Combinatorial modulation of protein prenylation.

The cell has >60 different farnesylated proteins. Many critically important signal transduction proteins are post-translationally modified with attachment of a farnesyl isoprenoid catalyzed by protein farnesyltransferase (FTase). Recently, it has been shown that farnesyl diphosphate (FPP) analogues can alter the peptide substrate specificity of FTase. We have used combinatorial screening of FPP analogues and peptide substrates to identify patterns in FTase substrate selectivity. Each FPP analogue displays a unique pattern of substrate reactivity with the tested peptides; FTase efficiently catalyzes the transfer of an FPP analogue selectively to one peptide and not another. Furthermore, we have demonstrated that these analogues can enter cells and be incorporated into proteins. These FPP analogues could serve as selective tools to examine the role prenylation plays in individual protein function.