Modification of eukaryotic signaling proteins by C-terminal methylation reactions

Eukaryotic polypeptides that are initially synthesized with the C-terminal sequence -Cys-Xaa-Xaa-Xaa, including a variety of signal-transducing proteins, such as small G-proteins, large G-proteins and cGMP phosphodiesterases, can be targeted for a series of sequential post-translational modifications. This processing pathway includes the isoprenylation of the cysteine residue with a farnesyl or geranylgeranyl moiety, followed by proteolysis of the three terminal residues and alpha-carboxyl methyl esterification of the cysteine residue. The potential reversibility of the last step suggests that it may be involved in modulating the function of these proteins. Firstly, methylation may play a role in the activation of cellular peptides or proteins. Secondly, this modification may aid in the membrane attachment of cytosolic precursor proteins. Thirdly, methylation may protect the polypeptide from C-terminal proteolytic degradation once the three terminal amino acid residues are removed. Finally, reversible methylation may directly regulate the function of its target proteins. Therapeutically, inhibitors of C-terminal isoprenylcysteine methylation or demethylation reactions may prove to be useful pharmacological tools as anti-cancer and anti-inflammatory agents.