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Structural mobility of the human prion protein probed by backbone hydrogen exchange

Nature Structural Biology volume 6, pages 740–743 (1999)Cite this article

Abstract

Prions, the causative agents of Creutzfeldt-Jacob Disease (CJD) in humans and bovine spongiform encephalopathy (BSE) and scrapie in animals, are principally composed of PrPSc, a conformational isomer of cellular prion protein (PrPC). The propensity of PrPC to adopt alternative folds suggests that there may be an unusually high proportion of alternative conformations in dynamic equilibrium with the native state. However, the rates of hydrogen/deuterium exchange demonstrate that the conformation of human PrPC is not abnormally plastic. The stable core of PrPC has extensive contributions from all three α-helices and shows protection factors equal to the equilibrium constant for the major unfolding transition. A residual, hyper-stable region is retained upon unfolding, and exchange analysis identifies this as a small nucleus of ~10 residues around the disulfide bond. These results show that the most likely route for the conversion of PrPC to PrPSc is through a highly unfolded state that retains, at most, only this small nucleus of structure, rather than through a highly organized folding intermediate.

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Figure 1: Aromatic CD measured at 290 nm (open triangles), overlaid with amide CD measured at 222 nm (open circles).
Figure 2: Structure and exchange protection in human PrP.
Figure 3: Stereo view of protected amide protons in human PrPC displayed on the backbone conformation of mouse PrPC (ref. 6; moPrP).

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Acknowledgements

This work was funded by the Wellcome Trust and the Medical Research Council. A.R.C. and J.P.W. are Lister Institute Research Fellows. The Krebs Institute is a BBSRC-funded center.

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Author notes

  1. Laszlo L. P. Hosszu, Nicola J. Baxter, Graham S. Jackson, Jonathan P. Waltho and C. Jeremy Craven: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurogenetics, Prion Disease Group, Imperial College School of Medicine at St. Mary's, London, W2 1NY, UK

    Laszlo L. P. Hosszu, Nicola J. Baxter, Graham S. Jackson, Aisling Power & Anthony R. Clarke

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

    Laszlo L. P. Hosszu, Anthony R. Clarke & John Collinge

  3. Krebs Institute for Biomolecular Research, Dept. of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, S10 2TN, UK

    Jonathan P. Waltho & C. Jeremy Craven

Authors
  1. Laszlo L. P. Hosszu
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  2. Nicola J. Baxter
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Correspondence to Anthony R. Clarke.

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Hosszu, L., Baxter, N., Jackson, G. et al. Structural mobility of the human prion protein probed by backbone hydrogen exchange. Nat Struct Mol Biol 6, 740–743 (1999). https://doi.org/10.1038/11507

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