Structural biology of yeast prions.

酵母朊病毒的结构生物学。

• 批准号: 9057094
• 负责人: Zhefeng Guo
• 金额: $ 29.26万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9057094
• 关键词: Adopted; Affect; Algorithms; Amino Acids; Amyloid Fibrils; Amyloid Proteins; Animals; Biological Models; Bovine Spongiform Encephalopathy; Cattle; Collaborations; Computing Methodologies; Consumption; Creutzfeldt-Jakob Syndrome; Data; Development; Docking; Electron Spin Resonance Spectroscopy; Electrons; Family; Foundations; Frequencies; Goat; Health; Heterogeneity; Human; Infection; Knowledge; Lead; Mammals; Measurement; Measures; Methods; Modeling; Molecular Chaperones; Molecular Conformation; Neurodegenerative Disorders; Phenotype; Positioning Attribute; Prion Diseases; Prions; Proteins; Protocols documentation; Public Health; Research Proposals; Resolution; Scrapie; Sheep; Site; Spin Labels; Structural Models; Structure; Therapeutic; Time; Variant; amyloid structure; base; beef; economic impact; fetal; globular protein; insight; prion hypothesis; prion-based; programs; protein structure prediction; research study; solid state nuclear magnetic resonance; structural biology; tool; yeast prion

DESCRIPTION (provided by applicant): Prions are the basis of several fatal neurodegenerative disorders such as Creutzfeldt-Jakob disease in humans, mad cow disease in cattle, and scrapie in sheep. In yeast, prions have been found to underlie several non-Mendelian phenotypes. Despite differences in sequence, yeast prions share similar features with human prions including infectivity, prion strain phenomenon, and species barrier. Therefore, yeast prions are excellent model systems to study the mechanism of prion diseases. Several key aspects of human prion diseases are unambiguously illustrated using yeast prions, including the protein only hypothesis, conformational variations as the basis of prion strains, and involvement of chaperones. A knowledge gap in the prion field is the lack of detailed high-resolution structures for prion fibrils. In this project, we aim to determine fibril structures of he yeast prion protein Ure2, one of the best studied yeast prions, under quiescent and agitated conditions. It has been proposed that different fibril structures are the basis of different prion strains. Our preliminary studies have shown that Ure2 fibrils indeed adopt different structures under quiescent and agitated conditions. Full- atom structural models of Ure2 fibrils under these two conditions will bring insights into the structural basis of prion strains and mechanism of prio propagation. This project consists of three specific aims. In Aim 1, we will determine the ¿-strand and turn/loop regions in Ure2 fibril under quiescent and agitated conditions. In Aim 2, we will obtain an extensive set of inter-residue distance constraints for quiescent and agitated Ure2 fibrils. In Aim 3, we will use the experimental constraints and structure prediction program Rosetta to calculate atomic- level structure models for quiescent and agitated Ure2 fibrils.

描述（由申请人提供）：朊病毒是几种致命的神经退行性疾病的基础，例如人类的克雅氏病、牛的疯牛病和羊的痒病。在酵母中，朊病毒被发现是几种非孟德尔表型的基础。尽管序列不同，酵母朊病毒与人类朊病毒具有相似的特征，包括感染性、朊病毒菌株现象和物种屏障，因此，酵母朊病毒是研究朊病毒机制的优秀模型系统。使用酵母朊病毒明确地说明了人类朊病毒疾病的几个关键方面，包括仅蛋白质假设、作为朊病毒株基础的构象变异以及 朊病毒领域的一个知识空白是缺乏朊病毒原纤维的详细高分辨率结构。在这个项目中，我们的目标是确定酵母朊病毒蛋白 Ure2 的原纤维结构，这是研究最深入的酵母朊病毒之一。有人提出，不同的原纤维结构是不同朊病毒株的基础，我们的初步研究表明，Ure2 原纤维确实在静止和搅拌条件下采用不同的结构。这两种条件下的 Ure2 原纤维的全原子结构模型将深入了解朊病毒株的结构基础和 prio 传播机制。在目标 1 中，我们将确定 ¿在目标 2 中，我们将获得静态和搅动 Ure2 原纤维中的一组广泛的残基间距离约束。在目标 3 中，我们将使用实验约束和条件。结构预测程序 Rosetta 用于计算静态和搅动的 Ure2 原纤维的原子级结构模型。