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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Molecular basis for recognition of methylated and specific DNA sequences by the zinc finger protein Kaiso
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Molecular basis for recognition of methylated and specific DNA sequences by the zinc finger protein Kaiso

机译：锌指蛋白Kaiso识别甲基化和特定DNA序列的分子基础

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摘要

Methylation of CpG dinucleotides in DNA is a common epigenetic modification in eukaryotes that plays a central role in maintenance of genome stability, gene silencing, genomic imprinting, development and disease. Kaiso, a bif unctional Cys_2His_2 zinc finger protein implicated in tumor-cell proliferation, binds to both methylated CpG (mCpG) sites and a specific nonmethylated DNA motif (TCCTGCNA) and represses transcription by recruiting chromatin remodeling co-repression machinery to target genes. Here we report structures of the Kaiso zinc finger DNA-binding domain in complex with its non-methylated, sequence-specific DNA target (KBS) and with a symmetrically methylated DNA sequence derived from the promoter region of E-cadherin. Recognition of specific bases in the major groove of the core KBS and mCpG sites is accomplished through both classical and methyl CH…O hydrogen-bonding interactions with residues in the first two zinc fingers, whereas residues in the C-terminal extension following the third zinc finger bind in the opposing minor groove and are required for high-affinity binding. The C-terminal region is disordered in the free protein and adopts an ordered structure upon binding to DNA. The structures of these Kaiso complexes provide insights into the mechanism by which a zinc finger protein can recognize mCpG sites as well as a specific, nonmethylated regulatory DNA sequence.
机译：CpG二核苷酸在DNA中的甲基化是真核生物中常见的表观遗传修饰，在维持基因组稳定性，基因沉默，基因组印迹，发育和疾病中起着核心作用。 Kaiso是一种与肿瘤细胞增殖有关的功能性Cys_2His_2锌指蛋白，可与甲基化CpG（mCpG）位点和特定的非甲基化DNA基序（TCCTGCNA）结合，并通过向目标基因募集染色质重塑共抑制机制来抑制转录。在这里，我们报告了Kaiso锌指DNA结合结构域的结构，该结构与其非甲基化序列特异性DNA靶标（KBS）以及源自E-钙粘蛋白启动子区域的对称甲基化DNA序列复合。 KBS和mCpG核心位点主要凹槽中特定碱基的识别是通过经典CH2和氢CH…O与前两个锌指中的残基进行氢键相互作用而完成的，而在第三锌后的C端延伸中的残基手指绑定在相对的小凹槽中，并且需要高亲和力绑定。游离蛋白质的C端区域无序，并在与DNA结合时采用有序结构。这些Kaiso复合物的结构提供了对锌指蛋白可以识别mCpG位点以及特定的非甲基化调控DNA序列的机制的深刻见解。

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