Structure of the human TSC:WIPI3 lysosomal recruitment complex.

Bayly-Jones, C; Lupton, CJ; D'Andrea, L; Chang, Y-G; Jones, GD; Steele, JR; Venugopal, H; Schittenhelm, RB; Halls, ML; Ellisdon, AM

Structure of the human TSC:WIPI3 lysosomal recruitment complex.

Bayly-Jones, C Lupton, CJ D'Andrea, L Chang, Y-G Jones, GD Steele, JR Venugopal, H Schittenhelm, RB Halls, ML Ellisdon, AM

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Publisher:: American Association for the Advancement of Science (AAAS)
Publication Type:: Journal Article
Citation:: Sci Adv, 2024, 10, (47), pp. eadr5807
Issue Date:: 2024-11-22

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Field	Value	Language
dc.contributor.author	Bayly-Jones, C
dc.contributor.author	Lupton, CJ
dc.contributor.author	D'Andrea, L
dc.contributor.author	Chang, Y-G
dc.contributor.author	Jones, GD
dc.contributor.author	Steele, JR
dc.contributor.author	Venugopal, H
dc.contributor.author	Schittenhelm, RB
dc.contributor.author	Halls, ML
dc.contributor.author	Ellisdon, AM
dc.date.accessioned	2024-12-02T01:19:28Z
dc.date.available	2024-12-02T01:19:28Z
dc.date.issued	2024-11-22
dc.identifier.citation	Sci Adv, 2024, 10, (47), pp. eadr5807
dc.identifier.issn	2375-2548
dc.identifier.issn	2375-2548
dc.identifier.uri	http://hdl.handle.net/10453/182228
dc.description.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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	American Association for the Advancement of Science (AAAS)
dc.relation.ispartof	Sci Adv
dc.relation.isbasedon	10.1126/sciadv.adr5807
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Humans
dc.subject.mesh	Lysosomes
dc.subject.mesh	Cryoelectron Microscopy
dc.subject.mesh	Protein Binding
dc.subject.mesh	Models, Molecular
dc.subject.mesh	Tuberous Sclerosis Complex 1 Protein
dc.subject.mesh	Mechanistic Target of Rapamycin Complex 1
dc.subject.mesh	Mutation
dc.subject.mesh	Membrane Proteins
dc.subject.mesh	Protein Conformation
dc.subject.mesh	Tuberous Sclerosis
dc.subject.mesh	Phosphatidylinositol Phosphates
dc.subject.mesh	Binding Sites
dc.subject.mesh	Lysosomes
dc.subject.mesh	Humans
dc.subject.mesh	Tuberous Sclerosis
dc.subject.mesh	Phosphatidylinositol Phosphates
dc.subject.mesh	Membrane Proteins
dc.subject.mesh	Cryoelectron Microscopy
dc.subject.mesh	Binding Sites
dc.subject.mesh	Protein Conformation
dc.subject.mesh	Protein Binding
dc.subject.mesh	Mutation
dc.subject.mesh	Models, Molecular
dc.subject.mesh	Mechanistic Target of Rapamycin Complex 1
dc.subject.mesh	Tuberous Sclerosis Complex 1 Protein
dc.subject.mesh	Humans
dc.subject.mesh	Lysosomes
dc.subject.mesh	Cryoelectron Microscopy
dc.subject.mesh	Protein Binding
dc.subject.mesh	Models, Molecular
dc.subject.mesh	Tuberous Sclerosis Complex 1 Protein
dc.subject.mesh	Mechanistic Target of Rapamycin Complex 1
dc.subject.mesh	Mutation
dc.subject.mesh	Membrane Proteins
dc.subject.mesh	Protein Conformation
dc.subject.mesh	Tuberous Sclerosis
dc.subject.mesh	Phosphatidylinositol Phosphates
dc.subject.mesh	Binding Sites
dc.title	Structure of the human TSC:WIPI3 lysosomal recruitment complex.
dc.type	Journal Article
utslib.citation.volume	10
utslib.location.activity	United States
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Provost
pubs.organisational-group	University of Technology Sydney/Provost/Jumbunna
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by-nc/4.0/
dc.date.updated	2024-12-02T01:19:22Z
pubs.issue	47
pubs.publication-status	Published
pubs.volume	10
utslib.citation.issue	47

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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http://hdl.handle.net/10453/182228