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Updated: Jan 15, 2026
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Construction of Model Lipid Membranes Incorporating G-protein Coupled Receptors GPCRs
Published on: February 5, 2022
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Structural insight into GPR155-mediated cholesterol sensing and signal transduction
Delin Li1, Xiaokang Zhang2, Jie Feng3
1Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China; Innovative Vaccine and lmmunotherapy Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Shanxi Academy of Advanced Research and Innovation, Taiyuan 030032, China.
Science Bulletin
|October 8, 2025
Summary
Cholesterol (CHL) sensing by lysosomal GPR155 involves dynamic domain rearrangements. CHL binding triggers a lever-like helix to transmit signals, explaining how GPR155 activates mTORC1 signaling.
Area of Science:
- Cell Biology
- Structural Biology
- Biochemistry
Background:
- Cholesterol (CHL) is vital for cell membranes and hormone synthesis.
- Lysosomes are key cholesterol sorting stations and sites of mTORC1 activation.
- GPR155 links lysosomal CHL levels to mTORC1 via GATOR1.
Purpose of the Study:
- Elucidate the mechanism of signal transduction from CHL binding to GPR155's soluble domains.
- Understand how GPR155 senses cholesterol sufficiency and communicates with GATOR1.
- Determine the structural basis for CHL sensing by GPR155.
Main Methods:
- Cryo-electron microscopy (cryo-EM) to determine GPR155 structures.
- Molecular dynamics (MD) simulations to analyze dynamic rearrangements.
- Biochemical assays to study protein interactions.
Main Results:
- Three cryo-EM structures revealed GPR155 in different conformations with CHL.
- CHL binding causes domain movements, widening a crevice between transporter and GPCR domains.
- A novel helix acts as a lever, transmitting CHL-induced conformational changes to soluble domains.
Conclusions:
- GPR155 directly senses cholesterol levels at the lysosome.
- A specific helix mediates signal transduction from the transmembrane to soluble domains of GPR155.
- This mechanism explains how cellular cholesterol status is communicated to mTORC1.
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