A GAIN in understanding autoproteolytic G protein-coupled receptors and polycystic kidney disease proteins

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A large and poorly understood class of G protein‐coupled receptors (GPCRs) are involved in cell adhesion and contain an autoproteolytic site known as the GPCR proteolysis site (GPS) located immediately N‐terminal to the first transmembrane span. This motif of ∼50 amino acids is also found juxtaposed to the first transmembrane span of an unrelated family of proteins associated with polycystic kidney disease (PKD), but its structural and functional roles were not clear. In this issue of The EMBO Journal , Arac et al use X‐ray crystallography to show that the GPS motif is merely the C‐terminal end of a much larger GPCR autoproteolysis inducing (GAIN) domain. Atomic models for two of these ancient domains allow one to map the sites of mutations associated with cancer or PKD, and hint at functional roles other than autoproteolysis.