Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-020-20522-4
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Funding
- National key R&D program of China [2016YFA0500700]
- National Natural Science Foundation of China [31770781, 31830107, 31821002, 32030055]
- Shanghai Municipal Science and Technology Major Project [2017SHZDZX01]
- Science and Technology Major Project of Inner Mongolia Autonomous Region of China
- National Ten-Thousand Talent Program
- National Program for support of Top-Notch Young Professionals
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB08000000]
- Shanghai Municipal Science and Technology Commission [19JC1411500]
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The Tuberous sclerosis complex (TSC) consists of TSC1, TSC2, and TBC1D7 in a 2:2:1 stoichiometry, forming an arch-shaped structure. The complex includes two TSC1 coiled-coils and one TBC1D7 bridging over the TSC2 dimer, showing asymmetry. The TSC2 GAP domains are symmetrically cradled within the core module formed by TSC2 dimerization domain and central coiled-coil of TSC1, revealing mechanisms of TSC complex assembly and GAP activity.
Tuberous sclerosis complex (TSC) integrates upstream stimuli and regulates cell growth by controlling the activity of mTORC1. TSC complex functions as a GTPase-activating protein (GAP) towards small GTPase Rheb and inhibits Rheb-mediated activation of mTORC1. Mutations in TSC genes cause tuberous sclerosis. In this study, the near-atomic resolution structure of human TSC complex reveals an arch-shaped architecture, with a 2:2:1 stoichiometry of TSC1, TSC2, and TBC1D7. This asymmetric complex consists of two interweaved TSC1 coiled-coil and one TBC1D7 that spans over the tail-to-tail TSC2 dimer. The two TSC2 GAP domains are symmetrically cradled within the core module formed by TSC2 dimerization domain and central coiled-coil of TSC1. Structural and biochemical analyses reveal TSC2 GAP-Rheb complimentary interactions and suggest a catalytic mechanism, by which an asparagine thumb (N1643) stabilizes.-phosphate of GTP and accelerate GTP hydrolysis of Rheb. Our study reveals mechanisms of TSC complex assembly and GAP activity.
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