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

Charles Bayly-Jones, Christopher J. Lupton, Alastair C. Keen, Shuqi Dong, Chantel Mastos, Wentong Luo, Chunyi Qian, Gareth D. Jones, Hari Venugopal, Yong-Gang Chang, Ronald J. Clarke, Michelle L. Halls () and Andrew M. Ellisdon ()
Additional contact information
Charles Bayly-Jones: Monash University
Christopher J. Lupton: Monash University
Alastair C. Keen: Monash University
Shuqi Dong: Monash University
Chantel Mastos: Monash University
Wentong Luo: Monash University
Chunyi Qian: Monash University
Gareth D. Jones: Monash University
Hari Venugopal: Monash University
Yong-Gang Chang: Monash University
Ronald J. Clarke: University of Sydney
Michelle L. Halls: Monash University
Andrew M. Ellisdon: Monash University

Nature, 2024, vol. 634, issue 8036, 1238-1244

Abstract: 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 availability1. 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.

Date: 2024
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DOI: 10.1038/s41586-024-08012-9

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