Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40

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

doi:10.1038/nature25023

Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40

Journal Article · Wed Dec 13 00:00:00 EST 2017 · Nature (London)

DOI:https://doi.org/10.1038/nature25023· OSTI ID:1430356

Yang, Haijuan ^[1]; Jiang, Xiaolu ^[1]; Li, Buren ^[1]; Yang, Hyo J. ^[1]; Miller, Meredith ^[1]; Yang, Angela ^[1]; Dhar, Ankita ^[1]; Pavletich, Nikola P. ^[1]

Memorial Sloan Kettering Cancer Center, New York, NY (United States)

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. Here, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: Howard Hughes Medical Inst.; National Inst. of Health

OSTI ID:: 1430356

Journal Information:: Nature (London), Journal Name: Nature (London) Journal Issue: 7685 Vol. 552; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Regulation of TORC2 function and localization by Rab5 GTPases in Saccharomyces cerevisiae Locke, Melissa N.; Thorner, Jeremy Cell Cycle, Vol. 18, Issue 10 https://doi.org/10.1080/15384101.2019.1616999	journal	May 2019
Weak membrane interactions allow Rheb to activate mTORC1 signaling without major lysosome enrichment Angarola, Brittany; Ferguson, Shawn M. Molecular Biology of the Cell, Vol. 30, Issue 22 https://doi.org/10.1091/mbc.e19-03-0146	journal	October 2019
Differential metabolic sensitivity of insulin-like-response- and TORC1-dependent overgrowth in Drosophila fat cells Devilliers, Maelle; Garrido, Damien; Poidevin, Mickael Genetics, Vol. 217, Issue 1 https://doi.org/10.1093/genetics/iyaa010	journal	November 2020
Next Generation Strategies for Geroprotection via mTORC1 Inhibition Dumas, Sabrina N.; Lamming, Dudley W. The Journals of Gerontology: Series A, Vol. 75, Issue 1 https://doi.org/10.1093/gerona/glz056	journal	February 2019
Regulation of mTORC1 by Small GTPases in Response to Nutrients Zhu, Min; Wang, Xiu-qi The Journal of Nutrition, Vol. 150, Issue 5 https://doi.org/10.1093/jn/nxz301	journal	January 2020
Energetic adaptations: Metabolic control of endocytic membrane traffic Rahmani, Sadia; Defferrari, Marina S.; Wakarchuk, Warren W. Traffic, Vol. 20, Issue 12 https://doi.org/10.1111/tra.12705	journal	November 2019
Architecture of human Rag GTPase heterodimers and their complex with mTORC1 Anandapadamanaban, Madhanagopal; Masson, Glenn R.; Perisic, Olga Science, Vol. 366, Issue 6462 https://doi.org/10.1126/science.aax3939	journal	October 2019
Structural basis for the docking of mTORC1 on the lysosomal surface Rogala, Kacper B.; Gu, Xin; Kedir, Jibril F. Science, Vol. 366, Issue 6464 https://doi.org/10.1126/science.aay0166	journal	October 2019
AMPK directly activates mTORC2 to promote cell survival during acute energetic stress Kazyken, Dubek; Magnuson, Brian; Bodur, Cagri Science Signaling, Vol. 12, Issue 585 https://doi.org/10.1126/scisignal.aav3249	journal	June 2019
Signaling Pathways Involved in the Regulation of mRNA Translation Roux, Philippe P.; Topisirovic, Ivan Molecular and Cellular Biology, Vol. 38, Issue 12 https://doi.org/10.1128/mcb.00070-18	journal	April 2018
Ibrutinib therapy downregulates AID enzyme and proliferative fractions in chronic lymphocytic leukemia Morande, Pablo Elías; Sivina, Mariela; Uriepero, Angimar Blood, Vol. 133, Issue 19 https://doi.org/10.1182/blood-2018-09-876292	journal	May 2019
Active receptor tyrosine kinases, but not Brachyury, are sufficient to trigger chordoma in zebrafish D'Agati, Gianluca; Cabello, Elena María; Frontzek, Karl Disease Models & Mechanisms, Vol. 12, Issue 7 https://doi.org/10.1242/dmm.039545	journal	June 2019
Mechanical Stretch Induces mTOR Recruitment and Activation at the Phosphatidic Acid-Enriched Macropinosome in Muscle Cell Lin, Shan-Shan; Liu, Ya-Wen Frontiers in Cell and Developmental Biology, Vol. 7 https://doi.org/10.3389/fcell.2019.00078	journal	May 2019
Sotetsuflavone Induces Autophagy in Non-Small Cell Lung Cancer Through Blocking PI3K/Akt/mTOR Signaling Pathway in Vivo and in Vitro Wang, Shaohui; Xu, Xiaoling; Hu, Yanlan Frontiers in Pharmacology, Vol. 10 https://doi.org/10.3389/fphar.2019.01460	journal	December 2019
Targeting mTOR and Metabolism in Cancer: Lessons and Innovations Magaway, Cedric; Kim, Eugene; Jacinto, Estela Cells, Vol. 8, Issue 12 https://doi.org/10.3390/cells8121584	journal	December 2019
Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update Evangelisti, Camilla; Chiarini, Francesca; McCubrey, James International Journal of Molecular Sciences, Vol. 19, Issue 7 https://doi.org/10.3390/ijms19071878	journal	June 2018
Active receptor tyrosine kinases, but not Brachyury, are sufficient to trigger chordoma in zebrafish Gianluca, D'Agati,; María, Cabello, Elena; Karl, Frontzek, The Company of Biologists Ltd. https://doi.org/10.5167/uzh-179586	text	January 2019
In vivo identification of GTPase interactors by mitochondrial relocalization and proximity biotinylation Gillingham, Alison K.; Bertram, Jessie; Begum, Farida eLife, Vol. 8 https://doi.org/10.7554/eLife.45916	journal	July 2019

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