Within the extensive range of self-propagating pathologic protein aggregates of mammals, prions are the most clearly infectious (e.g., ∼10⁹ lethal doses per milligram). The structures of such lethal assemblies of PrP molecules have been poorly understood. Here we report a near-atomic core structure of a brain-derived, fully infectious prion (263K strain). Cryo-electron microscopy showed amyloid fibrils assembled with parallel in-register intermolecular β sheets. Each monomer provides one rung of the ordered fibril core, with N-linked glycans and glycolipid anchors projecting outward. Thus, single monomers form the templating surface for incoming monomers at fibril ends, where prion growth occurs. Comparison to another prion strain (aRML) revealed major differences in fibril morphology but, like 263K, an asymmetric fibril cross-section without paired protofilaments. These findings provide structural insights into prion propagation, strains, species barriers, and membrane pathogenesis. This structure also helps frame considerations of factors influencing the relative transmissibility of other pathologic amyloids.

在哺乳动物广泛的自我繁殖病理蛋白聚集体中，朊病毒是最明显的传染性（例如，~ ^{10 9}每毫克致死剂量）。对这种致命的 PrP 分子组装的结构知之甚少。在这里，我们报告了一种脑源性、完全传染性朊病毒（263K 株）的近原子核心结构。冷冻电子显微镜显示淀粉样蛋白原纤维与平行的配准分子间β折叠组装在一起。每个单体提供一个有序的原纤维核心，N-连接聚糖和糖脂锚点向外突出。因此，单个单体在原纤维末端形成模板表面，用于进入单体，在此处发生朊病毒生长。与另一种朊病毒株 (aRML) 的比较揭示了原纤维形态的主要差异，但与 263K 一样，它是一种没有成对原丝的不对称原纤维横截面。这些发现为朊病毒传播、菌株、物种屏障和膜发病机制提供了结构性见解。