An interdomain hydrogen bond in the Rag GTPases maintains stable mTORC1 signaling in sensing amino acids
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AuthorsEgri, Shawn B.
UMass Chan AffiliationsGraduate School of Biomedical Sciences
Program in Molecular Medicine
Document TypeJournal Article
mTOR complex 1 (mTORC1)
Amino Acids, Peptides, and Proteins
Biochemistry, Biophysics, and Structural Biology
Enzymes and Coenzymes
Nucleic Acids, Nucleotides, and Nucleosides
MetadataShow full item record
AbstractCellular growth and proliferation are primarily dictated by the mechanistic target of rapamycin complex 1 (mTORC1), which balances nutrient availability against the cell's anabolic needs. Central to the activity of mTORC1 is the RagA-RagC GTPase heterodimer, which under favorable conditions recruits the complex to the lysosomal surface to promote its activity. The RagA-RagC heterodimer has a unique architecture in that both subunits are active GTPases. To promote mTORC1 activity, the RagA subunit is loaded with GTP and the RagC subunit is loaded with GDP, while the opposite nucleotide-loading configuration inhibits this signaling pathway. Despite its unique molecular architecture, how the Rag GTPase heterodimer maintains the oppositely loaded nucleotide state remains elusive. Here, we applied structure-function analysis approach to the crystal structures of the Rag GTPase heterodimer and identified a key hydrogen bond that stabilizes the GDP-loaded state of the Rag GTPases. This hydrogen bond is mediated by the backbone carbonyl of Asn30 in the nucleotide-binding domain of RagA or Lys84 of RagC and the hydroxyl group on the side chain of Thr210 in the C-terminal roadblock domain of RagA or Ser266 of RagC, respectively. Eliminating this interdomain hydrogen bond abolishes the ability of the Rag GTPase to maintain its functional state, resulting in a distorted response to amino acid signals. Our results reveal that this long-distance interdomain interaction within the Rag GTPase is required for the maintenance and regulation of the mTORC1 nutrient-sensing pathway.
Egri SB, Shen K. An interdomain hydrogen bond in the Rag GTPases maintains stable mTORC1 signaling in sensing amino acids. J Biol Chem. 2021 Jul;297(1):100861. doi: 10.1016/j.jbc.2021.100861. Epub 2021 Jun 9. PMID: 34116056; PMCID: PMC8254048. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/41992
Rights© 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Except where otherwise noted, this item's license is described as © 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).