The JmjN Domain of Jhd2 Is Important for Its Protein Stability, and the Plant Homeodomain (PHD) Finger Mediates Its Chromatin Association Independent of H3K4 Methylation
The JmjN Domain of Jhd2 Is Important for Its Protein Stability, and the Plant Homeodomain (PHD) Finger Mediates Its Chromatin Association Independent of H3K4 Methylation
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DOI：
10.1074/jbc.m110.117333
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发表时间：
2010-08-06
影响因子：
4.8
通讯作者：
Sun, Zu-Wen
中科院分区：
文献类型：
--
作者：
Huang, Fu;Chandrasekharan, Mahesh B.;Sun, Zu-Wen
组蛋白赖氨酸甲基化是一个动态过程，在调控染色质结构和基因表达中起着重要作用。最近的研究已经确定Jhd 2，一个JmjC结构域的蛋白质，作为H3 K4特异性脱甲基酶在芽殖酵母。然而，关于Jhd 2的调节和功能的重要问题仍然没有答案。在这项研究中，我们表明，Jhd 2具有内在的活性，以消除所有三种状态的H3 K4甲基化在体内，并可以动态地与染色质调节H3 K4甲基化水平的活性和抑制的基因和端粒区域。我们发现Jhd 2的植物同源结构域（PHD）指对于其在体内的染色质缔合是重要的。然而，这种关联并不依赖于H3 K4甲基化和H3 N-末端尾，这表明存在Jhd 2结合核小体的替代机制。我们还提供了证据表明，JmjN结构域及其与JmjC催化结构域的相互作用是重要的Jhd 2功能和Not 4（E3连接酶）监测结构完整性的结构域间的相互作用，以保持整体蛋白水平的Jhd 2。我们发现，S451 R突变在人类SMCX（Jhd 2的同源物），这已被链接到精神发育迟滞，和同源T359 R突变Jhd 2影响这两种蛋白质的蛋白质稳定性。因此，我们的研究结果为携带SMCX突变体的患者中观察到的缺陷提供了一种机制解释，并表明存在一种涉及Not 4的保守途径，该途径调节酵母Jhd 2和人SMCX的蛋白质稳定性。
Histone lysine methylation is a dynamic process that plays an important role in regulating chromatin structure and gene expression. Recent studies have identified Jhd2, a JmjC domain-containing protein, as an H3K4-specific demethylase in budding yeast. However, important questions regarding the regulation and functions of Jhd2 remain unanswered. In this study, we show that Jhd2 has intrinsic activity to remove all three states of H3K4 methylation in vivo and can dynamically associate with chromatin to modulate H3K4 methylation levels on both active and repressed genes and at the telomeric regions. We found that the plant homeodomain (PHD) finger of Jhd2 is important for its chromatin association in vivo. However, this association is not dependent on H3K4 methylation and the H3 N-terminal tail, suggesting the presence of an alternative mechanism by which Jhd2 binds nucleosomes. We also provide evidence that the JmjN domain and its interaction with the JmjC catalytic domain are important for Jhd2 function and that Not4 (an E3 ligase) monitors the structural integrity of this interdomain interaction to maintain the overall protein levels of Jhd2. We show that the S451R mutation in human SMCX (a homolog of Jhd2), which has been linked to mental retardation, and the homologous T359R mutation in Jhd2 affect the protein stability of both of these proteins. Therefore, our findings provide a mechanistic explanation for the observed defects in patients harboring this SMCX mutant and suggest the presence of a conserved pathway involving Not4 that modulates the protein stability of both yeast Jhd2 and human SMCX.