Lee Sangho, Eisenberg David
Howard Hughes Medical Institute, Molecular Biology Institute, UCLA-DOE Institute for Genomics and Proteomics and Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095-1570, USA.
Nat Struct Biol. 2003 Sep;10(9):725-30. doi: 10.1038/nsb961. Epub 2003 Aug 3.
The infectious form of prion protein, PrP(Sc), self-propagates by its conversion of the normal, cellular prion protein molecule PrP(C) to another PrP(Sc) molecule. It has not yet been demonstrated that recombinant prion protein can convert prion protein molecules from PrP(C) to PrP(Sc). Here we show that recombinant hamster prion protein is converted to a second form, PrP(RDX), by a redox process in vitro and that this PrP(RDX) form seeds the conversion of other PrP(C) molecules to the PrP(RDX) form. The converted form shows properties of oligomerization and seeded conversion that are characteristic of PrP(Sc). We also find that the oligomerization can be reversed in vitro. X-ray fiber diffraction suggests an amyloid-like structure for the oligomerized prion protein. A domain-swapping model involving intermolecular disulfide bonds can account for the stability and coexistence of two molecular forms of prion protein and the capacity of the second form for self-propagation.
朊病毒蛋白的感染性形式PrP(Sc)，通过将正常的细胞朊病毒蛋白分子PrP(C)转化为另一个PrP(Sc)分子来自我增殖。目前尚未证实重组朊病毒蛋白能将朊病毒蛋白分子从PrP(C)转化为PrP(Sc)。在此我们表明，重组仓鼠朊病毒蛋白在体外通过氧化还原过程转化为第二种形式PrP(RDX)，并且这种PrP(RDX)形式引发其他PrP(C)分子向PrP(RDX)形式的转化。转化后的形式表现出PrP(Sc)特有的寡聚化和引发转化特性。我们还发现寡聚化在体外可以逆转。X射线纤维衍射表明寡聚化的朊病毒蛋白具有类似淀粉样的结构。一个涉及分子间二硫键的结构域交换模型可以解释朊病毒蛋白两种分子形式的稳定性和共存以及第二种形式的自我增殖能力。
