Reversible Conversion of Monomeric Human Prion Protein Between Native and Fibrilogenic Conformations

Abstract

Prion propagation involves the conversion of cellular prion protein (PrP^C) into a disease-specific isomer, PrP^Sc, shifting from a predominantly α-helical to β-sheet structure. Here, conditions were established in which recombinant human PrP could switch between the native α conformation, characteristic of PrP^C, and a compact, highly soluble, monomeric form rich in β structure. The soluble β form (β-PrP) exhibited partial resistance to proteinase K digestion, characteristic of PrP^Sc, and was a direct precursor of fibrillar structures closely similar to those isolated from diseased brains. The conversion of PrP^C to β-PrP in suitable cellular compartments, and its subsequent stabilization by intermolecular association, provide a molecular mechanism for prion propagation.