The cellular isoform of prion protein (PrP C ) is a plasma membrane glycoprotein whose conformational conversion into PrP Sc is the central molecular event in the propagation of infectious prions. However, the physiological function of PrP C has remained uncertain. The finding that PrP C binds copper ions with low micromolar affinity, coupled with several other observations, has led to the proposal that the protein plays a role in copper homeostasis. Using biochemical techniques, we had shown previously that copper ions rapidly and reversibly stimulate endocytosis of PrP C from the cell surface. In this report, we employ immunofluorescence microscopy to further investigate the specificity and kinetics of metal effects on PrP C trafficking and to identify the intracellular compartments to which internalized PrP C is delivered in response to copper and zinc. We find that both of these metals stimulate redistribution of surface PrP C to a subset of transferrin-containing early endosomes as well as to Golgi compartments. These results are consistent with models in which PrP C plays a role in the cellular uptake or efflux of transition metals.

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