Abstract

The conformational change of the recombinant, murine prion protein (PrP) from an α-helical to a β-sheet enriched state was monitored by time-resolved Fourier transform infrared (FT-IR) spectroscopy. The α-to-β transition is induced by reduction of the single disulfide bond in PrP. This transition is believed to generate the scrapie form PrP^Sc, the supposed infectious agent of transmissible spongiform encephalopathies. We followed the kinetics of this conformational change using a novel method for amide I band analysis of the infrared (IR) spectra. The amide I analysis provides the secondary structure. The amide I decomposition was calibrated with the three dimensional structure of cellular PrP solved by nuclear magnetic resonance (NMR). The novel secondary structure analysis provides a root mean squared deviation (RMSD) of only 3% as compared to the NMR structure. Reduction of α-helical PrP caused the transient accumulation of a partially unfolded intermediate, followed by formation of a state with higher β-sheet than α-helical structure contents. The novel approach allows us to now determine the secondary structure of the β-sheet conformation. This was not determined by either NMR or X-ray. The experiments were performed in a double-sealed security cuvette developed for IR analysis of potentially infectious PrP samples outside the biosafety laboratory.

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