Folding of prion protein to its native alpha-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.
Baskakov
I V
IV
Institute for Neurodegenerative Diseases, Department of Neurology, University of California, San Francisco, California 94143, USA.
Legname
G
G
Prusiner
S B
SB
Cohen
F E
FE
D002942:Circular Dichroism; D007700:Kinetics; D011328:Prions / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding; D013816:Thermodynamics
D011328:Prions