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Investigating the Spreading and Toxicity of Prion-like Proteins Using the Metazoan Model Organism C. elegans
Published on: January 8, 2015
Prion proteins with pathogenic and protective mutations show similar structure and dynamics
Sung-Hun Bae1, Giuseppe Legname, Ana Serban
1Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 90237, USA.
Biochemistry
|July 22, 2009
Summary
Prion protein (PrP) dynamics reveal how mutations cause neurodegenerative diseases. Lower pH destabilizes PrP structure, suggesting disease initiation involves non-native intermediates and potentially the folded C-terminal region.
Area of Science:
- Biochemistry
- Neuroscience
- Structural Biology
Background:
- Prion diseases, such as Creutzfeldt-Jakob disease, stem from prion protein (PrP) conformational changes.
- The precise mechanisms of PrP conformational change initiation and propagation remain largely unknown.
- Understanding PrP dynamics is crucial for elucidating the pathogenesis of these fatal neurodegenerative disorders.
Purpose of the Study:
- To investigate the backbone dynamics of wild-type and mutant mouse prion protein (PrP) at different pH levels.
- To elucidate the structural impact of pathogenic and protective PrP mutations.
- To explore the relationship between PrP dynamics, pH, and disease mechanisms.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy was used to study the backbone dynamics of wild-type and mutant mouse PrP(89-230).
- Experiments were conducted at physiological (pH 5.5) and acidic (pH 3.5) conditions to mimic cellular environments.
- Chemical shift analysis and motion analysis (microsecond and nanosecond timescales) were employed.
Main Results:
- Mutations P101L and H186R (pathogenic) and Q167R and Q218K (protective) showed distinct chemical shift changes.
- Lowering pH significantly disordered the C-terminal half of the second helix in both wild-type and mutant PrP.
- The H186R mutation induced disorder even at pH 5.5, and pH-dependent motion changes were observed across various protein regions.
Conclusions:
- PrP mutations can influence protein dynamics and stability, particularly at acidic pH.
- Disease-associated mutations may act on non-native PrP intermediates (PrP*) after initial conversion.
- PrPSc formation might initiate within the structured C-terminal region, challenging previous hypotheses of N-terminal initiation.
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