Abstract
BackgroundPrion 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 FindingsHere, 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 ∼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/SignificanceWe 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.
Highlights
Prion diseases are fatal neurodegenerative disorders characterized by dementia, motor dysfunction, and spongiform degeneration of the brain [1]
B. 50 mg/ml trypsin or Proteinase K (PK) was incubated with normal, variant CJD (vCJD) MM
Emerging evidence suggests that the octapeptide sequences may play a role in propagating prions
Summary
Prion diseases are fatal neurodegenerative disorders characterized by dementia, motor dysfunction, and spongiform degeneration of the brain [1]. Digestion with Proteinase K (PK) leaves behind a core particle termed PrPres (for resistant PrP) or PrP27–30 (for 27–30 kDa PK-resistant fragments) that consists of the carboxy-terminal two-thirds of the protein. Because PrP27–30 remains infectious and because of the scarcity of tools to isolate full-length PrPSc, the amino-terminus has remained relatively unexamined in the context of aggregated PrP. 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 stillelusive 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
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