Open AccessConversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins.
Author(s) -
Kaihui Pan,
Michael A. Baldwin,
Jack Nguyen,
Marı́a Gasset,
Ana Serban,
Darlene Groth,
Ingrid Mehlhorn,
Ziwei Huang,
R.J. Fletterick,
Fred E. Cohen
Publication year - 1993
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.90.23.10962
Subject(s) - scrapie , chemistry , circular dichroism , protein secondary structure , beta sheet , biophysics , proteolysis , protein structure , crystallography , conformational change , alpha helix , fibril , helix (gastropod) , prion protein , biochemistry , biology , enzyme , pathology , medicine , ecology , disease , snail
Prions are composed largely, if not entirely, of prion protein (PrPSc in the case of scrapie). Although the formation of PrPSc from the cellular prion protein (PrPC) is a post-translational process, no candidate chemical modification was identified, suggesting that a conformational change features in PrPSc synthesis. To assess this possibility, we purified both PrPC and PrPSc by using nondenaturing procedures and determined the secondary structure of each. Fourier-transform infrared (FTIR) spectroscopy demonstrated that PrPC has a high alpha-helix content (42%) and no beta-sheet (3%), findings that were confirmed by circular dichroism measurements. In contrast, the beta-sheet content of PrPSc was 43% and the alpha-helix 30% as measured by FTIR. As determined in earlier studies, N-terminally truncated PrPSc derived by limited proteolysis, designated PrP 27-30, has an even higher beta-sheet content (54%) and a lower alpha-helix content (21%). Neither PrPC nor PrPSc formed aggregates detectable by electron microscopy, while PrP 27-30 polymerized into rod-shaped amyloids. While the foregoing findings argue that the conversion of alpha-helices into beta-sheets underlies the formation of PrPSc, we cannot eliminate the possibility that an undetected chemical modification of a small fraction of PrPSc initiates this process. Since PrPSc seems to be the only component of the "infectious" prion particle, it is likely that this conformational transition is a fundamental event in the propagation of prions.