TSC1 binding to lysosomal PIPs is required for TSC complex translocation and mTORC1 regulation

Autor(en): Fitzian, Katharina
Bruckner, Anne
Brohee, Laura
Zech, Reinhard
Antoni, Claudia
Kiontke, Stephan
Gasper, Raphael
Matos, Anna Livia Linard
Beel, Stephanie
Wilhelm, Sabine
Gerke, Volker
Ungermann, Christian 
Nellist, Mark
Raunser, Stefan
Demetriades, Constantinos
Oeckinghaus, Andrea
Kummel, Daniel 
Stichwörter: Biochemistry & Molecular Biology; Cell Biology; COLOCALIZATION; FUNCTIONAL ASSESSMENT; GTPASE; IDENTIFICATION; KINASE; SMALL-ANGLE SCATTERING; STRUCTURAL BASIS; SUITE; TUBEROUS SCLEROSIS GENE; VARIANTS
Erscheinungsdatum: 2021
Herausgeber: CELL PRESS
Enthalten in: MOLECULAR CELL
Band: 81
Ausgabe: 13
Startseite: 2705+
Zusammenfassung: 
The TSC complex is a critical negative regulator of the small GTPase Rheb and mTORC1 in cellular stress signaling. The TSC2 subunit contains a catalytic GTPase activating protein domain and interacts with multiple regulators, while the precise function of TSC1 is unknown. Here we provide a structural characterization of TSC1 and define three domains: a C-terminal coiled-coil that interacts with TSC2, a central helical domain that mediates TSC1 oligomerization, and an N-terminal HEAT repeat domain that interacts with membrane phosphatidylinositol phosphates (PIPs). TSC1 architecture, oligomerization, and membrane binding are conserved in fungi and humans. We show that lysosomal recruitment of the TSC complex and subsequent inactivation of mTORC1 upon starvation depend on the marker lipid PI3,5P(2), demonstrating a role for lysosomal PIPs in regulating TSC complex and mTORC1 activity via TSC1. Our study thus identifies a vital role of TSC1 in TSC complex function and mTORC1 signaling.
ISSN: 10972765
DOI: 10.1016/j.molcel.2021.04.019

Show full item record

Page view(s)

5
Last Week
0
Last month
1
checked on Jun 19, 2024

Google ScholarTM

Check

Altmetric