Structural insights into histone demethylation by JMJD2 family members
Structural insights into histone demethylation by JMJD2 family members
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DOI：
10.1016/j.cell.2006.04.024
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发表时间：
2006-05-19
期刊：
影响因子：
64.5
通讯作者：
Zhang, Gongyi
中科院分区：
文献类型：
--
作者：
Chen, Zhongzhou;Zang, Jianye;Zhang, Gongyi
组蛋白的翻译后修饰调节染色质结构和基因表达。组蛋白去甲基酶是一个新出现的转录因子家族的成员，它从组蛋白尾部的赖氨酸残基中去除甲基，从而调节靶基因的转录活性。含有JmjC结构域的蛋白质被预测为去甲基酶。例如，含有JmjC的蛋白JMJD2A被鉴定为H3-K9me3-和H3-K36me3特异的去甲基酶。在此，用X射线结晶学测定了在Fe2+存在下α-酮戊二酸与不含α-酮戊二酸的JMJD2A的催化核心区的结构。核心域的结构由JmjN结构域、JmjC结构域、C-末端结构域和锌指基序组成，揭示了形成潜在底物结合口袋的独特元件。定点突变结合去甲基酶活性分析使我们能够为JMJD2组蛋白去甲基酶家族的底物选择提出一个分子模型。
Posttranslational modifications of histones regulate chromatin structure and gene expression. Histone demethylases, members of a newly emerging transcription-factor family, remove methyl groups from the lysine residues of the histone tails and thereby regulate the transcriptional activity of target genes. JmjC-domaincontaining proteins have been predicted to be demethylases. For example, the JmjC-containing protein JMJD2A has been characterized as a H3-K9me3- and H3-K36me3-specific demethylase. Here, structures of the catalytic-core domain of JMJD2A with and without alpha-ketoglutarate in the presence of Fe2+ have been determined by X-ray crystallography. The structure of the core domain, consisting of the JmjN domain, the JmjC domain, the C-terminal domain, and a zinc-finger motif, revealed the unique elements that form a potential substrate binding pocket. Sited-directed mutagenesis in conjunction with demethylase activity assays allowed us to propose a molecular model for substrate selection by the JMJD2 histone demethylase family.