Prenylation is a universal and irreversible post-translational modification occurring on proteins involved in various cellular processes, including survival, proliferation, and migration. The prenylation process consists of enzymatically catalyzed covalent attachment of an isoprenyl lipid, either a 15-C farnesyl or 20-C geranylgeranyl moiety, to the Cys residue located in the four residues from the CT in the target protein via a thioether linkage. Proteins undergoing prenylation share a C-terminally conserved consensus recognition CaaX motif, of which X determines the type of prenylation on the protein. The mevalonate (HMG-CoA reductase) pathway synthesizes lipids for protein prenylation. The rate-limiting enzyme; HMG-CoA reductase of the mevalonate pathway is the primary target for cholesterol-lowering medications and anticancer drug development. Our previous study shows that clinically used mevalonate pathway inhibitors, statins not only significantly disrupt PM localization of Gβγ but also perturb GPCR-G protein signaling and associated cell behaviors in a Gγ subtype-dependent manner. However, in the present work, we identified crucial residues on Gγ that regulate the efficacy of its prenylation and during post-prenylations processing. Therefore, our findings demonstrate the molecular underpinnings of differential prenylation sensitivities of G proteins under cholesterol synthesis inhibition and hypolipidemic conditions.
