farnesylation

Farnesylation is a post-translational lipid modification in which a farnesyl group, a 15-carbon isoprenoid, is covalently attached to the thiol group of a cysteine residue near the C-terminus of a subset of proteins. The transfer is catalyzed by farnesyltransferase (FTase), a heterodimeric enzyme that uses farnesyl pyrophosphate (FPP) as the donor molecule, derived from the mevalonate pathway.

Substrates for farnesylation typically include proteins with a CaaX motif at their C-terminus, where C is cysteine, a and a are aliphatic residues, and X influences recognition and processing. After the farnesyl group is attached, the AAX tripeptide is usually removed by Rce1 protease, producing a prenylated cysteine, which is then methylated by Icmt. This sequence of events generates a highly hydrophobic C-terminus that promotes association with cellular membranes, facilitating localization to the inner surface of the plasma membrane or other organelle membranes.

Biological role: Farnesylation is essential for the membrane targeting and function of many signaling proteins, including members of the Ras and Rho families, as well as lamins. For Ras proteins, farnesylation is often required for proper signaling; some proteins can alternatively undergo geranylgeranylation if farnesylation is impaired.

Clinical relevance: Farnesyltransferase inhibitors (FTIs) have been developed and tested as anti-cancer therapies, with mixed outcomes due to alternative prenylation pathways and varying dependence on farnesylation among targets. FTIs have also been explored for other conditions, including premature aging syndromes.