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

• DOI: 10.1126/science.283.5409.1935
• Publication Date: 2002-07-27T09:37:46Z
• Authors: G. S. Jackson; L. L. P. Hosszu; A. Power; A. F. Hill; J. Kenney; H. Saibil; C. J. Craven; J. P. Waltho; A. R. Clarke; J. Collinge
• Keywords: 0301 basic medicine; 570; Protein Folding; PrPSc Proteins; Prions; Protein Conformation; Circular Dichroism; Spectrum Analysis; 610; Hydrogen-Ion Concentration; Protein Structure, Secondary; Recombinant Proteins; Protein Structure, Tertiary; Molecular Weight; 03 medical and health sciences; Solubility; Humans; Protein Isoforms; PrPC Proteins; Endopeptidase K; Nuclear Magnetic Resonance, Biomolecular; Oxidation-Reduction

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.