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; Yanhui Xu

doi:10.1038/s41467-020-20522-4

Structural insights into TSC complex assembly and GAP activity on Rheb

Nat Commun. 2021 Jan 12;12(1):339. doi: 10.1038/s41467-020-20522-4.

Authors

Huirong Yang^{1

2

3

4}, Zishuo Yu⁵, Xizi Chen⁵, Jiabei Li⁵, Ningning Li⁶, Jiaxuan Cheng⁶, Ning Gao⁶, Hai-Xin Yuan⁷, Dan Ye⁷, Kun-Liang Guan⁸, Yanhui Xu^{9

10

11

12}

Affiliations

¹ Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College of Fudan University, Shanghai, 200032, China. yanghr@fudan.edu.cn.
² The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, China, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032, China. yanghr@fudan.edu.cn.
³ Human Phenome Institute, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200433, China. yanghr@fudan.edu.cn.
⁴ State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock School of Life Sciences, Inner Mongolia University, Hohhot, 010070, China. yanghr@fudan.edu.cn.
⁵ Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College of Fudan University, Shanghai, 200032, China.
⁶ State Key Laboratory of Membrane Biology, Peking-Tsinghua Joint Center for Life Sciences, School of Life Sciences, Peking University, 100871, Beijing, China.
⁷ The Molecular and Cell Biology Research Lab, The Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
⁸ Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
⁹ Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College of Fudan University, Shanghai, 200032, China. xuyh@fudan.edu.cn.
¹⁰ The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, China, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032, China. xuyh@fudan.edu.cn.
¹¹ Human Phenome Institute, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200433, China. xuyh@fudan.edu.cn.
¹² State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock School of Life Sciences, Inner Mongolia University, Hohhot, 010070, China. xuyh@fudan.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biocatalysis
GTPase-Activating Proteins / metabolism*
HEK293 Cells
Humans
Models, Molecular
Protein Binding
Protein Domains
Protein Multimerization
Ras Homolog Enriched in Brain Protein / metabolism*
Tuberous Sclerosis Complex 1 Protein / chemistry*
Tuberous Sclerosis Complex 1 Protein / metabolism*
Tuberous Sclerosis Complex 1 Protein / ultrastructure
Tuberous Sclerosis Complex 2 Protein / chemistry*
Tuberous Sclerosis Complex 2 Protein / metabolism*
Tuberous Sclerosis Complex 2 Protein / ultrastructure

Substances

GTPase-Activating Proteins
Ras Homolog Enriched in Brain Protein
Tuberous Sclerosis Complex 1 Protein
Tuberous Sclerosis Complex 2 Protein