The role of water in the primary nucleation of protein amyloid aggregation
The role of water in the primary nucleation of protein amyloid aggregation
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DOI：
10.1016/j.bpc.2020.106520
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发表时间：
2021-02-01
影响因子：
3.8
通讯作者：
Cremades, Nunilo
中科院分区：
文献类型：
--
作者：
Camino, Jose D.;Gracia, Pablo;Cremades, Nunilo
淀粉样蛋白聚集的复杂构象景观及其相关的物理化学和细胞因子的调制的理解是阐明淀粉样蛋白相关疾病的病理学的一些分子基础，并开发和评估有效的疾病特异性治疗，以减少或消除这些疾病的潜在来源的毒性的先决条件。长期以来，蛋白质与溶剂化水的相互作用被认为是介导其功能和折叠的基础;然而，水在蛋白质淀粉样蛋白聚集过程中的相关性在很大程度上被忽视了。在这里，我们提供了一个角度的作用，水在触发初级淀粉样成核的内在无序蛋白（IDPs）的基础上最近的实验证据。淀粉样蛋白聚集的起始可能是由于蛋白质分子间相互作用和蛋白质表面水化层性质之间的协同效应。虽然疏水性和亲水性IDPs的自组装由于大的水熵贡献而在化学上是有利的，但预计大的去溶剂化能垒，特别是对于亲水性IDPs的成核。在高度水合的条件下，初级成核是缓慢的，通过成核活性表面的存在而促进（异相成核）。然而，在水活性差的条件下，例如在通过液-液相分离产生的蛋白质液滴内部发现的那些条件下，去溶剂化能垒显著降低，并且成核可以在溶液的本体中非常迅速地发生（均质成核），从而产生结构上不同的淀粉样蛋白多晶型物。因此，水在调节淀粉样蛋白成核的跃迁自由能中起关键作用，从而控制该过程的起始，并决定优选的初级成核的类型和所产生的淀粉样蛋白多晶型物的类型，其可以根据蛋白质分子在细胞中遇到的特定微环境而变化。
The understanding of the complex conformational landscape of amyloid aggregation and its modulation by relevant physicochemical and cellular factors is a prerequisite for elucidating some of the molecular basis of pathology in amyloid related diseases, and for developing and evaluating effective disease-specific therapeutics to reduce or eliminate the underlying sources of toxicity in these diseases. Interactions of proteins with solvating water have been long considered to be fundamental in mediating their function and folding; however, the relevance of water in the process of protein amyloid aggregation has been largely overlooked. Here, we provide a perspective on the role water plays in triggering primary amyloid nucleation of intrinsically disordered proteins (IDPs) based on recent experimental evidences. The initiation of amyloid aggregation likely results from the synergistic effect between both protein intermolecular interactions and the properties of the water hydration layer of the protein surface. While the self-assembly of both hydrophobic and hydrophilic IDPs would be thermodynamically favoured due to large water entropy contributions, large desolvation energy barriers are expected, particularly for the nucleation of hydrophilic IDPs. Under highly hydrating conditions, primary nucleation is slow, being facilitated by the presence of nucleation-active surfaces (heterogeneous nucleation). Under conditions of poor water activity, such as those found in the interior of protein droplets generated by liquid-liquid phase separation, however, the desolvation energy barrier is significantly reduced, and nucleation can occur very rapidly in the bulk of the solution (homogeneous nucleation), giving rise to structurally distinct amyloid polymorphs. Water, therefore, plays a key role in modulating the transition free energy of amyloid nucleation, thus governing the initiation of the process, and dictating the type of preferred primary nucleation and the type of amyloid polymorph generated, which could vary depending on the particular micmenvironment that the protein molecules encounter in the cell.