FIBER DIFFRACTION FROM AMYLOID FILAMENTS

淀粉样蛋白丝的纤维衍射

• 批准号: 8361289
• 负责人: Gerald J Stubbs
• 金额: $ 2.37万
• 依托单位: ILLINOIS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361289
• 关键词: Agreement; Alzheimer' s Disease; Amyloid; Amyloidosis; Biophysics; Bovine Spongiform Encephalopathy; Cessation of life; Crystallography; Data; Disease; Drug Design; Fiber; Filament; Funding; Grant; Methods; Modeling; Molecular Conformation; National Center for Research Resources; Peptides; PrP; PrP amyloid; Preparation; Principal Investigator; Prion Diseases; Prions; Proteins; Reporting; Research; Research Infrastructure; Resources; Source; Specimen; Structure; Time; United States National Institutes of Health; cost; improved; insoluble fiber; protein folding; 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 are formed when proteins change conformation to form insoluble fibers that cause severe damage and death. Amyloidoses include Alzheimer's and prion diseases including BSE ("mad cow disease"). Mammalian prions are formed by the protein PrP. Amyloids share a cross-beta structure, but have resisted characterization by crystallography and NMR. Fiber diffraction offers the best hope for structure determination; improved methods of specimen preparation and synchrotron radiation offer unprecedented opportunities to obtain improved data. Structural studies are needed to answer fundamental protein folding questions and for drug design. We collected data at BioCARS under the BioCAT/BioCARS agreement in October 2009 and August 2010, and at BioCAT in April 2010. We collected data from the fungal prion HET-s (the first good quality fiber diffraction data from infectious HET-s), from a low-pH form, and from fibrils formed under several extreme conditions. These data show that HET-s and other amyloids are far more polymorphic than had been realized, and that the protein can change form over time. This observation has great significance for understanding of amyloids in general, and for the diseases with which they are associated. We collected data from a 21-residue fragment of PrP, described as a model for infectious PrP. A variety of preparations of the Alzheimer's-associated peptide A¿ all appear to yield the same form, not identical to that reported from ssNMR, although it is related.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 当蛋白质改变构象形成不溶纤维时，就会形成淀粉样蛋白，从而导致严重的损伤和死亡。淀粉样变性包括阿尔茨海默氏症和包括疯牛病(疯牛病)在内的普恩病毒疾病。哺乳动物的Prion是由PrP蛋白形成的。淀粉样蛋白具有交叉β结构，但不能通过结晶学和核磁共振进行表征。纤维衍射为结构测定提供了最好的希望；改进的样品制备方法和同步辐射提供了前所未有的机会来获得更好的数据。为了回答基本的蛋白质折叠问题和药物设计，需要进行结构研究。我们在2009年10月和2010年8月根据BioCAT/BioCARS协议在BioCARS收集了数据，并于2010年4月在BioCAT收集了数据。 我们收集的数据来自真菌Pron Het-S(第一个高质量的纤维衍射数据，来自感染性的Het-S)，来自低pH形式，以及在几个极端条件下形成的纤维。这些数据表明，HET-S和其他淀粉样蛋白的多态性比人们所认识的要多得多，而且这种蛋白质可以随着时间的推移而改变形式。这一观察结果对于了解淀粉样蛋白及其相关疾病具有重要意义。 我们收集了PrP的21个残基片段的数据，该片段被描述为感染性PrP的模型。 阿尔茨海默氏症相关多肽A？的各种制剂似乎都产生了相同的形式，尽管与ss核磁共振报告的形式不同，但它们是相关的。