NR ASKH
AU Levin,J.; Bertsch,U.; Kretzschmar,H.A.; Giese,A.
TI Single particle analysis of manganese-induced prion protein aggregates
QU Biochemical and Biophysical Research Communications 2005 Apr 22; 329(4): 1200-7
PT journal article
AB Prion diseases are characterized by the conversion of the cellular prion protein (PrPc) to a disease-specific aggregated isoform (PrPsc). We have shown that Mn(2+) ions amplify aggregation, whereas Cu(2+) has an inhibitory effect. To characterize Mn(2+)-induced aggregates, we used cross-correlation analysis as well as scanning for intensely fluorescent targets in an SDS-dependent aggregation assay with fluorescently labeled PrP. We found that the effect of Mn(2+) was mainly due to the association of preformed PrP oligomers to larger aggregates, rapidly reversible by EDTA, and independent of the histidine-dependent copper-binding sites of PrP, suggesting that Mn(2+) induces reversible intermolecular binding. In contrast, the inhibitory effect of Cu(2+) required binding to histidine-containing binding sites, indicating that binding of copper affects the structure of PrPc which in turn modifies the susceptibility to manganese and the ability to aggregate. These findings suggest that copper and manganese may also affect prion propagation in vivo.
MH Binding Sites; Copper/metabolism; Edetic Acid/pharmacology; Humans; Manganese/*pharmacology; Prions/genetics/*metabolism; Protein Binding/drug effects; Protein Denaturation/drug effects; Research Support, Non-U.S. Gov't
AD Zentrum für Neuropathologie und Prionforschung, Ludwig-Maximilians-Universität München, Germany.
SP englisch
PO USA