Becht Dustin C, Song Jiabao, Selvam Karthik, Yin Kejun, Bai Weizhi, Zhao Yingming, Wu Ronghu, Zheng Y George, Kutateladze Tatiana G
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA.
Structure. 2025 Jul 3;33(7):1233-1239.e5. doi: 10.1016/j.str.2025.04.010. Epub 2025 May 7.
Metabolically regulated lysine acylation modifications in proteins play a major role in epigenetic processes and cellular homeostasis. A new type of histone acylation, lysine methacrylation, has recently been identified but remains poorly characterized. Here, we show that lysine methacrylation can be generated through metabolism of sodium methacrylate and enzymatically removed in cells, and that the YEATS domain but not bromodomain recognizes this modification. Structural and biochemical analyses reveal the π-π-π-stacking mechanism for binding of the YEATS domain of ENL to methacrylated histone H3K18 (H3K18mc). Using mass spectrometry proteomics, we demonstrate that methacrylate induces global methacrylation of a set of proteins that differs from the set of methacrylated proteins associated with valine metabolism. These findings suggest that high levels of methacrylate may potentially perturb cellular functions of these proteins by altering protein methacrylation profiles.
蛋白质中代谢调控的赖氨酸酰化修饰在表观遗传过程和细胞稳态中起主要作用。最近发现了一种新型的组蛋白酰化，即赖氨酸甲基丙烯酰化，但对其特征了解甚少。在这里，我们表明赖氨酸甲基丙烯酰化可以通过甲基丙烯酸钠的代谢产生，并在细胞中被酶促去除，并且YEATS结构域而非溴结构域识别这种修饰。结构和生化分析揭示了ENL的YEATS结构域与甲基丙烯酰化组蛋白H3K18（H3K18mc）结合的π-π-π堆积机制。使用质谱蛋白质组学，我们证明甲基丙烯酸酯诱导一组蛋白质的全局甲基丙烯酰化，这组蛋白质不同于与缬氨酸代谢相关的甲基丙烯酰化蛋白质组。这些发现表明，高水平的甲基丙烯酸酯可能通过改变蛋白质甲基丙烯酰化谱来潜在地扰乱这些蛋白质的细胞功能。
