Title : A nove
l evolutionarily conserve
d domain of cel
l-adhesion GPCRs mediates autoproteolysis
Abstract :
- The G protein-couple d receptor ( GPCR ) Proteolysis Site ( GPS ) of cel l-adhesion GPCRs an d polycystic kidney d isease ( PKD ) proteins constitutes a highly conserve d autoproteolysis sequence , but its cataly tic mechanism r emains unkn o wn
- Here, we show that unexpectedly the ∼40-residue GPS motif represents an integra l part of a much l arge r ∼320-residue domain that we terme d GPCR-Autoproteolysis INducing (GAIN) domain
- Crysta l structures of GAIN domains from tw o distantly relate d cel l-adhesion GPCRs reveale d a conserve d nove l fol d in which the GPS motif forms five β-strands that are tightly integrate d int o the overall GAIN domain
- The GAIN domain is evolutionarily conserve d from tetrahymena t o mammals, is the only extracellula r domain share d by all human cell-adhesion GPCRs an d PKD proteins, an d is the locus of multiple human disease mutations
- Functionally , the GAIN domain is both necessary an d sufficient fo r autoproteolysis, suggesting an autoproteolytic mechanism whereby the overall GAIN domain fine-tunes the chemica l environment in the GPS t o catalyse peptide bon d hydrolysis
- Thus, the GAIN domain embodies a unique, evolutionarily ancient an d widesprea d autoproteolytic fol d whose function is likely relevant fo r GPCR signalling an d fo r multiple human diseases