Environmental Conditions Affect the Kinetics of Nucleation of Amyloid Fibrils and Determine Their Morphology
Environmental Conditions Affect the Kinetics of Nucleation of Amyloid Fibrils and Determine Their Morphology
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DOI：
10.1016/j.bpj.2010.10.039
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发表时间：
2010-12-01
影响因子：
3.4
通讯作者：
Conejero Lara, Francisco
中科院分区：
文献类型：
--
作者：
Morel, Bertrand;Varela, Lorena;Conejero Lara, Francisco
为了了解和解决淀粉样蛋白相关疾病，研究调节蛋白质淀粉样蛋白形成的因素至关重要。我们以前的研究证明，α血影蛋白SH3（Spc SH3）的N47 A突变体结构域在温和的酸性条件下迅速形成淀粉样原纤维在这里，我们分析了实验条件如何影响组装的动力学和原纤维的最终形态，卷曲原纤维的早期形成发生在蛋白质的相当大的构象变化和伴随的小寡聚体的形成这些过程通过盐浓度和温度的增加以及在较小程度上通过pH的降低而强烈加速。这些事件中的速率限制步骤具有高活化焓，其通过NaCl浓度的增加而显著降低。结果表明，环境变量对蛋白质溶剂化的影响在决定成核动力学、组装途径和最终纤维形态方面是至关重要的
To understand and tackle amyloid related diseases it is crucial to investigate the factors that modulate amyloid formation of proteins Our previous studies proved that the N47A mutant of the alpha spectrin SH3 (Spc SH3) domain forms amyloid fibrils quickly under mildly acidic conditions Here we analyze how experimental conditions influence the kinetics of assembly and the final morphology of the fibrils Early formation of curly fibrils occurs after a considerable conformational change of the protein and the concomitant formation of small oligomers These processes are strongly accelerated by an increase in salt concentration and temperature and to a lesser extent by a reduction in pH The rate limiting step in these events has a high activation enthalpy which is significantly reduced by an increase in NaCl concentration At low to moderate NaCl concentrations the curly fibrils convert to straight and twisted amyloid fibrils after long incubation times but only in the presence of soluble species in the mixture which suggests that the curly fibrils and the twisted amyloid fibrils are diverging assembly pathways The results suggest that the influence of environmental variables on protein solvation is crucial in determining the nucleation kinetics the pathway of assembly, and the final fibril morphology