Structural basis for the docking of mTORC1 on the lysosomal surface

Area of Science:

• Cellular Biology
• Molecular Biology
• Biochemistry

Background:

• The mechanistic target of rapamycin complex 1 (mTORC1) is a key regulator of cell growth.
• mTORC1 activity is controlled by nutrients and growth factors, influencing its localization to the lysosome.
• The Rag GTPase-Ragulator complex mediates nutrient-dependent mTORC1 recruitment to the lysosome.

Purpose of the Study:

• To elucidate the structural basis of mTORC1 interaction with the Rag GTPase-Ragulator complex.
• To understand how nutrient availability regulates mTORC1 localization and activation at the lysosome.
• To provide a structural model for active mTORC1 at the lysosomal surface.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to determine the structure of the Raptor-Rag-Ragulator supercomplex.
• Biochemical assays and mutational analyses were used to assess the functional impact of Rag-Raptor interactions.
• Comparative structural analysis with mTORC1-Rheb complex was performed.

Main Results:

• The cryo-EM structure revealed detailed interactions between the Raptor subunit and the Rag GTPases, defining the nucleotide-sensing mechanism.
• Raptor directly senses the nucleotide-bound state of RagA and RagC, crucial for mTORC1 recruitment.
• Disruption of Rag-Raptor binding impaired mTORC1 lysosomal localization and signaling, confirming the functional importance of these interactions.

Conclusions:

• The study provides a high-resolution structure of the mTORC1-Rag-Ragulator complex, revealing how nutrient signals are transmitted to mTORC1.
• The findings clarify the molecular mechanism by which mTORC1 is localized to the lysosome and activated.
• A model for active mTORC1 docked on the lysosome was proposed, integrating structural and functional data.