Chen Zhongzhou, Zang Jianye, Whetstine Johnathan, Hong Xia, Davrazou Foteini, Kutateladze Tatiana G, Simpson Michael, Mao Qilong, Pan Cheol-Ho, Dai Shaodong, Hagman James, Hansen Kirk, Shi Yang, Zhang Gongyi
Department of Immunology, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Cell. 2006 May 19;125(4):691-702. doi: 10.1016/j.cell.2006.04.024. Epub 2006 May 4.
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-domain-containing 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.
组蛋白的翻译后修饰调节染色质结构和基因表达。组蛋白去甲基化酶是一个新出现的转录因子家族成员，可从组蛋白尾部的赖氨酸残基上去除甲基基团，从而调节靶基因的转录活性。含JmjC结构域的蛋白质被预测为去甲基化酶。例如，含JmjC的蛋白质JMJD2A已被鉴定为一种H3-K9me3和H3-K36me3特异性去甲基化酶。在此，通过X射线晶体学确定了在Fe2+存在下有和没有α-酮戊二酸的JMJD2A催化核心结构域的结构。核心结构域由JmjN结构域、JmjC结构域、C末端结构域和一个锌指基序组成，其结构揭示了形成潜在底物结合口袋的独特元件。定点诱变结合去甲基化酶活性测定使我们能够提出JMJD2组蛋白去甲基化酶家族选择底物的分子模型。
