Perturbation of the stability of amyloid fibrils through alteration of electrostatic interactions.
Perturbation of the stability of amyloid fibrils through alteration of electrostatic interactions.
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DOI：
10.1016/j.bpj.2011.04.039
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发表时间：
2011-06
影响因子：
3.4
通讯作者：
S. Shammas;T. Knowles;A. Baldwin;C. MacPhee;M. Welland;C. Dobson;Glyn L. Devlin
中科院分区：
文献类型：
--
作者：
S. Shammas;T. Knowles;A. Baldwin;C. MacPhee;M. Welland;C. Dobson;Glyn L. Devlin
蛋白质和肽自组装成聚合淀粉样纤维是一个具有重要意义的过程，从蛋白质错误折叠疾病的理解到新型纳米生物材料的发现。在这项研究中，我们探测在pH 2.0下制备的原纤维的稳定性，并通过操纵原纤维结构内的静电相互作用组成的蛋白质胰岛素。我们证明了强静电排斥足以破坏连接胰岛素分子的氢键交叉β网络，并最终导致原纤维解离。这种解离的程度与考虑多肽链的净全局电荷的胶体模型的预测很好地相关，尽管该过程的动力学受单个氨基酸的电荷状态的调节。我们发现原纤维在其形成条件下是最稳定的。在原纤维保持完整的条件下，交叉-β网络的部分破坏导致其稳定性降低。总之，这些结果支持的论点，淀粉样蛋白的稳定性的主要决定因素源于结构化的核心中的相互作用，并显示如何控制静电相互作用可以用来表征的因素，调节原纤维的稳定性。
The self-assembly of proteins and peptides into polymeric amyloid fibrils is a process that has important implications ranging from the understanding of protein misfolding disorders to the discovery of novel nanobiomaterials. In this study, we probe the stability of fibrils prepared at pH 2.0 and composed of the protein insulin by manipulating electrostatic interactions within the fibril architecture. We demonstrate that strong electrostatic repulsion is sufficient to disrupt the hydrogen-bonded, cross-βnetwork that links insulin molecules and ultimately results in fibril dissociation. The extent of this dissociation correlates well with predictions for colloidal models considering the net global charge of the polypeptide chain, although the kinetics of the process is regulated by the charge state of a single amino acid. We found the fibrils to be maximally stable under their formation conditions. Partial disruption of the cross-βnetwork under conditions where the fibrils remain intact leads to a reduction in their stability. Together, these results support the contention that a major determinant of amyloid stability stems from the interactions in the structured core, and show how the control of electrostatic interactions can be used to characterize the factors that modulate fibril stability.