The infectious pathogen responsible for
prion diseases is the misfolded, aggregated form of the
prion protein, PrPSc. In contrast to recent progress in studies of laboratory rodent-adapted
prions, current understanding of the molecular basis of human
prion diseases and, especially, their vast phenotypic diversity is very limited. Here, we have purified
proteinase resistant PrPSc aggregates from two major phenotypes of
sporadic Creutzfeldt-Jakob disease (sCJD), determined their conformational stability and replication
tempo in vitro, as well as characterized structural organization using recently emerged approaches based on
hydrogen/
deuterium (H/D) exchange coupled with mass spectrometry. Our data clearly demonstrate that these phenotypically distant
prions differ in a major way with regard to their structural organization, both at the level of the
polypeptide backbone (as indicated by backbone
amide H/D exchange data) as well as the quaternary packing arrangements (as indicated by H/D exchange kinetics for
histidine side chains). Furthermore, these data indicate that, in contrast to previous observations on yeast and some murine
prion strains, the replication rate of sCJD
prions is primarily determined not by conformational stability but by specific structural features that control the growth rate of
prion protein aggregates.