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铜诱导的α-Synuclein的基质二元化需要胺
Dinendra L Abeyawardhane1, Ricardo D Fernández1, Denver R Heitger1
1Department of Chemistry , Virginia Commonwealth University , Richmond , Virginia 23284 , United States.
Journal of the American Chemical Society
|November 14, 2018
概括
与铜结合的α-synuclein (αS) 激活氧气,导致交叉链接并可能影响帕金森症
科学领域:
- 神经科学
- 生物化学
- 蛋白质化学
背景情况:
- 阿尔法-同核素 (αS) 聚合对帕金森病的发病具有重要作用.
- 对于生物标志物的发展至关重要的是了解αS的翻译后修饰,如滴素的形成.
- 导致这些变化的精确机制在很大程度上仍未明确.
研究的目的:
- 调查铜 (Cu) 和特定αS残留物在dityrosine交联中的机械作用.
- 阐明H50残留在αS交联和聚合中的作用.
- 探索铜和交联对αS聚合倾向的影响.
主要方法:
- 研究了与铜结合的N-终端乙化αS (NAcαS) 及其与氧的相互作用 (O2).
- 利用位点定向的突变发生,用H50替换谷氨酸 (Q) 来产生H50Q-αS.
- 分析了分子间和分子内交联模式和聚合倾向.
主要成果:
- 激活O2,促进分子间 (纤维核) 和分子内 (C端) 双铁交联.
- H50Q突变取消了分子间交叉链接和局部交叉链接到C端区域.
- 与NAc-αS-CuI相比,H50Q-αS-CuI表现出增强的聚合.
结论:
- 素50 (H50) 在促进αS中的分子间双链接方面起着至关重要的作用.
- 在CuI/O2反应过程中,需要长距离的histidine协调来稳定CuI到CuII的过渡.
- 铜和分子间交联可能调节αS纤维化,为帕金森病的机制提供了洞察力.
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