Adhesion G protein-coupled receptors—Structure and functions

Adhesion G protein-coupled receptors (aGPCRs) are an ancient class of receptors that represent some of the largest transmembrane-integrated proteins in humans. First recognized as surface markers on immune cells, it took more than a decade to appreciate their 7-transmembrane structure, which is reminiscent of GPCRs. Roughly 30 years went by before the first functional proof of an interaction with a G protein was published. Besides classic features of GPCRs (extracellular N terminus, 7-transmembrane region, intracellular C terminus), aGPCRs display a distinct N-terminal structure, which harbors the highly conserved GPCR autoproteolysis-inducing (GAIN) domain with the GPCR proteolysis site (GPS) in addition to several functional domains. Several human diseases have been associated with variants of aGPCRs and subsequent animal models have been established to investigate these phenotypes. Much progress has been made in recent years to decipher the structure and functions of these receptors. This chapter gives an overview of our current understanding with respect to the molecular structural patterns governing aGPCR activation and the contribution of these giant molecules to the development of pathologies.