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 
-helical to 
-sheet structure. Here,
conditions were established in which recombinant human PrP could switch
between the native conformation, characteristic of
PrPC, and a compact, highly soluble, monomeric form rich in
structure. The soluble form (-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 -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
