9J3Z

Cryo-EM structure of lysosome cholesterol sencing protein in L state

Summary for 9J3Z

• Entry DOI: 10.2210/pdb9j3z/pdb
• EMDB information: 61128
• Descriptor: Lysosomal cholesterol signaling protein,G protein-coupled receptor 155 fusion protein, (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: lipid binding protein
• Biological source: Nomascus leucogenys; More
• Total number of polymer chains: 2
• Total formula weight: 197472.11

Authors

Qian, H.W.,Wang, Z.H. (deposition date: 2024-08-08, release date: 2025-04-02, Last modification date: 2025-06-25)

Primary citation

Wang, Z.,He, J.,Yang, Y.,He, Y.,Qian, H.
Structural basis for cholesterol sensing of LYCHOS and its interaction with indoxyl sulfate.
Nat Commun, 16:2815-2815, 2025

PubMed Abstract: The lysosome serves as an essential nutrient-sensing hub within the cell, where the mechanistic target of rapamycin complex 1 (mTORC1) is activated. Lysosomal cholesterol signaling (LYCHOS), a lysosome membrane protein, has been identified as a cholesterol sensor that couples cholesterol concentration to mTORC1 activation. However, the molecular basis is unknown. Here, we determine the cryo-electron microscopy (cryo-EM) structure of human LYCHOS at a resolution of 3.1 Å, revealing a cholesterol-like density at the interface between the permease and G-protein coupled receptor (GPCR) domains. Advanced 3D classification reveals two distinct states of LYCHOS. Comparative structural analysis between these two states demonstrated a cholesterol-related movement of GPCR domain relative to permease domain, providing structural insights into how LYCHOS senses lysosomal cholesterol levels. Additionally, we identify indoxyl sulfate (IS) as a binding ligand to the permease domain, confirmed by the LYCHOS-IS complex structure. Overall, our study provides a foundation and indicates additional directions for further investigation of the essential role of LYCHOS in the mTORC1 signaling pathway.

PubMed: 40118871
DOI: 10.1038/s41467-025-58087-9

Experimental method

ELECTRON MICROSCOPY (3.5 Å)