Extremely rapid folding of the C-terminal domain of the prion protein without kinetic intermediates

The kinetics of folding of mPrP(121-231), the structured 111-residue domain of the murine cellular prion protein PrPC, were investigated by stopped-no w fluorescence using the variant F175W, which has the same overall structur e and stability as wild-type mPrP(121-231) but shows a strong fluorescence change upon unfolding. At 22 degrees C and pH 7.0, folding of mPrP( 121-231 )-F175W is too fast to be observable by stopped-flow techniques. folding at 4 degrees C occurs with a deduced half-life of similar to 170 mu s without detectable intermediates, possibly the fastest protein-folding reaction kn own so far. Thus, propagation of the abnormal, oligomeric prion protein PrP Sc, which is supposed to be the causative agent of transmissible spongiform encephalopathies, is unlikely to follow a mechanism where kinetic folding intermediates of PrPC are a source of PrPSc subunits.