DOI: 10.1073/pnas.96.5.2042. Copper binding to the prion protein: Structural implications of four identical cooperative binding sites

Copper binding to the prion protein: Structural implications of four identical cooperative binding sites

10.1073/pnas.96.5.2042

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Evidence is growing to support a functional role for the prion protein (PrP) in copper metabolism. Copper ions appear to bind to the protein in a highly conserved octapeptide repeat region (sequence PHGGGWGQ) near the N terminus. To delineate the site and mode of binding of Cu(II) to the PrP, the copper-binding properties of peptides of varying lengths corresponding to 2-, 3-, and 4-octarepeat sequences have been probed by using various spectroscopic techniques. A two-octarepeat peptide binds a single Cu(II) ion with K d ≈ 6 μM whereas a four-octarepeat peptide cooperatively binds four Cu(II) ions. Circular dichroism spectra indicate a distinctive structuring of the octarepeat region on Cu(II) binding. Visible absorption, visible circular dichroism, and electron spin resonance spectra suggest that the coordination sphere of the copper is identical for 2, 3, or 4 octarepeats, consisting of a square-planar geometry with three nitrogen ligands and one oxygen ligand. Consistent with the pH dependence of Cu(II) binding, proton NMR spectroscopy indicates that the histidine residues in each octarepeat are coordinated to the Cu(II) ion. Our working model for the structure of the complex shows the histidine residues in successive octarepeats bridged between two copper ions, with both the Nɛ2 and Nδ1 imidazole nitrogen of each histidine residue coordinated and the remaining coordination sites occupied by a backbone amide nitrogen and a water molecule. This arrangement accounts for the cooperative nature of complex formation and for the apparent evolutionary requirement for four octarepeats in the PrP.

Bibliography

Viles, J. H., Cohen, F. E., Prusiner, S. B., Goodin, D. B., Wright, P. E., & Dyson, H. J. (1999). Copper binding to the prion protein: Structural implications of four identical cooperative binding sites. Proceedings of the National Academy of Sciences, 96(5), 2042â2047.

Authors 6

John H. Viles (first)
Fred E. Cohen (additional)
Stanley B. Prusiner (additional)
David B. Goodin (additional)
Peter E. Wright (additional)
H. Jane Dyson (additional)

References 34 Referenced 431

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Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:32 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 5:40 p.m.)
Indexed	1 month, 4 weeks ago (July 7, 2025, 1:25 a.m.)
Issued	26 years, 6 months ago (March 2, 1999)
Published	26 years, 6 months ago (March 2, 1999)
Published Online	26 years, 6 months ago (March 2, 1999)
Published Print	26 years, 6 months ago (March 2, 1999)

Funders 0

None

BibTeX

@article{Viles_1999, title={Copper binding to the prion protein: Structural implications of four identical cooperative binding sites}, volume={96}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.96.5.2042}, DOI={10.1073/pnas.96.5.2042}, number={5}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Viles, John H. and Cohen, Fred E. and Prusiner, Stanley B. and Goodin, David B. and Wright, Peter E. and Dyson, H. Jane}, year={1999}, month=mar, pages={2042–2047} }

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  "abstract": "<jats:p>\n            Evidence is growing to support a functional role for the prion protein (PrP) in copper metabolism. Copper ions appear to bind to the protein in a highly conserved octapeptide repeat region (sequence PHGGGWGQ) near the N terminus. To delineate the site and mode of binding of Cu(II) to the PrP, the copper-binding properties of peptides of varying lengths corresponding to 2-, 3-, and 4-octarepeat sequences have been probed by using various spectroscopic techniques. A two-octarepeat peptide binds a single Cu(II) ion with\n            <jats:italic>K</jats:italic>\n            <jats:sub>d</jats:sub>\n            \u2248 6 \u03bcM whereas a four-octarepeat peptide cooperatively binds four Cu(II) ions. Circular dichroism spectra indicate a distinctive structuring of the octarepeat region on Cu(II) binding. Visible absorption, visible circular dichroism, and electron spin resonance spectra suggest that the coordination sphere of the copper is identical for 2, 3, or 4 octarepeats, consisting of a square-planar geometry with three nitrogen ligands and one oxygen ligand. Consistent with the pH dependence of Cu(II) binding, proton NMR spectroscopy indicates that the histidine residues in each octarepeat are coordinated to the Cu(II) ion. Our working model for the structure of the complex shows the histidine residues in successive octarepeats bridged between two copper ions, with both the N\u025b2 and N\u03b41 imidazole nitrogen of each histidine residue coordinated and the remaining coordination sites occupied by a backbone amide nitrogen and a water molecule. This arrangement accounts for the cooperative nature of complex formation and for the apparent evolutionary requirement for four octarepeats in the PrP.\n          </jats:p>",
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