CHEMICAL BIOLOGY OF PROTEIN ISOPRENYLATION METHYLATION

Isoprenylation/methylation is an important dual hydrophobic post-trans lational modification which occurs at or near a carboxyl terminal cyst eine residue. All known G proteins are modified in this way, making th e pathway of central interest for an understanding of signal transduct ion. Ln this review, aspects of the molecular enzymology of isoprenyla tion/methylation are reviewed. The functional significance of these mo difications is discussed, with special reference to the signal transdu cing G proteins. Of further interest is the possible regulatory role o f methylation, since this step is the only reversible one in the pathw ay. The biochemical and functional consequences of isoprenylation/meth ylation are of especial interest. Isoprenylation/methylation is genera lly assumed to enhance the abilities of modified proteins to associate with membranes. This can be due either to hydrophobic lipid-lipid or lipid-protein interactions. Available evidence, taken largely from stu dies on visual signal transduction and ras signalling pathways, strong ly points to enhanced membrane binding being a consequence of hydropho bic lipid-lipid interactions. An exciting possibility that also emerge s is concerned with whether isoprenylation may also have additional ro les, in addition to enhancing the membrane partitioning ability of the modified protein. In a simple mechanism of this type, the isoprenylat ed/methylated cysteine residue would be specifically recognized by ano ther protein. While no compelling case can yet be made for an effector role for the isoprenylated/methylated cysteine moiety mediating prote in-protein interactions, recent studies on the pharmacology of isopren ylated cysteine analogs suggests the possibility of such a role.