The cellular prion protein binds copper in vivo

Nature. 1997 Dec 18-25;390(6661):684-7. doi: 10.1038/37783.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Cells, Cultured
  • Cerebellum / cytology
  • Cerebellum / metabolism
  • Copper / blood
  • Copper / metabolism*
  • Electrophysiology
  • Humans
  • In Vitro Techniques
  • Kidney / metabolism
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Muscles / metabolism
  • PrPC Proteins / metabolism*
  • Protein Binding
  • Purkinje Cells / metabolism
  • Synapses

Substances

  • PrPC Proteins
  • Copper