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Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40
Open accessAbstract
The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, energy levels, and growth factors. It contains the atypical kinase mTOR and the RAPTOR subunit that binds to the Tor signalling sequence (TOS) motif of substrates and regulators. mTORC1 is activated by the small GTPase RHEB (Ras homologue enriched in brain) and inhibited by PRAS40. Here we present the 3.0 ångström cryo-electron microscopy structure of mTORC1 and the 3.4 ångström structure of activated RHEB-mTORC1. RHEB binds to mTOR distally from the kinase active site, yet causes a global conformational change that allosterically realigns active-site residues, accelerating catalysis. Cancer-associated hyperactivating mutations map to structural elements that maintain the inactive state, and we provide biochemical evidence that they mimic RHEB relieving auto-inhibition. We also present crystal structures of RAPTOR-TOS motif complexes that define the determinants of TOS recognition, of an mTOR FKBP12-rapamycin-binding (FRB) domain-substrate complex that establishes a second substrate-recruitment mechanism, and of a truncated mTOR-PRAS40 complex that reveals PRAS40 inhibits both substrate-recruitment sites. These findings help explain how mTORC1 selects its substrates, how its kinase activity is controlled, and how it is activated by cancer-associated mutations.
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“High resolution structures of mTORC1 have provided a previously unprecedented look at how mTORC1 is activated by nutrients and how it is inhibited by rapamycin 155–157.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [157]
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“Cryo-electron microscopy has revealed that Rheb-GTP binds allosterically to mTOR, resulting in a global conformational change that allosterically realigns the active-site residues to enable substrate phosphorylation 157.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [157]
In the citing paper
“Cross-linking of mTORC1 in the presence of RhebGTPgS and 4EBP1, another well-known mTORC1 substrate (Burnett et al., 1998), yielded the cryo-EM structure of mTORC1 bound to Rheb (Yang et al., 2017).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Yang et al., 2017
In the citing paper
“Density corresponding to Rheb was observed at the N-terminal portions of the N- HEAT, M-HEAT and FAT domains, thereby resulting in a four-way interface where Rheb switch I residues bound the M-HEAT solenoid and FAT domain, and switch II formed contacts with all three mTORC1 domains.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Yang et al., 2017
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Metadata
- Authors
- Yang, H., Jiang, X., Li, B., Yang, H. J., Miller, M., Yang, A., Dhar, A., & Pavletich, N. P.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Pavletich, Nikola P.
- Venue
- Nature
- Published
- 2017-12
- Volume
- 552
- Issue
- 7685
- Pages
- 368-373
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5750076
- OpenAlex
- W2773300145
- Cited by
- 548
- References
- 55
- Citations by year
- 2026: 55 · 2025: 65 · 2024: 68 · 2023: 66 · 2022: 63 · 2021: 80 · 2020: 74 · 2019: 53 · 2018: 23
- FWCI
- 16.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Memorial Sloan-Kettering Cancer Center (CA008748)
- National Institutes of Health (CA008748)
- National Cancer Institute (P30CA008748)
- National Institute of General Medical Sciences (P41GM103310, R01GM064644)
- 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
- mTORC1, Rheb, PRAS40, allosteric activation, allosteric inhibition, raptors, substrate recognition, cancer-associated mutations, mTOR hyperactivation, protein complex structure, cell growth regulation
- MeSH terms
- Protein Domains, Ras Homolog Enriched in Brain Protein, Mechanistic Target of Rapamycin Complex 1, Regulatory-Associated Protein of mTOR, Binding Sites, Enzyme Activation, Humans, Models, Molecular, Mutation, Neoplasms, Protein Binding, Substrate Specificity, Signal Transduction, Crystallography, X-Ray, Sirolimus, Catalytic Domain, Cryoelectron Microscopy, Amino Acid Motifs, Tacrolimus Binding Protein 1A, Ribosomal Protein S6 Kinases, 70-kDa, Adaptor Proteins, Signal Transducing, Biocatalysis
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