Several lines of evidence have suggested that copper ions play a role in the biology of both PrPc and PrPSc, the normal and pathologic forms of the prion protein. To further investigate this intriguing connection, we have analyzed how copper ions affect the biochemical properties of PrPc extracted from the brains of transgenic mice and from transfected cells. We report that the metal rapidly and reversibly induces PrPc to become protease-resistant and detergent-insoluble. Although these two properties are commonly associated with PrPSc, we demonstrate using a conformation-dependent immunoassay that copper-treated PrP is structurally distinct from PrPSc. The effect of copper requires the presence of at least one of the five octapeptide repeats normally present in the N-terminal half of the protein, consistent with the idea that the metal alters the biochemical properties of PrP by directly binding to this region. These results suggest potential roles for copper in prion diseases, as well as in the physiological function of PrPC.
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