ArticleScience advances2024
Structure of the human TSC:WIPI3 lysosomal recruitment complex.
Article in Science advances, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- YIF1A activates mTORC1 signaling to promote cellular senescence.Cell death & disease · 2026Article
- AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.Developmental cell · 2025Article
- Evolution of growth factor signaling to the TSC complex to regulate mTORC1.Science signaling · 2025Review
- New insights into tuberous sclerosis complex: from structure to pathogenesis.Frontiers in cell and developmental biology · 2025Review
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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-Å 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.
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Registered trials
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