TORC2 Structure and Function

Trends Biochem Sci. 2016 Jun;41(6):532-545. doi: 10.1016/j.tibs.2016.04.001. Epub 2016 May 5.

Abstract

The target of rapamycin (TOR) kinase functions in two multiprotein complexes, TORC1 and TORC2. Although both complexes are evolutionarily conserved, only TORC1 is acutely inhibited by rapamycin. Consequently, only TORC1 signaling is relatively well understood; and, at present, only mammalian TORC1 is a validated drug target, pursued in immunosuppression and oncology. However, the knowledge void surrounding TORC2 is dissipating. Acute inhibition of TORC2 with small molecules is now possible and structural studies of both TORC1 and TORC2 have recently been reported. Here we review these recent advances as well as observations made from tissue-specific mTORC2 knockout mice. Together these studies help define TORC2 structure-function relationships and suggest that mammalian TORC2 may one day also become a bona fide clinical target.

Keywords: cancer; conditional knockout mouse model; cryo-electron microscopy; membrane tension homeostasis; metabolism; subunit conservation; subunit topology; target of rapamycin complex 2 (TORC2); therapeutic potential.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology*
  • Binding Sites
  • Gene Expression Regulation
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Mice, Knockout
  • Models, Molecular
  • Multiprotein Complexes / antagonists & inhibitors
  • Multiprotein Complexes / chemistry*
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Interaction Domains and Motifs
  • Protein Subunits / chemistry*
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Signal Transduction
  • Sirolimus / pharmacology
  • Structure-Activity Relationship
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / chemistry*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Antibiotics, Antineoplastic
  • Multiprotein Complexes
  • Protein Subunits
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Sirolimus