Cited by 549PI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase SignalingMetabolism, Diabetes, and Cancer

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Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40

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Yang, Haijuan, Jiang, Xiaolu, Li, Buren, Yang, Hyo J., Miller, Meredith, Yang, Angela, Dhar, Ankita, Pavletich, Nikola P.·2017·Nature

DOI 10.1038/nature25023PMC PMC5750076

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Abstract

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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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.
ORCID: Yang, Haijuan
Jiang, Xiaolu
Li, Buren
Yang, Hyo J.
Pavletich, Nikola P.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2017-12
Volume: 552
Issue: 7685
Pages: 368-373
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature25023
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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Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40

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