FIBER DIFFRACTION FROM MAMMALIAN PRIONS

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？s病、II型糖尿病、遗传性淀粉样变性和多种朊病毒疾病，包括克雅氏病、疯牛病（？疯牛病？），还有羊瘙痒病哺乳动物朊病毒是由朊病毒蛋白PrP折叠成异常结构而形成的感染性蛋白聚集体。 淀粉样蛋白？根据定义？共享交叉β结构，但结构细节尚不清楚。淀粉样纤维抵抗晶体学和NMR的表征。纤维衍射是一种有效的方法，用于确定丝状组件的结构细节，并结合电子显微镜提供了最好的希望，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，了解淀粉样蛋白形成的过程，以及合理的药物设计。 我们使用非常少量的材料在受控条件下在高磁场中制造定向溶胶和干燥纤维。磁场已被证明有助于淀粉样蛋白定向。人工合成朊病毒开辟了获取材料的新可能性。朊病毒可用性的提高，标本制备方法的改进，以及高强度、高质量的同步加速器辐射，共同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。

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 Alzheimer?s 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 infections protein aggregates formed by the prion protein PrP when it folds into aberrant structures. Amyloids ? by definition ? share a cross-beta structure, but the structural details are not known. Amyloid fibers have resisted characterization by crystallography and NMR. Fiber diffraction is an effective method for determining the structural details of filamentous assemblies, and in combination with electron microscopy 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 the process of amyloid formation, and for rational drug design. We use very small quantities of material to make oriented sols and dried fibers in high magnetic fields under controlled conditions. Magnetic fields have been shown to assist amyloid orientation. Synthetic prions have opened up new possibilities of obtaining material. 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.