Nature Structural Biology
6, 740 - 743 (1999)
doi:10.1038/11507
Structural mobility of the human prion protein probed by backbone hydrogen
exchangeLaszlo L. P. Hosszu1, 2, 3, Nicola J. Baxter1, 2, Graham S. Jackson1, 2, Aisling Power2, Anthony R. Clarke2, 3, Jonathan P. Waltho4, C. Jeremy Craven4
& John Collinge31
These authors contributed equally to this work. 2
Prion Disease Group, Department of Neurogenetics, Imperial
College School of Medicine at St. Mary's, London, W2
1NY, UK. 3
Department of Biochemistry, School of Medical Sciences,
University of Bristol, Bristol, BS8 1TD,
UK. 4
Krebs Institute for Biomolecular Research, Dept. of
Molecular Biology and Biotechnology, University of Sheffield,
Sheffield S10 2TN, UK.
Correspondence should be addressed to Anthony R. Clarke a.r.clarke@sm.ic.ac.ukPrions, 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  -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.
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