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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References
Pan, K. M. et al. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc. Natl Acad. Sci. USA 90, 10962–10966 (1993).
McKinley, M. P., Bolton, D. C. & Prusiner, S. B. Aprotease-resistant protein is a structural component of the scrapie prion. Cell 35, 57–62 (1983).
Oesch, B. et al. Acellular gene encodes scrapie PrP 27–30 protein. Cell 40, 735–746 (1985).
Daude, N., Lehmann, S. & Harris, D. A. Identification of intermediate steps in the conversion of a mutant prion protein to a scrapie-like form in cultured cells. J. Biol. Chem. 272, 11604–11612 (1997).
Fischer, M. et al. Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO J. 15, 1255–1264 (1996).
Mehlhorn, I. et al. High-level expression and characterization of a purified 142-residue polypeptide of the prion protein. Biochemistry 35, 5528–5537 (1996).
Weiss, S., Rieger, R., Edenhofer, F., Fisch, E. & Winnacker, E. L. Recombinant prion protein rPrP27-30 from Syrian golden hamster reveals proteinase K sensitivity. Biochem. Biophys. Res. Commun. 219, 173–179 (1996).
Kaneko, K. et al. Molecular properties of complexes formed between the prion protein and synthetic peptides. J. Mol. Biol. 270, 574–586 (1997).
Lansbury, P. T. & Caughey, B. The chemistry of scrapie infection: implications of the ‘ice 9’ metaphor. Chem. Biol. 2, 1–5 (1995).
Parchi, P. et al. Molecular basis of phenotypic variability in sporadic Creutzfeldt–Jakob disease. Ann. Neurol. 39, 767–778 (1996).
Schätzl, H. M., Da Costa, M., Taylor, L., Cohen, F. E. & Prusiner, S. B. Prion protein gene variation among primates. J. Mol. Biol. 245, 362–374 (1995).
Riek, R. et al. NMR structure of the mouse prion protein domain PrP(121–231). Nature 382, 180–182 (1996).
Glockshuber, R. et al. Three-dimensional NMR structure of a self-folding domain of the prion protein PrP (121–231). Trends Biochem. Sci. 22, 241–242 (1997).
Telling, G. C. et al. Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell 83, 79–900 (1995).
Billeter, M. et al. Prion protein NMR structure and species barrier for prion diseases. Proc. Natl Acad. Sci. USA 84, 7281–7285 (1997).
Warwicker, J. & Gane, P. J. Amodel for prion protein dimersization based on alpha-helical packing. Biochem. Biophys. Res. Commun. 226, 777–782 (1996).
Padian, E. A. & Love, W. E. Refined crystal structure of deoxyhemoglobin S. II. Molecular interactions in the crystal. J. Biol. Chem. 260, 8280–8291 (1985).
Huang, Z., Prusiner, S. B. & Cohen, F. E. Scrapie prions: a three-dimensional model of an infectious fragment. Fold. Design 1, 13–19 (1996).
Kitamoto, T., Mohri, S. & Tateishi, J. Organ distribution of proteinase-resistant prion protein in humans and mice with Creutzfeldt–Jakob disease. J. Gen. Virol. 70, 3371–3379 (1989).
Chandler, R. L. Encephalopathy in mice produced by inoculation with scrapie brain material. Lancet i, 1378–1379 (1961).
Goldmann, W., Hunter, N., Martin, T., Dawson, M. & Hope, J. Different forms of the bovine PrP gene have five or six copies of a short, G-C-rich element within the protein-coding exon. J. Gen. Virol. 72, 201–204 (1991).
Bueler, H. et al. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356, 577–582 (1992).
Kennett, R. H. Monoclonal Antibodies. Hybridomas: A New Dimension in Biological Analysis (eds Kennett, R. H., McKearn, T. J. &Bechtol, K. B.) 365–367 (Plenum, New York, (1980)).
Oesch, B., Jensen, M., Nilsson, P. & Fogh, J. Properties of the scrapie prion protein: quantitative analysis of protease resistance. Biochemistry 33, 5926–5931 (1994).
Priola, S. A., Caughey, B., Wehrly, K. & Chesebro, B. A60-kDa prion protein (PrP) with properties of both the normal and scrapie-associated forms of PrP. J. Biol. Chem. 270, 3299–3305 (1995).
Riek, R., Hornemann, S., Wider, G., Glockshuber, R. & Wüthrich, K. NMR characterization of the full-length recombinant murine prion protein, m PrP(23–231). FEBS Lett. 413, 282–288 (1997).
Koradi, R., Billeter, M. & Wüthrich, K. MOLMOL: a program for display and analysis of macromolecular structures. J. Mol. Graph. 14, 51–55 (1996).
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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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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DOI: https://doi.org/10.1038/36337