选择性非甲基化CpGDNA识别机制
Bo Duan1, Dihong Fu1, Chaoqun Zhang1
1Beijing Nuclear Magnetic Resonance Center, College of Chemistry and Molecular Engineering, and School of Life Sciences, Peking University, Beijing 100871, China.
Journal of the American Chemical Society
|May 13, 2021
概括
转录因子TCF和GEF蛋白质使用C指结合非甲基化DNA. CpG甲基化阻止了结合,揭示了一个关键的表观遗传调节机制.
科学领域:
- 表观遗传学
- 结构生物学
- 分子生物学
背景情况:
- CpG甲基化是关键的表观遗传调节剂,但其对转录因子结合的影响尚不清楚.
- 转录因子家族如TCF (T细胞因子) 和GEF (葡萄糖转运体4增强因子) 对于基因调节至关重要.
- 了解这些因素如何与DNA相互作用,尤其是在甲基化过程中,至关重要.
研究的目的:
- 阐明TCF和GEF蛋白选择性地结合非甲基化DNA的分子机制.
- 确定通过C指域识别特定DNA序列的结构基础.
- 研究CpG甲基化对这些蛋白质的DNA结合亲和力的影响.
主要方法:
- 核磁共振 (NMR) 光谱测定与DNA复合的人类GEF家族蛋白HDBP1 (C-clampHDBP1) 的C-域结构.
- 从人类TCF1E (C-clampTCF1E) 中分析C-clamp域的DNA结合机制.
- 对DNA识别动机及其跨物种的保存进行分析.
主要成果:
- C-clamp域采用独特的指折叠,并通过"Arg·Trp-Lys-Lys"图案将RCCGGDNA序列结合在一起.
- CpG二核酸对通过键与蛋白质骨干和侧链结合至关重要.
- CpG位点的甲基化显著减少或消除了蛋白质结合.
- 同性模型显示TCF1E使用类似的Arg·Arg-Lys-Lys动机,更喜欢RCCGC序列.
- 已识别的DNA识别动机在GEF和TCF家族中保存,从到人.
结论:
- TCF和GEF蛋白通过其C指域选择性地准非甲基化CpG位点.
- CpG甲基化作为一个分子开关,防止这些转录因子的结合.
- 这种机制突出了非甲基化CpG结合蛋白用于表观遗传调节的共同策略.
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