Molecular basis of sequence‐dependent differential prenylation inhibition and statin sensitivity of G proteins

Abstract

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.