Peptide‐based probes for lysine deacetylases

Histone deacetylases (HDACs) erase acetylation marks of lysine residues in histones and non-histone proteins and thereby modulate the function and activity of these proteins. Alterations in protein acetylation levels and HDAC activity are transformations that occur in a wide range of diseases including cancer. Consequently, HDACs have been established as promising drug targets. Importantly, these enzymes do not operate as single proteins but constitute the catalytic domains of large multi-subunit HDAC complexes that modulate HDAC activity and specificity. Recombinant assembly of such HDAC complexes is very challenging and consequently there is only little information about their biochemical activity. We have developed peptide-based HDAC probes contain hydroxamate amino acids of various lengths replace modified lysine residues. The interaction profiles of the endogenous human HDACs were studied with different sets of probes, which showed how substrate recognition and composition of HDAC complexes is modulated by the sequence context of the acetylation sites. We further demonstrated that the interaction profiles reflect the catalytic activity of respective HDACs. These results underline the utility of the newly established peptide-probes for deciphering activity, substrate selectivity and composition of endogenous HDAC complexes, which can hardly be achieved otherwise