Dot1L 介导的 H2B 泛素化与 H3 甲基化的串扰机制。
Mechanism of Cross-talk between H2B Ubiquitination and H3 Methylation by Dot1L.
机构信息
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
出版信息
Cell. 2019 Mar 7;176(6):1490-1501.e12. doi: 10.1016/j.cell.2019.02.002. Epub 2019 Feb 11.
Methylation of histone H3 K79 by Dot1L is a hallmark of actively transcribed genes that depends on monoubiquitination of H2B K120 (H2B-Ub) and is an example of histone modification cross-talk that is conserved from yeast to humans. We report here cryo-EM structures of Dot1L bound to ubiquitinated nucleosome that show how H2B-Ub stimulates Dot1L activity and reveal a role for the histone H4 tail in positioning Dot1L. We find that contacts mediated by Dot1L and the H4 tail induce a conformational change in the globular core of histone H3 that reorients K79 from an inaccessible position, thus enabling this side chain to insert into the active site in a position primed for catalysis. Our study provides a comprehensive mechanism of cross-talk between histone ubiquitination and methylation and reveals structural plasticity in histones that makes it possible for histone-modifying enzymes to access residues within the nucleosome core.
Dot1L 介导的组蛋白 H3 K79 甲基化是活跃转录基因的标志，依赖于 H2B K120 的单泛素化（H2B-Ub），是组蛋白修饰交叉对话的一个例子，从酵母到人都保守。我们在这里报告了 Dot1L 与泛素化核小体结合的冷冻电镜结构，展示了 H2B-Ub 如何刺激 Dot1L 的活性，并揭示了组蛋白 H4 尾巴在定位 Dot1L 中的作用。我们发现 Dot1L 和 H4 尾巴介导的接触诱导组蛋白 H3 球状核心的构象变化，使 K79 从不可及的位置重新定向，从而使该侧链能够插入活性位点，为催化做好准备。我们的研究提供了组蛋白泛素化和甲基化之间交叉对话的综合机制，并揭示了组蛋白的结构可塑性，使组蛋白修饰酶能够进入核小体核心内的残基。
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