Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain
Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain
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DOI：
10.1074/jbc.m803514200
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发表时间：
2008-09-26
影响因子：
4.8
通讯作者：
Carfi, Andrea
中科院分区：
文献类型：
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作者：
Bottomley, Matthew J.;Lo Surdo, Paola;Carfi, Andrea
组蛋白脱乙酰酶 (HDAC) 调节染色质状态和基因表达，其抑制具有重要的治疗意义。迄今为止，尚未鉴定出 IIa 类 HDAC 的生物底物，并且仅证明了对乙酰化赖氨酸的低活性。在这里，我们描述了组蛋白脱乙酰酶 4 催化结构域 (HDAC4cd) 的抑制剂结合和无抑制剂结构以及对乙酰化赖氨酸具有增强酶活性的 HDAC4cd 活性位点突变体。所呈现的结构与活性数据相结合，为 IIa 类 HDAC 对乙酰化赖氨酸的固有低酶活性提供了分子基础，并揭示了可指导类特异性抑制剂设计的活性位点特征。此外，这些结构揭示了所有 IIa 类酶中保守的构象灵活的锌结合结构域。重要的是，协调结构锌离子的残基突变或 IIa 类选择性抑制剂的结合阻止了 HDAC4 与 N-CoR 中心点 HDAC3 阻遏物复合物的结合。总之，这些数据表明结构锌结合域在 IIa 类 HDAC 功能的调节中发挥着关键作用。
Histone deacetylases (HDACs) regulate chromatin status and gene expression, and their inhibition is of significant therapeutic interest. To date, no biological substrate for class IIa HDACs has been identified, and only low activity on acetylated lysines has been demonstrated. Here, we describe inhibitor-bound and inhibitor-free structures of the histone deacetylase-4 catalytic domain (HDAC4cd) and of an HDAC4cd active site mutant with enhanced enzymatic activity toward acetylated lysines. The structures presented, coupled with activity data, provide the molecular basis for the intrinsically low enzymatic activity of class IIa HDACs toward acetylated lysines and reveal active site features that may guide the design of class-specific inhibitors. In addition, these structures reveal a conformationally flexible structural zinc-binding domain conserved in all class IIa enzymes. Importantly, either the mutation of residues coordinating the structural zinc ion or the binding of a class IIa selective inhibitor prevented the association of HDAC4 with the N-CoR center dot HDAC3 repressor complex. Together, these data suggest a key role of the structural zinc-binding domain in the regulation of class IIa HDAC functions.