Folding of Prion Protein to Its Native α-Helical Conformation Is under Kinetic Control*

The recombinant mouse prion protein (MoPrP) can be folded either to a monomeric α-helical or oligomeric β-sheet-rich isoform. By using circular dichroism spectroscopy and size-exclusion chromatography, we show that the β-rich isoform of MoPrP is thermodynamically more stable than the native α-helical isoform. The conformational transition from the α-helical to β-rich isoform is separated by a large energetic barrier that is associated with unfolding and with a higher order kinetic process related to oligomerization. Under partially denaturing acidic conditions, MoPrP avoids the kinetic trap posed by the α-helical isoform and folds directly to the thermodynamically more stable β-rich isoform. Our data demonstrate that the folding of the prion protein to its native α-helical monomeric conformation is under kinetic control.

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