MODIFICATION OF EUKARYOTIC SIGNALING PROTEINS BY C-TERMINAL METHYLATION REACTIONS

Eukaryotic polypeptides that are initially synthesized with the C-term inal sequence -Cys-Xaa-Xaa-Xaa, including a variety of signal-transduc ing proteins, such as small G-proteins, large G-proteins and cGMP phos phodiesterases, can be targeted for a series of sequential post-transl ational modifications. This processing pathway includes the isoprenyla tion of the cysteine residue with a farnesyl or geranylgeranyl moiety, followed by proteolysis of the three terminal residues and alpha-carb oxyl methyl esterification of the cysteine residue. The potential reve rsibility of the last step suggests that it may be involved in modulat ing the function of these proteins. Firstly, methylation may play a ro le 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-ter minal proteolytic degradation once the three terminal amino acid resid ues 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-infl ammatory agents.