Examining how functional protein aggregates evade protein quality control degradation systems

蛋白质的聚集（或结块）通常对细胞有害，因此细胞含有精心设计的防止蛋白质聚集的机制。然而，某些蛋白质已经进化形成功能蛋白聚集体，用于调节各种细胞活动。该项目将研究功能性蛋白质聚集体如何逃避蛋白质质量控制系统的设计，以降解聚集倾向的蛋白质。这些研究将提供对蛋白质进化的深入了解，并将为蛋白质设计提供工具。这项实验工作将与教育机会相结合。本项目的部分研究将在本科实验课程的背景下进行，该课程的设计是独立研究和传统实验课程的混合体。与单独的独立项目相比，课堂的结构化环境将允许培养更多的学生，从而扩大本科生的研究机会。此外，PI将继续他的生物化学基础推广计划。本课程通过动手生物化学和基因实验，向小学生介绍生物化学和遗传学的科学方法和领域。实验工作将利用酵母朊蛋白作为模型系统。酵母朊病毒是由蛋白质从可溶形式转化为不可溶聚集形式的结构转化而产生的。这些朊病毒可以稳定地从母细胞传递到子细胞，从而使朊病毒成为基于蛋白质的遗传元件。该项目建立在令人兴奋的初步结果的基础上，表明氨基酸序列的细微变化可以显著改变蛋白质聚集和降解之间的平衡。利用该实验系统，研究人员将定量定义允许某些蛋白质聚集体逃避细胞抗聚集机制的氨基酸序列特征，并探索这些蛋白质逃避降解的机制。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Aggregation (or clumping) of proteins is generally harmful to cells, so cells contain elaborate machinery designed to prevent protein aggregation. However, certain proteins have evolved to form functional protein aggregates that are used to regulate various cellular activities. This project will examine how functional protein aggregates evade the protein quality control systems designed to degrade aggregation-prone proteins. These studies will offer insight into protein evolution, and will provide tools for protein design. This experimental work will be integrated with educational opportunities. Some of the research in this project will be conducted in the context of an undergraduate laboratory course, which is designed as a hybrid of independent research and traditional laboratory classes. The structured environment of the class will allow for training of many more students than would be possible with separate independent projects, thereby expanding undergraduate research opportunities. Additionally, the PI will continue his Biochemistry is Elementary outreach program. This program uses hands-on biochemistry and genetic experiments to introduce elementary school students to the scientific method and the fields of biochemistry and genetics. The experimental work will utilize yeast prion proteins as a model system. Yeast prions result from the structural conversion of proteins from a soluble form into an insoluble aggregated form. These prions can be stably passed from mother to daughter cells, allowing the prions to act as protein-based genetic elements. This project builds on exciting preliminary results demonstrating that subtle changes in amino acid sequence can dramatically change the balance between protein aggregation and degradation. Using this experimental system, the researchers will quantitatively define the amino acid sequence features that allow certain protein aggregates to evade the cellular anti-aggregation machinery, and explore the mechanism by which these proteins evade degradation.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.