波谱学杂志 ›› 2016, Vol. 33 ›› Issue (2): 179-187.doi: 10.11938/cjmr20160201

• 研究论文 • 上一篇    下一篇

乙酰化修饰抑制α-synuclein的纤维化聚集

翟紫凝1,2, 吴琼1, 李从刚1   

  1. 1. 中国科学院生物磁共振分析重点实验室, 波谱与原子分子物理国家重点实验室, 武汉磁共振中心(中国科学院 武汉物理与数学研究所), 湖北 武汉 430071;
    2. 中国科学院大学, 北京 100049
  • 收稿日期:2015-05-13 修回日期:2016-04-18 出版日期:2016-06-05 发布日期:2016-06-05
  • 通讯作者: 李从刚,电话:027-87199319,E-mail:conggangli@wipm.ac.cn. E-mail:conggangli@wipm.ac.cn
  • 基金资助:

    Ministry of Science and Technology of China (2013CB910200);National Natural Science Foundation of China (21173258, 21120102038 and 21221064).

Lysine Acetylation Inhibits α-Synuclein Fibrillation

ZHAI Zi-ning1,2, WU Qiong1, LI Cong-gang1   

  1. 1. Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan(Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences), Wuhan 430071, China;
    2. University of Chinese Academy of Sciences, Beijing 100049, China
  • Received:2015-05-13 Revised:2016-04-18 Online:2016-06-05 Published:2016-06-05
  • Supported by:

    Ministry of Science and Technology of China (2013CB910200);National Natural Science Foundation of China (21173258, 21120102038 and 21221064).

摘要:

天然无结构蛋白α-synuclein(α-syn)的纤维化聚集是帕金森病的特征表现.静电相互作用已被证明会显著影响α-syn的聚集.该文通过简单的赖氨酸乙酰化修饰改变蛋白的净电荷,研究静电效应对于α-syn的构象和纤维化聚集的影响.核磁共振(NMR)实验结果表明乙酰化后的α-syn仍然是无序结构,而且展现出比野生型更加伸展的构象.由于N端和C端都高度带负电荷,结构打开会更加暴露NAC区域,静电排斥和疏水作用共同存在,但ThT荧光实验发现乙酰化修饰抑制了它的纤维化聚集,因此我们认为这里静电排斥占据主导作用.这种依赖电荷的作用机理会帮助我们更好地理解α-syn的纤维化聚集,而乙酰化修饰也提供了一种抑制聚集的新方法.

关键词: 液体核磁共振(liquid-state NMR), 乙酰化修饰, 纤维化聚集, α-synuclein

Abstract:

Fibrils of intrinsically disordered protein α-synuclein (α-syn) are hallmarks of Parkinson's disease. Electrostatic interactions are known to contribute significantly on α-syn aggregation. Here we studied how α-syn conformation and fibrillation were affected by changing the net charge of the protein via acetylation of lysine side chains. NMR spectroscopy results showed that lysine-acetylated α-syn remained disordered, and showed a more extended conformation, relative to wild-type protein. Acetylation inhibited α-syn fibrillation, revealed by thioflavin (ThT) fluorescence assay. The N- and C-terminals of the acetylated protein were highly negative charged, causing increased exposure of the non-amyloid-β component (NAC) region. It is proposed that, with the charge distribution in the acetylated protein, electrostatic repulsion, instead of hydrophobic effect, may contribute predominately to the aggregation. This charge-effect mechanism may constitute a new strategy to inhibit α-syn fibrillation.

Key words: liquid-state NMR, acetylation, fibrillation, α-synuclein

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