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对TET介导氧化基质偏好的结构洞察
Lulu Hu1,2,3, Junyan Lu4, Jingdong Cheng1,2
1Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
Nature
|November 3, 2015
概括
十-十一转位 (TET) 蛋白质氧化DNA甲基化. 由于基质构成和氧化效率,TET1和TET2对5-甲基细胞因子 (5mC) 的活性高于5-甲基细胞因子 (5hmC) 或5-甲基细胞因子 (5fC). 这表明5hmC是一个稳定的表观遗传标记.
科学领域:
- 表观遗传学
- 分子生物学
- 生物化学
背景情况:
- DNA甲基化是一个关键的表观遗传调节剂.
- 十一转位 (TET) 蛋白通过氧化5-甲基细胞素 (5mC) 来调解DNA脱甲基化.
- TET蛋白反复地将5mC转化为5甲基 (5hmC),5甲基 (5fC) 和5甲基 (5caC).
研究的目的:
- 研究人类TET1和TET2蛋白质的基质偏好.
- 阐明不同DNA甲基化衍生物TET蛋白活性的结构基础.
- 了解TET蛋白活性对5hmC作为表观遗传标记的稳定性的影响.
主要方法:
- 测定TET2-5hmC-DNA和TET2-5fC-DNA复合物的晶体结构.
- 对TET蛋白活性和基质氧化效率的生物化学分析.
- 用5mC,5hmC和5fC基质对TET2-DNA复合物的比较结构分析.
主要成果:
- 与5hmC-DNA和5fC-DNA相比,人类的TET1和TET2在5mC-DNA上表现出更高的酶活性.
- 晶体结构显示了TET2催化腔内5mC,5hmC和5fC的相似结合,但改变基的方向不同.
- 生物化学数据表明,5hmC和5fC的受限构造阻碍了高效的抽取,导致这些基质的催化效率降低.
结论:
- TET蛋白质基质的偏好是由5mC衍生物的内在特性决定的,特别是修改后的细胞因子基的构造和结能力.
- TET蛋白对5hmC的反应性降低表明它是一种相对稳定的表观遗传标记.
- 进化优化了TET蛋白质以产生和维持5hmC,可能用于各种调节功能.
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