Fitzian, Katharina, Bruckner, Anne, Brohee, Laura ORCID: 0000-0001-8498-1579, 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 ORCID: 0000-0001-7813-7726, Oeckinghaus, Andrea and Kummel, Daniel (2021). TSC1 binding to lysosomal PIPs is required for TSC complex translocation and mTORC1 regulation. Mol. Cell, 81 (13). S. 2705 - 2731. CAMBRIDGE: CELL PRESS. ISSN 1097-4164

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Fitzian, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruckner, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brohee, LauraUNSPECIFIEDorcid.org/0000-0001-8498-1579UNSPECIFIED
Zech, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Antoni, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kiontke, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gasper, RaphaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Matos, Anna Livia LinardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beel, StephanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wilhelm, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerke, VolkerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ungermann, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nellist, MarkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raunser, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Demetriades, ConstantinosUNSPECIFIEDorcid.org/0000-0001-7813-7726UNSPECIFIED
Oeckinghaus, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kummel, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-598659
DOI: 10.1016/j.molcel.2021.04.019
Journal or Publication Title: Mol. Cell
Volume: 81
Number: 13
Page Range: S. 2705 - 2731
Date: 2021
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1097-4164
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TUBEROUS SCLEROSIS GENE; SMALL-ANGLE SCATTERING; FUNCTIONAL ASSESSMENT; STRUCTURAL BASIS; COLOCALIZATION; VARIANTS; GTPASE; KINASE; SUITE; IDENTIFICATIONMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59865

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