Evolutionary identification of residues related to G protein coupling selectivity in aminergic GPCRs/

Official URL: https://risc01.sabanciuniv.edu/record=b2760571_(Table of contents)

G protein-coupled receptors (GPCRs) are coupled to four different subfamilies of G proteins namely Gs, Gi, Gq, and G12/13, in a selective way. However, receptor-wide determinants of selective G protein coupling and G protein specific activation mechanisms remained under investigated. Here, we analyzed aminergic receptors and its orthologs from different phylogenetic levels to reveal positions that are specifically evolved and conserved for the receptors that are coupled to similar G proteins. By co-analyzing these evolutionary conserved amino acids with available structures of the receptors, we revealed specific activation mechanisms for Gs, Gi1, Go, and Gq. To verify that these pathways could play role in determining coupling selectivity we investigated Gs-specific activation mechanism further. By the help of molecular dynamics simulations, we demonstrated that G7x41 is important for receptor activation and it might determine Gs coupling selectivity by promoting outwards movement of TM6. Lastly, we summarized our findings into a model of G protein selectivity called “sequential switches of activation” explaning three major molecular switches controlling GPCR activation: ligand binding, G protein selective activation mechanisms, and G protein contact.