Generic residue numbering of the GAIN domain of adhesion GPCRs

Abstract

The GPCR autoproteolysis inducing (GAIN) domain is an ancient protein fold ubiquitous in adhesion G protein-coupled receptors (aGPCR). It contains a concealed tethered agonist element, which is necessary and sufficient for receptor activation. The GAIN domain is a hotspot for pathological mutations. However, the low primary sequence conservation of GAIN domains has thus far hindered the knowledge transfer across different GAIN domains in human receptors as well as species orthologs. Here, we present a scheme for generic residue numbering of GAIN domains based on structural alignments of six experimental and more than 14,000 modeled GAIN domain structures. This scheme is implemented in the GPCR database (GPCRdb) and elucidates the domain topology across different aGPCRs and their homologs in a large panel of species. We identify conservation hotspots and cancer-enriched positions in human aGPCRs and show the transferability of positional and structural information between GAIN domain homologs. The GAIN-GRN scheme provides a robust strategy to allocate structural homologies at the primary and secondary levels also to GAIN folds of GAIN domains of polycystic kidney disease 1/PKD1-like proteins, which now renders positions in both GAIN domain types comparable to one another.