Kinetic characterization and substrate specificity studies of Protein Arginine Deiminase 4

BIOL 218

Monica Bhatia, bhatia@mail.chem.sc.edu, Department of Chemistry & Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, SC 29208 and Paul R. Thompson, thompson@mail.chem.sc.edu, Department of Chemistry and Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, SC 29208.
Eukaryotic gene expression is regulated at the level of chromatin through post-translational modifications of histones. Protein Arginine Deiminase 4 (PAD4) is a novel transcriptional regulator which catalyzes the deimination of histone arginine residues to citrulline. We report the first detailed kinetic characterization of PAD4 and its calcium dependence. The role of active site residues has also been probed using site directed mutagenesis. Our results suggest that active site cleft is highly sensitive to any changes that alter either substrate binding or catalysis. Current efforts are aimed at elucidating the substrate specificity determinants using N-terminal tail of histone H4 as a model substrate. Effect of distal and proximal residues on arginine deimination will be presented with respect to charge, location and modification status. Our studies have already aided the synthesis of most potent PAD4 inhibitors reported so far, and will guide the design of future PAD4 inhibitors, which can be used for treating Rheumatoid Arthritis, where a dysregulated PAD activity has been suspected.
 

Frontiers in Chemical Biology
5:00 PM-7:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Biological Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007