NR ABTB
AU Brown,D.R.; Qin,K.; Herms,J.W.; Madlung,A.; Manson,J.; Strome,R.; Fraser,P.E.; Kruck,T.; von Bohlen,A.; Schulz-Schaeffer,W.J.; Giese,A.; Westaway,D.; Kretzschmar,H.A.
TI The cellular prion protein binds copper in vivo
QU Nature 1997 Dec 18-25; 390(6661): 684-7
PT journal article
AB 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.
MH Animal; Brain/metabolism; Cells, Cultured; Cerebellum/cytology/metabolism; Copper/blood/*metabolism; Electrophysiology; Human; In Vitro; Kidney/metabolism; Liver/metabolism; Mice; Mice, Inbred C57BL; Muscles/metabolism; PrPc Proteins/*metabolism; Protein Binding; Purkinje Cells/metabolism; Support, Non-U.S. Gov't; Synapses
AD Department of Neuropathology, Georg-August-Universität Göttingen, Germany.
SP englisch
PO England