Functional and pathological aggregation by prion-like domains

朊病毒样结构域的功能性和病理性聚集

• 批准号: 10552656
• 负责人: Eric D Ross
• 金额: $ 37.54万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10552656
• 关键词: Affect; Amino Acid Sequence; Amyloid; Amyotrophic Lateral Sclerosis; Area; Biological; Cell physiology; Cells; Cellular Stress; Degenerative Disorder; Dementia; Disease; Genome; Human; Link; Mediating; Mutation; Organism; Pathogenicity; Pathologic; Pathology; Physiology; Proteins; Regulation; Role; Work; cell growth regulation; design; frontotemporal lobar dementia amyotrophic lateral sclerosis; insight; prion-like; protein aggregation; yeast prion

PROJECT SUMMARY Hundreds of human proteins contain prion-like domains (PrLDs), defined as domains with compositional similarity to the yeast prion domains. In recent years, a growing number of PrLDs in various organisms have been shown to form functional assemblies that regulate cellular activities. Additionally, mutations in PrLDs have been linked to various degenerative disorders, including amyotrophic lateral sclerosis and frontotemporal dementia. Disease-associated mutations tend to increase the aggregation propensity of the PrLDs. This observation has led to the hypothesis that many PrLDs are designed to mediate dynamic reversible interactions involved in cellular regulation, and that mutations stabilize these interactions, resulting in dysregulation of the underlying cellular processes. Despite the importance of PrLDs in both normal physiology and pathology, numerous basic questions remain about the regulation of functional PrLD aggregation, and the relationship between functional and pathogenic aggregation. My lab has been a leader in efforts to define the sequence basis for aggregation of PrLDs. During the next 5 years, we will build on this work, focusing on three major areas: 1) We will define the sequence determinants of PrLDs that mediate the formation of dynamic functional assemblies. In recent years, my lab and others have made substantial progress in defining how the amino acid sequence of PrLDs affects formation of stable amyloid aggregates, but much less is known about the sequence determinants of the dynamic multi-component assemblies formed by some PrLDs. 2) We will examine the relationship between the dynamic functional assemblies formed by many PrLDs and the more stable aggregates seen in various diseases. 3) We will identify additional PrLDs involved in functional protein assemblies, and explore their mechanism of action. While PrLDs are highly over-represented in eukaryotic genomes, the functions of only a small subset of these PrLDs is known. We have identified two new PrLD- containing proteins involved in regulation of cellular stress responses. Therefore, we will characterize the mechanism of action of these two proteins, and screen for other functional PrLDs. Collectively, these studies will provide insight into the role of PrLDs in biological regulation and disease.

项目摘要 数百种人类蛋白包含prion状域（PRLD），定义为具有成分的域 与酵母菌prion域相似。近年来，各种生物体中越来越多的PRLD已 已显示形成调节细胞活性的功能组件。另外，PRLD中的突变 与各种退化性疾病有关，包括肌萎缩性侧索硬化和额颞 失智。疾病相关的突变倾向于增加PRLD的聚集倾向。这 观察结果导致了以下假设：许多PRLD旨在介导动态可逆 涉及细胞调节的相互作用，该突变稳定了这些相互作用，导致 基础细胞过程的失调。尽管PRLD在两种正常生理学中都很重要 和病理学，关于功能性PRLD聚集的调节以及 功能和致病性聚集之间的关系。我的实验室一直是定义的领导者 PRLD聚集的顺序基础。在接下来的5年中，我们将在这项工作上进行，重点关注三个 主要领域：1）我们将定义介导动态形成的PRLD的序列决定因素 功能组件。近年来，我的实验室和其他人在确定如何定义 PRLD的氨基酸序列会影响稳定的淀粉样蛋白聚集体的形成，但对 某些PRLD形成的动态多组分组件的序列决定因素。 2）我们会的 检查许多PRLD形成的动态功能组件之间的关系，更多 在各种疾病中看到的稳定骨料。 3）我们将确定与功能蛋白有关的其他PRLD 集会，并探索他们的作用机理。 prld在真核方面高度代表 基因组，仅知道这些prld的一小部分的功能。我们已经确定了两个新的prld- 包含参与细胞应激反应调节的蛋白质。因此，我们将表征 这两种蛋白质的作用机理，并筛选其他功能性PRLD。总的来说，这些研究 将洞悉PRLD在生物调节和疾病中的作用。