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（由适用提供）：prions是几种致命的神经退行性疾病的基础，例如人类中的克鲁特兹菲尔特 - jakob病，牛的疯牛病和绵羊的crap。在酵母中，已经发现王室是几种非孟德尔表型的基础。尽管序列差异差异，但酵母菌pr与人类王室具有相似的特征，包括感染，病毒菌株现象和物种障碍。因此，酵母菌是研究prion疾病机制的出色模型系统。使用酵母菌病毒，包括仅蛋白质假设，构象变异作为prion菌株的基础和 伴侣的参与。知识领域的知识差距是缺乏针对prion纤维的详细高分辨率结构。在该项目中，我们旨在确定在静止和搅动条件下研究的酵母菌蛋白URE2的原纤维结构，这是研究最佳的酵母菌蛋白原之一。已经提出，不同的原纤维结构是不同prion菌株的基础。我们的初步研究表明，URE2原纤维确实在静止和搅动条件下采用了不同的结构。在这两种情况下，URE2原纤维的完整原子结构模型将使洞察力和PRIO传播机理的结构基础。该项目由三个具体目标组成。在AIM 1中，我们将在静止和搅动条件下确定URE2原纤维中的strand和turn/loop区域。在AIM 2中，我们将获得一组静止和搅动的URE2纤维的广泛的沉重距离约束。在AIM 3中，我们将使用实验约束和结构预测程序Rosetta来计算静止和搅动的Ure2纤维的原子水平结构模型。