Molecular Basis of the Rapamycin Insensitivity of Target Of Rapamycin Complex 2
Copyright policy )Molecular Basis of the Rapamycin Insensitivity of Target Of Rapamycin Complex 2
Target of Rapamycin (TOR) plays central roles in the regulation of eukaryote growth as the hub of two essential multiprotein complexes: TORC1, which is rapamycin-sensitive, and the lesser characterized TORC2, which is not. TORC2 is a key regulator of lipid biosynthesis and Akt-mediated survival signaling. In spite of its importance, its structure and the molecular basis of its rapamycin insensitivity are unknown. Using crosslinking-mass spectrometry and electron microscopy, we determined the architecture of TORC2. TORC2 displays a rhomboid shape with pseudo-2-fold symmetry and a prominent central cavity. Our data indicate that the C-terminal part of Avo3, a subunit unique to TORC2, is close to the FKBP12-rapamycin-binding domain of Tor2. Removal of this sequence generated a FKBP12-rapamycin-sensitive TORC2 variant, which provides a powerful tool for deciphering TORC2 function in vivo. Using this variant, we demonstrate a role for TORC2 in G2/M cell-cycle progression.
- University of Zurich Switzerland
- French Institute of Health and Medical Research France
- University of Bordeaux France
- University of Bristol United Kingdom
- Inserm France
Cell Cycle Proteins/chemistry/genetics/metabolism, Drug Resistance/genetics, Antifungal Agents, Multiprotein Complexes/chemistry/genetics/metabolism, 590, Drug Resistance, Cell Cycle Proteins, Binding Sites/genetics, Mass Spectrometry, Phosphatidylinositol 3-Kinases, Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism/ultrastructure, Microscopy, Sirolimus/metabolism/pharmacology, Blotting, TOR Serine-Threonine Kinases, Cell Cycle, TOR Serine-Threonine Kinases/chemistry/genetics/metabolism, Western, 570, Protein Structure, Saccharomyces cerevisiae Proteins, Blotting, Western, Mechanistic Target of Rapamycin Complex 2, Saccharomyces cerevisiae, Electron, Phosphatidylinositol 3-Kinases/chemistry/genetics/metabolism, Molecular Biology, Mass Spectrometry/methods, Sirolimus, Binding Sites, Carrier Proteins/chemistry/genetics/metabolism, Biocatalysis/drug effects, Cell Biology, Protein Structure, Tertiary, Microscopy, Electron, Multiprotein Complexes, Mutation, Biocatalysis, Saccharomyces cerevisiae/drug effects/genetics/metabolism, Carrier Proteins, Antifungal Agents/metabolism/pharmacology, Tertiary, Cell Cycle/drug effects/genetics, ddc: ddc:590, ddc: ddc:570
Cell Cycle Proteins/chemistry/genetics/metabolism, Drug Resistance/genetics, Antifungal Agents, Multiprotein Complexes/chemistry/genetics/metabolism, 590, Drug Resistance, Cell Cycle Proteins, Binding Sites/genetics, Mass Spectrometry, Phosphatidylinositol 3-Kinases, Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism/ultrastructure, Microscopy, Sirolimus/metabolism/pharmacology, Blotting, TOR Serine-Threonine Kinases, Cell Cycle, TOR Serine-Threonine Kinases/chemistry/genetics/metabolism, Western, 570, Protein Structure, Saccharomyces cerevisiae Proteins, Blotting, Western, Mechanistic Target of Rapamycin Complex 2, Saccharomyces cerevisiae, Electron, Phosphatidylinositol 3-Kinases/chemistry/genetics/metabolism, Molecular Biology, Mass Spectrometry/methods, Sirolimus, Binding Sites, Carrier Proteins/chemistry/genetics/metabolism, Biocatalysis/drug effects, Cell Biology, Protein Structure, Tertiary, Microscopy, Electron, Multiprotein Complexes, Mutation, Biocatalysis, Saccharomyces cerevisiae/drug effects/genetics/metabolism, Carrier Proteins, Antifungal Agents/metabolism/pharmacology, Tertiary, Cell Cycle/drug effects/genetics, ddc: ddc:590, ddc: ddc:570
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