结构洞察 TSC 复合物组装和 Rheb 上的 GAP 活性。
Structural insights into TSC complex assembly and GAP activity on Rheb.
机构信息
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.
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.
出版信息
Nat Commun. 2021 Jan 12;12(1):339. doi: 10.1038/s41467-020-20522-4.
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.
结节性硬化症复合物 (TSC) 通过调控 mTORC1 的活性整合上游刺激信号并调节细胞生长。TSC 复合物作为小 GTPase Rheb 的 GTP 酶激活蛋白 (GAP)，抑制 Rheb 介导的 mTORC1 激活。TSC 基因的突变会导致结节性硬化症。在这项研究中，人源 TSC 复合物的近原子分辨率结构揭示了一个拱形结构，由 TSC1、TSC2 和 TBC1D7 以 2:2:1 的比例组成。这个不对称的复合物由两个交织的 TSC1 卷曲螺旋和一个横跨 TSC2 二聚体尾部到尾部的 TBC1D7 组成。两个 TSC2 GAP 结构域对称地镶嵌在由 TSC2 二聚化结构域和 TSC1 中心卷曲螺旋组成的核心模块中。结构和生化分析揭示了 TSC2 GAP-Rheb 的互补相互作用，并提出了一种催化机制，其中天冬酰胺拇指 (N1643) 稳定 GTP 的 γ-磷酸基团并加速 Rheb 的 GTP 水解。我们的研究揭示了 TSC 复合物组装和 GAP 活性的机制。
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