The protein prenyltransferases, protein farnesyltransferase (FTase) and protein geranylgeranyltransferase-I (GGTase-I), catalyze the attachment of a 15-carbon farnesyl or 20-carbon geranylgeranyl moiety, respectively, to a cysteine near the C-terminus of a substrate protein. Substrates of the prenyltransferases are involved in a myriad of signaling pathways and processes within cells, although the entire complement of prenylated proteins has not yet been determined. Furthermore, inhibitors targeting the prenylation pathway are being developed as therapeutics for the treatment of a variety of diseases. The minimal requirement for substrate recognition by FTase and GGTase-I is a CZaX motif, where C is the cysteine where the prenyl group is attached, Z is variable, a is a small aliphatic amino acid, and X is variable, conferring some selectivity between FTase and GGTase-I. The peptide substrate selectivity can be readily altered by mutagenesis of FTase and used to create unique prenylation sites in cellular proteins. Furthermore, the structure of the prenyldiphosphate substrate alters peptide substrate selectivity, complicating the use of alkyne-modified prenyldiphosphate substrates for identification of protein substrates. Additionally, the prenylated proteome includes a number of bacterial and viral proteins where the eukaryotic prenylation machinery is hijacked to localize these proteins to membranes. Finally, the peptide substrate selectivity of GGTase-I from the pathogen, C. albicans GGTase-I is significantly broader, including recognition of substrates with large amino acids at the 'a' site, consistent with the enlarged binding pocket observed in the C. albicans GGTase-I structure. In summary, these data improve the functional characterization of prenylated proteins in both human and pathogenic organisms.

Protein prenyltransferases:  Defining the prenylated proteome

247th National Meeting (2014)

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