7A0N

Structure of TSC1 NTD and linker domain

Summary for 7A0N

• Entry DOI: 10.2210/pdb7a0n/pdb
• Descriptor: Uncharacterized protein,Uncharacterized protein (1 entity in total)
• Functional Keywords: tsc1, gap, gtpase, signaling protein
• Biological source: Chaetomium thermophilum (strain DSM 1495 / CBS 144.50 / IMI 039719); More
• Total number of polymer chains: 4
• Total formula weight: 217811.53

Authors

Fitzian, K.,Kuemmel, D. (deposition date: 2020-08-10, release date: 2021-05-26, Last modification date: 2024-11-06)

Primary citation

Fitzian, K.,Bruckner, A.,Brohee, L.,Zech, R.,Antoni, C.,Kiontke, S.,Gasper, R.,Linard Matos, A.L.,Beel, S.,Wilhelm, S.,Gerke, V.,Ungermann, C.,Nellist, M.,Raunser, S.,Demetriades, C.,Oeckinghaus, A.,Kummel, D.
TSC1 binding to lysosomal PIPs is required for TSC complex translocation and mTORC1 regulation.
Mol.Cell, 81:2705-, 2021

PubMed 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, 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.

PubMed: 33974911
DOI: 10.1016/j.molcel.2021.04.019

Experimental method

X-RAY DIFFRACTION (4.3 Å)