Protein aggregation in a variable environment

蛋白质执行生命的工作。这些线性聚合物中的大多数必须折叠成特定的形式才能发挥作用。然而，在极端温度等压力条件下，正确折叠的蛋白质可能会展开，从而失去它们的功能。然后，它们也可以错误折叠，导致替代的非功能形式。物种已经进化出各种方法来防止蛋白质展开，并在蛋白质展开时进行补救。北温带海洋中的许多物种经受住了挑战稳定蛋白质折叠的温度。因此，这些物种是研究允许保持折叠的功能蛋白的适应的理想选择。人们对细胞内蛋白质折叠的保存有很多了解；最近，正确折叠的蛋白质的可逆聚集被发现在热应激期间是适应的[10]。然而，在细胞外环境中保护功能性折叠蛋白的适应，特别是在血浆中的适应，还没有被很好地理解。因此，这项拟议的研究旨在使用互补策略来检查北方鱼类冬季比目鱼的细胞外适应。在一种方法中，将在血浆蛋白质中研究折叠保存，以确定可逆的天然蛋白质聚集和可能改变折叠的小分子(化学伴侣)对蛋白质的陪伴。在另一种方法中，将使用螺旋血浆抗冻蛋白(AFP)来研究折叠失败的机制。由于特定的冰结合，AFP可以从其功能螺旋结构转换为错误折叠的聚集体，称为淀粉样蛋白。冰结合在这一过渡中的作用将得到界定。此外，AFP的淀粉样蛋白将被用作内源性模板，用于交叉播种其他血浆蛋白中的异常折叠。我们还将研究天然化学伴侣对这些过程的影响。综上所述，这些结果将表明，在什么条件下，冬季比目鱼血浆蛋白以及支持或反对折叠的小分子可以维持正常折叠。这些发现对于理解冬季比目鱼和其他物种可能在我们变暖的沿海环境中生存的机制至关重要。此外，由于蛋白平衡被打乱，淀粉样蛋白在帕金森氏症和阿尔茨海默氏症等疾病中积聚，这些结果也可能在预防某些形式的人类神经退化方面得到应用。

Proteins carry out the work of life. Most of these linear polymers must fold into specific forms in order to function. However, under stressful conditions such as temperature extremes, properly folded proteins can unfold and thereby lose their functionality. They can also then misfold, resulting in alternative non-functional forms. Species have evolved various means of preventing protein unfolding and of remedying it when it occurs. Many species in our north temperate oceans withstand temperatures that challenge stable protein folding. Therefore, these species are ideal for the study of adaptations that allow maintenance of folded, functional proteins. There is a great deal known about protein fold preservation within cells; most recently, reversible aggregation of correctly folded proteins was found to be adaptive during heat stress [10]. However, the adaptations that protect functional folded proteins in the extracellular milieu, and specifically in blood plasma, are not as well understood. Therefore, the proposed research aims to examine extracellular adaptations in a northern fish species, the winter flounder, using complementary strategies. In one approach, fold preservation will be studied in blood plasma proteins in order to identify reversible native protein aggregation and protein chaperoning by small molecules (chemical chaperones) that may alter folding. In the other approach, mechanisms of folding failure will be examined using a helical plasma antifreeze protein (AFP). As a result of specific ice binding, the AFP can convert from its functional helical structure to a misfolded aggregate referred to as amyloid. The role of ice binding in this transition will be defined. In addition, the amyloid form of AFP will be used as an endogenous template for cross-seeding of aberrant folding in other plasma proteins. The effects of natural chemical chaperones on these processes will also be examined. Together, these results will indicate the conditions under which normal folding can be maintained in winter flounder plasma proteins, along with small molecules that favour or counter it. These findings will be critical to the understanding of mechanisms by which winter flounder and other species might survive in our warming coastal environments. Furthermore, since proteostasis is disrupted and amyloids accumulate in diseases such as Parkinson’s and Alzheimer’s, these results may also find application in the prevention of some forms of human neurodegeneration.