Full restoration of specific infectivity and strain properties from pure mammalian prion protein
Full restoration of specific infectivity and strain properties from pure mammalian prion protein
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DOI：
10.1371/journal.ppat.1007662
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发表时间：
2019-03-01
期刊：
影响因子：
6.7
通讯作者：
Supattapone, Surachai
中科院分区：
文献类型：
--
作者：
Burke, Cassandra;Walsh, Daniel;Supattapone, Surachai
仅蛋白假说预测传染性哺乳动物朊病毒仅由PrPSc组成，PrPSc是正常朊病毒蛋白PrPC的错误折叠构象。然而，仅含蛋白的PrPSc制剂缺乏显著水平的朊病毒传染性，这导致了另一种假设，即形成感染性朊病毒需要辅因子分子。在这里，我们证明了具有亲本株特性和完全特异性感染性的朊病毒可以在体外从仅蛋白的PrPSc中恢复。修复反应快速、有效，需要大量田鼠PrPC底物、翻译后修饰和辅因子分子。据我们所知，这是第一个在未经适应的情况下从纯PrP恢复传染性哺乳动物朊病毒基本特性的报告。这些发现为朊病毒传染性的统一假设提供了证据，其中仅蛋白PrPSc的全局结构准确地存储了潜在的感染和菌株信息，但辅因子分子控制了一个可逆开关，揭示了生物传染性。朊病毒是一种罕见的传染性病原体，总是导致致命的脑部疾病。与细菌或病毒等传统传染因子不同，朊病毒不具有DNA或RNA等核酸，因此尚不清楚它们如何能够复制并引起感染。一个领先的模型是，朊病毒完全由具有异常形状的特定蛋白质分子组成，该蛋白质分子有能力强迫其他蛋白质分子在自我强化过程中改变成相同的异常形状。尽管这种模式很有吸引力，但还没有人能够仅从纯蛋白质中制造出具有传染性的朊病毒。在这里，我们首次表明，纯蛋白质即使是非传染性的，也可以在潜伏状态下忠实地存储和传递特定的感染信息（菌株特性）。
The protein-only hypothesis predicts that infectious mammalian prions are composed solely of PrPSc, a misfolded conformer of the normal prion protein, PrPC. However, protein-only PrPSc preparations lack significant levels of prion infectivity, leading to the alternative hypothesis that cofactor molecules are required to form infectious prions. Here, we show that prions with parental strain properties and full specific infectivity can be restored from protein-only PrPSc in vitro. The restoration reaction is rapid, potent, and requires bank vole PrPC substrate, post-translational modifications, and cofactor molecules. To our knowledge, this represents the first report in which the essential properties of an infectious mammalian prion have been restored from pure PrP without adaptation. These findings provide evidence for a unified hypothesis of prion infectivity in which the global structure of protein-only PrPSc accurately stores latent infectious and strain information, but cofactor molecules control a reversible switch that unmasks biological infectivity.Author summary Prions are unusual infectious agents that cause invariably fatal brain diseases. Unlike conventional infectious agents such as bacteria or viruses, prions do not possess nucleic acids such as DNA or RNA, and therefore it is not clear how they are able to replicate and cause infection. A leading model is that prions are composed exclusively of a specific protein molecule with an abnormal shape, which has the ability to coerce other protein molecules to change into the same abnormal shape in a self-reinforcing process. Although this model is attractive, no one has ever been able to make potently infectious prions from only pure protein. Here, we show for the first time that pure protein can faithfully store and transmit specific infectious information (strain properties) in a latent state even though it is non-infectious.