The infectious form of prion protein, PrPSc, self-propagates by its conversion of the normal, cellular prion protein molecule PrPC to another PrPSc molecule. It has not yet been demonstrated that recombinant prion protein can convert prion protein molecules from PrPC to PrPSc. Here we show that recombinant hamster prion protein is converted to a second form, PrPRDX, by a redox process in vitro and that this PrPRDX form seeds the conversion of other PrPC molecules to the PrPRDX form. The converted form shows properties of oligomerization and seeded conversion that are characteristic of PrPSc. 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.
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We thank S.B. Prusiner's laboratory for helping us in fermentation of HisPrP(90–231), M. Gingery for electron microscopy, M.R. Sawaya for building the model of the PrPRDX fibril, R.L. Garrell's laboratory for helping us in g-factor analysis, M. Apostol for assistance and P.D. Boyer, T.E. Creighton and A.K. Chamberlain for critical reading of the manuscript. This work was supported by the Howard Hughes Medical Institute and the US National Institutes of Health.
The authors declare no competing financial interests.
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Lee, S., Eisenberg, D. Seeded conversion of recombinant prion protein to a disulfide-bonded oligomer by a reduction-oxidation process. Nat Struct Mol Biol 10, 725–730 (2003). https://doi.org/10.1038/nsb961
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