9JBF

Cryo-EM structure of the human LYCHOS Y57A mutant in complex with cholesteryl hemisuccinate in the contracted state

9JBF の概要

• エントリーDOI: 10.2210/pdb9jbf/pdb
• 関連するPDBエントリー: 9JBE
• EMDBエントリー: 61312
• 分子名称: Lysosomal cholesterol signaling protein, CHOLESTEROL HEMISUCCINATE, 1,2-Distearoyl-sn-glycerophosphoethanolamine, ... (6 entities in total)
• 機能のキーワード: permease-like domain, gpcr-like domain, cholesterol, mtorc1, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 207924.81

構造登録者

Yu, S.,Liang, L. (登録日: 2024-08-27, 公開日: 2025-07-16, 最終更新日: 2025-08-27)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3.21 Å)