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首页> 外文期刊>Biochemistry >CH···O Hydrogen Bonds Mediate Highly Specific Recognition of Methylated CpG Sites by the Zinc Finger Protein Kaiso
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CH···O Hydrogen Bonds Mediate Highly Specific Recognition of Methylated CpG Sites by the Zinc Finger Protein Kaiso

机译：Ch···氢键通过锌指蛋白Kaiso介导对甲基化CpG位点的高度特异性识别

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摘要

Many eukaryotic transcription factors recognize the epigenetic marker 5-methylcytosine (mC) at CpG sites in DNA. Despite their structural diversity, methyl-CpG-binding proteins (MBPs) share a common mode of recognition of mC methyl groups that involves hydrophobic pockets and weak hydrogen bonds of the CH···O type. The zinc finger protein Kaiso possesses a remarkably high specificity for methylated over unmethylated CpG sites. A key contribution to this specificity is provided by glutamate 535 (E535), which is optimally positioned to form multiple interactions with mCpG, including direct CH···O hydrogen bonds. To examine the role of E535 and CH···O hydrogen bonding in the preferential recognition of mCpG sites, we determined the structures of wild type Kaiso (WT) and E535 mutants and characterized their interactions with methylated DNA by nuclear magnetic resonance spectroscopy (NMR), X-ray crystallography, and in vitro protein–DNA binding assays. Our data show that Kaiso favors an mCpG over a CpG site by 2 orders of magnitude in affinity and that an important component of this effect is the presence of hydrophobic and CH···O contacts involving E535. Moreover, we present the first direct evidence for formation of a CH···O hydrogen bond between an MBP and 5-methylcytosine by using experimental (NMR) and quantum mechanical chemical shift analysis of the mC methyl protons. Together, our findings uncover a critical function of methyl-specific interactions, including CH···O hydrogen bonds, that optimize the specificity and affinity of MBPs for methylated DNA and contribute to the precise control of gene expression.
机译：许多真核转录因子识别DNA中CpG位点的表观遗传标记5-甲基胞嘧啶（MC）。尽管它们的结构多样性，甲基-CpG结合蛋白（MBPS）共享涉及CH···O型疏水袋和弱氢键的MC甲基的共同识别模式。锌指蛋白Kaiso对未甲基化的CpG位点上甲基化具有显着高的特异性。对这种特异性的关键贡献由谷氨酸535（E535）提供，该谷氨酸535（E535）提供，其最佳地定位以形成与MCPG的多个相互作用，包括Direct CH ...氢键。为了检查E535和CH ... O氢键在MCPG位点的优先识别中的作用，我们确定了野生型Kaiso（WT）和E535突变体的结构，并通过核磁共振光谱表征与甲基化DNA的相互作用（NMR ），X射线晶体学和体外蛋白质-DNA结合测定。我们的数据显示，KAISO在亲和力的2个数量级上使用CPG站点的MCPG，并且这种效果的重要组成部分是涉及E535的疏水性和CH ...的存在。此外，我们通过使用MC甲基质子的实验（NMR）和量子机械化学转换分析，介绍了MBP和5-甲基胞菌溶胶之间的CH ...氢键的第一种直接证据。我们的研究结果在一起发现了甲基特异性相互作用的关键函数，包括CH ...氢键，可以优化Mbps对甲基化DNA的特异性和亲和力，并有助于基因表达的精确控制。

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  • 来源
    《Biochemistry》 |2018年第14期|共12页
  • 作者

    EvgeniaN. Nikolova; Robyn L. Stanfield; H. Jane Dyson; Peter E. Wright;

  • 作者单位

    Department of Integrative Structural and Computational Biology and Skaggs Institute of Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road La Jolla California 92037 United States;

    Department of Integrative Structural and Computational Biology and Skaggs Institute of Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road La Jolla California 92037 United States;

    Department of Integrative Structural and Computational Biology and Skaggs Institute of Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road La Jolla California 92037 United States;

    Department of Integrative Structural and Computational Biology and Skaggs Institute of Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road La Jolla California 92037 United States;

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  • 正文语种 eng
  • 中图分类 生物化学;
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