Substrate Specificity in Lysine Deacetylases

Lysine deacetylases (KDACs) catalyze the hydrolysis of e-N-acetyl lysine residues in proteins to generate an unmodified lysine residue and acetate. Acetylation and deacetylation is a widely-used signaling mechanism which plays a critical role in transcriptional regulation, cell cycle progression, and developmental events. Perturbations in this process have been linked to diseases, including cancer and inflammation. While thousands of acetylated proteins have been identified, little is known concerning the specificity profiles of individual KDACs. Our aim is to identify the essential elements involved in molecular recognition of substrate proteins by KDACs. Assays performed using standard commercial reagents and acetylated peptides as substrates suggest that KDACs and their variants have distinct specificity profiles. To better understand this in a biologically relevant context, we have developed a general, highly sensitive assay for peptide substrates that more closely resemble natural KDAC substrates. Ac...