Amelioration of aggregate cytotoxicity by catalytic conversion of protein oligomers into amyloid fibrils
Amelioration of aggregate cytotoxicity by catalytic conversion of protein oligomers into amyloid fibrils
复制标题
通过将蛋白质寡聚体催化转化为淀粉样原纤维来改善聚集细胞毒性
DOI：
10.1039/d0nr01481h
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发表时间：
2020
期刊：
影响因子：
6.7
通讯作者：
Sarah Perrett
中科院分区：
文献类型：
--
作者：
Jie Yang;Alex;er J. Dear;Qiong-Qiong Yao;Zhenyan Liu;Christopher M. Dobson;Tuomas P. J. Knowles;Si Wu;Sarah Perrett
肽和蛋白质聚集成淀粉样原纤维是一种与生物功能和功能障碍相关的分子自组装现象，特别是在神经退行性疾病的背景下。在聚集过程早期形成的寡聚物种通常与细胞毒性有关。外部分子如肽已被发现影响淀粉样蛋白形成动力学并调节这一细胞过程。本文采用单分子FRET和整体动力学分析相结合的方法，定量研究了8残基肽（LQVNIGNR）对酵母朊蛋白Ure2形成原纤维的影响。这种肽来源于Ure2朊蛋白结构域的一段，形成囊泡组装体，通过催化方式促进低聚中间体向纤维状物质的构象转化，从而加速Ure2纤维的形成。这减少了寡聚物的寿命，从而改善了细胞毒性。LQVNIGNR肽被发现可以加速不相关蛋白的纤维形成，包括Tau和α-Synuclein，这表明它具有催化纤颤的一般能力。本研究为研究淀粉样蛋白聚集的外在因素的微观机制提供了一个总体策略。这种方法可以很容易地应用于其他淀粉样蛋白系统，并证明加速低聚物转化是减少淀粉样蛋白毒性的一种有前途的策略。
The aggregation of peptides and proteins into amyloid fibrils is a molecular self-assembly phenomenon associated with both biological function and malfunction, notably in the context of neurodegenerative diseases. Oligomeric species formed early in the aggregation process are generally associated with cytotoxicity. Extrinsic molecules such as peptides have been found to influence amyloid formation kinetics and regulate this cellular process. Here, we use single-molecule FRET and bulk assays combined with global kinetic analysis to study quantitatively the effect of an 8-residue peptide (LQVNIGNR) on fibril formation by the yeast prion protein Ure2. This peptide, which is derived from a segment of the Ure2 prion domain, forms vesicular assemblies that accelerate fibril formation of Ure2 by promoting conformational conversion of oligomeric intermediates into fibrillar species in a catalytic manner. This reduces oligomer longevity and consequently ameliorates cytotoxicity. The LQVNIGNR peptide was found to accelerate fibril formation of unrelated proteins including Tau and α-Synuclein, suggesting a general ability to catalyse fibrillation. This study provides a general strategy for investigating the microscopic mechanism of extrinsic factors on amyloid aggregation. This approach can readily be applied to other amyloid systems and demonstrates that acceleration of oligomer conversion is a promising strategy to reduce amyloid toxicity.