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Cell-free formation of protease-resistant prion protein

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Abstract

THE infectious agent (or 'prion') of the transmissible spongiform encephalopathies (TSEs) such as scrapie resembles a virus in that it replicates in vivo and has distinct strains1, but it was postulated long ago to contain only protein2,3. More recently, PrPSc, a pathogenic, scrapie-associated form of the host-encoded prion protein (PrP), was identified as a possible primary TSE agent protein4–6. PrPSc is defined biochemically by its insolubility and resistance to proteases7 and is derived post-translationally from normal, protease-sensitive PrP (PrPc)8,9. The conversion seems to involve conformational change rather than covalent modification10–13. However, the conversion mechanism and the relationship of PrPSc formation to TSE agent replication remain unclear. Here we report the conversion of PrPc to protease-resistant forms similar to PrPSc in a cell-free system composed of substantially purified constituents. This conversion was selective and required the presence of preexisting PrPSc, providing direct evidence that PrPSc derives from specific PrPc–PrPSc interactions.

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Authors and Affiliations

  1. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA

    David A. Kocisko, Jon H. Come & Peter T. Lansbury

  2. Laboratory of Persistent Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, 59840, USA

    David A. Kocisko, Jon H. Come, Suzette A. Priola, Bruce Chesebro, Gregory J. Raymond & Byron Caughey

Authors
  1. David A. Kocisko
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  2. Jon H. Come
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  3. Suzette A. Priola
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  4. Bruce Chesebro
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  5. Gregory J. Raymond
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  6. Peter T. Lansbury
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  7. Byron Caughey
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Kocisko, D., Come, J., Priola, S. et al. Cell-free formation of protease-resistant prion protein. Nature 370, 471–474 (1994). https://doi.org/10.1038/370471a0

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