title: Copper binding is the governing determinant of prion protein turnover.
abstract: The cellular isoform of the prion protein (PrP(c)) is located at the cell membrane, anchored externally by a glycosylphosphatidylinositol (GPI) anchor. It is a copper (Cu) binding glycoprotein with a rapid basal turnover. Previous studies have shown that exposure of cells to Cu causes internalisation of PrP(c) in vitro. In this study, we show that physiological levels of Cu promote internalisation of PrP(c). Interaction between PrP(c) and Cu was found to be the overriding factor in stimulating the internalisation response with other metals showing no effect. Deletion mutation studies have shown that two domains are essential for copper-induced internalisation to occur. These two domains are the octameric repeat region, encompassing amino acids 51-89, and the palindromic region, amino acids 112-119 with the sequence AGAAAAGA. The decrease in detectable levels of PrP(c) at the cell surface following Cu treatment was found to be the result of rapid internalisation rather than loss into the surrounding environment. These results have implications for both normal metabolism of PrP(c) and the possible mechanism of conversion of PrP(c) to PrP(sc).
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Cathryn L
authors.initials: CL
authors.lastname: Haigh
authors.forename: Kate
authors.initials: K
authors.lastname: Edwards
authors.forename: David R
authors.initials: DR
authors.lastname: Brown
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D003300:Copper / Q000494:pharmacology / Q000502:physiology*; D017931:DNA Primers; D005786:Gene Expression Regulation; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011328:Prions / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D011328:Prions; D003300:Copper