TORC1 organized in inhibited domains (TOROIDs) regulate TORC1 activity

Article Article scientifique Lettre TORC1 organized in inhibited domains (TOROIDs) regulate TORC1 activity eng 2017 author Prouteau Manoel 698431 author Desfosses Ambroise author Sieben Christian author Bourgoint Clelia 795211 author Mozaffari Nour Lydia 781010 author Demurtas Davide author Mitra Alok K author Guichard Paul 845268 author Manley Suliana author Loewith Robbie Joséph 630703 265-269 10.1038/nature24021 28976958 0028-0836 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. Alleles Catalytic Domain Cryoelectron Microscopy Enzyme Activation Glucose/deficiency/metabolism/pharmacology Mechanistic Target of Rapamycin Complex 1/chemistry/metabolism/ultrastructure Monomeric GTP-Binding Proteins/deficiency/genetics Saccharomyces cerevisiae/drug effects/enzymology/genetics/ultrastructure Saccharomyces cerevisiae Proteins/genetics Dewey 570 Dewey 590 23 Institut de génétique et de génomique 0DH 43 Département de biologie moléculaire 161 46 Département de biologie cellulaire 165 false 841 Groupe Guichard 814 Groupe Loewith Nature 550 7675 107ea39c-4060-45f8-a828-a37678e2efa1 Article (Published version) Restricted TOROID.pdf 21440086 application/pdf restrictedAccess Centres et instituts / Institut de génétique et de génomique Faculté des sciences / Section de biologie / Département de biologie moléculaire Faculté des sciences / Section de biologie / Département de biologie cellulaire

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TORC1 organized in inhibited domains (TOROIDs) regulate TORC1 activity	Nature			2017	510	0

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Mozaffari, Nour Lydia