Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40 Journal Article

Authors: Yang, H.; Jiang, X.; Li, B.; Yang, H. J.; Miller, M.; Yang, A.; Dhar, A.; Pavletich, N. P.
Article Title: Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40
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. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Keywords: controlled study; protein expression; protein phosphorylation; gene mutation; mutation; nonhuman; protein conformation; protein motif; metabolism; enzyme inhibition; fluorescence polarization; enzyme activity; protein purification; initiation factor 4e; consensus development; binding site; crystal structure; conformational transition; catalysis; protein secondary structure; protein structure; molecular docking; enzyme; substrate; inhibition; michaelis constant; drug; mammalian target of rapamycin complex 1; map; arabidopsis thaliana; rheb protein; cells and cell components; cancer; human; priority journal; article; toscana virus
Journal Title: Nature
Volume: 552
Issue: 7685
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2017-12-21
Start Page: 368
End Page: 373
Language: English
DOI: 10.1038/nature25023
PROVIDER: scopus
PMCID: PMC5750076
PUBMED: 29236692
Notes: Article -- Export Date: 1 February 2018 -- Source: Scopus
Citation Impact
MSK Authors
  1. Haijuan Yang
    12 Yang
  2. Hyo Jung Yang
    3 Yang
  3. Xiaolu Jiang
    1 Jiang
  4. Buren Li
    1 Li
  5. Meredith Ann Miller
    2 Miller
  6. Angela Yang
    1 Yang
  7. Ankita Dhar
    3 Dhar