the lipid kinase PIKfyve, generating PI(3,5)P2 from PI3P and the lipid phosphatase Fig4, reversing the reaction. Fig4 is active as a lipid phosphatase in the ternary complex, whereas PIKfyve within the complex cannot access membrane-incorporated phosphoinositides due to steric constraints. We find further that the phosphoinositide-directed activities of both PIKfyve and Fig4 are regulated by protein-directed activities within the complex. PIKfyve autophosphorylation represses its lipid kinase activity and stimulates Fig4 lipid phosphatase activity. Further, Fig4 is also a protein phosphatase acting on PIKfyve to stimulate its lipid kinase activity, explaining why catalytically active Fig4 is required for maximal PI(3,5)P2 production by PIKfyve in vivo.
| + | == Function == |
| - | | + | [https://www.uniprot.org/uniprot/FIG4_HUMAN FIG4_HUMAN] Dual specificity phosphatase component of the PI(3,5)P2 regulatory complex which regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) (PubMed:17556371, PubMed:33098764). Catalyzes the dephosphorylation of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) to form phosphatidylinositol 3-phosphate (PubMed:33098764). Has serine-protein phosphatase activity acting on PIKfyve to stimulate its lipid kinase activity, its catalytically activity being required for maximal PI(3,5)P2 production (PubMed:33098764). In vitro, hydrolyzes all three D5-phosphorylated polyphosphoinositide and although displaying preferences for PtdIns(3,5)P2, it is capable of hydrolyzing PtdIns(3,4,5)P3 and PtdIns(4,5)P2, at least in vitro (PubMed:17556371).<ref>PMID:17556371</ref> <ref>PMID:33098764</ref> |
| - | Insights into Lysosomal PI(3,5)P2 Homeostasis from a Structural-Biochemical Analysis of the PIKfyve Lipid Kinase Complex.,Lees JA, Li P, Kumar N, Weisman LS, Reinisch KM Mol Cell. 2020 Oct 15. pii: S1097-2765(20)30686-9. doi:, 10.1016/j.molcel.2020.10.003. PMID:33098764<ref>PMID:33098764</ref>
| + | |
| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 7k1w" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lees, J A]] | + | [[Category: Lees JA]] |
| - | [[Category: Li, P]] | + | [[Category: Li P]] |
| - | [[Category: Reinisch, K M]] | + | [[Category: Reinisch KM]] |
| - | [[Category: Lipid binding protein]]
| + | |
| - | [[Category: Lipid kinase]]
| + | |
| - | [[Category: Lipid phosphatase]]
| + | |
| - | [[Category: Protein complex]]
| + | |
| Structural highlights
Disease
FIG4_HUMAN Amyotrophic lateral sclerosis;Bilateral parasagittal parieto-occipital polymicrogyria;Charcot-Marie-Tooth disease type 4J;Yunis-Varon syndrome. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.
Function
FIG4_HUMAN Dual specificity phosphatase component of the PI(3,5)P2 regulatory complex which regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) (PubMed:17556371, PubMed:33098764). Catalyzes the dephosphorylation of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) to form phosphatidylinositol 3-phosphate (PubMed:33098764). Has serine-protein phosphatase activity acting on PIKfyve to stimulate its lipid kinase activity, its catalytically activity being required for maximal PI(3,5)P2 production (PubMed:33098764). In vitro, hydrolyzes all three D5-phosphorylated polyphosphoinositide and although displaying preferences for PtdIns(3,5)P2, it is capable of hydrolyzing PtdIns(3,4,5)P3 and PtdIns(4,5)P2, at least in vitro (PubMed:17556371).[1] [2]
References
- ↑ Sbrissa D, Ikonomov OC, Fu Z, Ijuin T, Gruenberg J, Takenawa T, Shisheva A. Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex. J Biol Chem. 2007 Aug 17;282(33):23878-91. PMID:17556371 doi:10.1074/jbc.M611678200
- ↑ Lees JA, Li P, Kumar N, Weisman LS, Reinisch KM. Insights into Lysosomal PI(3,5)P2 Homeostasis from a Structural-Biochemical Analysis of the PIKfyve Lipid Kinase Complex. Mol Cell. 2020 Oct 15. pii: S1097-2765(20)30686-9. doi:, 10.1016/j.molcel.2020.10.003. PMID:33098764 doi:http://dx.doi.org/10.1016/j.molcel.2020.10.003
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