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

Abstract

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, G₁₂ and G_13. The structures reveal distinctive ligand engaging model and activation conformations of GPR110. The structures also unveil the rarely explored GPCR/G₁₂ and GPCR/G₁₃ engagements. A comparison of G_q, G_s, G_i, G₁₂ and G₁₃ engagements with GPR110 reveals details of G-protein engagement, including a dividing point at the far end of the alpha helix 5 (αH5) of Gα subunit that separates G_q/G_s engagements from G_i/G₁₂/G₁₃ engagements. This is also where G_q/G_s bind the receptor through both hydrophobic and polar interaction, while G_i/G₁₂/G₁₃ 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.