Oral Presentation The 35th Biennial Conference of the Society of Crystallographers in Australia and New Zealand 2024 (Crystal 35)

LYCHOS (GPR155) is a human hybrid of a plant-like PIN transporter and GPCR (112665)

Charles Bayly-Jones 1
  1. Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

Lysosomes play 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 cholesteroldependent 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 (cryo-EM) structures of human LYCHOS, revealing a homodimeric transmembrane assembly of a transporter-like domain fused to a G proteincoupled 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 a highly 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 with greater structural similarity to plant auxin transporters than known human transporters. Activity assays support a model whereby the LYCHOS transporter and GPCR domains coordinate to sense cholesterol and regulate mTORC1 activation.