Letter | Published:

Binding of disease-associated prion protein to plasminogen

Nature volume 408, pages 479483 (23 November 2000) | Download Citation

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Abstract

Transmissible spongiform encephalopathies are associated with accumulation of PrPSc, a conformer of a cellular protein called PrP C. PrPSc is thought to replicate by imparting its conformation onto PrPC (ref. 1), yet conformational discrimination between PrPC and PrPSc has remained elusive. Because deposition of PrPSc alone is not enough to cause neuropathology2, PrPSc probably damages the brain by interacting with other cellular constituents. Here we find activities in human and mouse blood which bind PrPSc and prion infectivity, but not PrPC. We identify plasminogen, a pro-protease implicated in neuronal excitotoxicity3,4, as a PrPSc-binding protein. Binding is abolished if the conformation of PrPSc is disrupted by 6M urea or guanidine. The isolated lysine binding site 1 of plasminogen (kringles I–III) retains this binding activity, and binding can be competed for with lysine. Therefore, plasminogen represents the first endogenous factor discriminating between normal and pathological prion protein. This unexpected property may be exploited for diagnostic purposes.

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Acknowledgements

We are grateful to D. Voelkel for providing fractionated human plasma, to P. Sonderegger, C. Weissmann, T. Lührs, and W. Schaffner for critical advice, and to M. Maissen and R. Hardegger for experimental help. This study was supported by grants from the European Union (Bundesamt für Bildung und Wissenschaft), the Swiss National Research Programs to A.A. and by a grant-in-aid of the SigmaXi foundation to M.B.F.

Author information

Author notes

    • Michael B. Fischer
    •  & Christiane Roeckl

    These authors contributed equally to this study.

Affiliations

  1. *Institute for Neuropathology, University Hospital of Zurich, CH-8091 Zürich, Switzerland

    • Michael B. Fischer
    • , Christiane Roeckl
    • , Petra Parizek
    •  & Adriano Aguzzi
  2. ‡Baxter Hyland Immuno, Industriestrasse 67, A-1221 Vienna, Austria

    • Hans Peter Schwarz

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Correspondence to Adriano Aguzzi.

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DOI

https://doi.org/10.1038/35044100

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