National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):17954-9. doi: 10.1073/pnas.1208517109. Epub 2012 Oct 17.
Recognition of methylated histone tail lysine residues by tudor domains plays important roles in epigenetic control of gene expression and DNA damage response. Previous studies revealed the binding of methyllysine in a cage of aromatic residues, but the molecular mechanism by which the sequence specificity for surrounding histone tail residues is achieved remains poorly understood. In the crystal structure of a trimethylated histone H3 lysine 4 (H3K4) peptide bound to the tudor-like domains of Spindlin1 presented here, an atypical mode of methyllysine recognition by an aromatic pocket of Spindlin1 is observed. Furthermore, the histone sequence is recognized in a distinct manner involving the amino terminus and a pair of arginine residues of histone H3, and disruption of the binding impaired stimulation of pre-RNA expression by Spindlin1. Our analysis demonstrates considerable diversities of methyllysine recognition and sequence-specific binding of histone tails by tudor domains, and the revelation furthers the understanding of tudor domain proteins in deciphering epigenetic marks on histone tails.
组蛋白尾部赖氨酸残基的甲基化识别由 tudor 结构域发挥重要作用，在基因表达和 DNA 损伤反应的表观遗传调控中发挥重要作用。先前的研究揭示了甲基赖氨酸在芳香族残基笼中的结合，但对于周围组蛋白尾部残基的序列特异性如何实现的分子机制仍知之甚少。在本文呈现的与 Spindlin1 的 tudor 样结构域结合的三甲基化组蛋白 H3 赖氨酸 4（H3K4）肽的晶体结构中，观察到 Spindlin1 的芳香口袋对甲基赖氨酸识别的一种非典型模式。此外，组蛋白序列以一种独特的方式被识别，涉及组蛋白 H3 的氨基末端和一对精氨酸残基，并且结合的破坏会损害 Spindlin1 对前 RNA 表达的刺激。我们的分析表明，tudor 结构域对甲基化赖氨酸的识别和组蛋白尾部的序列特异性结合具有很大的多样性，这一发现进一步加深了对 tudor 结构域蛋白在破译组蛋白尾部表观遗传标记方面的理解。
