title: 4.4 Å Resolution Cryo-EM structure of human mTOR Complex 1.
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.
authors.affiliation: Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032, China.|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.|State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200433, China.
authors.forename: Huirong
authors.initials: H
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Jia
authors.initials: J
authors.lastname: Wang
authors.affiliation: Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032, China.|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.|State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200433, China.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Liu
authors.affiliation: Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032, China.|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.|State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200433, China.
authors.forename: Xizi
authors.initials: X
authors.lastname: Chen
authors.affiliation: National Center for Protein Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: National Institute of Biological Sciences, Beijing, 102206, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Tan
authors.affiliation: National Institute of Biological Sciences, Beijing, 102206, China.
authors.forename: Meng-Qiu
authors.initials: MQ
authors.lastname: Dong
authors.affiliation: National Center for Protein Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
authors.forename: Catherine C L
authors.initials: CC
authors.lastname: Wong
authors.affiliation: 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.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032, China. xuyh@fudan.edu.cn.|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.|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.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Wang
mesh_terms: D002460:Cell Line; D020285:Cryoelectron Microscopy / Q000379:methods; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000648:ultrastructure*; D020836:Protein Structure, Quaternary; D058570:TOR Serine-Threonine Kinases / Q000737:chemistry* / Q000648:ultrastructure*
chemical_list: D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: cryo-electron microscopy; mTORC1; structure