Architecture of human Rag GTPase heterodimers and their complex with mTORC1
Name
EMS84335.pdf
Description
Accepted version
Size
3.42 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Anandapadamanaban, Madhanagopal
Masson, Glenn R
Perisic, Olga
Berndt, Alex
Kaufman, Jonathan
Johnson, Chris M
Santhanam, Balaji
Rogala, Kacper B
Sabatini, David M
Williams, Roger L
Date Issued
2019
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Version
Author's final manuscript
Abstract
© 2019 American Association for the Advancement of Science. All rights reserved. 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/RagCGDPnucleotide 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.
MIT Department
Whitehead Institute for Biomedical Research
Massachusetts Institute of Technology. Department of Biology
Howard Hughes Medical Institute
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1126/SCIENCE.AAX3939
