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，从而失去功能。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防止蛋白质解折叠的方法，并在发生时进行补救。我们北温带海洋中的许多物种都能承受挑战稳定蛋白质折叠的温度。因此，这些物种是研究允许维持折叠功能蛋白质的适应性的理想选择。关于细胞内的蛋白质折叠保存有很多已知的知识;最近，发现正确折叠的蛋白质的可逆聚集在热应激期间是适应性的[10]。然而，在细胞外环境中，特别是在血浆中保护功能性折叠蛋白的适应性还没有得到很好的理解。因此，拟议的研究旨在研究细胞外适应的北方鱼类，冬比目鱼，使用互补策略。在一种方法中，将在血浆蛋白中研究折叠保存，以鉴定可逆的天然蛋白质聚集和可能改变折叠的小分子（化学分子伴侣）的蛋白质伴侣作用。在另一种方法中，将使用螺旋血浆抗冻蛋白（AFP）检查折叠失败的机制。作为特异性冰结合的结果，AFP可以从其功能性螺旋结构转化为被称为淀粉样蛋白的错误折叠聚集体。冰结合在这一转变中的作用将被定义。此外，AFP的淀粉样蛋白形式将被用作在其他血浆蛋白中交叉接种异常折叠的内源性模板。天然化学伴侣对这些过程的影响也将被检查。总之，这些结果将表明在何种条件下，正常折叠可以保持在冬比目鱼血浆蛋白，沿着的小分子，有利于或counterit. These研究结果将是至关重要的机制，冬比目鱼和其他物种可能生存在我们的沿海环境变暖的理解。此外，由于蛋白质稳态被破坏，淀粉样蛋白在帕金森病和阿尔茨海默病等疾病中积累，这些结果也可能用于预防某些形式的人类神经变性。

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.