Illuminating cholesterol-mTORC1 signaling: LYCHOS in focus

Area of Science:

• Cell Biology
• Structural Biology
• Biochemistry

Background:

• Lysosomes play a vital role in cellular cholesterol homeostasis.
• The mechanistic Target of Rapamycin Complex 1 (mTORC1) pathway is sensitive to cellular nutrient levels, including cholesterol.
• LYCHOS is a lysosomal transmembrane protein implicated in cholesterol sensing.

Purpose of the Study:

• To determine the first high-resolution structure of the lysosomal transmembrane protein LYCHOS.
• To elucidate the molecular mechanism by which LYCHOS senses cholesterol.
• To understand the structural basis for LYCHOS-mediated regulation of mTORC1.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to determine the structure of LYCHOS.
• Biochemical assays were used to investigate protein-ligand interactions.
• Structural analysis was performed to identify key functional domains and interfaces.

Main Results:

• The cryo-EM structure reveals LYCHOS exists as a homodimer.
• Cholesterol is engaged at the interface between the transporter and GPCR-like domains.
• Auxin binds to the transporter-like domain, suggesting a multi-domain functional mechanism.

Conclusions:

• The structure of LYCHOS provides unprecedented insight into lysosomal cholesterol sensing.
• Multi-domain coordination within LYCHOS is critical for its function in sensing cholesterol.
• This work lays the foundation for understanding how lysosomal lipid levels regulate mTORC1 signaling.