9JBE

Cryo-EM structure of the human LYCHOS in complex with cholesterol and cholesteryl hemisuccinate in the contracted state

This is a non-PDB format compatible entry.

Summary for 9JBE

• Entry DOI: 10.2210/pdb9jbe/pdb
• EMDB information: 61311
• Descriptor: Lysosomal cholesterol signaling protein, CHOLESTEROL HEMISUCCINATE, 1,2-Distearoyl-sn-glycerophosphoethanolamine, ... (6 entities in total)
• Functional Keywords: permease-like domain, gpcr-like domain, cholesterol, mtorc1, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 206019.97

Authors

Yu, S.,Liang, L. (deposition date: 2024-08-27, release date: 2025-07-16, Last modification date: 2025-08-27)

Primary citation

Yu, S.,Ding, J.H.,Wang, J.L.,Wang, W.,Zuo, P.,Yang, A.,Dai, Z.,Yin, Y.,Sun, J.P.,Liang, L.
Structural insights into cholesterol sensing by the LYCHOS-mTORC1 pathway.
Nat Commun, 16:6792-6792, 2025

PubMed Abstract: The lysosomal cholesterol sensor LYCHOS regulates mTORC1 signaling by coupling cholesterol sensing to GATOR1-Rag GTPase modulation, yet its structural mechanisms remain unclear. Here we report six cryo-electron microscopy structures of human LYCHOS, depicting five distinct states. These are categorized into a contracted state when complexed with a sufficient amount of the cholesterol analogue cholesteryl hemisuccinate (CHS), and an expanded state when CHS is deficient. The structure forms a homodimer, within each monomer the transmembrane region is divided into a permease-like domain (PLD) and a GPCR-like domain (GLD) with two clearly defined adjacent cholesterol binding sites between them. Cholesterol binding induces a translation of GLD towards PLD and exposes the cytosolic extension of transmembrane 15, which interacts with GATOR1. Our results elucidate the structural mechanism of cholesterol sensing by the mTORC1 pathway, providing a structural basis for developing inhibitors that selectively target mTORC1 pathway by blocking LYCHOS in its expanded state.

PubMed: 40702016
DOI: 10.1038/s41467-025-61966-w

Experimental method

ELECTRON MICROSCOPY (3.31 Å)