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Prion (PrPSc)-specific epitope defined by a monoclonal antibody

Abstract

Prions are infectious particles causing transmissible spongiform encephalopathies (TSEs). They consist, at least in part, of an isoform (PrPSc) of the ubiquitous cellular prion protein (PrPC). Conformational differences between PrPCand PrPScare evident from increased β-sheet content and protease resistance in PrPSc(refs 1,2,3). Here we describe a monoclonal antibody, 15B3, that can discriminate between the normal and disease-specific forms of PrP. Such an antibody has been long sought as it should be invaluable for characterizing the infectious particle as well as for diagnosis of TSEs such as bovine spongiform encephalopathy (BSE) or Creutzfeldt–Jakob disease (CJD) in humans. 15B3 specifically precipitates bovine, murine or human PrPSc, but not PrPC, suggesting that it recognizes an epitope common to prions from different species. Using immobilized synthetic peptides, we mapped three polypeptide segments in PrP as the 15B3 epitope. In the NMR structure of recombinant mouse PrP, segments 2 and 3 of the 15B3 epitope are near neighbours in space, and segment 1 is located in a different part of the molecule. We discuss models forthe PrPSc-specific epitope that ensure close spatial proximity of all three 15B3 segments, either by intermolecular contacts in oligomeric forms of the prion protein or by intramolecular rearrangement.

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Figure 1: Immunoprecipitation of bovine, mouse and human PrP with monoclonal antibodies 15B3 and 6H4.
Figure 3: The epitope of the monoclonal antibody 15B3 in the three-dimensional prion protein structure.
Figure 2: Determination of epitopes for mAbs 15B3 and 6H4.

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Acknowledgements

We thank C. Weissmann for discussion and for PrP null mice, and M. Schwab and his group (Brain Research Institute) for support and encouragement at an early stage of this project. This work was supported by grants from the Schweizerische Nationalfonds to B.O. (SPP Biotechnolgie), K.W. and R.G., from the Herman Herzer-Foundation, Basel, to B.O., and a fellowship from the Ciba Foundation to M.M.

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Correspondence to C. Korth.

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Korth, C., Stierli, B., Streit, P. et al. Prion (PrPSc)-specific epitope defined by a monoclonal antibody. Nature 390, 74–77 (1997). https://doi.org/10.1038/36337

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