title: Factors affecting the substrate specificity of histone deacetylases.
abstract: Histone deacetylases (HDACs) catalyze the deacetylation of epsilon-acetyl-lysine residues within the N-terminal tail of core histones and thereby mediate changes in the chromatin structure and regulate gene expression in eukaryotic cells. So far, surprisingly little is known about the substrate specificities of different HDACs. Here, we prepared a library of fluorogenic tripeptidic substrates of the general format Ac-P(-2)-P(-1)-Lys(Ac)-MCA (P(-1), P(-2)=all amino acids except cysteine) and measured their HDAC-dependent conversion in a standard fluorogenic HDAC assay. Different HDAC subtypes can be ranked according to their substrate selectivity: HDAH > HDAC8 > HDAC1 > HDAC3 > HDAC6. HDAC1, HDAC3, and HDAC6 exhibit a similar specificity profile, whereas both HDAC8 and HDAH have rather distinct profiles. Furthermore, it was shown that second-site modification (e.g., phosphorylation) of substrate sequences as well as corepressor binding can modulate the selectivity of enzymatic substrate conversion.
authors.affiliation: Department of Molecular Genetics and Preparative Molecular Biology, Institute for Microbiology and Genetics, University of Goettingen, Grisebachstr. 8, 37077 Goettingen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Riester
authors.forename: Christian
authors.initials: C
authors.lastname: Hildmann
authors.forename: Sylvia
authors.initials: S
authors.lastname: Grünewald
authors.forename: Thomas
authors.initials: T
authors.lastname: Beckers
authors.forename: Andreas
authors.initials: A
authors.lastname: Schwienhorst
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D004789:Enzyme Activation; D006655:Histone Deacetylases / Q000737:chemistry* / Q000145:classification*; D008969:Molecular Sequence Data; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D006655:Histone Deacetylases