farnesylationsite

A farnesylation site refers to a C-terminal CaaX motif in certain proteins that serves as the site for farnesylation, the covalent attachment of a 15-carbon farnesyl group to a cysteine residue by the enzyme farnesyltransferase (FTase). The farnesyl group is donated by farnesyl pyrophosphate as part of the protein prenylation pathway. The CaaX motif consists of Cys (C), two aliphatic residues (a, a), and a terminal residue (X). The identity of X influences substrate recognition; FTase typically recognizes motifs where X favors farnesylation, while other motifs may be substrates for geranylgeranyltransferase I (GGTase I) instead, allowing alternative prenylation if FTase is inhibited or absent.

After farnesylation, the terminal aaX residues are usually cleaved by Rce1 protease, and the new C-terminus carboxyl group is methylated by ICMT, completing maturation and enhancing membrane association. The modification commonly targets proteins involved in signaling and trafficking, including members of the Ras and Rho families, as well as other membrane-anchored proteins in various organisms.

Biological significance: Farnesylation promotes membrane localization and protein–protein interactions essential for signaling. Because of its role in oncogenic Ras signaling, farnesylation has been a target for anticancer drug development, with farnesyltransferase inhibitors (FTIs) entering clinical investigation. Some proteins are redirected to alternative prenylation pathways when FTase activity is blocked, which can limit the effectiveness of FTIs.