Background: Prion diseases are fatal neurodegenerative disorders characterized by misfolding and aggregation of the normal prion protein PrP(C). Little is known about the details of the structural rearrangement of physiological PrP(C) into a still-elusive disease-associated conformation termed PrP(Sc). Increasing evidence suggests that the amino-terminal octapeptide sequences of PrP (huPrP, residues 59-89), though not essential, play a role in modulating prion replication and disease presentation.
Methodology/principal findings: Here, we report that trypsin digestion of PrP(Sc) from variant and sporadic human CJD results in a disease-specific trypsin-resistant PrP(Sc) fragment including amino acids approximately 49-231, thus preserving important epitopes such as the octapeptide domain for biochemical examination. Our immunodetection analyses reveal that several epitopes buried in this region of PrP(Sc) are exposed in PrP(C).
Conclusions/significance: We conclude that the octapeptide region undergoes a previously unrecognized conformational transition in the formation of PrP(Sc). This phenomenon may be relevant to the mechanism by which the amino terminus of PrP(C) participates in PrP(Sc) conversion, and may also be exploited for diagnostic purposes.