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Architecture of human Rag GTPase heterodimers and their complex with mTORC1

DOI: 10.1126/science.aax3939 DOI Help

Authors: Madhanagopal Anandapadamanaban (MRC Laboratory of Molecular Biology) , Glenn R. Masson (MRC Laboratory of Molecular Biology) , Olga Perisic (MRC Laboratory of Molecular Biology) , Alex Berndt (MRC Laboratory of Molecular Biology) , Jonathan Kaufman (MRC Laboratory of Molecular Biology) , Chris M. Johnson (MRC Laboratory of Molecular Biology) , Balaji Santhanam (MRC Laboratory of Molecular Biology) , Kacper B. Rogala (Whitehead Institute for Biomedical Research) , David M. Sabatini (Whitehead Institute for Biomedical Research; Massachusetts Institute of Technology; Howard Hughes Medical Institute, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Broad Institute of MIT and Harvard) , Roger L. Williams (MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science , VOL 366 , PAGES 203 - 210

State: Published (Approved)
Published: October 2019
Diamond Proposal Number(s): 23268

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.

Subject Areas: Biology and Bio-materials

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