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Impact of a KDAC4 Active Site Residue on Activity and Specificity
Author(s) -
Bryant Jenae R,
Toro Tasha B,
Watt Terry J
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.834.19
Subject(s) - acetylation , lysine , residue (chemistry) , active site , peptide , biochemistry , chemistry , enzyme , substrate specificity , amino acid , gene
Acetylation of lysine is a common post‐translational modification to proteins. Lysine deacetylases (KDACs) react with acetylated lysines, catalyzing the hydrolysis of ɛ‐N‐acetyl lysine to generate an unmodified lysine residue and acetate. Perturbations in this system have been linked to specific diseases, including cancer. Thus, determining the mechanism of KDAC function and substrate specificity could ultimately lead to new therapeutics for these diseases. Recent studies suggest that a semi‐conserved active site residue appears to be important for enzymatic activity. We are evaluating the activity of several KDAC4 variants to determine how the active site residue affects enzyme function and substrate specificity. In this study, KDAC4 variants were expressed and tested for activity against a panel of peptide substrates. A gain‐of‐function variant had a specificity profile that was distinct from wild‐type KDAC4 and from other KDACs. The identified peptide substrates are the first biologically relevant substrates to have demonstrated reactivity with any KDAC4 variant, and provide insight into the substrate specificity and function of KDAC4.