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

Christl Gaubitz, Taiana M. Oliveira, Manoel Prouteau, Alexander Leitner, Manikandan Karuppasamy, G Konstantinidis, D Rispal, S Eltschinger, GC Robinson, S Thore, Ruedi Aebersold, Christiane Schaffitzel, Robbie Loewith

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

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.
Original languageEnglish
Pages (from-to)977-988
Number of pages11
JournalMolecular Cell
Volume58
Issue number6
Early online date28 May 2015
DOIs
Publication statusPublished - 16 Jun 2015

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