LYCHOS is a human hybrid of a plant-like PIN transporter and a GPCR

• 成果类型: Article
• 署名作者: Bayly-Jones, Charles; Lupton, Christopher J.; Keen, Alastair C.; Dong, Shuqi; Mastos, Chantel; Luo, Wentong; Qian, Chunyi; Jones, Gareth D.; Venugopal, Hari; Chang, Yong-Gang; Clarke, Ronald J.; Halls, Michelle L.; Ellisdon, Andrew M.
• 署名单位: Monash University; University of Sydney; Monash University; Monash University; University of Sydney
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3902
• DOI: 10.1038/s41586-024-08012-9
• 发表日期: 2024-10-31
• 页码: 1238-+
• 关键词: rag gtpases; complex; GROWTH

摘要

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(1). 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)(2). 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.