Structural insight into autoinhibition and histone H3-induced activation of DNMT3A
Structural insight into autoinhibition and histone H3-induced activation of DNMT3A
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DNMT3A 自身抑制和组蛋白 H3 诱导激活的结构洞察
DOI：
10.1038/nature13899
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发表时间：
2015-01-29
期刊：
影响因子：
64.8
通讯作者：
Xu, Yanhui
中科院分区：
文献类型：
--
作者：
Guo, Xue;Wang, Ling;Xu, Yanhui
DNA甲基化是一种重要的表观遗传修饰，通过调节基因表达、基因组印记和表观遗传，对各种发育过程至关重要。哺乳动物基因组DNA甲基化是在胚胎发育过程中由DNA甲基转移酶DNMT 3A和DNMT 3B建立的，甲基化模式随发育阶段和细胞类型而变化。DNA甲基转移酶3样蛋白（DNMT 3L）是DNMT 3酶的无催化活性的部分，其刺激Dnmt 3a的酶活性。最近的研究已经建立了DNA甲基化和组蛋白修饰之间的联系，并揭示了组蛋白指导的DNA甲基化的建立机制。Dnmt 3a的ATRX-DNMT 3-DNMT 3L（ADD）结构域识别未甲基化的组蛋白H3（H3 K4 me 0）。组蛋白H3尾在体外刺激Dnmt 3的酶活性，但其分子机制尚不清楚。在这里，我们表明，DNMT 3A存在于一个自动抑制的形式，组蛋白H3尾刺激其活动在一个DNMT 3L独立的方式。我们分别在3.82和2.90 nm分辨率下测定了DNMT 3A-DNMT 3L（自抑制形式）和DNMT 3A-DNMT 3L-H3（活性形式）复合物的晶体结构。结构和生化分析表明，DNMT 3A的ADD结构域与催化结构域（CD）相互作用，并通过阻断其DNA结合亲和力来抑制其酶活性。组蛋白H3（但不是H3 K4 me 3）破坏ADD-CD相互作用，诱导ADD结构域的大的移动，并且因此释放DNMT 3A的自抑制。这一发现增加了DNA甲基化的另一层调控，以确保当存在未甲基化的H3 K4时，该酶主要在适当的靶向位点被激活，并强烈支持H3 K4 me 3与哺乳动物基因组中的DNA甲基化之间的负相关性。我们的研究提供了一个新的见解，意想不到的自抑制和组蛋白H3诱导的激活的de novoDNA甲基转移酶后，其最初的基因组定位。
DNA methylation is an important epigenetic modification that is essential for various developmental processes through regulating gene expression, genomic imprinting, and epigenetic inheritance,,,,. Mammalian genomic DNA methylation is established during embryogenesis byde novoDNA methyltransferases, DNMT3A and DNMT3B,,, and the methylation patterns vary with developmental stages and cell types,,,. DNA methyltransferase 3-like protein (DNMT3L) is a catalytically inactive paralogue of DNMT3 enzymes, which stimulates the enzymatic activity of Dnmt3a. Recent studies have established a connection between DNA methylation and histone modifications, and revealed a histone-guided mechanism for the establishment of DNA methylation. The ATRX–DNMT3–DNMT3L (ADD) domain of Dnmt3a recognizes unmethylated histone H3 (H3K4me0),,. The histone H3 tail stimulates the enzymatic activity of Dnmt3ain vitro,, whereas the molecular mechanism remains elusive. Here we show that DNMT3A exists in an autoinhibitory form and that the histone H3 tail stimulates its activity in a DNMT3L-independent manner. We determine the crystal structures of DNMT3A–DNMT3L (autoinhibitory form) and DNMT3A–DNMT3L-H3 (active form) complexes at 3.82 and 2.90 Å resolution, respectively. Structural and biochemical analyses indicate that the ADD domain of DNMT3A interacts with and inhibits enzymatic activity of the catalytic domain (CD) through blocking its DNA-binding affinity. Histone H3 (but not H3K4me3) disrupts ADD–CD interaction, induces a large movement of the ADD domain, and thus releases the autoinhibition of DNMT3A. The finding adds another layer of regulation of DNA methylation to ensure that the enzyme is mainly activated at proper targeting loci when unmethylated H3K4 is present, and strongly supports a negative correlation between H3K4me3 and DNA methylation across the mammalian genome,,,. Our study provides a new insight into an unexpected autoinhibition and histone H3-induced activation of thede novoDNA methyltransferase after its initial genomic positioning.