Abstract
Prenylation is an important post‐translational modification for many proteins whereby attachment of a lipid leads to membrane localization. Two enzymes responsible for the majority of prenylation, protein farnesyltransferase (FTase) and protein geranylgeranyltransferase type I (GGTase‐I), are proposed to recognize a “Ca1a2X” box motif at the C‐terminus of target proteins; however, recent work has demonstrated that this model is incomplete. Furthermore, the interactions between the protein substrate and residues within the enzyme core that are responsible for substrate specificity are not defined. We are identifying these interactions by screening the activity of panels of peptide substrates with FTase. Investigation of the structure‐activity parameters at the a2 position of peptide substrates indicates that both hydrophobic and steric components contribute to recognition and suggests that interactions with both the protein and the isoprenoid substrate modulate specificity. These data provide a better understanding of the features necessary for recognition and catalysis by FTase that may aid in designing new FTase inhibitors as anticancer and antiparasitic agents. This work may also provide novel tools for deciphering the roles played by prenylation and prenylated proteins within the cell.
Supported by NIH grants GM040602 (CAF) and CA078819 (RAG) and NIH postdoctoral fellowship GM078894 (JLH).