9C9I

Structure of the TSC1:WIPI3 complex

Summary for 9C9I

• Entry DOI: 10.2210/pdb9c9i/pdb
• Descriptor: WD repeat domain phosphoinositide-interacting protein 3, Hamartin (2 entities in total)
• Functional Keywords: tsc, tuberous sclerosis complex, tsc1, tsc2, tbc1d7, wipi3, end-some, mtor, cell growth, gene regulation
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 9
• Total formula weight: 158339.64

Authors

D'Andrea, L.,Bayly-Jones, C.,Lupton, C.J.,Ellisdon, A.M. (deposition date: 2024-06-14, release date: 2024-12-04)

Primary citation

Bayly-Jones, C.,Lupton, C.J.,D'Andrea, L.,Chang, Y.G.,Jones, G.D.,Steele, J.R.,Venugopal, H.,Schittenhelm, R.B.,Halls, M.L.,Ellisdon, A.M.
Structure of the human TSC:WIPI3 lysosomal recruitment complex.
Sci Adv, 10:eadr5807-eadr5807, 2024

PubMed 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.

PubMed: 39565846
DOI: 10.1126/sciadv.adr5807

Experimental method

X-RAY DIFFRACTION (3.18 Å)