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Nat Commun. 2017 Nov 23;8(1):1729. doi: 10.1038/s41467-017-01862-0.

Cryo-EM structure of Saccharomyces cerevisiae target of rapamycin complex 2.

Author information

1
European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, 38042, Grenoble, France.
2
Department of Molecular Biology, Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, 30 Quai Ernest Ansermet, CH1211, Geneva, Switzerland.
3
Department of Molecular Biology, Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, 30 Quai Ernest Ansermet, CH1211, Geneva, Switzerland. robbie.loewith@unige.ch.
4
Swiss National Centre for Competence in Research (NCCR) in Chemical Biology, University of Geneva, 30 Quai Ernest-Ansermet, Bristol, CH1211 Geneva, Switzerland. robbie.loewith@unige.ch.
5
European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, 38042, Grenoble, France. christiane.berger-schaffitzel@bristol.ac.uk.
6
School of Biochemistry, University of Bristol, University Walk, Bristol, BS8 1TD, UK. christiane.berger-schaffitzel@bristol.ac.uk.

Abstract

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.

PMID:
29170376
PMCID:
PMC5700991
DOI:
10.1038/s41467-017-01862-0
[Indexed for MEDLINE]
Free PMC Article

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