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Protein Cell. 2016 Dec;7(12):878-887. doi: 10.1007/s13238-016-0346-6. Epub 2016 Dec 1.

4.4 Å Resolution Cryo-EM structure of human mTOR Complex 1.

Yang H1,2,3, Wang J4, Liu M1,2,3, Chen X1,2,3, Huang M5, Tan D6, Dong MQ6, Wong CC5, Wang J7, Xu Y8,9,10, Wang HW11.

Author information

1
Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032, China.
2
Key Laboratory of Molecular Medicine, Ministry of Education, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032, China.
3
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200433, China.
4
Ministry of Education Key Laboratory of Protein Sciences, Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
5
National Center for Protein Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
6
National Institute of Biological Sciences, Beijing, 102206, China.
7
Ministry of Education Key Laboratory of Protein Sciences, Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China. jwwang@tsinghua.edu.cn.
8
Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032, China. xuyh@fudan.edu.cn.
9
Key Laboratory of Molecular Medicine, Ministry of Education, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032, China. xuyh@fudan.edu.cn.
10
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200433, China. xuyh@fudan.edu.cn.
11
Ministry of Education Key Laboratory of Protein Sciences, Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China. hongweiwang@tsinghua.edu.cn.

Abstract

Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates signals from growth factors, cellular energy levels, stress and amino acids to control cell growth and proliferation through regulating translation, autophagy and metabolism. Here we determined the cryo-electron microscopy structure of human mTORC1 at 4.4 Å resolution. The mTORC1 comprises a dimer of heterotrimer (mTOR-Raptor-mLST8) mediated by the mTOR protein. The complex adopts a hollow rhomboid shape with 2-fold symmetry. Notably, mTORC1 shows intrinsic conformational dynamics. Within the complex, the conserved N-terminal caspase-like domain of Raptor faces toward the catalytic cavity of the kinase domain of mTOR. Raptor shows no caspase activity and therefore may bind to TOS motif for substrate recognition. Structural analysis indicates that FKBP12-Rapamycin may generate steric hindrance for substrate entry to the catalytic cavity of mTORC1. The structure provides a basis to understand the assembly of mTORC1 and a framework to characterize the regulatory mechanism of mTORC1 pathway.

KEYWORDS:

cryo-electron microscopy; mTORC1; structure

PMID:
27909983
PMCID:
PMC5205667
DOI:
10.1007/s13238-016-0346-6
[Indexed for MEDLINE]
Free PMC Article

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