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

Author

Listed:
  • Manikandan Karuppasamy

    (Grenoble Outstation)

  • Beata Kusmider

    (University of Geneva)

  • Taiana M. Oliveira

    (Grenoble Outstation)

  • Christl Gaubitz

    (University of Geneva)

  • Manoel Prouteau

    (University of Geneva)

  • Robbie Loewith

    (University of Geneva
    University of Geneva)

  • Christiane Schaffitzel

    (Grenoble Outstation
    University of Bristol)

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.

Suggested Citation

  • Manikandan Karuppasamy & Beata Kusmider & Taiana M. Oliveira & Christl Gaubitz & Manoel Prouteau & Robbie Loewith & Christiane Schaffitzel, 2017. "Cryo-EM structure of Saccharomyces cerevisiae target of rapamycin complex 2," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01862-0
    DOI: 10.1038/s41467-017-01862-0
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