BPS2026 – Understanding the structural and functional landscape of cholesterol sensing and auxin signaling by human transceptor GPR155

Auxin signaling, long established in plants, was considered absent in mammals due to the lack of canonical biosynthetic genes and transport machinery. Yet, gut microbiota-derived indole metabolites, including auxin (IAA), can be taken up by human cells, where they support neuronal development, synaptic plasticity, and neuroprotection. Recent studies have highlighted a novel auxin-cholesterol crosstalk in mammalian systems, mediated by GPR155 (LYCHOS), an orphan lysosomal membrane protein highly expressed in the brain. GPR155 is a polymodal “transceptor” that uniquely combines a GPCR domain with a transporter domain. Aberrant GPR155 expression is linked to several neurological disorders, including Parkinson’s, Alzheimer’s, and Huntington’s diseases, suggesting a broader role in neuronal physiology and pathology. Here, we present the structural characterization of human GPR155, revealing both monomeric and cholesterol-sensitive dimeric states. The transporter domain adopts an inward-open conformation, while the GPCR domain is structurally inactive, with luminal loop 7 occupying the orthosteric pocket. Cholesterol concentration governs dimeric assembly: under low cholesterol, the transporter domain resembles plant PIN transporters and supports auxin transport, whereas high cholesterol promotes a unique dimer stabilized by cholesterol molecules. To further investigate the functionality of GPR155, we performed electrophysiological recordings in a lipid bilayer system to characterize the kinetics of auxin transport. Interestingly, these recordings also revealed voltage-dependent activity of the transceptor. Altogether, these findings will serve as a springboard for understanding the dynamic regulatory mechanism through which cholesterol modulates auxin transport and GPR155 activity. These insights will advance our understanding of cross-species auxin signaling in mammals and enable rational strategies for targeting GPR155 in neurological disorders.