Conformational Stability of Mammalian Prion Protein Amyloid Fibrils Is Dictated by a Packing Polymorphism within the Core Region [Molecular Bases of Disease]
December 12th, 2013 by Cobb, N. J., Apostol, M. I., Chen, S., Smirnovas, V., Surewicz, W. K.
Mammalian prion strains are believed to arise from the propagation of distinct conformations of the misfolded prion protein, PrPSc. One key operational parameter used to define differences between strains has been conformational stability of PrPSc as defined by resistance to thermal and/or chemical denaturation. However, the structural basis of these stability differences is unknown. To bridge this gap, we have generated two strains of recombinant human prion protein amyloid fibrils that show dramatic differences in conformational stability and have characterized them by a number of biophysical methods. Backbone amide hydrogen/deuterium exchange experiments revealed that, in sharp contrast to previously studied strains of infectious amyloid formed from yeast prion protein Sup35, differences in β-sheet core size do not underlie differences in conformational stability between strains of mammalian prion protein amyloid. Instead, these stability differences appear to be dictated by distinct packing arrangements (i.e., steric zipper interfaces) within the amyloid core, as indicated by distinct X-ray fiber diffraction patterns and large strain-dependent differences in hydrogen/deuterium exchange kinetics for histidine side chains within the core region. While the present study is limited to synthetic prion protein amyloid fibrils, a similar structural basis for strain-dependent conformational stability may apply to brain-derived PrPSc, especially since large strain-specific differences in PrPSc stability are often observed despite a similar size of the PrPSc core region.