Abstract

Significance Adhesion G protein-coupled receptors (GPCRs) regulate tissue development and cancer progression. Intact adhesion GPCRs are unique two-protomer receptors that undergo biosynthetic self-proteolyzation at a conserved site between the extracellular domain and the seven transmembrane (7TM) domain. We demonstrate the activation mechanism of adhesion GPCRs. The 7TM domain N-terminal stalk lies encrypted within the noncovalently bound extracellular domain. When the extracellular domain is dissociated, perhaps naturally by ligand action, the 7TM stalk is revealed. We demonstrate that the stalk acts as a tethered agonist of the 7TM to facilitate direct activation of heterotrimeric G proteins. Synthetic peptides comprising adhesion GPCR 7TM domain stalks are sufficient receptor agonists, raising the possibility for the development of adhesion GPCR synthetic peptide modulators.