Prion-related encephalopathies are characterized by cerebral accumulation of a post-translationally modified form of the cellular prion protein (PrP(C)), designated PrP(Sc). Evidence suggests that the conversion from PrP(C) to PrP(Sc) involves changes in the secondary structure leading to an increase in β-sheet content. We have previously shown that a synthetic peptide homologous to residues 106-126 of human PrP, belonging to a predicted α-helical domain, exhibits a β-sheet conformation, forms amyloid-like fibrils, and is neurotoxic in vitro. The present study investigated how different chemicophysical conditions such as pH and ionic strength or a membrane-like environment influenced the secondary structure of this peptide. PrP 106-126 exhibited a predominantly β-sheet structure in 200 mM phosphate buffer, pH 5.0, but a combination of β-sheet and random coil structure in 200 mM phosphate buffer, pH 7.0, or in deionized water. The addition of trifluoro-ethanol (50% final concentration) to solutions of peptide in deionized water induced the appearance of an α-helical secondary structure, but did not modify the β-sheet conformation of the peptide dissolved in 200 mM phosphate buffer, pH 5.0. In the presence of micelles formed by a 5% solution of sodium dodecyl sulfate, PrP 106-126 showed a high content of α- helix. When the peptide was dissolved in 5 mM phosphate buffer, pH 7.4, and incubated with liposomes, it changed from a prevalently random coil structure to a β-sheet conformation. The environment-dependent conformational polymorphism of PrP 106-126 and its marked tendency to form stable β-sheet structures at acidic pH could account for the shift from α-helix to β- sheet associated with the conversion of PrP(C) to PrP(Sc), which occurs most likely in the endosomal-lysosomal compartment.
|Number of pages||4|
|Journal||Journal of Biological Chemistry|
|Publication status||Published - Mar 18 1994|
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