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

Abstract

EMBO J 31 6, 1364–1378 (2012); published online January 14 2012

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.

Figure 1

The conserved structural core of the extracellular regions of cell-adhesion GPCRs, as revealed by new structures of latrophilin and BAI3. Arac et al revealed that regions formerly known as the stalk and the GPCR autoproteolyic site (GPS) fold into a single GAIN domain that is conserved in all 33 mammalian cell-adhesion GPCRs and in proteins related to PKD1. The GAIN domain catalyses its own proteolysis in a tight turn between the last two strands of the domain. The α-helical subdomain of the GAIN domains of latrophilin and BAI3 interacts with a HormR domain, although this domain is not found in all cell-adhesion GPCRs. However, this interdomain contact, and/or a direct interaction with the transmembrane helical bundle, may allow the GAIN domain to autoinhibit transmembrane signalling to heterotrimeric G proteins or other factors inside the cell.