Structural insights into TSC complex assembly and GAP activity on Rheb

Huirong Yang (), Zishuo Yu, Xizi Chen, Jiabei Li, Ningning Li, Jiaxuan Cheng, Ning Gao, Hai-Xin Yuan, Dan Ye, Kun-Liang Guan and Yanhui Xu ()
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Huirong Yang: Shanghai Medical College of Fudan University
Zishuo Yu: Shanghai Medical College of Fudan University
Xizi Chen: Shanghai Medical College of Fudan University
Jiabei Li: Shanghai Medical College of Fudan University
Ningning Li: Peking University
Jiaxuan Cheng: Peking University
Ning Gao: Peking University
Hai-Xin Yuan: Fudan University
Dan Ye: Fudan University
Kun-Liang Guan: University of California San Diego
Yanhui Xu: Shanghai Medical College of Fudan University

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract 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 γ-phosphate of GTP and accelerate GTP hydrolysis of Rheb. Our study reveals mechanisms of TSC complex assembly and GAP activity.

Date: 2021
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DOI: 10.1038/s41467-020-20522-4

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