High-resolution structure and strain comparison of infectious mammalian prions
High-resolution structure and strain comparison of infectious mammalian prions
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DOI：
10.1016/j.molcel.2021.08.011
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发表时间：
2021-11-04
期刊：
影响因子：
16
通讯作者：
Caughey, Byron
中科院分区：
文献类型：
--
作者：
Kraus, Allison;Hoyt, Forrest;Caughey, Byron
在哺乳动物的广泛的自繁殖病理性蛋白质聚集体中，朊病毒是最明显的感染性（例如，类似于每毫克10（9）个致命剂量）。这种致命的PrP分子组装体的结构一直知之甚少。在这里，我们报告了一个近原子核心结构的脑源性，完全传染性朊病毒（263 K株）。冷冻电子显微镜显示淀粉样蛋白原纤维与平行对齐的分子间B片组装。每个单体提供有序原纤维核心的一个梯级，N-连接聚糖和糖脂锚向外突出。因此，单个单体在原纤维末端形成进入单体的模板表面，在那里发生朊病毒生长。与另一种朊病毒株（aRML）的比较显示，原纤维形态存在重大差异，但与263 K一样，原纤维横截面不对称，没有成对的原丝。这些发现提供了结构的见解朊病毒的繁殖，菌株，物种的障碍，和膜发病机制。这种结构也有助于框架的考虑因素影响其他病理性淀粉样蛋白的相对传递性。
Within the extensive range of self-propagating pathologic protein aggregates of mammals, prions are the most clearly infectious (e.g., similar to 10(9) 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 b 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.