Insight into freeze resistance and proteostasis from protective proteins and small organic molecules of marine species

从海洋物种的保护性蛋白质和小有机分子深入了解抗冻性和蛋白质稳态

• 批准号: 217438-2011
• 负责人: Ewart, Vanya
• 金额: $ 2.19万
• 依托单位: Dalhousie University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=523793
• 关键词: Insight; into; freeze; resistance; proteostasis

Proteins can become unwound (unfolded) under stressful conditions. Therefore, this proposal aims to understand how species in cold ocean and intertidal environments maintain folded proteins. The focus is on antifreeze proteins, which bind to ice and inhibit its growth, and on chemical chaperones, which are small molecules that promote proper protein folding. The blue mussel antifreeze protein will be purified and characterized. This protein and two antifreeze proteins from winter flounder will then serve as models for the study of protein folding enhancement by chemical chaperones. The antifreeze proteins will be ideal models in this work because they appear to have divergent folding limitations. The chemical chaperones of interest include those that occur naturally in the mussel and a selection of other compounds. Chaperone activity will be evaluated using standard tests for protein folding. Where appropriate, there will be more detailed structural studies on the proteins. This work will provide a novel characterized antifreeze protein from the mussel and insight into the chaperoning molecules in this species. This work will define parameters causing amyloid formation in the short winter flounder antifreeze protein and indicate the possibility of amyloid prevention by chemical chaperones. This work will also show whether the longer, highly active antifreeze protein of winter flounder forms amyloid or non-amyloid aggregates upon denaturation and it will allow us to determine whether the long antifreeze protein can be chaperoned to maintain its fold. Overall, this research will provide greater understanding of amyloid formation and chemical chaperone function. We anticipate the following specific outcomes: (1) enhanced molecular-level understanding of the species that inhabit extreme marine and intertidal environments, (2) biological strategies used by these species that could be applied artificially for the stabilization of tissues, cells or proteins in other contexts, and (3) compounds and processes that could be used to prevent or treat diseases of protein folding (such as several neurological diseases in humans).

蛋白质可以在压力条件下展开(展开)。因此，这项提议旨在了解寒冷海洋和潮间带环境中的物种如何维持折叠蛋白质。重点放在与冰结合并抑制其生长的抗冻蛋白和化学伴侣蛋白上，化学伴侣蛋白是促进蛋白质正确折叠的小分子。蓝色贻贝抗冻蛋白将被提纯和鉴定。然后，这种蛋白质和两种来自冬季比目鱼的抗冻蛋白质将作为研究化学伴侣促进蛋白质折叠的模型。在这项工作中，抗冻蛋白将是理想的模型，因为它们似乎具有不同的折叠限制。感兴趣的化学伴侣包括那些天然存在于贻贝中的化合物和一系列其他化合物。伴侣活性将使用蛋白质折叠的标准测试进行评估。在适当的情况下，将对这些蛋白质进行更详细的结构研究。这项工作将提供一种来自贻贝的新型抗冻蛋白，并深入了解该物种的陪伴分子。这项工作将确定在短冬比目鱼抗冻蛋白中导致淀粉样蛋白形成的参数，并表明化学伴侣预防淀粉样蛋白的可能性。这项工作还将显示更长的、高活性的冬季比目鱼抗冻蛋白在变性后是否形成淀粉样聚集体或非淀粉样聚集体，它将使我们能够确定是否可以伴随长抗冻蛋白以保持其折叠。总体而言，这项研究将提供对淀粉样蛋白形成和化学伴侣功能的更多了解。我们期待以下具体成果：(1)提高对生活在极端海洋和潮间带环境中的物种的分子水平的了解，(2)这些物种所使用的生物策略，这些策略可以被人为地用于稳定其他环境中的组织、细胞或蛋白质，以及(3)可用于预防或治疗蛋白质折叠疾病(如人类的几种神经疾病)的化合物和方法。