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TORC1 organized in inhibited domains (TOROIDs) regulate TORC1 activity

Desfosses, Ambroise
Sieben, Christian
Demurtas, Davide
Mitra, Alok K
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Published in Nature. 2017, vol. 550, no. 7675, p. 265-269
Abstract The target of rapamycin (TOR) is a eukaryotic serine/threonine protein kinase that functions in two distinct complexes, TORC1 and TORC2, to regulate growth and metabolism. GTPases, responding to signals generated by abiotic stressors, nutrients, and, in metazoans, growth factors, play an important but poorly understood role in TORC1 regulation. Here we report that, in budding yeast, glucose withdrawal (which leads to an acute loss of TORC1 kinase activity) triggers a similarly rapid Rag GTPase-dependent redistribution of TORC1 from being semi-uniform around the vacuolar membrane to a single, vacuole-associated cylindrical structure visible by super-resolution optical microscopy. Three-dimensional reconstructions of cryo-electron micrograph images of these purified cylinders demonstrate that TORC1 oligomerizes into a higher-level hollow helical assembly, which we name a TOROID (TORC1 organized in inhibited domain). Fitting of the recently described mammalian TORC1 structure into our helical map reveals that oligomerization leads to steric occlusion of the active site. Guided by the implications from our reconstruction, we present a TOR1 allele that prevents both TOROID formation and TORC1 inactivation in response to glucose withdrawal, demonstrating that oligomerization is necessary for TORC1 inactivation. Our results reveal a novel mechanism by which Rag GTPases regulate TORC1 activity and suggest that the reversible assembly and/or disassembly of higher-level structures may be an underappreciated mechanism for the regulation of protein kinases.
Keywords AllelesCatalytic DomainCryoelectron MicroscopyEnzyme ActivationGlucose/deficiency/metabolism/pharmacologyMechanistic Target of Rapamycin Complex 1/chemistry/metabolism/ultrastructureMonomeric GTP-Binding Proteins/deficiency/geneticsSaccharomyces cerevisiae/drug effects/enzymology/genetics/ultrastructureSaccharomyces cerevisiae Proteins/genetics
PMID: 28976958
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Research groups Groupe Guichard
Groupe Loewith
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PROUTEAU, Manoel et al. TORC1 organized in inhibited domains (TOROIDs) regulate TORC1 activity. In: Nature, 2017, vol. 550, n° 7675, p. 265-269. doi: 10.1038/nature24021 https://archive-ouverte.unige.ch/unige:103217

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Deposited on : 2018-03-27

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