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Prions, the causative agents of Creutzfeldt-Jacob Disease (CJD) in humans and bovine spongiform encephalopathy (BSE) and scrapie in animals, are principally composed of PrPSc, a

conformational isomer of cellular prion protein (PrPC). The propensity of PrPC to adopt alternative folds suggests that there may be an unusually high proportion of alternative conformations

in dynamic equilibrium with the native state. However, the rates of hydrogen/deuterium exchange demonstrate that the conformation of human PrPC is not abnormally plastic. The stable core of

PrPC has extensive contributions from all three α-helices and shows protection factors equal to the equilibrium constant for the major unfolding transition. A residual, hyper-stable region

is retained upon unfolding, and exchange analysis identifies this as a small nucleus of ~10 residues around the disulfide bond. These results show that the most likely route for the

conversion of PrPC to PrPSc is through a highly unfolded state that retains, at most, only this small nucleus of structure, rather than through a highly organized folding intermediate.

This work was funded by the Wellcome Trust and the Medical Research Council. A.R.C. and J.P.W. are Lister Institute Research Fellows. The Krebs Institute is a BBSRC-funded center.

Laszlo L. P. Hosszu, Nicola J. Baxter, Graham S. Jackson, Jonathan P. Waltho and C. Jeremy Craven: These authors contributed equally to this work.

Department of Neurogenetics, Prion Disease Group, Imperial College School of Medicine at St. Mary's, London, W2 1NY, UK

Laszlo L. P. Hosszu, Nicola J. Baxter, Graham S. Jackson, Aisling Power & Anthony R. Clarke

Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK

Krebs Institute for Biomolecular Research, Dept. of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, S10 2TN, UK

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