Scientists Map How Cholesterol Controls Cell Growth Through mTOR Pathway

This groundbreaking structural biology study reveals the molecular mechanism by which cells sense cholesterol levels to control growth and metabolism through the mTORC1 pathway, a central regulator of aging and longevity. The research addresses a fundamental question in cell biology: how cholesterol abundance is communicated to mTORC1, the master growth regulator that becomes dysregulated in aging.

Using cryo-electron microscopy, researchers determined six high-resolution structures of human LYCHOS (lysosomal cholesterol signaling protein) in different states. They discovered LYCHOS exists in two main conformations: an expanded state when cholesterol is deficient and a contracted state when bound to cholesterol or its analogue cholesteryl hemisuccinate (CHS). The structures revealed LYCHOS forms a homodimer with each monomer containing 17 transmembrane helices divided into a permease-like domain (PLD) and a GPCR-like domain (GLD).

The key finding is that LYCHOS contains two adjacent cholesterol binding sites (CBS1 and CBS2) located between the PLD and GLD domains. When cholesterol binds, it induces a conformational change that shifts the GLD toward the PLD, exposing a cytosolic extension of transmembrane helix 15. This exposed region contains the LYCHOS effector domain (LED) that directly interacts with GATOR1, a protein complex that normally inhibits mTORC1. The binding affinity between purified LYCHOS and GATOR1 was measured at 7.6 μM.

The cholesterol binding sites are formed by specific aromatic residues including Tyr57, Phe43, and Phe50, which were previously shown to be critical for LYCHOS function. The Y57A mutation, which disrupts cholesterol sensing, was used to obtain the highest resolution structure (3.21 Å). These structural insights explain how cholesterol abundance on lysosomal membranes is translated into mTORC1 activation signals.

This discovery has significant implications for understanding metabolic regulation and aging, as mTORC1 hyperactivation is associated with age-related diseases while controlled inhibition can extend lifespan. The structural data provides a foundation for developing selective mTORC1 pathway inhibitors that could target LYCHOS in its expanded state, potentially offering new therapeutic approaches for longevity interventions.