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Structural and functional characterization of rapamycin-resistant TORC2

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Defense Thèse de doctorat : Univ. Genève, 2015 - Sc. 4853 - 2015/11/13
Abstract TORC2 is nucleated by Target of Rapamycin (TOR), a protein kinase of the phosphatidylinositol 3-kinase-related kinase (PIKK) family. TOR kinases are validated drug targets which can be inhibited by rapamycin, facilitating elucidation of TORC1 signaling. TORC2 cannot be inhibited by rapamycin, and the lack of specific inhibitors has impeded progress in understanding the functions of this essential complex. The EM reconstruction revealed a rhomboid shape with C2 pseudo-symmetry and a prominent central cavity. We found that the TORC2-specific subunit Avo3 is proximal to the rapamycin binding domain of Tor2. Building on this observation, we successfully engineered a yeast strain in which TORC2, but not TORC1, is inhibited by rapamycin. We leveraged this unique tool to study TORC2 function and regulation, demonstrating that acute TORC2 inhibition abolishes actin polarization and leads to cell-cycle arrest.
Keywords Cell growthTORC2EM reconstructionRapamycinAvo3
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URN: urn:nbn:ch:unige-789947
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Research group Groupe Loewith
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GAUBITZ, Christl. Structural and functional characterization of rapamycin-resistant TORC2. Université de Genève. Thèse, 2015. https://archive-ouverte.unige.ch/unige:78994

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Deposited on : 2016-01-06

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