Structures and Activities of Prions and Prion Proteins

朊病毒和朊病毒蛋白的结构和活性

• 批准号: 10692033
• 负责人: BYRON CAUGHEY
• 金额: $ 32.92万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10692033
• 关键词: Amyloid; Amyloid Fibrils; Bovine Spongiform Encephalopathy; Brain; Chronic Wasting Disease; Creutzfeldt-Jakob Syndrome; Cryoelectron Microscopy; Disease; Goals; Hamsters; Link; Molecular; Molecular Conformation; Mus; Neurodegenerative Disorders; Pathogenesis; Pathologic; Polysaccharides; Post-Translational Protein Processing; PrP; Prion Diseases; Prions; Reporting; Resolution; Scrapie; Structure; Variant; Work; base; disease transmission; transmission process

Little is known about the structural basis of prion strains. The previous fiscal year we determined the first high-resolution structure of a bona fide brain-derived infectious mammalian prion, the hamster 263K strain. This year we have added a high (3.0 ) resolution cryo-electron microscopy-based structure of a second prion strain, namely the mouse anchorless RML scrapie strain which, like the 263K strain, is an amyloid fibril a parallel in-register intermolecular -sheet (PIRIBS)-based core. Several structural motifs are shared between these ex vivo prion strains, including an amino-proximal steric zipper and three -arches. However, detailed comparisons reveal variations in these shared structural topologies and other features. Unlike 263K and wildtype RML prions, the anchorless RML prions lack glycophosphatidylinositol anchors and are severely deficient in N-linked glycans. Nonetheless, the similarity of our anchorless RML structure to one reported for wildtype RML prion fibrils in a recent preprint indicates that these post-translational modifications do not substantially alter the amyloid core conformation. This work demonstrates both common and divergent structural features of prion strains at the near-atomic level.

关于prion菌株的结构基础知之甚少。上一个财政年度，我们确定了真正的脑部传染性哺乳动物prion的第一个高分辨率结构，即仓鼠263K菌株。今年，我们添加了高（3.0）分辨率的冷冻电子显微镜基于第二个prion菌株的结构，即小鼠无锚rml crapie菌株，与263K菌株一样，它是淀粉样蛋白纤维，这是一种平行的内部分子间 - 分子 - sheet（Piribs）基于基于的核心。这些离体prion菌株之间共享了几个结构基序，包括氨基 - 固定空间拉链和三个架构。但是，详细的比较揭示了这些共享的结构拓扑和其他特征的变化。与263K和WildType RML prions不同，无锚固rml Prions缺乏糖磷脂酰肌醇锚固剂，并且在N连接的聚糖中严重缺乏。但是，在最近的预印刷中，我们的无锚rml结构与野生型RML prion纤维报道的相似性表明，这些翻译后修饰并没有实质性改变淀粉样蛋白核心构象。这项工作表明了近原子水平的prion菌株的常见结构特征和不同的结构特征。