9 Structure and function of isoprenylcysteine carboxylmethyltransferase (Icmt): A key enzyme in CaaX processing.

Proteins that terminate in a C-terminal CaaX motif undergo three sequential posttranslational modifications: isoprenylation of the cysteine residue, endoproteolysis of the -aaX residues, and methylation of the isoprenylated cysteine by an isoprenylcysteine carboxylmethyltransferase (Icmt). Among the proteins that contain this CaaX sequence are the Ras superfamily of G-proteins and other signal transduction proteins, the nuclear lamins, and the yeasta-factor mating pheromone. Icmt is a mechanistically intriguing enzyme that is unique among S-adenosyl-l-methionine (SAM)-dependent methyltransferases in that it is an integral membrane enzyme localized to the endoplasmic reticulum. It must also accommodate chemically diverse cofactor and substrate molecules; namely, the hydrophilic methyl-donating cofactor SAM and a lipophilic isoprenylated protein substrate, respectively. A complete picture of the cellular consequences of carboxylmethylation of isoprenylated proteins is still emerging. It is known, however, that methylation is critical for the proper localization of the CaaX protein Ras and may be essential for oncogenic transformation. Thus,Icmt may prove to be an excellent chemotherapeutic target. In this review, the structure and function of the family of Icmt enzymes are discussed, as well as recent advances in the development of small-molecule inhibitors of this key enzyme in the CaaX posttranslational processing pathway.