Heme promotes transcriptional and demethylase activities of Gis1, a member of the histone demethylase JMJD2/KDM4 family.
Heme promotes transcriptional and demethylase activities of Gis1, a member of the histone demethylase JMJD2/KDM4 family.
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DOI：
10.1093/nar/gkx1051
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发表时间：
2018-01-09
影响因子：
14.9
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Lal S;Comer JM;Konduri PC;Shah A;Wang T;Lewis A;Shoffner G;Guo F;Zhang L
酵母Gis 1蛋白是一种转录调节因子，属于含有JmjC结构域的脱甲基酶JMJD 2/KDM 4亚家族，该结构域从酵母到人类高度保守。它们在组蛋白甲基化、细胞信号传导和肿瘤发生中具有重要功能。除了作为许多蛋白质的辅因子外，已知血红素直接调节从转录调节因子到钾通道的蛋白质的活性。在这里，我们报告了一种新的机制，血红素调控Gis 1转录和组蛋白去甲基化酶的活动。我们发现，两个Gis 1模块，JmjN + JmjC结构域和锌指（ZnF），可以结合血红素特异性在体外。体内功能分析表明，ZnF，而不是JmjN + JmjC结构域，促进血红素激活的转录活性。同样，纯化的Gis 1蛋白的脱甲基酶活性的测量表明，全长Gis 1和JmjN + JmjC结构域都具有脱甲基酶活性。然而，血红素增强全长Gis 1的脱甲基酶活性，但不增强JmjN + JmjC结构域的脱甲基酶活性，这可以赋予血红素激活不相关蛋白的转录活性。这些结果表明，Gis 1代表一类新的多功能血红素传感和信号蛋白，血红素结合的ZnF刺激Gis 1去甲基化酶和转录活性。
The yeast Gis1 protein is a transcriptional regulator belonging to the JMJD2/KDM4 subfamily of demethylases that contain a JmjC domain, which are highly conserved from yeast to humans. They have important functions in histone methylation, cellular signaling and tumorigenesis. Besides serving as a cofactor in many proteins, heme is known to directly regulate the activities of proteins ranging from transcriptional regulators to potassium channels. Here, we report a novel mechanism governing heme regulation of Gis1 transcriptional and histone demethylase activities. We found that two Gis1 modules, the JmjN + JmjC domain and the zinc finger (ZnF), can bind to heme specifically in vitro. In vivo functional analysis showed that the ZnF, not the JmjN + JmjC domain, promotes heme activation of transcriptional activity. Likewise, measurements of the demethylase activity of purified Gis1 proteins showed that full-length Gis1 and the JmjN + JmjC domain both possess demethylase activity. However, heme potentiates the demethylase activity of full-length Gis1, but not that of the JmjN + JmjC domain, which can confer heme activation of transcriptional activity in an unrelated protein. These results demonstrate that Gis1 represents a novel class of multi-functional heme sensing and signaling proteins, and that heme binding to the ZnF stimulates Gis1 demethylase and transcriptional activities.
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影响因子：
64.5
作者：
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通讯作者：
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影响因子：
16.6
作者：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.1114514109
发表时间：
2012-02-07
影响因子：
11.1
作者：
Barr, Ian;Smith, Aaron T.;Guo, Feng
通讯作者：
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