Cryo-EM structures of human GPR155 elucidate its regulatory and transport mechanisms

GPR155 is a polymodal lysosomal membrane “transceptor” comprising both a transporter domain and a GPCR domain, predominantly expressed in brain. GPR155 facilitates cholesterol-dependent mTORC1 signaling and is implicated in neurological disorders like Huntington’s disease. The GPCR domain likely does not bind extracellular ligands canonically, and the functional relationship between GPR155 domains remains unclear. Here, we report the first structures of monomeric human GPR155 and two distinct dimers, revealing an inward-open transporter domain and an inactivated GPCR domain with a unique luminal loop 7 conformation occupying orthosteric pocket. The dimeric assembly is cholesterol-sensitive: at low cholesterol, the transporter domain resembles plant PIN transporters and transports auxin molecules; at high cholesterol, it forms a unique dimer stabilized by cholesterol. Altogether, these findings have implications for uncovering new lysosomal signaling pathways.