Exploring Protein Lipidation with Chemical Biology

Protein lipidation is the covalent attachment of a lipid group to protein. Lipids modify large numbers of eukaryotic proteins and regulate protein function and localization. The realization that S-prenylation is essential for proper protein function has stimulated the development of small molecule S-prenyltransferase inhibitors to block the activity of oncogenic Ras and other S-prenylated proteins that malfunction in various disease states. Protein N-myristoylation refers to the irreversible addition of myristic acid to eukaryotic and viral proteins through an amide linkage to an N-terminal glycine residue. The process of depalmitoylation is less well characterized. The lysosomal enzyme responsible for degradation of S-palmitoylated proteins may be protein palmitoylthioesterase 1 (PPT1). Short amino acid sequences that encode the recognition motifs for modification are sufficient for lipidation to occur in cells. For example, the last 10 amino acids of H-Ras are sufficient for CaaX processing and S-palmitoylation in cells when transplanted onto a soluble protein.