Protein folding, function and engineering

蛋白质折叠、功能和工程

• 批准号: 184036-2011
• 负责人: Meiering, Elizabeth
• 金额: $ 4.01万
• 依托单位: University of Waterloo
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=569689
• 关键词: Protein; folding; function; engineering

Proteins are the molecular machines of life, performing a huge range of functions, from acting as catalysts, to specifically recognizing and binding other molecules, to structural support roles. The order of amino acids in a protein, i.e. its primary sequence, encodes how the protein folds into its functional "native" structure. Despite extensive study, the mechanisms by which primary sequence determines protein folding and function remain unclear. Understanding these mechanisms is of tremendous importance because, ultimately, such an understanding will give us the ability to rationally predict the behaviour of any protein (such as a misfunctional mutant protein that causes disease). It will also give us the ability to engineer or design proteins for any desired application in biotechnology or medicine. Tremendous recent advances in knowledge of protein sequences and in protein modeling have set the stage for making dramatic advances in understanding how sequence determines folding and function. For example, we used sequence information and modeling successfully to engineer the first completely 3-fold symmetric globular protein, called ThreeFoil, which is extremely stable and has sugar binding functionality. Since many protein engineering attempts fail, sometimes in subtle ways, we now need to analyze ThreeFoil further to fully understand the outcome of our engineering. We also propose to extend our studies on ThreeFoil to related proteins, including other types of natural and designed symmetric proteins. One of these, called Hisactophilin, plays a central role in controlling the movement of cells by its reversible binding to cell membranes and other cytoskeletal proteins in response to pH signals generated by the cell's environment. We are using Hisactophilin as a model to understanding signaling and regulated, reversible binding by proteins. We are also studying the damaging effects of ultrasound on these and other proteins, which is important for many applications of ultrasound for industrial and medical applications. Together, our in depth studies will lead to important new knowledge on how proteins work and how they can be controlled.

蛋白质是生命的分子机器，发挥着广泛的功能，从充当催化剂，到专门识别和结合其他分子，再到结构支持角色。蛋白质中氨基酸的顺序，即其初级序列，编码蛋白质如何折叠成其功能的“天然”结构。尽管进行了广泛的研究，但初级序列决定蛋白质折叠和功能的机制仍然不清楚。了解这些机制非常重要，因为最终，这样的理解将使我们能够合理预测任何蛋白质的行为(例如导致疾病的功能失调的突变蛋白质)。它还将使我们有能力为生物技术或医学中的任何期望的应用设计或设计蛋白质。最近在蛋白质序列知识和蛋白质建模方面的巨大进步为理解序列如何决定折叠和功能奠定了基础。例如，我们成功地利用序列信息和建模设计了第一个完全3倍对称的球状蛋白，称为ThreeFoil，它非常稳定，具有糖结合功能。由于许多蛋白质工程尝试都失败了，有时是以微妙的方式，我们现在需要进一步分析ThreeFoil，以充分了解我们工程的结果。我们还建议将我们对ThreeFoil的研究扩展到相关蛋白质，包括其他类型的天然和设计的对称蛋白质。其中一种被称为Hisactophlin，它通过与细胞膜和其他细胞骨架蛋白的可逆结合来控制细胞的运动，以响应细胞环境产生的pH信号。我们正在使用Hisactophlin作为一个模型来理解信号和蛋白质调节的、可逆的结合。我们还在研究超声波对这些蛋白质和其他蛋白质的破坏作用，这对超声波在工业和医疗应用中的许多应用都很重要。总之，我们的深入研究将带来关于蛋白质如何工作以及如何控制它们的重要新知识。