Document Type




Format of Original

10 p.

Publication Date



American Chemical Society

Source Publication

Journal of the American Chemical Society

Source ISSN


Original Item ID

doi: 10.1021/ja053254z


The prion protein (PrP) binds Cu2+ in its N-terminal octarepeat domain. This unusual domain is comprised of four or more tandem repeats of the fundamental sequence PHGGGWGQ. Previous work from our laboratories demonstrates that at full copper occupancy, each HGGGW segment binds a single Cu2+. However, several recent studies suggest that low copper occupancy favors different coordination modes, possibly involving imidazoles from histidines in adjacent octapeptide segments. This is investigated here using a combination of X-band EPR, S-band EPR, and ESEEM, along with a library of modified peptides designed to favor different coordination interactions. At pH 7.4, three distinct coordination modes are identified. Each mode is fully characterized to reveal a series of copper-dependent octarepeat domain structures. Multiple His coordination is clearly identified at low copper stoichiometry. In addition, EPR detected copper−copper interactions at full occupancy suggest that the octarepeat domain partially collapses, perhaps stabilizing this specific binding mode and facilitating cooperative copper uptake. This work provides the first complete characterization of all dominant copper coordination modes at pH 7.4.


Accepted version. Journal of the American Chemical Society, Vol. 127, No. 36 (September 2005): 12647-12656. DOI. © 2005 American Chemical Society. Used with permission.

Brian Bennett was affiliated with Medical College of Wisconsin at the time of publication.

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