低聚物
化学
纤维
分子动力学
单体
肽
生物物理学
蛋白质聚集
淀粉样蛋白(真菌学)
淀粉样纤维
淀粉样β
蛋白质折叠
生物化学
计算化学
聚合物
有机化学
疾病
生物
医学
无机化学
病理
作者
Thomas C. T. Michaels,Anđela Šarić,Samo Curk,Katja Bernfur,Paolo Arosio,Georg Meisl,Alexander J. Dear,Samuel I. Cohen,Christopher M. Dobson,Sara Linse,Tuomas P. J. Knowles
出处
期刊:Nature Chemistry
[Springer Nature]
日期:2020-04-13
卷期号:12 (5): 445-451
被引量:212
标识
DOI:10.1038/s41557-020-0452-1
摘要
Oligomeric species populated during the aggregation of the Aβ42 peptide have been identified as potent cytotoxins linked to Alzheimer’s disease, but the fundamental molecular pathways that control their dynamics have yet to be elucidated. By developing a general approach that combines theory, experiment and simulation, we reveal, in molecular detail, the mechanisms of Aβ42 oligomer dynamics during amyloid fibril formation. Even though all mature amyloid fibrils must originate as oligomers, we found that most Aβ42 oligomers dissociate into their monomeric precursors without forming new fibrils. Only a minority of oligomers converts into fibrillar structures. Moreover, the heterogeneous ensemble of oligomeric species interconverts on timescales comparable to those of aggregation. Our results identify fundamentally new steps that could be targeted by therapeutic interventions designed to combat protein misfolding diseases. Aβ42 oligomers are key toxic species associated with protein aggregation; however, the molecular pathways determining the dynamics of oligomer populations have remained unknown. Now, direct measurements of oligomer populations, coupled to theory and computer simulations, define and quantify the dynamics of Aβ42 oligomers formed during amyloid aggregation.
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