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Prion Protein α-to-β Transition Monitored by Time-Resolved Fourier Transform Infrared Spectroscopy

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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 PrPSc, 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.

Keywords: BAND DECOMPOSITION; CURVE FITTING; FOURIER TRANSFORM INFRARED SPECTROSCOPY; FT-IR SPECTROSCOPY; PRION PROTEIN; PROTEIN FOLDING

Document Type: Research Article

DOI: http://dx.doi.org/10.1366/000370207782217680

Affiliations: 1: University of California, San Francisco, Institute for Neurodegenerative Diseases, 513 Parnassus Ave., San Francisco, California 94143-0518 2: Eidgenössische Technische Hochschule-Hönggerberg, Institut für Molekularbiologie und Biophysik, 8093 Zürich, Switzerland; Prionics AG, Wagisstrasse 27a, 8952 Schlieren, Switzerland 3: Eidgenössische Technische Hochschule-Hönggerberg, Institut für Molekularbiologie und Biophysik, 8093 Zürich, Switzerland 4: Ruhr-Universitaet Bochum, Lehrstuhl fuer Biophysik, Universitaetsstr. 150, 44780 Bochum, Germany

Publication date: October 1, 2007

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