title: Conformational stability of mammalian prion protein amyloid fibrils is dictated by a packing polymorphism within the core region.
abstract: Mammalian prion strains are believed to arise from the propagation of distinct conformations of the misfolded prion protein PrP(Sc). One key operational parameter used to define differences between strains has been conformational stability of PrP(Sc) 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 the 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. Although this study was limited to synthetic prion protein amyloid fibrils, a similar structural basis for strain-dependent conformational stability may apply to brain-derived PrP(Sc), especially because large strain-specific differences in PrP(Sc) stability are often observed despite a similar size of the PrP(Sc) core region.
authors: From the Departments of Physiology and Biophysics.
authors: Nathan J
authors: NJ
authors: Cobb
authors: Marcin I
authors: MI
authors: Apostol
authors: Shugui
authors: S
authors: Chen
authors: Vytautas
authors: V
authors: Smirnovas
authors: Witold K
authors: WK
authors: Surewicz
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006801:Humans; D008322:Mammals; D011110:Polymorphism, Genetic; D018620:PrPSc Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017096:Prion Diseases / Q000235:genetics* / Q000378:metabolism; D055550:Protein Stability; D017433:Protein Structure, Secondary; D057165:Proteostasis Deficiencies / Q000235:genetics*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000682:Amyloid; D018620:PrPSc Proteins; D011994:Recombinant Proteins
keywords: Amyloid; Neurodegenerative Diseases; Prions; Protein Aggregation; Protein Misfolding