Structural characterization of toxic oligomers that are kinetically trapped during α-synuclein fibril formation
Structural characterization of toxic oligomers that are kinetically trapped during α-synuclein fibril formation
复制标题
DOI：
10.1073/pnas.1421204112
复制
发表时间：
2015-04-21
影响因子：
11.1
通讯作者：
Cremades, Nunilo
中科院分区：
文献类型：
--
作者：
Chen, Serene W.;Drakulic, Srdja;Cremades, Nunilo
我们描述了在淀粉样蛋白形成过程中积累的α-突触核蛋白的稳定毒性寡聚体的分离和详细的结构表征。我们的方法使我们能够识别不同的分组的低聚物，并通过使用冷冻电子显微镜（cryoEM）图像重建技术来探测它们的分子结构。尽管这些低聚物存在于一系列尺寸范围内，具有不同的β折叠含量和暴露的疏水性程度和性质，但它们都具有中空圆柱形结构，与某些类型的淀粉样蛋白原纤维相似，这表明至少某些形式的淀粉样蛋白的积累。低聚物可能是其β折叠结构重排速率非常缓慢的结果。我们的研究结果揭示了蛋白质错误折叠过程的内在多样性，以及在自组装过程的早期阶段获得的β-折叠几何形状在决定单个寡聚物物种的动力学稳定性和病理性质方面发挥的关键作用。
We describe the isolation and detailed structural characterization of stable toxic oligomers of alpha-synuclein that have accumulated during the process of amyloid formation. Our approach has allowed us to identify distinct subgroups of oligomers and to probe their molecular architectures by using cryo-electron microscopy (cryoEM) image reconstruction techniques. Although the oligomers exist in a range of sizes, with different extents and nature of beta-sheet content and exposed hydrophobicity, they all possess a hollow cylindrical architecture with similarities to certain types of amyloid fibril, suggesting that the accumulation of at least some forms of amyloid oligomers is likely to be a consequence of very slow rates of rearrangement of their beta-sheet structures. Our findings reveal the inherent multiplicity of the process of protein misfolding and the key role the beta-sheet geometry acquired in the early stages of the self-assembly process plays in dictating the kinetic stability and the pathological nature of individual oligomeric species.