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Pathway complexity of prion protein assembly into amyloid
Ilia V Baskakov1, Giuseppe Legname, Michael A Baldwin
1Institute for Neurodegenerative Diseases, University of California, San Francisco, California 94143, USA.
The Journal of Biological Chemistry
|March 26, 2002
Summary
The prion protein (PrP) can misfold into abnormal forms, including beta-oligomers and amyloid fibrils. Experimental conditions, like pH, influence which misfolded prion structures form, impacting disease.
Area of Science:
- Biochemistry
- Neuroscience
- Structural Biology
Background:
- The cellular prion protein (PrP(C)) misfolds into pathogenic isoforms (PrP(Sc)) under disease conditions.
- PrP(Sc) aggregates into beta-rich multimers and can form amyloid fibrils.
- A proteolytically resistant core (PrP 27-30) is derived from PrP(Sc).
Purpose of the Study:
- To investigate the kinetic pathways of prion protein amyloid formation in vitro.
- To characterize the distinct abnormal isoforms of the prion protein.
- To understand how experimental conditions influence prion misfolding pathways.
Main Methods:
- Used unglycosylated recombinant PrP corresponding to the PrP 27-30 core.
- Studied amyloid formation kinetics in vitro.
- Analyzed structural properties and binding characteristics of abnormal isoforms.
Main Results:
- Recombinant PrP formed two non-native isoforms: a beta-oligomer and amyloid fibrils.
- Kinetic data suggest beta-oligomers are not on the amyloid formation pathway.
- Acidic pH favored beta-oligomer formation, while neutral pH favored amyloid.
- Both isoforms had high beta-sheet content and bound ANS, but were structurally distinct.
Conclusions:
- Prion protein misfolding can follow multiple pathways, forming distinct abnormal isoforms.
- Environmental factors like pH significantly influence the preferred misfolding pathway.
- The existence of distinct abnormal isoforms may explain challenges in in vitro refolding and disease variability.