EGOC inhibits TOROID polymerization by structurally activating TORC1

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Target of rapamycin complex 1 (TORC1) is a crucial protein kinase regulating cell growth and homeostasis.
• In yeast, glucose deprivation induces TORC1 to form inactive TOROID condensates on the vacuole surface.
• The precise molecular mechanisms driving TORC1 redistribution remain largely unknown.

Purpose of the Study:

• To elucidate the mechanisms controlling TORC1 redistribution into TOROID structures upon glucose depletion.
• To investigate the role of the EGO complex (EGOC) in regulating TORC1 localization and activity.
• To determine the structural basis of TORC1-TORC1 and TORC1-EGOC interactions within TOROID condensates.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine the structure of TORC1 within TOROIDs.
• In vivo experiments to interrogate key protein-protein interactions.
• Manipulation of EGO complex (EGOC) activity to assess its impact on TORC1 localization.

Main Results:

• Acute modulation of EGO complex (EGOC) activity directly controls TOROID formation and distribution, independent of other nutrient pathways.
• The 3.9-Å cryo-EM structure reveals TORC1-TORC1 and TORC1-EGOC interaction interfaces.
• Glucose-dependent EGOC activation binds TORC1, preventing polymerization and promoting the release of active TORC1.

Conclusions:

• EGO complex (EGOC) plays a pivotal role in glucose-mediated regulation of TORC1 localization and activity.
• Structural insights reveal how EGOC binding to TORC1 prevents TOROID assembly and facilitates active TORC1 release.
• This mechanism provides a direct link between nutrient sensing and TORC1 signaling dynamics.