Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability
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mTOR complex I (mTORC1) is a central growth regulator that senses amino acids through a pathway that converges on the Rag GTPases, an obligate heterodimer of two related GTPases. Despite their central role in amino acid sensing, it is unknown why the Rag GTPases are heterodimeric and whether their subunits communicate with each other. Here, we find that the binding of guanosine triphosphate (GTP) to one subunit inhibits the binding and induces the hydrolysis of GTP by the other. This intersubunit communication pushes the Rag GTPases into either of two stable configurations, which represent active "on" or "off" states that interconvert via transient intermediates. Subunit coupling confers on the mTORC1 pathway its capacity to respond rapidly to the amino acid level. Thus, the dynamic response of mTORC1 requires intersubunit communication by the Rag GTPases, providing a rationale for why they exist as a dimer and revealing a distinct mode of control for a GTP-binding protein.
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Kinetic analyses of nucleotide binding suggest that binding of a GTP molecule to one Rag establishes a dominant, conformation-driven effect on the nucleotide binding pocket of the partner Rag, reducing affinity for GTP and stimulating GTP hydrolysis in the partner active site such that the heterodimer exists stably in a singly-GTP-bound state.
“Kinetic analyses of nucleotide binding suggest that the binding of a GTP molecule to one Rag establishes a dominant, conformation-driven, effect on the nucleotide binding pocket of the partner Rag, reducing affinity for GTP and stimulating GTP hydrolysis in the partner active site such that the heterodimer exists stably in a singly-GTP-bound state.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Shen et al., 2017
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- Authors
- Shen, K., Choe, A., & Sabatini, D. M.
- Affiliations
- Broad Institute (US)
- Whitehead Institute for Biomedical Research (US)
- Corresponding author
- Sabatini, David M.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 68
- Issue
- 3
- Pages
- 552-565.e8
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC5746184
- OpenAlex
- W2765487476
- Cited by
- 101
- References
- 48
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 6 · 2023: 15 · 2022: 16 · 2021: 14 · 2020: 13 · 2019: 13 · 2018: 11
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-11-16)
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 367 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- NIH (R01 CA103866, R01 CA129105, R37 AI47389)
- Department of Defense (W81XWH-15-1-0230)
- Life Sciences Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- Rag GTPases, mTORC1, intersubunit communication, amino acid sensing, GTP binding, GTP hydrolysis, allosteric regulation, G proteins, growth signaling
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Amino Acids, Binding Sites, Enzyme Stability, Guanosine Triphosphate, Humans, Hydrolysis, Kinetics, Models, Molecular, Protein Binding, Protein Conformation, Structure-Activity Relationship, Transfection, Signal Transduction, Monomeric GTP-Binding Proteins, Protein Subunits, Protein Multimerization, HEK293 Cells
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