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TORC1 organized in inhibited domains (TOROIDs) regulate TORC1 activity.
Manoël Prouteau1,2, Ambroise Desfosses3, Christian Sieben4,5
1Department of Molecular Biology, University of Geneva, 30 quai Ernest-Ansermet, CH1211 Geneva, Switzerland.
Nature
|October 5, 2017
Summary
Glucose withdrawal rapidly inactivates the target of rapamycin complex 1 (TORC1) in yeast. This inactivation involves TORC1 forming a higher-order helical structure called a TOROID, regulated by Rag GTPases.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The target of rapamycin (TOR) kinase regulates cell growth and metabolism through TORC1 and TORC2 complexes.
- GTPases are known to influence TORC1 activity in response to various signals, but their precise role is not fully understood.
Purpose of the Study:
- To investigate the mechanism of TORC1 regulation by GTPases during glucose withdrawal in budding yeast.
- To elucidate the structural basis of TORC1 inactivation.
Main Methods:
- Super-resolution optical microscopy to visualize TORC1 localization.
- Cryo-electron microscopy and 3D reconstruction to determine the structure of TORC1 assemblies.
- Genetic manipulation to create TOR1 alleles affecting TORC1 assembly and activity.
Main Results:
- Glucose withdrawal induces rapid, Rag GTPase-dependent redistribution of TORC1 into a vacuole-associated cylindrical structure.
- Cryo-EM revealed TORC1 oligomerizes into a hollow helical assembly, termed TOROID.
- TORC1 oligomerization sterically occludes the active site, leading to inactivation.
- A specific TOR1 mutation preventing TOROID formation also prevented TORC1 inactivation.
Conclusions:
- TORC1 inactivation upon glucose withdrawal is mediated by its assembly into a higher-order TOROID structure.
- Rag GTPases are key regulators of this TORC1 assembly and subsequent inactivation.
- Reversible assembly of protein kinases into higher-order structures represents a novel regulatory mechanism.
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