Article ; Online: Cryo-EM insight into the structure of MTOR complex 1 and its interactions with Rheb and substrates.
2019 Volume 8
Abstract: The mechanistic target of rapamycin (MTOR) is a giant protein kinase that, together with the accessory proteins Raptor and mLst8, forms a complex of over 1 MDa known as MTOR complex 1 (MTORC1). MTORC1, through its protein kinase activity, controls the ... ...
| Abstract | The mechanistic target of rapamycin (MTOR) is a giant protein kinase that, together with the accessory proteins Raptor and mLst8, forms a complex of over 1 MDa known as MTOR complex 1 (MTORC1). MTORC1, through its protein kinase activity, controls the accretion of cell mass through the regulation of gene transcription, mRNA translation, and protein turnover. MTORC1 is activated in an interdependent manner by insulin/growth factors and nutrients, especially amino acids, and is inhibited by stressors such as hypoxia and by the drug rapamycin. The action of insulin/growth factors converges on the small GTPase Rheb, which binds directly to the MTOR polypeptide in MTORC1 and, in its GTP-bound state, initiates kinase activation. Biochemical studies established that MTORC1 exists as a dimer of the MTOR/Raptor/mLst8 trimer, and progressive refinements in cryo-electron microscopy (cryo-EM) have enabled an increasingly clear picture of the architecture of MTORC1, culminating in a deep understanding of how MTORC1 interacts with and phosphorylates its best-known substrates-the eIF-4E binding protein/4E-BP, the p70 S6 kinase/S6K1B, and PRAS40/AKT1S1-and how this is inhibited by rapamycin. Most recently, Rheb-GTP has been shown to bind to MTORC1 in a cooperative manner at an allosteric site remote from the kinase domain that twists the latter into a catalytically competent configuration. Herein, we review the recent cryo-EM and associated biochemical studies of MTORC1 and seek to integrate these new results with the known physiology of MTORC1 regulation and signaling. |
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| MeSH term(s) | Animals ; Cryoelectron Microscopy ; Humans ; Mechanistic Target of Rapamycin Complex 1/chemistry ; Ras Homolog Enriched in Brain Protein/chemistry |
| Chemical Substances | Ras Homolog Enriched in Brain Protein ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) |
| Language | English |
| Publishing date | 2019-01-03 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review |
| ZDB-ID | 2699932-8 |
| ISSN | 2046-1402 ; 2046-1402 |
| ISSN (online) | 2046-1402 |
| ISSN | 2046-1402 |
| DOI | 10.12688/f1000research.16109.1 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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