Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes
Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes
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DOI：
10.1073/pnas.0608970103
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发表时间：
2006-12-12
影响因子：
11.1
通讯作者：
Prusiner, Stanley B.
中科院分区：
文献类型：
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作者：
Legname, Giuseppe;Nguyen, Hoang-Oanh B.;Prusiner, Stanley B.
在传代合成朊病毒时，出现了两种分离株，其孵育时间相差近100天。使用构象稳定性测定，我们确定了使50%的致病朊病毒蛋白（PrPSc）分子变性所需的盐酸胍（Gdn-HCl）浓度，表示为[Gdn-HCl]（1/2）值。对于编码较短和较长孵育时间的两种朊病毒分离株，[Gdn-HCl]1/2值分别为2.9和3.7 M，被发现。当孵育时间作为[Gdn-HCl]1/2值的函数作图时，发现线性关系，相关系数为0.93。这些发现表明：（1）不太稳定的朊病毒比稳定的朊病毒复制得更快，（h）PrPSc结构状态的连续性加密了大量的孵育时间表型。我们的数据认为，细胞机器必须存在大量的不同的PrPSc构象，其中每一个加密一个独特的生物表型，反映了一个特定的孵育时间繁殖。PrPSc前所未有的可塑性的生物物理解释仍有待确定。
On passaging synthetic prions, two isolates emerged with incubation times differing by nearly 100 days. Using conformational-stability assays, we determined the guanidine hydrochloride (Gdn-HCI) concentration required to denature 50% of disease-causing prion protein (PrPSc) molecules, denoted as the [Gdn-HCI](1/2) value. For the two prion isolates enciphering shorter and longer incubation times, [Gdn-HCI]1/2 values of 2.9 and 3.7 M, respectively, were found. intrigued by this result, we measured the conformational stabilities of 30 prion isolates from synthetic and naturally occurring sources that had been passaged in mice. When the incubation times were plotted as a function of the [Gdn-HCI]1/2 values, a linear relationship was found with a correlation coefficient of 0.93. These findings demonstrate that (1) less stable prions replicate more rapidly than do stable prions, and (h) a continuum of PrPSc structural states enciphers a multitude of incubation-time phenotypes. Our data argue that cellular machinery must exist for propagating a large number of different PrPSc conformers, each of which enciphers a distinct biological phenotype as reflected by a specific incubation time. The biophysical explanation for the unprecedented plasticity of PrPSc remains to be determined.