8Z8Z

Cryo-EM structure of LYCHOS

This is a non-PDB format compatible entry.

Summary for 8Z8Z

• Entry DOI: 10.2210/pdb8z8z/pdb
• EMDB information: 39851
• Descriptor: Lysosomal cholesterol signaling protein,Fluorescent Protein, 2-acetamido-2-deoxy-beta-D-glucopyranose, [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate, ... (8 entities in total)
• Functional Keywords: lysosome, gpcr-like, transporter, cholesterol, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 263044.10

Authors

Xiong, Q.,Zhu, Z.,Li, T.,Zhou, Z.,Chao, Y.,Qu, Q.,Li, D. (deposition date: 2024-04-22, release date: 2025-01-01, Last modification date: 2025-06-04)

Primary citation

Xiong, Q.,Zhu, Z.,Li, T.,Li, X.,Zhou, Z.,Chao, Y.,Yang, C.,Feng, S.,Qu, Q.,Li, D.
Molecular architecture of human LYCHOS involved in lysosomal cholesterol signaling.
Nat.Struct.Mol.Biol., 32:905-913, 2025

PubMed Abstract: Lysosomal membrane protein LYCHOS (lysosomal cholesterol signaling) translates cholesterol abundance to mammalian target of rapamycin activation. Here we report the 2.11-Å structure of human LYCHOS, revealing a unique fusion architecture comprising a G-protein-coupled receptor (GPCR)-like domain and a transporter domain that mediates homodimer assembly. The NhaA-fold transporter harbors a previously uncharacterized intramembrane Na pocket. The GPCR-like domain is stabilized, by analogy to canonical GPCRs, in an inactive state through 'tethered antagonism' by a lumenal loop and strong interactions at the cytosol side preventing the hallmark swing of the sixth transmembrane helix seen in active GPCRs. A cholesterol molecule and an associated docosahexaenoic acid (DHA)-phospholipid are entrapped between the transporter and GPCR-like domains, with the DHA-phospholipid occupying a pocket previously implicated in cholesterol sensing, indicating inter-domain coupling via dynamic lipid-protein interactions. Our work provides a high-resolution framework for functional investigations of the understudied LYCHOS protein.

PubMed: 39824977
DOI: 10.1038/s41594-024-01474-5

Experimental method

ELECTRON MICROSCOPY (2.11 Å)