A role for intermolecular disulfide bonds in prion diseases?
A role for intermolecular disulfide bonds in prion diseases?
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DOI：
10.1073/pnas.071066598
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发表时间：
2001-03
影响因子：
11.1
通讯作者：
E. Welker;W. Wedemeyer;H. Scheraga
中科院分区：
文献类型：
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作者：
E. Welker;W. Wedemeyer;H. Scheraga
朊病毒疾病中的关键事件似乎是朊病毒蛋白PrP从其正常细胞同种型（PrPC）转化为异常的“羊瘙痒病”同种型（PrPSc）。早期的研究在羊瘙痒病亚型中没有检测到共价修饰，并得出结论，PrPC → PrPSc转化是一种不涉及化学反应的纯构象转变。然而，对现有生化数据的重新检查表明，PrPC → PrPSc转化还涉及PrPC的（唯一）分子内二硫键的共价反应。具体地说，这些数据与感染性朊病毒由通过分子间二硫键连接的PrPSc聚合物组成的假设一致。因此，PrPC → PrPSc转化不仅可能涉及构象转变，还可能涉及这种PrPSc聚合物的末端硫醇盐与PrPC单体的二硫键之间的硫醇/二硫键交换反应。这一假说似乎解释了朊病毒疾病的几个不寻常的特征。
The key event in prion diseases seems to be the conversion of the prion protein PrP from its normal cellular isoform (PrPC) to an aberrant “scrapie” isoform (PrPSc). Earlier studies have detected no covalent modification in the scrapie isoform and have concluded that the PrPC → PrPSc conversion is a purely conformational transition involving no chemical reactions. However, a reexamination of the available biochemical data suggests that the PrPC → PrPSc conversion also involves a covalent reaction of the (sole) intramolecular disulfide bond of PrPC. Specifically, the data are consistent with the hypothesis that infectious prions are composed of PrPSc polymers linked by intermolecular disulfide bonds. Thus, the PrPC → PrPSc conversion may involve not only a conformational transition but also a thiol/disulfide exchange reaction between the terminal thiolate of such a PrPSc polymer and the disulfide bond of a PrPC monomer. This hypothesis seems to account for several unusual features of prion diseases.