The Octarepeat Region of the Prion Protein Is Conformationally Altered in PrPSc

Background: Prion diseases are fatal neurodegenerative disorders characterized by misfolding and aggregation of the normal prion protein PrPC. Little is known about the details of the structural rearrangement of physiological PrPC into a still-elusive disease-associated conformation termed PrPSc. 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 PrPSc from variant and sporadic human CJD results in a disease-specific trypsin-resistant PrPSc fragment including amino acids similar to 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 PrPSc are exposed in PrPC. Conclusions/Significance: We conclude that the octapeptide region undergoes a previously unrecognized conformational transition in the formation of PrPSc. This phenomenon may be relevant to the mechanism by which the amino terminus of PrPC participates in PrPSc conversion, and may also be exploited for diagnostic purposes.