9ce3
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | The entry | + | ==Structure of the TSC:WIPI3 lysosomal recruitment complex== |
| + | <StructureSection load='9ce3' size='340' side='right'caption='[[9ce3]], [[Resolution|resolution]] 2.90Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9ce3]] is a 8 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=9CE3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9CE3 FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.9Å</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=9ce3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9ce3 OCA], [https://pdbe.org/9ce3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9ce3 RCSB], [https://www.ebi.ac.uk/pdbsum/9ce3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9ce3 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/TSC2_HUMAN TSC2_HUMAN] Lymphangioleiomyomatosis;Adult hepatocellular carcinoma;Isolated focal cortical dysplasia type IIb;Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis;Isolated focal cortical dysplasia type IIa;Tuberous sclerosis complex. 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 == | ||
| + | [https://www.uniprot.org/uniprot/TSC2_HUMAN TSC2_HUMAN] Catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth (PubMed:12172553, PubMed:12271141, PubMed:12842888, PubMed:12906785, PubMed:15340059, PubMed:22819219, PubMed:24529379, PubMed:28215400, PubMed:33436626, PubMed:35772404). Within the TSC-TBC complex, TSC2 acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1 (PubMed:12172553, PubMed:12820960, PubMed:12842888, PubMed:12906785, PubMed:15340059, PubMed:22819219, PubMed:24529379, PubMed:33436626). In absence of nutrients, the TSC-TBC complex inhibits mTORC1, thereby preventing phosphorylation of ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) by the mTORC1 signaling (PubMed:12172553, PubMed:12271141, PubMed:12842888, PubMed:12906785, PubMed:22819219, PubMed:24529379, PubMed:28215400, PubMed:35772404). The TSC-TBC complex is inactivated in response to nutrients, relieving inhibition of mTORC1 (PubMed:12172553, PubMed:24529379). Involved in microtubule-mediated protein transport via its ability to regulate mTORC1 signaling (By similarity). Also stimulates the intrinsic GTPase activity of the Ras-related proteins RAP1A and RAB5 (By similarity).[UniProtKB:P49816]<ref>PMID:12172553</ref> <ref>PMID:12271141</ref> <ref>PMID:12820960</ref> <ref>PMID:12842888</ref> <ref>PMID:12906785</ref> <ref>PMID:15340059</ref> <ref>PMID:22819219</ref> <ref>PMID:24529379</ref> <ref>PMID:28215400</ref> <ref>PMID:33436626</ref> <ref>PMID:35772404</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Tuberous sclerosis complex (TSC) is targeted to the lysosomal membrane, where it hydrolyzes RAS homolog-mTORC1 binding (RHEB) from its GTP-bound to GDP-bound state, inhibiting mechanistic target of rapamycin complex 1 (mTORC1). Loss-of-function mutations in TSC cause TSC disease, marked by excessive tumor growth. Here, we overcome a high degree of continuous conformational heterogeneity to determine the 2.8-A cryo-electron microscopy (cryo-EM) structure of the complete human TSC in complex with the lysosomal recruitment factor WD repeat domain phosphoinositide-interacting protein 3 (WIPI3). We discover a previously undetected amino-terminal TSC1 HEAT repeat dimer that clamps onto a single TSC wing and forms a phosphatidylinositol phosphate (PIP)-binding pocket, which specifically binds monophosphorylated PIPs. These structural advances provide a model by which WIPI3 and PIP-signaling networks coordinate to recruit TSC to the lysosomal membrane to inhibit mTORC1. The high-resolution TSC structure reveals previously unrecognized mutational hotspots and uncovers crucial insights into the mechanisms of TSC dysregulation in disease. | ||
| - | + | Structure of the human TSC:WIPI3 lysosomal recruitment complex.,Bayly-Jones C, Lupton CJ, D'Andrea L, Chang YG, Jones GD, Steele JR, Venugopal H, Schittenhelm RB, Halls ML, Ellisdon AM Sci Adv. 2024 Nov 22;10(47):eadr5807. doi: 10.1126/sciadv.adr5807. Epub 2024 Nov , 20. PMID:39565846<ref>PMID:39565846</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 9ce3" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Bayly-Jones C]] | ||
| + | [[Category: D'Andrea L]] | ||
| + | [[Category: Ellisdon AM]] | ||
| + | [[Category: Lupton CJ]] | ||
Current revision
Structure of the TSC:WIPI3 lysosomal recruitment complex
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