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

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.