Structural basis of adhesion GPCR GPR110 activation by stalk peptide and G-proteins coupling

aGPCRs play key roles in multiple physiological processes. Here the authors report cryo-EM structures of GPR110 in complexes with G(q), G(s), G(i), G(12) and G(13) protein to reveal a detailed mechanism of aGPCR activation via the tethered stalk peptide and principles of G-protein coupling and selectivity on GPR110. Adhesion G protein-coupled receptors (aGPCRs) are keys of many physiological events and attractive targets for various diseases. aGPCRs are also known to be capable of self-activation via an autoproteolysis process that removes the inhibitory GAIN domain on the extracellular side of receptor and releases a stalk peptide to bind and activate the transmembrane side of receptor. However, the detailed mechanism of aGPCR activation remains elusive. Here, we report the cryo-electron microscopy structures of GPR110 (ADGRF1), a member of aGPCR, in complex with G(q), G(s), G(i), G(12) and G(13.) The structures reveal distinctive ligand engaging model and activation conformations of GPR110. The structures also unveil the rarely explored GPCR/G(12) and GPCR/G(13) engagements. A comparison of G(q), G(s), G(i), G(12) and G(13) engagements with GPR110 reveals details of G-protein engagement, including a dividing point at the far end of the alpha helix 5 (alpha H5) of G alpha subunit that separates G(q)/G(s) engagements from G(i)/G(12)/G(13) engagements. This is also where G(q)/G(s) bind the receptor through both hydrophobic and polar interaction, while G(i)/G(12)/G(13) engage receptor mainly through hydrophobic interaction. We further provide physiological evidence of GPR110 activation via stalk peptide. Taken together, our study fills the missing information of GPCR/G-protein engagement and provides a framework for understanding aGPCR activation and GPR110 signaling.