The structures of prion protein (PrP)–based mammalian prions have long been elusive. However, cryo-EM has begun to reveal the near-atomic resolution structures of fully infectious ex vivo mammalian prion fibrils as well as relatively innocuous synthetic PrP amyloids. Comparisons of these various types of PrP fibrils are now providing initial clues to structural features that correlate with pathogenicity. As first indicated by electron paramagnetic resonance and solid-state NMR studies of synthetic amyloids, all sufficiently resolved PrP fibrils of any sort (n > 10) have parallel in-register intermolecular β-stack architectures. Cryo-EM has shown that infectious brain-derived prion fibrils of the rodent-adapted 263K and RML scrapie strains have much larger ordered cores than the synthetic fibrils. These bona fide prion strains share major structural motifs, but the conformational details and the overall shape of the fibril cross sections differ markedly. Such motif variations, as well as differences in sequence within the ordered polypeptide cores, likely contribute to strain-dependent templating. When present, N-linked glycans and glycophosphatidylinositol (GPI) anchors project outward from the fibril surface. For the mouse RML strain, these posttranslational modifications have little effect on the core structure. In the GPI-anchored prion structures, a linear array of GPI anchors along the twisting fibril axis appears likely to bind membranes in vivo, and as such, may account for pathognomonic membrane distortions seen in prion diseases. In this review, we focus on these infectious prion structures and their implications regarding prion replication mechanisms, strains, transmission barriers, and molecular pathogenesis.

长期以来，基于朊病毒蛋白 (PrP) 的哺乳动物朊病毒的结构一直难以捉摸。然而，冷冻电镜已经开始揭示完全传染性离体的近原子分辨率结构哺乳动物朊病毒原纤维以及相对无害的合成 PrP 淀粉样蛋白。这些不同类型的 PrP 原纤维的比较现在为与致病性相关的结构特征提供了初步线索。正如电子顺磁共振和合成淀粉样蛋白的固态核磁共振研究首先表明的那样，任何类型（n > 10）的所有充分分辨的 PrP 原纤维都具有平行的注册内分子间 β-堆叠结构。Cryo-EM 表明，适应啮齿动物的 263K 和 RML 痒病菌株的传染性脑源性朊病毒原纤维具有比合成原纤维大得多的有序核心。这些真正的朊病毒菌株共享主要的结构基序，但构象细节和原纤维横截面的整体形状明显不同。这样的主题变化，以及有序多肽核心内的序列差异，可能有助于应变依赖性模板。当存在时，N-连接聚糖和糖磷脂酰肌醇 (GPI) 锚从原纤维表面向外突出。对于小鼠 RML 品系，这些翻译后修饰对核心结构几乎没有影响。在 GPI 锚定的朊病毒结构中，沿扭曲原纤维轴的 GPI 锚线性阵列似乎可能与膜结合在体内，因此，可能是朊病毒疾病中出现的特征性膜变形的原因。在这篇综述中，我们关注这些传染性朊病毒结构及其对朊病毒复制机制、菌株、传播障碍和分子发病机制的影响。