ジャーナル: Science / 年: 2019 タイトル: Architecture of human Rag GTPase heterodimers and their complex with mTORC1. 著者: Madhanagopal Anandapadamanaban / Glenn R Masson / Olga Perisic / Alex Berndt / Jonathan Kaufman / Chris M Johnson / Balaji Santhanam / Kacper B Rogala / David M Sabatini / Roger L Williams / 要旨: The Rag guanosine triphosphatases (GTPases) recruit the master kinase mTORC1 to lysosomes to regulate cell growth and proliferation in response to amino acid availability. The nucleotide state of Rag ...The Rag guanosine triphosphatases (GTPases) recruit the master kinase mTORC1 to lysosomes to regulate cell growth and proliferation in response to amino acid availability. The nucleotide state of Rag heterodimers is critical for their association with mTORC1. Our cryo-electron microscopy structure of RagA/RagC in complex with mTORC1 shows the details of RagA/RagC binding to the RAPTOR subunit of mTORC1 and explains why only the RagA/RagC nucleotide state binds mTORC1. Previous kinetic studies suggested that GTP binding to one Rag locks the heterodimer to prevent GTP binding to the other. Our crystal structures and dynamics of RagA/RagC show the mechanism for this locking and explain how oncogenic hotspot mutations disrupt this process. In contrast to allosteric activation by RHEB, Rag heterodimer binding does not change mTORC1 conformation and activates mTORC1 by targeting it to lysosomes.
A: Ras-related GTP-binding protein A B: Ras-related GTP-binding protein A C: Ras-related GTP-binding protein C D: Ras-related GTP-binding protein C ヘテロ分子
構造決定の手法: 分子置換 / 解像度: 2.63→46.62 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.929 / SU B: 34.282 / SU ML: 0.327 / SU R Cruickshank DPI: 0.9608 / 交差検証法: THROUGHOUT / σ(F): 0 / ESU R: 0.961 / ESU R Free: 0.356 詳細: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED