英国剑桥MRC实验室分子生物学Roger L. Williams研究组，通过冷冻电镜结构揭示了Rag鸟苷三磷酸酶（GTPases）异质二聚体的结构及其与mTORC1形成复合物。相关论文2019年10月11日发表于《科学》。

与mTORC1结合的RagA / RagC的冷冻电镜结构显示了RagA / RagC与mTORC1的RAPTOR亚基结合的细节，并解释了为什么只有RagAGTP / RagCGDP核苷酸状态与mTORC1结合。先前的动力学研究表明，GTP与一个Rag结合会锁定异二聚体，以防止GTP与另一个Rag结合。

RagA / RagC晶体结构和动力学表明了这种锁定的机理，并解释了致癌热点突变如何破坏该过程。与RHEB的变构激活相反，Rag异二聚体结合不会改变mTORC1构象，而是通过将mTORC1靶向溶酶体来激活它。

据介绍，Rag GTPases将主要激酶mTORC1募集到溶酶体，以响应氨基酸的可用性来调节细胞的生长和增殖。Rag异二聚体的核苷酸状态对于它们与mTORC1的结合至关重要。

附：英文原文

Title: Architecture of human Rag GTPase heterodimers and their complex with mTORC1

Author: 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

Issue&Volume: Volume 366 Issue 6462

Abstract: 

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 RagAGTP/RagCGDP 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.

DOI: 10.1126/science.aax3939

Source:https://science.sciencemag.org/content/366/6462/203