Structural insights into a dual-specificity histone demethylase ceKDM7A from Caenorhabditis elegans
Structural insights into a dual-specificity histone demethylase ceKDM7A from Caenorhabditis elegans
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秀丽隐杆线虫双特异性组蛋白去甲基化酶 ceKDM7A 的结构见解
DOI：
10.1038/cr.2010.86
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发表时间：
2010-06
期刊：
影响因子：
--
通讯作者：
Wang, Ping
中科院分区：
文献类型：
--
作者：
Feng, Xiang;Chen, Charlie Degui;Zhou, Lu;Zhang, Wen;Yang, Ying;Lin, Yan;Dong, Yuhui;Lin, Hanqing;Wang, Yiqin;Liu, Yi;Xu, Yanhui;Gong, Rui;Hou, Haifeng;Yang, Huirong;Li, Ze;Hu, Lulu;Wang, Ping
组蛋白赖氨酸甲基化可以被包含 JmjC 结构域的蛋白质以序列和甲基化状态特异性的方式去除。然而，如何确定底物特异性以及如何调节酶在很大程度上是未知的。我们最近发现ceKDM7A是一种含有PHD和JmjC结构域的蛋白，是一种对H3K9me2和H3K27me2具有特异性的组蛋白去甲基化酶，并且PHD指与H3K4me3的结合引导体内的去甲基化活性。为了深入了解酶活性和 PHD 指功能的分子机制，我们解析了 apo 形式的酶的六种晶体结构，以及与含有 H3K4me3、H3K9me2 和 H3K27me2 修饰的各种组合的单个或两个肽的复合物。这些结构表明 H3K9me2 和 H3K27me2 以类似的方式与 ceKDM7A 相互作用，并且肽结合特异性由特定相互作用的网络决定。结构的几何测量还表明，与 PHD 指相关的 H3K4me3 和与 JmjC 结构域结合的 H3K9me2 来自两个独立的分子，表明存在反式组蛋白肽结合机制。因此，我们的系统结构研究不仅揭示了催化结构域对底物的识别，更重要的是揭示了ceDKM7A对H3K9me2和H3K27me2双重特异性的分子机制。
Histone lysine methylation can be removed by JmjC domain-containing proteins in a sequence-and methylation-state-specific manner. However, how substrate specificity is determined and how the enzymes are regulated were largely unknown. We recently found that ceKDM7A, a PHD-and JmjC domain-containing protein, is a histone demethylase specific for H3K9me2 and H3K27me2, and the PHD finger binding to H3K4me3 guides the demethylation activity in vivo. To provide structural insight into the molecular mechanisms for the enzymatic activity and the function of the PHD finger, we solved six crystal structures of the enzyme in apo form and in complex with single or two peptides containing various combinations of H3K4me3, H3K9me2, and H3K27me2 modifications. The structures indicate that H3K9me2 and H3K27me2 interact with ceKDM7A in a similar fashion, and that the peptide-binding specificity is determined by a network of specific interactions. The geometrical measurement of the structures also revealed that H3K4me3 associated with the PHD finger and H3K9me2 bound to the JmjC domain are from two separate molecules, suggesting a trans-histone peptide-binding mechanism. Thus, our systemic structural studies reveal not only the substrate recognition by the catalytic domain but also more importantly, the molecular mechanism of dual specificity of ceDKM7A for both H3K9me2 and H3K27me2.
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