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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-\u00c5 cryo\u2013electron microscopy (cryo-EM) structure of the complete human TSC in complex with the lysosomal recruitment factor WD repeat domain phosphoinositide\u2013interacting 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)\u2013binding 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.<\/jats:p>","DOI":"10.1126\/sciadv.adr5807","type":"journal-article","created":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T18:59:41Z","timestamp":1732129181000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":11,"title":["Structure of the human TSC:WIPI3 lysosomal recruitment complex"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7573-7715","authenticated-orcid":true,"given":"Charles","family":"Bayly-Jones","sequence":"first","affiliation":[{"name":"Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4617-4853","authenticated-orcid":true,"given":"Christopher 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