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GF signalling through the tuberous sclerosis complex regulates the lysosomally localized small GTPase RAS homologue enriched in brain (RHEB)\n                    <jats:sup>3<\/jats:sup>\n                    . Direct binding of RHEB\u2013GTP to the mTOR kinase subunit of mTORC1 allosterically activates the kinase by inducing a large-scale conformational change\n                    <jats:sup>4<\/jats:sup>\n                    . Here we reconstituted mTORC1 activation on membranes by RHEB, RAGs and Ragulator. Cryo-electron microscopy showed that RAPTOR and mTOR interact directly with the membrane. Full engagement of the membrane anchors is required for optimal alignment of the catalytic residues in the mTOR kinase active site. Converging signals from GFs and nutrients drive mTORC1 recruitment to and activation on lysosomal membrane in a four-step process, consisting of (1) RAG\u2013Ragulator-driven recruitment to within ~100\u2009\u00c5 of the lysosomal membrane; (2) RHEB-driven recruitment to within ~40\u2009\u00c5; (3) RAPTOR\u2013membrane engagement and intermediate enzyme activation; and (4) mTOR\u2013membrane engagement and full enzyme activation. RHEB and membrane engagement combined leads to full catalytic activation and structurally explains GF and nutrient signal integration at the lysosome.\n                  <\/jats:p>","DOI":"10.1038\/s41586-025-09545-3","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T15:02:50Z","timestamp":1758121370000},"page":"536-543","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Structural basis for mTORC1 activation on the lysosomal membrane"],"prefix":"10.1038","volume":"647","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2398-9344","authenticated-orcid":false,"given":"Zhicheng","family":"Cui","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3838-7242","authenticated-orcid":false,"given":"Alessandra","family":"Esposito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8615-4654","authenticated-orcid":false,"given":"Gennaro","family":"Napolitano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1381-4604","authenticated-orcid":false,"given":"Andrea","family":"Ballabio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5054-5445","authenticated-orcid":false,"given":"James H.","family":"Hurley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,17]]},"reference":[{"key":"9545_CR1","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1016\/j.cell.2022.04.013","volume":"185","author":"S Battaglioni","year":"2022","unstructured":"Battaglioni, S., Benjamin, D., Walchli, M., Maier, T. & Hall, M. 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