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TitleStructure of the human TSC:WIPI3 lysosomal recruitment complex.
Journal, issue, pagesSci Adv, Vol. 10, Issue 47, Page eadr5807, Year 2024
Publish dateNov 22, 2024
AuthorsCharles Bayly-Jones / Christopher J Lupton / Laura D'Andrea / Yong-Gang Chang / Gareth D Jones / Joel R Steele / Hari Venugopal / Ralf B Schittenhelm / Michelle L Halls / Andrew M Ellisdon /
PubMed AbstractTuberous 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 ...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.
External linksSci Adv / PubMed:39565846 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.76 - 3.86 Å
Structure data

45492

9ce3

EMDB-45492, PDB-9ce3:
Structure of the TSC:WIPI3 lysosomal recruitment complex
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-45510: The WIPI3:TSC lysosomal docking complex (consensus reconstruction)
Method: EM (single particle) / Resolution: 3.45 Å

EMDB-45511: The WIPI3:TSC lysosomal docking complex (focused reconstruction; core)
Method: EM (single particle) / Resolution: 2.76 Å

EMDB-45512: The WIPI3:TSC lysosomal docking complex (focused reconstruction; TSC1 N-terminus)
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-45513: The WIPI3:TSC lysosomal docking complex (focused reconstruction; TBC1D7)
Method: EM (single particle) / Resolution: 2.93 Å

EMDB-45514: The WIPI3:TSC lysosomal docking complex (focused reconstruction; TBC1D7/TSC2)
Method: EM (single particle) / Resolution: 2.96 Å

EMDB-45515: The WIPI3:TSC lysosomal docking complex (focused reconstruction; WIPI3)
Method: EM (single particle) / Resolution: 3.62 Å

EMDB-45529: The WIPI3:TSC lysosomal docking complex (focused reconstruction; WIPI3 TSC2)
Method: EM (single particle) / Resolution: 3.86 Å

PDB-9c9i:
Structure of the TSC1:WIPI3 complex
Method: X-RAY DIFFRACTION / Resolution: 3.18 Å

Source
  • homo sapiens (human)
KeywordsGENE REGULATION / TSC / Tuberous sclerosis complex / TSC1 / TSC2 / TBC1D7 / WIPI3 / end-some / MTOR / cell growth / ONCOPROTEIN / tumour suppressor / GTPase-activating proteins (GAP) / TSC-mTORC pathway

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