SOLUTION STRUCTURE OF OLIGOMERIC PRION PROTEIN FOLDING INTERMEDIATES

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。次级项目的主要支助 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。 为子项目列出的总成本可能 代表子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 朊病毒是一种感染性蛋白质，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。虽然朊病毒形成大的纤维状聚集体的倾向是众所周知的，但哺乳动物朊病毒的非纤维状组装体已被认为是感染和细胞死亡的重要物种;然而，对其分子结构知之甚少。 较小的PrP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，并确定它们在朊病毒疾病发病机制中的潜在作用。 我们已经确定了样品条件，在该条件下，折叠的叙利亚仓鼠PrP（90-231）（含有与某些人朊病毒病相关的F198 S突变）将形成稳定的β-折叠，该β-折叠含有寡聚体，该寡聚体表现出与所报道的人PrPSc和全长ShaPrP形成的淀粉样原纤维相似的蛋白酶K抗性。BioCAT正在进行的SAXS研究将有助于详细表征在ShaPrP（90-231）-F198 S错误折叠期间形成的富含β折叠的寡聚体的分子结构和动态行为;这些研究将深入了解某些家族性朊病毒疾病病例的分子机制。

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.