Matching structure with function: the GAIN domain of Adhesion-GPCR and PKD1-like proteins

• The newly discovered GAIN domain is the hallmark structural element of Adhesion-GPCR and PKD1-like proteins.
• Understanding of the GAIN domain has potential pharmacological implications.
• We summarize the emerging models of GAIN domain function.
• We discuss the impact of this domain on respective receptor signaling.

Elucidation of structural information can greatly facilitate the understanding of molecular function. A recent example is the description of the G-protein-coupled receptor (GPCR) autoproteolysis-inducing (GAIN) domain, an evolutionarily ancient fold present in Adhesion-GPCRs (aGPCRs) and polycystic kidney disease 1 (PKD1)-like proteins. In the past, the peculiar autoproteolytic capacity of both membrane protein families at the conserved GPCR proteolysis site (GPS) had not been described in detail. The physiological performance of aGPCRs and PKD1-like proteins is thought to be regulated through the GPS, but it is debated how. A recent report provides pivotal details by discovery and analysis of the GAIN domain structure that incorporates the GPS motif. Complementary studies have commenced to analyze physiological requirements of the GAIN domain for aGPCR function, indicating that it serves as the linchpin for multiple receptor signals. Structural analysis and functional assays now allow for the dissection of the biological duties conferred through the GAIN domain.