STUDIES OF PRPSC STRUCTURE BY FIBER DIFFRACTION

淀粉样蛋白是一种错误折叠的蛋白质，在结构上与Prion相似，并且包括Prion。淀粉样蛋白与 包括常见的神经退行性疾病在内的40多种不同疾病的病因 阿尔茨海默氏症和帕金森氏症。该项目的长期目标包括对 导致淀粉样蛋白形成和疾病病理的途径，以指导 改进了普里恩病和其他淀粉样变性的治疗和诊断方法。在 由病毒引起的传染性淀粉样变性，病毒蛋白(PrP)折叠成异常构象 PrPSc.在哺乳动物中，传染性病毒粒子仅由PrPSc分子组成。普恩病毒病 包括克雅氏病(CJD)和相关遗传性疾病以及传染性人类 疾病变种CJD和库鲁病。动物病毒病包括牛海绵状脑病(MAD 奶牛疾病“)，绵羊的瘙痒病和鹿的慢性消耗性疾病。我们的研究使用X射线纤维 衍射和各种辅助技术的目的是确定分子的结构。 几种不同的淀粉样蛋白。第一组淀粉样蛋白由非感染性多肽组成 淀粉样蛋白。这些对于结构分析来说更容易处理，并且将作为Pron结构的模型。 这些多肽包括那些与阿尔茨海默氏症、亨廷顿氏症和其他几种疾病有关的多肽。 第二类是由来自蛋白的类淀粉样多肽组成；其中包括55个残基 含有PrP突变P102L的Prion蛋白片段，可引起Gerstmann-Straussler- 舍因克病。第三组包括纯化的N-末端截短和全长PrPSc，它们是 有感染力。这些细胞将从感染瘙痒病的小鼠和仓鼠的大脑中分离出来。结构确定 将需要构建分子模型，并对这些模型进行开发和改进 使用来自X射线纤维折射率的数据。电子显微镜将提供低分辨率的限制 分子模型；在可能的情况下，公布来自X射线结晶学或固体的部分结构信息 国家核磁共振将被纳入其中。已发布的模型，这些模型通常与每个 其他的，将被评估。

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.