Protein prenylation: unique fats make their mark on biology

Key Points A large repertoire of eukaryotic proteins, termed prenylated proteins, are subject to post-translational modification by isoprenoid lipids. The attached lipid can markedly affect the cellular location of the prenylated protein, as well as its function. Prenylated proteins have been implicated in diseases ranging from cancer to inflammation and premature ageing. The enzymes that catalyse the reactions leading to a mature prenylated protein are under investigation as drug targets in various diseases. Learning more about the biochemistry of protein prenylation (modification by isoprenoid lipids) and its functional effects on target CAAX proteins has provided opportunities for therapeutic intervention in a range of human diseases. The modification of eukaryotic proteins by isoprenoid lipids, which is known as prenylation, controls the localization and activity of a range of proteins that have crucial functions in biological regulation. The roles of prenylated proteins in cells are well conserved across species, underscoring the biological and evolutionary importance of this lipid modification pathway. Genetic suppression and pharmacological inhibition of the protein prenylation machinery have provided insights into several cellular processes and into the aetiology of diseases in which prenylation is involved. The functional dependence of prenylation substrates, such as RAS proteins, on this modification and the therapeutic potential of targeting the prenylation process in pathological conditions accentuate the need to fully understand this form of post-translational modification.