乙酰化修饰抑制α-synuclein的纤维化聚集(英文)

Lysine Acetylation Inhibits α-Synuclein Fibrillation

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Th T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.

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（Th T） fluorescence assay. The N- and C-terminals of the acetylated protein were highly negative charged, causing increased exposure of the non-amyloid-b 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.