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Dimerization of a viral SET protein endows its function

机译:病毒SET蛋白的二聚化赋予其功能

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摘要

Histone. modifications are regarded as the most indispensible phenomena in epigenetics. Of these modifications, lysine methyla-tion is of the greatest complexity and importance as site- and state-specific lysine methylation exerts a plethora of effects on chromatin structure and gene transcription. Notably, paramecium bursaria chlorella viruses encode a conserved SET domain methyl-transferase, termed vSET, that functions to suppress host transcription by methylating histone H3 at lysine 27 (H3K27), a mark for eukaryotic gene silencing. Unlike mammalian lysine methyltrans-ferases (KMTs),.vSET functions only as a dimer, but the underlying mechanism has remained elusive. In this study, we demonstrate that dimeric vSET operates with negative cooperativity between the two active sites and engages in H3K27 methylation one site at a time. New atomic structures of vSET in the free form and a ternary complex with S-adenosyl homocysteine and a histone H3 peptide and biochemical analyses reveal the molecular origin for the negative cooperativity and explain the substrate specificity of H3K27 methyltransferases. Our study suggests a "walking" mechanism, by which vSET acts all by itself to globally methylate host H3K27, which is accomplished by the mammalian EZH2 KMT only in the context of the Polycomb repressive complex.
机译:组蛋白。修饰被认为是表观遗传学中最不可缺少的现象。在这些修饰中,赖氨酸甲基化具有最大的复杂性和重要性,因为特定于位点和状态的赖氨酸甲基化对染色质结构和基因转录有很多影响。值得注意的是,草履虫法氏囊小球藻病毒编码一个保守的SET域甲基转移酶,称为vSET,其功能是通过在赖氨酸27(H3K27)处甲基化组蛋白H3(真核基因沉默的标记)来抑制宿主转录。与哺乳动物赖氨酸甲基转移酶(KMT)不同,.vSET仅起二聚体的作用,但其潜在机制尚不清楚。在这项研究中,我们证明了二聚体vSET在两个活性位点之间具有负协同作用,并且一次参与一个位点的H3K27甲基化。游离形式的vSET的新原子结构以及与S-腺苷高半胱氨酸和组蛋白H3肽的三元复合物以及生化分析揭示了负协同性的分子来源并解释了H3K27甲基转移酶的底物特异性。我们的研究提出了一种“行走”机制,通过该机制,vSET自身全部作用于全局甲基化宿主H3K27,只有在Polycomb抑制复合体的情况下,这才由哺乳动物EZH2 KMT完成。

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