SOLUTION STRUCTURE OF OLIGOMERIC PRION PROTEIN FOLDING INTERMEDIATES

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。 Prion是一种具有感染性的蛋白质，它可以采用两种相对稳定的结构，并导致人类的克雅氏病和牛的疯牛病。虽然Pron形成大纤维聚集体的倾向是众所周知的，但哺乳动物Pron的非纤维聚集已被认为是感染和细胞死亡的重要物种；然而，人们对其分子结构知之甚少。PrP较小寡聚体的结构模型将使我们能够更好地了解它们与PrPSc(蛋白质的致病形式)的关系，并确定它们在PrP疾病发病机制中的潜在作用。我们已经确定了折叠的叙利亚仓鼠PrP(90-231)的样本条件，在该条件下，包含与某些人类Pron病相关的F198S突变的折叠的叙利亚仓鼠PrP将形成稳定的包含寡聚体的β-折叠，这些寡聚体表现出与已报道的人类PrPSc和由全长ShaPrP形成的淀粉样纤维类似的对蛋白酶K的抗性。BioCAT正在进行的SAXS研究将有助于详细描述在ShaPrP(90-231)-F198S错误折叠过程中形成的富含β-折叠的寡聚体的分子结构和动态行为；这些研究将为深入了解一些家族性Pron病病例的分子机制提供帮助。

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. Prions are infectious proteins that can adopt two relatively stable structures, and are responsible for Creutzfelt-Jacob disease in humans and BSE ("mad cow") disease in cattle. Although the tendency of prions to form large fibrillar aggregates is well-known, non-fibrillar assemblies of the mammalian prion have been implicated as important species for infection and cell death; however little is known of their molecular structure. A structural model for smaller oligomers of PrP will allow us to better understand their relationship with PrPSc (the pathogenic form of the protein), and to determine their potential role in the pathogenesis of prion diseases. We have identified sample conditions under which folded Syrian hamster PrP(90-231), containing the F198S mutation associated with some cases of human prion disease, will form stable beta-sheet containing oligomers which exhibit proteinase K resistance similar to that reported for human PrPSc and for amyloid fibrils formed by full length ShaPrP. The SAXS studies underway at BioCAT will contribute to a detailed characterization of the molecular structure and dynamic behaviour of beta-sheet rich oligomers formed during the mis-folding of ShaPrP(90-231)-F198S; these studies will provide insight into the molecular mechanisms underlying some cases of familial prion disease.