Combinatorial modulation of protein prenylation

BIOL 201

Amanda J. Krzysiak, krzysiak@pharmacy.purdue.edu1, Sarah A. Reigard1, Diwan S. Rawat2, Katherine A. Hicks3, Carol A. Fierke, fierke@umich.edu3, and Richard A. Gibbs1. (1) Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Dr, Heine Pharmacy Building, West Lafayette, IN 47907, (2) Department of Chemistry, University of Delhi, Delhi, 110007, India, (3) Departments of Chemistry and Biological Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, MI 48109-1055
It has been estimated that there are more than 60 farnesylated proteins in the cell (J. Mol. Biol 2004, 343, 417). These proteins, bearing a signature carboxyl-terminal CaaX motif, are post-translationally modified with a farnesyl isoprenoid through the action of farnesyltransferase(FTase). We have recently shown that FPP analogs can alter the peptide substrate specificity of FTase (Biochemistry 2005, 44, 11214). Combinatorial screening of FPP analogs and substrate peptides, including a 24-member CaaS library, have now been utilized to identify patterns in FTase substrate ability. Each FPP analog displays a unique substrate activity pattern with tested peptides. Some analogs will transfer selectively to one peptide and not another. These results have validated models for FTase peptide substrate selectivity, and have enhanced our insight into its complex process of combinatorial substrate recognition. Moreover, the FPP analogs could serve as tools to examine the role lipidation plays in a specific protein's functioning.

 

Enzymes
4:30 PM-6:30 PM, Wednesday, 13 September 2006 Moscone Center -- Hall D, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, 11 September 2006 Moscone Center -- Hall D, Sci-Mix

Division of Biological Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006