STUDIES OF PRPSC STRUCTURE BY FIBER DIFFRACTION

淀粉样蛋白是结构上类似于朊病毒并包括朊病毒的错误折叠蛋白质。淀粉样蛋白与 40多种不同疾病的病因包括常见的神经退行性疾病 阿尔茨海默氏症和帕金森氏症。该项目的长期目标包括： 导致淀粉样蛋白形成和疾病病理学的途径，以指导 朊病毒病和其他淀粉样变性的改进的治疗和诊断方法。在 由朊病毒引起的感染性淀粉样变性，朊病毒蛋白（PrP）折叠成异常构象， PrPSc。在哺乳动物中，感染性朊病毒颗粒仅由PrPSc分子组成。朊病毒病 包括Creutzfeldt-Jakob病（CJD）和相关的遗传性疾病以及传染性人类疾病， 变异型克雅二氏症和库鲁病。动物朊病毒病包括牛海绵状脑病（“mad 牛疾病”）、羊瘙痒病和鹿慢性消耗性疾病。我们的研究使用X射线纤维 衍射和各种互补技术的目的是确定的分子结构， 几种不同的淀粉样蛋白第一组淀粉样蛋白包括来源于非感染性的多肽。 淀粉样蛋白这些对于结构分析更易处理，并且将作为朊病毒结构的模型。 这些多肽包括与阿尔茨海默病、亨廷顿病和几种其它疾病相关的多肽。 第二组由朊病毒衍生的淀粉样蛋白生成肽组成;这些肽包括55个残基， 携带PrP突变P102 L的朊病毒蛋白片段，该突变导致Gerstmann-Straussler- Scheinker病第三组包括纯化的N-末端截短的全长PrPSc， 传染性这些将从羊瘙痒病感染的小鼠和仓鼠大脑中分离出来。结构测定 将需要构建分子模型，并发展和完善这些模型 用的是X射线纤维衍射的数据电子显微镜将提供低分辨率的限制， 分子模型;如果可用，来自X射线晶体学或固体的已发表的部分结构信息 国家NMR将被纳入。发表的模型，这是一般在每个显着的分歧 其他，将进行评估。

Amyloids are misfolded proteins that are structurally similar to and include prions.' Amyloids are implicated in the pathogeneis of more than 40 different diseases including the common neurodegenerative disorders Alzheimer's and Parkinson's diseases. The long-term goals of this project include characterization of the pathways leading to amyloid formation and disease pathology, in order to guide the development of improved therapeutic and diagnostic approaches to the prion diseases and other amyloidoses. In the infectious amyloidoses caused by prions, the prion protein (PrP) folds into aberrant conformation denoted PrPSc. The infectious prion particle is comprised solely of PrPSc molecules in mammals. Prion diseases include Creutzfeldt-Jakob disease (CJD) and related hereditary disorders as well as the infectious human maladies variant CJD and kuru. The animal prion diseases include bovine spongiform encephalopathy ("mad cow disease"), scrapie in sheep and chronic wasting disease in deer. Our studies using X-ray fiber diffraction and a variety of complementary techniques are aimed at determining the molecular structures of several different amyloids. The first group of amyloids comprise peptides derived from non-infectious amyloids. These are more tractable for structural analysis, and will serve as models for prion structure. These polypeptides include those associated with Alzheimer's, Huntington's, and several other diseases. The second group is composed of amyloidogenic peptides derived from prions; these include a 55-residue fragment of the prion protein harboring the PrP mutation P102L that causes Gerstmann-Straussler- Scheinker disease. The third group includes the purified N-terminally truncated and full-length PrPSc that are infectious. These will be isolated from scrapie-infected mouse and hamster brains. Structure determination will require the construction of molecular models, and the development and refinement of these models using data from X-ray fiber difraction. Electron microscopy will provide low-resolution constraints on molecular models; where available, published partial structure information from X-ray crystallography or solid state NMR will be incorporated. Published models, which are generally in marked disagreement with each other, will be evaluated.