title: The cellular prion protein binds copper in vivo.
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 disease. 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 PrPC exhibits 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 PrPC gene-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. Prnp0/0 mice 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 PrPC can exist in a Cu-metalloprotein form in vivo.
authors.affiliation: Department of Neuropathology, Georg-August-Universität Göttingen, Germany.
authors.forename: D R
authors.initials: DR
authors.lastname: Brown
authors.forename: K
authors.initials: K
authors.lastname: Qin
authors.forename: J W
authors.initials: JW
authors.lastname: Herms
authors.forename: A
authors.initials: A
authors.lastname: Madlung
authors.forename: J
authors.initials: J
authors.lastname: Manson
authors.forename: R
authors.initials: R
authors.lastname: Strome
authors.forename: P E
authors.initials: PE
authors.lastname: Fraser
authors.forename: T
authors.initials: T
authors.lastname: Kruck
authors.forename: A
authors.initials: A
authors.lastname: von Bohlen
authors.forename: W
authors.initials: W
authors.lastname: Schulz-Schaeffer
authors.forename: A
authors.initials: A
authors.lastname: Giese
authors.forename: D
authors.initials: D
authors.lastname: Westaway
authors.forename: H
authors.initials: H
authors.lastname: Kretzschmar
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D003300:Copper / Q000097:blood / Q000378:metabolism*; D004594:Electrophysiology; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009132:Muscles / Q000378:metabolism; D018621:PrPC Proteins / Q000378:metabolism*; D011485:Protein Binding; D011689:Purkinje Cells / Q000378:metabolism; D013569:Synapses
chemical_list: D018621:PrPC Proteins; D003300:Copper