Abstract
The normal cellular form of prion protein (PrPC) is a precursor to the pathogenic protease-resistant forms (PrPSc) believed to cause scrapie, bovine spongiform encephalopathy (BSE) and Creutzfeldt–Jakob disease1. Its amino terminus contains the octapeptide PHGGGWGQ, which is repeated four times and is among the best-preserved regions of mammalian PrPC. Here we show that the amino-terminal domain of PrPCexhibits five to six sites that bind copper (Cu(II)) presented as a glycine chelate. At neutral pH, binding occurs with positive cooperativity, with binding affinity compatible with estimates for extracellular, labile copper. Two lines of independently derived PrPCgene-ablated (Prnp0/0) mice exhibit severe reductions in the copper content of membrane-enriched brain extracts and similar reductions in synaptosomal and endosome-enriched subcellular fractions. Prnp0/0mice also have altered cellular phenotypes, including a reduction in the activity of copper/zinc superoxide dismutase and altered electrophysiological responses in the presence of excess copper. These findings indicate that PrPCcan exist in a Cu-metalloprotein form in vivo.
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Acknowledgements
We thank C. Weissmann for providing Prnp0/0 mice; S. Prusiner and R. Race for antisera; H. Kijewski, S. Hampe and E. Jaikaran for assistance; and B. Sarkar, C. Huang and J. Masuoka for discussions. This study was supported by research grants for the University of Toronto Connaught New Staff Fund, the University of Toronto Dean'Fund, and the Alzheimer Association of Ontario to D.W., as well as the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie, the Wilhelm Sander-Stiftung, and the Deutsche Forschungsgemeinschaft to H.K.
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Brown, D., Qin, K., Herms, J. et al. The cellular prion protein binds copper in vivo. Nature 390, 684–687 (1997). https://doi.org/10.1038/37783
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DOI: https://doi.org/10.1038/37783
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