FIBER DIFFRACTION FROM PRIONS, OTHER AMYLOIDS, AND FILAMENTOUS VIRUSES

朊病毒、其他淀粉样蛋白和丝状病毒的纤维衍射

• 批准号: 8362390
• 负责人: Gerald J Stubbs
• 金额: $ 0.03万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362390
• 关键词: Agriculture; Alzheimer' s Disease; Amyloid; Amyloid fibers; Amyloidosis; Biological; Biotechnology; Bovine Spongiform Encephalopathy; Brain; Cessation of life; Creutzfeldt-Jakob Syndrome; Cryoelectron Microscopy; Crystallography; Data; Disease; Drug Design; Electron Microscopy; Fiber; Filament; Funding; Grant; Methods; Modeling; Molecular Conformation; Molecular Structure; National Center for Research Resources; Parkinson Disease; Plant Viruses; PrP amyloid; Preparation; Principal Investigator; Prion Diseases; Prions; Proteins; Publishing; Radiation; Recombinant Proteins; Research; Research Infrastructure; Resources; Source; Specimen; Structure; Synchrotrons; United States National Institutes of Health; Virus; amyloid formation; amyloid structure; cost; food security; improved; pathogen; protein folding; recombinant PrP; solid state nuclear magnetic resonance; structural biology; synchrotron radiation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Amyloids and filamentous viruses are filamentous biological assemblies, not suited to structural analysis by crystallography or NMR, but well suited to fiber diffraction. Amyloid fibers are formed when proteins change conformation to form insoluble filaments that can cause severe damage and even death. Amyloidoses include Alzheimer?s and Parkinson?s diseases and a variety of prion diseases including Creutzfeldt-Jakob disease and BSE (?mad cow disease?). Mammalian prions are infectious aggregates formed by the aberrantly folded protein PrP. Amyloids share a cross-beta structure, but structural details are not known. Fiber diffraction with electron microscopy, solid state NMR, and other approaches offers the best hope for elucidating structures of amyloids including prions. Structural studies are needed to answer fundamental protein folding questions, to understand amyloid formation, and for rational drug design. Synthetic prions derived from infectious recombinant protein have opened up new possibilities. Improved prion availability, improved methods of specimen preparation, and intense, high quality synchrotron radiation offer unprecedented opportunities to obtain amyloid diffraction data. Filamentous plant viruses are of enormous importance to agriculture, biotechnology and food security, but little is known about their molecular structures. Our structures from synchrotron diffraction data with cryo-electron microscopy are the only published structure determinations for these important pathogens. We use very small quantities of material to make dried fibers under controlled conditions. Fiber diffraction data will be obtained from brain-derived mammalian prions, from prion strains derived from infectious recombinant PrP, from the fungal prion HET-s, from the Alzheimer?s amyloid alpha/beta and other amyloids, and from filamentous plant viruses. The data will be used to evaluate and improve competing models for amyloid structure, and to determine filamentous virus structures.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 淀粉样蛋白和丝状病毒是丝状生物组装体，不适合通过晶体学或NMR进行结构分析，但非常适合纤维衍射。当蛋白质改变构象形成不溶性细丝时，就会形成淀粉样纤维，这些细丝会导致严重的损伤甚至死亡。淀粉样变性包括阿尔茨海默病？s和帕金森？s疾病和各种朊病毒疾病，包括克雅氏病和疯牛病（？疯牛病？哺乳动物朊病毒是由异常折叠的PrP蛋白形成的感染性聚集体。淀粉样蛋白具有交叉β结构，但结构细节尚不清楚。纤维衍射与电子显微镜，固态核磁共振，和其他方法提供了最好的希望，阐明淀粉样蛋白，包括朊病毒的结构。结构研究需要回答基本的蛋白质折叠问题，了解淀粉样蛋白的形成，并为合理的药物设计。由传染性重组蛋白衍生的合成朊病毒开辟了新的可能性。朊病毒可用性的提高，标本制备方法的改进，以及高强度、高质量的同步辐射，为获得淀粉样蛋白衍射数据提供了前所未有的机会。 丝状植物病毒对农业、生物技术和粮食安全具有巨大的重要性，但对其分子结构知之甚少。我们的结构从同步辐射衍射数据与冷冻电子显微镜是唯一公布的结构确定这些重要的病原体。我们使用非常少量的材料在受控条件下制造干燥纤维。纤维衍射数据将从脑源性哺乳动物朊病毒，从感染性重组PrP衍生的朊病毒株，从真菌朊病毒HET-S，从阿尔茨海默病？s淀粉样蛋白α/β和其他淀粉样蛋白，以及来自丝状植物病毒。这些数据将用于评估和改进淀粉样蛋白结构的竞争模型，并确定丝状病毒结构。