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Can copper binding to the prion protein generate a misfolded form of the protein?

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Abstract

The native prion protein (PrP) has a two domain structure, with a globular folded α-helical C-terminal domain and a flexible extended N-terminal region. The latter can selectively bind Cu2+ via four His residues in the octarepeat (OR) region, as well as two sites (His96 and His111) outside this region. In the disease state, the folded C-terminal domain of PrP undergoes a conformational change, forming amorphous aggregates high in β-sheet content. Cu2+ bound to the ORs can be redox active and has been shown to induce cleavage within the OR region, a process requiring conserved Trp residues. Using computational modeling, we have observed that electron transfer from Trp residues to copper can be favorable. These models also reveal that an indole-based radical cation or Cu+ can initiate reactions leading to protein backbone cleavage. We have also demonstrated, by molecular dynamics simulations, that Cu2+ binding to the His96 and His111 residues in the remaining PrP N-terminal fragment can induce localized β-sheet structure, allowing us to suggest a potential mechanism for the initiation of β-sheet misfolding in the C-terminal domain by Cu2+.

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Notes

  1. The listed free energies in this section take into account a +20 kJ mol−1 energetic penalty to first exchange a His ligand for H2O from the Cu2+ coordination sphere prior to reduction to Cu+.

Abbreviations

CD:

Circular dichroism

DFT:

Density functional theory

MD:

Molecular dynamics

OR:

Octarepeat

PrP:

Prion protein

PrPC :

Cellular form of the prion protein

PrPSc :

Scrapie isoform of the prion protein

ROS:

Reactive oxygen species

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Acknowledgments

HJV holds a Scientist award from the Alberta Heritage Foundation for Medical Research. This research has been enabled by the use of WestGrid computing resources, which are funded in part by the Canada Foundation for Innovation, Alberta Innovation and Science, BC Advanced Education, and the participating research institutions. Operating support was obtained from the Canadian Genetic Diseases Network and the Alberta Agricultural Research Institute (to FRJ and HJV), as well as the Natural Sciences and Engineering Research Council (to AR). FRJ held a Canada Research Chairs award. MJP was the recipient of a Studentship award from the Alberta Ingenuity Fund.

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Authors and Affiliations

  1. Structural Biology Research Group, Department of Biological Sciences, University of Calgary, Calgary, AB, T2N 4N1, Canada

    M. Jake Pushie & Hans J. Vogel

  2. Department of Chemistry, University of Calgary, Calgary, AB, T2N 4N1, Canada

    Arvi Rauk

  3. Department of Biochemistry and Molecular Biology, The McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, T2N 4N1, Canada

    Frank R. Jirik

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Correspondence to Hans J. Vogel.

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Pushie, M.J., Rauk, A., Jirik, F.R. et al. Can copper binding to the prion protein generate a misfolded form of the protein?. Biometals 22, 159–175 (2009). https://doi.org/10.1007/s10534-008-9196-x

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  • DOI: https://doi.org/10.1007/s10534-008-9196-x

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