2.A.69.3.8
LYCHOS or GPR155 (GP155) or PGR22 of 870 aas and possibly 17 TMSs in a 15 + 2 TMS arrangement.  The N-terminal 10 TMSs may consist of 2 repeats, each of 5 TMSs in a LSLSL (L = large; S = small peak of hydrophobicity).  It may play a role in several types of cancer (Lee et al. 2022).  GPR155 matches the first 10 TMSs (5 + 5 TMS arrangement). TMSs 6 - 10 are similar to the N-terminal half of the sodium bile transporter of the AsbT (SLC10) family.  TMSs 11 - 17 are similar to GPCR proteins with 7 TMSs (Gyimesi and Hediger 2022).  LYCHOS signals cholesterol sufficiency to mTORC1 (Shin et al. 2022).  LYCHOS is a human hybrid of a plant-like PIN transporter and a GPCR (Bayly-Jones et al. 2024).  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 is a lysosomal transmembrane protein (10 + 7 TMSs) that functions as a cholesterol sensor, facilitating the cholesterol-dependent activation of the master protein kinase mechanistic target of rapamycin complex 1 (mTORC1). Bayly-Jones et al. 2024 determined several high-resolution cryo-EM structures of human LYCHOS, revealing a homodimeric transmembrane assembly of a transporter-like domain fused to a 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. 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 (Bayly-Jones et al. 2024).