Department of Chemistry, Umeå University, 901 87 Umeå, Sweden.
Arch Biochem Biophys. 2013 Apr 15;532(2):84-90. doi: 10.1016/j.abb.2013.01.012. Epub 2013 Feb 9.
In a recent study we discovered that a ring-fused 2-pyridone compound triggered fibrillization of a key protein in Parkinson's disease, α-synuclein. To reveal how variations in compound structure affect protein aggregation, we now prepared a number of strategic analogs and tested their effects on α-synuclein amyloid fiber formation in vitro. We find that, in contrast to the earlier templating effect, some analogs inhibit α-synuclein fibrillization. For both templating and inhibiting compounds, the key species formed in the reactions are α-synuclein oligomers that contain compound. Despite similar macroscopic appearance, the templating and inhibiting oligomers are distinctly different in secondary structure content. When the inhibitory oligomers are added in seed amounts, they inhibit fresh α-synuclein aggregation reactions. Our study demonstrates that small chemical changes to the same central fragment can result in opposite effects on protein aggregation.
在最近的一项研究中，我们发现一种环合的 2-吡啶酮化合物能引发帕金森病关键蛋白α-突触核蛋白的纤维化。为了揭示化合物结构的变化如何影响蛋白质聚集，我们现在制备了一些策略性类似物，并测试了它们对α-突触核蛋白体外淀粉样纤维形成的影响。我们发现，与早期的模板效应相反，一些类似物抑制α-突触核蛋白的纤维化。对于模板和抑制化合物，反应中形成的关键物质是含有化合物的α-突触核蛋白寡聚物。尽管宏观外观相似，但模板和抑制性寡聚物在二级结构含量上有明显的不同。当以种子量添加抑制性寡聚物时，它们会抑制新鲜α-突触核蛋白的聚集反应。我们的研究表明，对同一中心片段的微小化学变化会对蛋白质聚集产生相反的影响。
