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

• DOI: 10.1038/s41467-017-01862-0
• Publication Date: 2017-11-17T16:40:59Z
• Authors: Manikandan Karupp...; Beata Kusmider; Taiana M. Oliveira; Christl Gaubitz; Manoel Prouteau; Robbie Loewith; Christiane Schaff...
• Keywords: info:eu-repo/classification/ddc/570; Models, Molecular; 570; 0303 health sciences; Binding Sites; Saccharomyces cerevisiae Proteins; Science; info:eu-repo/classification/ddc/590; Q; Cryoelectron Microscopy; 590; Mechanistic Target of Rapamycin Complex 2; Saccharomyces cerevisiae; Article; 03 medical and health sciences; ddc:590; ddc:570; Protein Interaction Domains and Motifs; Carrier Proteins; Protein Structure, Quaternary; Transcription Factors

AbstractThe 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.