Factors affecting the substrate specificity of histone deacetylases
Factors affecting the substrate specificity of histone deacetylases
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DOI：
10.1016/j.bbrc.2007.03.158
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发表时间：
2007-06-01
影响因子：
3.1
通讯作者：
Schwienhorst, Andreas
中科院分区：
文献类型：
--
作者：
Riester, Daniel;Hildmann, Christian;Schwienhorst, Andreas
历史脱乙酰酶（Historic deacetylases, hdac）在真核细胞中催化核心组蛋白n端尾部epsilon-acetyl-lysine残基的去乙酰化，从而介导染色质结构的变化并调节基因表达。到目前为止，人们对不同hdac的底物特异性知之甚少。在这里，我们准备了一个通用格式Ac-P-2-P-1- lys (Ac)-MCA （P-1, P-2 =除半胱氨酸外的所有氨基酸）的荧光三肽底物库，并在标准荧光HDAC试验中测量了它们的HDAC依赖性转化。不同的HDAC亚型可根据其底物选择性进行排序：HDAH > HDAC8 > HDAC1 > HDAC3 > HDAC6。HDAC1、HDAC3和HDAC6表现出相似的特异性特征，而HDAC8和HDAH具有相当不同的特征。此外，研究表明底物序列的第二位点修饰（如磷酸化）以及辅抑制因子结合可以调节酶催化底物转化的选择性。(c) 2007爱思唯尔公司版权所有。
Historic 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. (c) 2007 Elsevier Inc. All rights reserved.