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Strain-specific prion-protein conformation determined by metal ions

Nature Cell Biology volume 1, pages 55–59 (1999)Cite this article

Abstract

In animals infected with a transmissible spongiform encephalopathy, or prion disease, conformational isomers (known as PrPSc proteins) of the wild-type, host-encoded cellular prion protein (PrPC) accumulate. The infectious agents, prions, are composed mainly of these conformational isomers, with distinct prion isolates or strains being associated with different PrPSc conformations and patterns of glycosylation. Here we show that two different human PrPSc types, seen in clinically distinct subtypes of classical Creutzfeldt–Jakob disease, can be interconverted in vitro by altering their metal-ion occupancy. The dependence of PrPSc conformation on the binding of copper and zinc represents a new mechanism for post-translational modification of PrP and for the generation of multiple prion strains, with widespread implications for both the molecular classification and the pathogenesis of prion diseases in humans and animals.

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Figure 1: Western blot of human PrPSc types 1–4 following treatment with protease K, using anti-PrP monoclonal antibody 3F4 for the western blot.
Figure 2: Mean duration of illness for CJD patients with PrPSc types 1 and 2.
Figure 3: Digestion of human PrPSc by proteinase K in the presence of metal chelators.
Figure 4: Both Cu2+ and Zn2+ interact with PrPSc.

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Acknowledgements

This work was funded by the Medical Research Council and Wellcome Trust. We thank R. Will, J. Ironside and colleagues at the National CJD Surveillance Unit for help with this study.

Correspondence and requests for materials should be addressed to J. C.

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Authors and Affiliations

  1. MRC Prion Unit and Department of Neurogenetics, Imperial College School of Medicine at St Mary’s, Norfolk Place, London, W2 1PG, UK

    Jonathan D.F. Wadsworth, Andrew F. Hill, Susan Joiner, Graham S. Jackson, Anthony R. Clarke & John Collinge

  2. Department of Biochemistry, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, UK

    Anthony R. Clarke

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  1. Jonathan D.F. Wadsworth
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Correspondence to John Collinge.

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Wadsworth, J., Hill, A., Joiner, S. et al. Strain-specific prion-protein conformation determined by metal ions. Nat Cell Biol 1, 55–59 (1999). https://doi.org/10.1038/9030

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