Structural basis for mTORC1 activation on the lysosomal membrane

Area of Science:

• Cellular signaling
• Molecular biology
• Biochemistry

Background:

• The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth, integrating growth factor (GF) and nutrient signals.
• mTORC1 activation involves the small GTPase RAS homologue enriched in brain (RHEB) binding to the mTOR kinase subunit, inducing conformational changes.
• Understanding mTORC1 regulation is crucial for comprehending cell growth and metabolic processes.

Purpose of the Study:

• To reconstitute and structurally elucidate the mechanism of mTORC1 activation on membranes.
• To understand how growth factor and nutrient signals are integrated at the lysosome to regulate mTORC1.
• To provide a structural basis for mTORC1 activation by RHEB and membrane engagement.

Main Methods:

• Reconstitution of mTORC1 activation complex on membranes using RHEB, RAGs, and Ragulator.
• Cryo-electron microscopy (Cryo-EM) to determine the structural basis of mTORC1 activation.
• Biochemical assays to assess enzyme activity and membrane interactions.

Main Results:

• mTORC1 components RAPTOR and mTOR directly interact with the membrane.
• Full catalytic activation requires engagement of membrane anchors for optimal alignment of active site residues.
• A four-step process involving RAG-Ragulator, RHEB, and membrane engagement leads to mTORC1 recruitment and full activation on the lysosomal membrane.
• RHEB and membrane engagement synergistically activate mTORC1, explaining signal integration.

Conclusions:

• The study provides a detailed structural mechanism for mTORC1 activation on lysosomal membranes.
• This mechanism explains how growth factor and nutrient signals converge to regulate cell growth and metabolism via mTORC1.
• The findings offer insights into potential therapeutic targets for diseases involving mTORC1 dysregulation.