Ras and many other oncogenic proteins undergo a series of post-translational modifications that are initiated by the attachment of an isoprenoid lipid. These processing steps are crucial for the proper functioning of the modified proteins and affect the transforming activity of oncogenic variants of Ras. The lipid group is attached to a cysteine residue that is four residues away from the C-terminus of the protein substrate by one of two closely related prenyltransferase enzymes: protein farnesyltransferase or protein genanylgeranyltransferase. Following attachment of the lipid, which occurs in the cytosol, the Ras protein is acted on by two additional enzymes: Rce1 and ICMT. Both of these are integral membrane proteins that reside in the membrane of the endoplasmic reticulum. Rce1 is a protease that cleaves off three residues at the C-terminus, leaving a newly-formed C-terminus adjacent to the lipid-modified-cysteine. This C-terminus is then methylated by the enzyme ICMT. After this final step, Ras is trafficked to the plasma membrane where it carries out its role in cell signaling. While the structural and mechanistic details of the reaction catalyzed by protein prenyltransferases are well understood, we lack structural information and an understanding of the mechanisms of Rce1 and ICMT. Recent evidence suggests that both enzymes may be good targets for developing new therapeutics for the treatment of cancer.
An understanding of the atomic mechanisms of Rce1 and ICMT would not only yield great insight into their specific reactions and potentially enable the development of new therapeutics, but it would also shed light on general mechanisms for how enzymatic membrane proteins catalyze reactions within the environment of the lipid bilayer. While the mechanisms of many soluble enzymes have been investigated for many years, this area of biochemistry is just beginning to be discovered.
