FIBER DIFFRACTION FROM AMYLOIDS INCLUDING PRIONS

来自包括朊病毒在内的淀粉样蛋白的纤维衍射

• 批准号: 8363695
• 负责人: Gerald J Stubbs
• 金额: $ 0.61万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363695
• 关键词: Alzheimer' s Disease; Amyloid; Amyloid Proteins; Amyloid fibers; Amyloidosis; Bovine Spongiform Encephalopathy; Brain; Cessation of life; Creutzfeldt-Jakob Syndrome; Crystallography; Data; Drug Design; Fiber; Filament; Funding; Grant; Hereditary Amyloidosis; Methods; Modeling; Molecular Conformation; National Center for Research Resources; Nature; Non-Insulin-Dependent Diabetes Mellitus; Preparation; Principal Investigator; Prion Diseases; Prions; Proteins; Recombinants; Research; Research Infrastructure; Resources; Scrapie; Source; Specimen; Structure; United States National Institutes of Health; amyloid formation; amyloid peptide; amyloid structure; cost; improved; protein aggregate; protein folding; structural biology; synchrotron radiation; yeast prion

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. Amyloid fibers are formed when normally soluble proteins change conformation to form insoluble filaments that can cause severe damage and even death. Amyloidoses include Alzheimers disease type II diabetes hereditary amyloidoses and a variety of prion diseases including Creutzfeldt-Jakob disease BSE (mad cow disease) and scrapie. Mammalian prions are infectious protein aggregates formed by the protein PrP when it folds into aberrant structures. Amyloids are also formed by yeast prion proteins. Amyloid proteins share a cross-beta structure but the structural details are not known. Amyloid fibers cannot be characterized by crystallography or NMR. Fiber diffraction is an effective method for determining the structural details of filamentous assemblies and offers the best hope for elucidating the structures of prions and other amyloids. Structural studies are needed to answer fundamental protein folding questions to understand amyloid formation and for rational drug design. We use very small quantities of material to make dried fibers under controlled conditions. Recombinant prions open up new possibilities of obtaining material but we have shown that there are structural differences between synthetic and brain-derived prions which have yet to be characterized fully. Improved prion availability improved methods of specimen preparation and intense high quality synchrotron radiation together offer an unprecedented opportunity to obtain improved amyloid diffraction data. Data will be obtained from synthetic amyloid peptides from mammalian scrapie-derived prions and from recombinant scrapie-derived prions. Wide-angle and low-angle data will be collected. We have shown that meridional data can determine the nature of the cross-beta structure and equatorial data can be used to describe protofilament structure. The complete diffraction data will be used to evaluate and improve competing models for amyloid structure.

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 子项目的主要研究者可能是由其他来源提供的， 包括其它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。 淀粉样纤维是在正常可溶性蛋白质改变构象形成不溶性细丝时形成的，这些细丝可导致严重损伤甚至死亡。淀粉样变性包括阿尔茨海默病、II型糖尿病、遗传性淀粉样变性和各种朊病毒疾病，包括克雅氏病、疯牛病和羊瘙痒病。哺乳动物朊病毒是由蛋白质PrP折叠成异常结构时形成的感染性蛋白质聚集体。淀粉样蛋白也由酵母朊病毒蛋白形成。 淀粉样蛋白具有交叉β结构，但结构细节尚不清楚。淀粉样纤维不能用晶体学或核磁共振表征。纤维衍射是一种有效的方法来确定丝状组装体的结构细节，并提供了最好的希望，阐明朊病毒和其他淀粉样蛋白的结构。结构研究需要回答基本的蛋白质折叠问题，以了解淀粉样蛋白的形成和合理的药物设计。 我们使用非常少量的材料在受控条件下制造干燥纤维。重组朊病毒开辟了新的可能性，获得材料，但我们已经表明，有合成和脑源性朊病毒之间的结构差异，尚未得到充分的特点。改进的朊病毒可用性、改进的样品制备方法和高质量的同步辐射一起为获得改进的淀粉样蛋白衍射数据提供了前所未有的机会。 数据将从哺乳动物羊瘙痒症衍生朊病毒和重组羊瘙痒症衍生朊病毒的合成淀粉样肽中获得。将收集广角和低角度数据。我们已经表明，赤道数据可以确定的性质的交叉β结构和赤道数据可以用来描述原丝结构。完整的衍射数据将用于评估和改进淀粉样蛋白结构的竞争模型。