The cellular prion protein binds copper in vivo

David R. Brown, Kefeng Qin, Jochen W. Herms, Axel Madlung, Jean Manson, Robert Strome, Paul E. Fraser, Theo Kruck, Alex von Bohlen, Walter Schulz-Schaeffer, Armin Giese, David Westaway and Hans Kretzschmar ()
Additional contact information
David R. Brown: Georg-August-Universität Göttingen
Kefeng Qin: Centre for Research in Neurodegenerative Diseases, Medical Biophysics, and Physiology, University of Toronto
Jochen W. Herms: Georg-August-Universität Göttingen
Axel Madlung: Georg-August-Universität Göttingen
Jean Manson: Neuropathogenesis Unit
Robert Strome: Centre for Research in Neurodegenerative Diseases, Medical Biophysics, and Physiology, University of Toronto
Paul E. Fraser: Centre for Research in Neurodegenerative Diseases, Medical Biophysics, and Physiology, University of Toronto
Theo Kruck: Centre for Research in Neurodegenerative Diseases, Medical Biophysics, and Physiology, University of Toronto
Alex von Bohlen: Institut für Spektrochemie und angewandte Spektroskopie
Walter Schulz-Schaeffer: Georg-August-Universität Göttingen
Armin Giese: Georg-August-Universität Göttingen
David Westaway: Centre for Research in Neurodegenerative Diseases, Medical Biophysics, and Physiology, University of Toronto
Hans Kretzschmar: Georg-August-Universität Göttingen

Nature, 1997, vol. 390, issue 6661, 684-687

Abstract: 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.

Date: 1997
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DOI: 10.1038/37783

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