9C9I

Structure of the TSC1:WIPI3 complex

9C9I の概要

• エントリーDOI: 10.2210/pdb9c9i/pdb
• 分子名称: WD repeat domain phosphoinositide-interacting protein 3, Hamartin (2 entities in total)
• 機能のキーワード: tsc, tuberous sclerosis complex, tsc1, tsc2, tbc1d7, wipi3, end-some, mtor, cell growth, gene regulation
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 158339.64

構造登録者

D'Andrea, L.,Bayly-Jones, C.,Lupton, C.J.,Ellisdon, A.M. (登録日: 2024-06-14, 公開日: 2024-12-04)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3.18 Å)