Department of Chemistry , Sookmyung Women's University , Cheongpa-ro 47-gil 100 , Yongsan-gu, Seoul 04310 , South Korea.
Biophysics Program and Department of Chemistry, Biomedical Engineering, and Macromolecular Science and Engineering , University of Michigan , Ann Arbor , Michigan 48109-1055 , United States.
ACS Nano. 2019 Aug 27;13(8):8766-8783. doi: 10.1021/acsnano.9b01578. Epub 2019 Jul 24.
Complex amyloid aggregation of amyloid-β (1-40) (Aβ) in terms of monomer structures has not been fully understood. Herein, we report the microscopic mechanism and pathways of Aβ aggregation with macroscopic viewpoints through tuning its initial structure and solubility. Partial helical structures of Aβ induced by low solvent polarity accelerated cytotoxic Aβ amyloid fibrillation, while predominantly helical folds did not aggregate. Changes in the solvent polarity caused a rapid formation of β-structure-rich protofibrils or oligomers aggregation-prone helical structures. Modulation of the pH and salt concentration transformed oligomers to protofibrils, which proceeded to amyloid formation. We reveal diverse molecular mechanisms underlying Aβ aggregation with conceptual energy diagrams and propose that aggregation-prone partial helical structures are key to inducing amyloidogenesis. We demonstrate that context-dependent protein aggregation is comprehensively understood using the macroscopic phase diagram, which provides general insights into differentiation of amyloid formation and phase separation from unfolded and folded structures.
淀粉样蛋白-β（1-40）（Aβ）的单体结构的复杂淀粉样聚集尚未被完全理解。在此，我们通过调节其初始结构和溶解度，从宏观角度报告了 Aβ 聚集的微观机制和途径。低溶剂极性诱导的 Aβ 部分螺旋结构加速了细胞毒性 Aβ 淀粉样纤维形成，而主要的螺旋折叠则没有聚集。溶剂极性的变化导致富含β-结构的原纤维或易于聚集的螺旋结构的寡聚物迅速形成。pH 值和盐浓度的调节将寡聚物转化为原纤维，然后进行淀粉样形成。我们通过概念能量图揭示了 Aβ 聚集的多种分子机制，并提出聚集倾向的部分螺旋结构是诱导淀粉样蛋白形成的关键。我们证明，使用宏观相图可以全面理解依赖于上下文的蛋白质聚集，这为区分淀粉样形成和相分离与未折叠和折叠结构提供了一般性的见解。
