The cellular prion protein binds copper in vivo.
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.
Brown
D R
DR
Department of Neuropathology, Georg-August-Universität Göttingen, Germany.
Qin
K
K
Herms
J W
JW
Madlung
A
A
Manson
J
J
Strome
R
R
Fraser
P E
PE
Kruck
T
T
von Bohlen
A
A
Schulz-Schaeffer
W
W
Giese
A
A
Westaway
D
D
Kretzschmar
H
H
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
D018621:PrPC Proteins; D003300:Copper