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Molecular Basis of the Rapamycin Insensitivity of Target Of Rapamycin Complex 2

Christl Gaubitz1, Taiana M Oliveira2, Manoel Prouteau1

  • 1Department of Molecular Biology and Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, 30 Quai Ernest Ansermet, CH1211 Geneva, Switzerland.

Molecular Cell
|June 2, 2015
PubMed

Insights

Researchers elucidated the structure of Target of Rapamycin Complex 2 (TORC2), revealing its rhomboid shape. They identified a unique subunit interaction explaining its insensitivity to rapamycin, and created a sensitive variant to study its role in cell division.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Target of Rapamycin (TOR) is crucial for regulating eukaryote growth.
  • TOR exists in two complexes: TORC1 (rapamycin-sensitive) and TORC2 (rapamycin-insensitive).
  • TORC2 regulates lipid biosynthesis and survival signaling, but its structure and rapamycin insensitivity mechanism are unknown.

Purpose of the Study:

  • Determine the architecture of TORC2.
  • Investigate the molecular basis of TORC2's rapamycin insensitivity.
  • Explore TORC2's function in cell cycle progression.

Main Methods:

  • Crosslinking-mass spectrometry
  • Electron microscopy
  • Genetic modification to create a rapamycin-sensitive TORC2 variant

Main Results:

  • TORC2 architecture determined as a rhomboid shape with a central cavity.
  • Identified a unique TORC2 subunit (Avo3) interaction site near the rapamycin-binding domain of Tor2.
  • Generated a rapamycin-sensitive TORC2 variant by altering the Avo3 subunit.
  • Demonstrated TORC2's role in G2/M cell-cycle progression using the variant.

Conclusions:

  • The study reveals the structural basis of TORC2 and its rapamycin insensitivity.
  • A novel rapamycin-sensitive TORC2 variant was created, enabling new avenues for functional studies.
  • TORC2 is implicated in regulating G2/M cell-cycle progression.

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