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PrPSc-Specific Antibody Reveals C-Terminal Conformational Differences between Prion Strains.
Eri Saijo1, Andrew G Hughson1, Gregory J Raymond1
1Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
Journal of Virology
|March 4, 2016
Summary
Prion strains exhibit distinct conformations, particularly near the C-terminus of the proteinase-resistant form of the prion protein (PrP(RES)). This structural variation influences prion disease characteristics and offers insights into strain-dependent biological differences.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Prion diseases are characterized by the misfolding of the prion protein (PrP) into a proteinase-resistant form (PrP(Sc)).
- Understanding the structural basis of prion strain variation is crucial for disease biology.
- Previous studies suggested N-terminal conformational differences among prion strains.
Purpose of the Study:
- To investigate strain-dependent conformational variations in PrP(Sc) using specific antibodies.
- To determine if C-terminal epitopes of PrP(Sc) differ among prion strains.
Main Methods:
- Purification of proteinase-resistant PrP(Sc) (PrP(RES)) from mouse brains infected with three distinct scrapie strains (Chandler, 22L, Me7).
- Systematic testing of antibody epitope accessibility using indirect enzyme-linked immunosorbent assay (ELISA).
- Utilizing a panel of anti-PrP and PrP(Sc)-specific antibodies, including a C-terminal conformational antibody.
Main Results:
- Most anti-PrP antibody epitopes were hidden in the folded PrP(RES) structure, becoming accessible after guanidine denaturation.
- A PrP(Sc)-specific C-terminal conformational antibody demonstrated differential reactivity across the three scrapie strains.
- These findings indicate strain-dependent conformational differences near the C termini of PrP(Sc) molecules within multimers.
Conclusions:
- Conformational variations exist near the C termini of PrP(Sc) molecules.
- These C-terminal differences contribute to the phenotypic distinctions observed between prion strains.
- The study provides evidence for strain-specific structural heterogeneity in PrP(Sc).
