8U54

The mTORC1 cholesterol sensor LYCHOS (GPR155)

8U54 の概要

• エントリーDOI: 10.2210/pdb8u54/pdb
• EMDBエントリー: 41912
• 分子名称: Integral membrane protein GPR155, 2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total)
• 機能のキーワード: pin-formed, gpcr, cholesterol, auxin, transporter, cell-growth, mtorc1, cancer, 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: 198996.20

構造登録者

Bayly-Jones, C.,Lupton, C.J.,Ellisdon, A.M. (登録日: 2023-09-12, 公開日: 2024-09-18, 最終更新日: 2024-11-13)

主引用文献

Bayly-Jones, C.,Lupton, C.J.,Keen, A.C.,Dong, S.,Mastos, C.,Luo, W.,Qian, C.,Jones, G.D.,Venugopal, H.,Chang, Y.G.,Clarke, R.J.,Halls, M.L.,Ellisdon, A.M.
LYCHOS is a human hybrid of a plant-like PIN transporter and a GPCR.
Nature, 634:1238-1244, 2024

PubMed Abstract: Lysosomes have crucial roles in regulating eukaryotic metabolism and cell growth by acting as signalling platforms to sense and respond to changes in nutrient and energy availability. LYCHOS (GPR155) is a lysosomal transmembrane protein that functions as a cholesterol sensor, facilitating the cholesterol-dependent activation of the master protein kinase mechanistic target of rapamycin complex 1 (mTORC1). However, the structural basis of LYCHOS assembly and activity remains unclear. Here we determine several high-resolution cryo-electron microscopy structures of human LYCHOS, revealing a homodimeric transmembrane assembly of a transporter-like domain fused to a G-protein-coupled receptor (GPCR) domain. The class B2-like GPCR domain is captured in the apo state and packs against the surface of the transporter-like domain, providing an unusual example of a GPCR as a domain in a larger transmembrane assembly. Cholesterol sensing is mediated by a conserved cholesterol-binding motif, positioned between the GPCR and transporter domains. We reveal that the LYCHOS transporter-like domain is an orthologue of the plant PIN-FORMED (PIN) auxin transporter family, and has greater structural similarity to plant auxin transporters than to known human transporters. Activity assays support a model in which the LYCHOS transporter and GPCR domains coordinate to sense cholesterol and regulate mTORC1 activation.

PubMed: 39358511
DOI: 10.1038/s41586-024-08012-9

実験手法

ELECTRON MICROSCOPY (2.65 Å)