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Structural insights into TSC complex assembly and GAP activity on Rheb

Author

Listed:
  • Huirong Yang

    (Shanghai Medical College of Fudan University
    Shanghai Medical College of Fudan University
    Fudan University
    Inner Mongolia 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
    Shanghai Medical College of Fudan University
    Fudan University
    Inner Mongolia University)

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.

Suggested Citation

  • Huirong Yang & Zishuo Yu & Xizi Chen & Jiabei Li & Ningning Li & Jiaxuan Cheng & Ning Gao & Hai-Xin Yuan & Dan Ye & Kun-Liang Guan & Yanhui Xu, 2021. "Structural insights into TSC complex assembly and GAP activity on Rheb," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20522-4
    DOI: 10.1038/s41467-020-20522-4
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    Cited by:

    1. Vasiliki Karalis & Franklin Caval-Holme & Helen S. Bateup, 2022. "Raptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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