Division of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, London, SW3 6JB, UK.
Nucleic Acids Res. 2014 Jan;42(1):661-71. doi: 10.1093/nar/gkt776. Epub 2013 Sep 18.
The delivery of site-specific post-translational modifications to histones generates an epigenetic regulatory network that directs fundamental DNA-mediated processes and governs key stages in development. Methylation of histone H4 lysine-20 has been implicated in DNA repair, transcriptional silencing, genomic stability and regulation of replication. We present the structure of the histone H4K20 methyltransferase Suv4-20h2 in complex with its histone H4 peptide substrate and S-adenosyl methionine cofactor. Analysis of the structure reveals that the Suv4-20h2 active site diverges from the canonical SET domain configuration and generates a high degree of both substrate and product specificity. Together with supporting biochemical data comparing Suv4-20h1 and Suv4-20h2, we demonstrate that the Suv4-20 family enzymes take a previously mono-methylated H4K20 substrate and generate an exclusively di-methylated product. We therefore predict that other enzymes are responsible for the tri-methylation of histone H4K20 that marks silenced heterochromatin.
组蛋白特异性翻译后修饰的传递生成了一个表观遗传调控网络，该网络指导基本的 DNA 介导过程，并控制发育的关键阶段。组蛋白 H4 赖氨酸-20 的甲基化与 DNA 修复、转录沉默、基因组稳定性和复制调控有关。我们展示了组蛋白 H4K20 甲基转移酶 Suv4-20h2 与其组蛋白 H4 肽底物和 S-腺苷甲硫氨酸辅因子复合物的结构。结构分析表明，Suv4-20h2 的活性位点与典型的 SET 结构域构型不同，产生了高度的底物和产物特异性。结合比较 Suv4-20h1 和 Suv4-20h2 的支持生化数据，我们证明 Suv4-20 家族酶采用先前单甲基化的 H4K20 底物，并生成专一地二甲基化产物。因此，我们预测其他酶负责标记沉默异染色质的组蛋白 H4K20 的三甲基化。
