Chemical biology of protein isoprenylation/methylation

Isoprenylation/methylation is an important dual hydrophobic post-translational modification which occurs at or near a carboxyl terminal cysteine residue. All known G proteins are modified in this way, making the pathway of central interest for an understanding of signal transduction. In this review, aspects of the molecular enzymology of isoprenylation/methylation are reviewed. The functional significance of these modifications is discussed, with special reference to the signal transducing G proteins. Of further interest is the possible regulatory role of methylation, since this step is the only reversible one in the pathway. The biochemical and functional consequences of isoprenylation/methylation are of especial interest. Isoprenylation/methylation is generally 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 studies on visual signal transduction and ras signalling pathways, strongly points to enhanced membrane binding being a consequence of hydrophobic lipid-lipid interactions. An exciting possibility that also emerges is concerned with whether isoprenylation may also have additional roles, in addition to enhancing the membrane partitioning ability of the modified protein. In a simple mechanism of this type, the isoprenylated/methylated cysteine residue would be specifically recognized by another protein. While no compelling case can yet be made for an effector role for the isoprenylated/methylated cysteine moiety mediating protein-protein interactions, recent studies on the pharmacology of isoprenylated cysteine analogs suggests the possibility of such a role.