Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-01862-0
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Funding
- FRISBI [ANR-10-INSB-05-02]
- GRAL [ANR-10-LABX-49-01]
- Rhone-Alpes Region
- Fondation Recherche Medicale (FRM)
- fonds FEDER
- Centre National de la Recherche Scientifique (CNRS)
- CEA
- University of Grenoble, EMBL
- GIS-Infrastructures en Biologie, Sante et Agronomie (IBISA)
- Association pour la Recherche sur le Cancer (ARC)
- Sinergia programme of the Swiss National Science Foundation
- European Research Council Grant programme
- NCCR in Chemical Biology
- BBSRC [BB/R000484/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/R000484/1] Funding Source: researchfish
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The target of rapamycin (TOR) kinase assembles into two distinct multiprotein complexes, conserved across eukaryote evolution. In contrast to TOR complex 1 (TORC1), TORC2 kinase activity is not inhibited by the macrolide rapamycin. Here, we present the structure of Saccharomyces cerevisiae TORC2 determined by electron cryo-microscopy. TORC2 contains six subunits assembling into a 1.4 MDa rhombohedron. Tor2 and Lst8 form the common core of both TOR complexes. Avo3/Rictor is unique to TORC2, but interacts with the same HEAT repeats of Tor2 that are engaged by Kog1/Raptor in mammalian TORC1, explaining the mutual exclusivity of these two proteins. Density, which we conclude is Avo3, occludes the FKBP12-rapamycin-binding site of Tor2's FRB domain rendering TORC2 rapamycin insensitive and recessing the kinase active site. Although mobile, Avo1/hSin1 further restricts access to the active site as its conserved-region-in-the-middle (CRIM) domain is positioned along an edge of the TORC2 active-site-cleft, consistent with a role for CRIM in substrate recruitment.
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