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The lysosomal cholesterol sensor LYCHOS regulates mTORC1 signaling. Structural studies reveal how cholesterol binding alters LYCHOS conformation, impacting GATOR1 interaction and mTORC1 pathway modulation.

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Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Structural Biology

Background:

  • The lysosomal cholesterol sensor LYCHOS is crucial for regulating mTORC1 signaling.
  • Understanding the structural basis of LYCHOS function is essential for deciphering its role in cellular cholesterol homeostasis and mTORC1 pathway modulation.
  • Previous knowledge on the precise structural mechanisms of LYCHOS-mediated cholesterol sensing and its downstream effects on GATOR1 interaction was limited.

Purpose of the Study:

  • To elucidate the structural mechanisms by which the lysosomal cholesterol sensor LYCHOS regulates mTORC1 signaling.
  • To determine the distinct conformational states of human LYCHOS in response to cholesterol binding.
  • To provide a structural foundation for the development of targeted mTORC1 pathway inhibitors.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was employed to determine high-resolution structures of human LYCHOS.
  • Six distinct cryo-EM structures were obtained, capturing five different functional states of the protein.
  • Analysis of structural changes upon binding of the cholesterol analogue cholesteryl hemisuccinate (CHS) was performed.

Main Results:

  • Six cryo-EM structures revealed five distinct states of the LYCHOS homodimer, transitioning between contracted (CHS-bound) and expanded (CHS-deficient) conformations.
  • The LYCHOS monomer comprises a permease-like domain (PLD) and a GPCR-like domain (GLD), with adjacent cholesterol binding sites.
  • Cholesterol binding induces a conformational shift, exposing a cytosolic extension of transmembrane 15 that interacts with GATOR1, thereby modulating mTORC1 signaling.

Conclusions:

  • The study elucidates the structural mechanism of cholesterol sensing by LYCHOS and its regulation of the mTORC1 pathway.
  • The findings provide a detailed structural basis for understanding how LYCHOS couples cholesterol levels to mTORC1 signaling via GATOR1.
  • These insights pave the way for designing specific inhibitors targeting the expanded state of LYCHOS to modulate the mTORC1 pathway.