Binding of disease-associated prion protein to plasminogen
Binding of disease-associated prion protein to plasminogen
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DOI：
10.1038/35044100
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发表时间：
2000-11-23
期刊：
影响因子：
64.8
通讯作者：
Aguzzi, A
中科院分区：
文献类型：
--
作者：
Fischer, MB;Roeckl, C;Aguzzi, A
传染性海绵状脑病与PrPSc的积累有关，PrPSc是一种称为PrPC的细胞蛋白的构象异构体。PrPSc被认为是通过将其构象赋予PrPC来复制的（参考文献1），但PrPC和PrPSc之间的构象区分仍然难以捉摸。因为单独的PrPSc沉积不足以引起神经病理学（2），PrPSc可能通过与其他细胞成分相互作用而损害大脑。在这里，我们发现在人类和小鼠血液中的活动，结合PrPSc和朊病毒感染性，但不是PrPC。我们鉴定了纤溶酶原，一种与神经元兴奋性毒性有关的蛋白酶原（3，4），作为PrPSc结合蛋白。如果PrPSc的构象被6 M尿素或胍破坏，则结合被废除。纤溶酶原的分离的赖氨酸结合位点1（Kringles I-III）保留了这种结合活性，并且可以与赖氨酸竞争结合。因此，纤溶酶原是区分正常和病理性朊蛋白的第一个内源性因子。这种意外的属性可以用于诊断目的。
Transmissible spongiform encephalopathies are associated with accumulation of PrPSc, a conformer of a cellular protein called PrPC. PrPSc is thought to replicate by imparting its conformation onto PrPC (ref. 1), yet conformational discrimination between PrPC and PrPSc has remained elusive. Because deposition of PrPSc alone is not enough to cause neuropathology(2), PrPSc probably damages the brain by interacting with other cellular constituents. Here we rnd activities in human and mouse blood which bind PrPSc and prion infectivity, but not PrPC. We identify plasminogen, a pro-protease implicated in neuronal excitotoxicity(3,4), as a PrPSc-binding protein. Binding is abolished if the conformation of PrPSc is disrupted by 6M urea or guanidine. The isolated lysine binding site 1 of plasminogen (kringles I-III) retains this binding activity, and binding can be competed for with lysine. Therefore, plasminogen represents the first endogenous factor discriminating between normal and pathological prion protein. This unexpected property may be exploited for diagnostic purposes.