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 alpha -helical or oligomeric beta -sheet-rich isoform. By using circular dichroism spectroscopy and size-exclusion chromatography, we show that the beta -rich isoform of MoPrP is thermodynamically more stable than the native alpha -helical isoform. The conformational transition from the alpha -helical to beta -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 alpha -helical isoform and folds directly to the thermodynamically more stable beta -rich isoform. Our data demonstrate that the folding of the prion protein to its native alpha -helical monomeric conformation is under kinetic control.