Prenylation

Prenylation is a post-translational lipid modification in which isoprenoid lipid groups are covalently attached to specific cysteine residues near the C-terminus of target proteins. The most common donors are farnesyl pyrophosphate and geranylgeranyl pyrophosphate, derived from the mevalonate pathway. The modification enhances the hydrophobicity of the protein and facilitates association with cellular membranes, which is often essential for its activity and localization.

There are two main classes of protein prenylation. Farnesylation attaches a 15-carbon farnesyl group to a CaaX motif at the protein’s C-terminus, where the last four residues (a, a, X) influence which enzyme acts. Geranylgeranylation attaches a 20-carbon geranylgeranyl group, typically to motifs that direct the enzyme to the substrate. In Rab proteins, a related process called Rab geranylgeranylation often adds two geranylgeranyl groups and requires Rab escort protein to deliver the substrate to the Rab geranylgeranyltransferase complex. The enzymes responsible are farnesyltransferase (FTase), geranylgeranyltransferase type I (GGTase I), and Rab geranylgeranyltransferase (RabGGTase).

Following lipid transfer, proteolytic processing usually removes the terminal tripeptide (AAX) by Rce1 protease, and a methyl group is added to the now-carboxylated cysteine by isoprenylcysteine carboxyl methyltransferase (ICMT). Rab substrates may undergo additional steps involving Rab escort protein.

Biologically, prenylation is essential for membrane localization and function of many signaling proteins, including small GTPases such as Ras, Rho, and Rab. Clinically, prenylation pathways are targets of research for cancer therapy, with inhibitors explored to block oncogenic signaling; however, alternative prenylation can complicate effectiveness.