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Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy
1Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana 59840.
Abstract:
The molecular basis of strain variation in scrapie diseases is unknown. The only identified component of the agent is the posttranslationally modified host prion protein (PrPSc). The biochemical and physical properties of PrP from two strains of transmissible mink encephalopathy (TME), called hyper (HY) and drowsy (DY), were compared to investigate if PrP heterogeneity could account for strain diversity. The degradation rate of PrPTME digested with proteinase K was found to be strain specific and correlated with inactivation of the TME titer. Edman protein sequencing revealed that the major N-terminal end of HY PrPTME commenced at least 10 amino acid residues prior to that of DY PrPTME after digestion with proteinase K. Analysis of the brain distribution of PrPTME exhibited a strain-specific pattern and localization of PrPTME to the perikarya of specific neuron populations. Our findings are consistent with HY and DY PrPTME having distinct protein conformations and/or strain-specific ligand interactions that influence PrPTME properties. We propose that PrPTME conformation could play a role in targeting TME strains to different neuron populations in which strain-specific formation occurs. These data are consistent with the idea that PrPTME protein structure determines the molecular basis of strain variation.
Insights
Strain variation in transmissible mink encephalopathy (TME) may stem from distinct prion protein (PrPSc) conformations. Differences in proteinase K digestion and N-terminal sequencing suggest structural variations underlie TME strain diversity.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- The molecular basis of strain variation in prion diseases like scrapie remains largely unknown.
- The primary identified component of the infectious agent is the post-translationally modified host prion protein (PrPSc).
Purpose of the Study:
- To investigate if heterogeneity in prion protein (PrP) properties could explain the diversity observed between different strains of transmissible mink encephalopathy (TME).
- Specifically comparing the biochemical and physical characteristics of PrP from two TME strains: hyper (HY) and drowsy (DY).
Main Methods:
- Comparing the degradation rates of PrPTME (prion protein from TME) digested with proteinase K for HY and DY strains.
- Utilizing Edman protein sequencing to analyze the N-terminal ends of HY and DY PrPTME after proteinase K digestion.
- Analyzing the distribution patterns of PrPTME within the brain tissue for both strains.
Main Results:
- The degradation rate of PrPTME by proteinase K was strain-specific and correlated with the inactivation of the TME infectious titer.
- Edman sequencing revealed that the N-terminal end of HY PrPTME was at least 10 amino acid residues longer than that of DY PrPTME after digestion.
- Brain distribution analysis showed strain-specific patterns and localization of PrPTME within specific neuronal populations.
Conclusions:
- Findings suggest that HY and DY TME strains possess distinct prion protein conformations and/or strain-specific ligand interactions.
- Prion protein conformation is proposed to influence the targeting of TME strains to specific neuron populations, leading to strain-specific formation.
- Prion protein structure is indicated as the determinant of the molecular basis for TME strain variation.