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Science 19 March 1999:
Vol. 283. no. 5409, pp. 1935 - 1937
DOI: 10.1126/science.283.5409.1935
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Reports

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

G. S. Jackson, 1 L. L. P. Hosszu, 12 A. Power, 1 A. F. Hill, 1 J. Kenney, 3 H. Saibil, 3 C. J. Craven, 2 J. P. Waltho, 2 A. R. Clarke, 14 J. Collinge 1*

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

1 Prion Disease Group, Department of Neurogenetics, Imperial College School of Medicine at St. Mary's, London W2 1NY, UK.
2 Krebs Institute for Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, UK.
3 Department of Crystallography, Birkbeck College, London WC1E 7HX, UK.
4 Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.
*   To whom correspondence should be addressed. E-mail: J.Collinge{at}ic.ac.uk

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