查看文章

The normal cellular form of prion protein (PrP^C) is a precursor to the pathogenic protease-resistant forms (PrP^Sc) 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 PrP^C. Here we show that the amino-terminal domain of PrP^Cexhibits 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 PrP^Cgene-ablated (Prnp^0/0) mice exhibit severe reductions in the copper content of membrane-enriched brain extracts and similar reductions in synaptosomal and endosome-enriched subcellular fractions. Prnp^0/0mice also have altered cellular …