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The prion protein globular domain and disease-related mutants studied by molecular dynamics simulations
1Lundberg Laboratory, Göteborg University, Sweden.
Abstract:
In humans, familial forms of transmissible spongiform encephalopathies (TSE; "prion diseases") have been shown to segregate with the exchange of individual amino acids in the prion protein (PrP) sequence. We used the NMR structure of the globular domain of mouse PrP in the cellular form (PrP(C)) as a starting point for investigations by long-time molecular dynamics (MD) simulations at ambient temperature of likely impacts of such mutations on the PrP(C) structure, making use of the fact that species-related amino acid replacements between mouse PrP and human PrP are spatially well separated from the disease-related mutations in human PrP. In the MD simulations these amino acid substitutions were found to have a variety of different effects on the protein structure, with some species showing altered packing of regular secondary structure elements, while other mutants showed no or only strictly localized changes of the structure near the variant amino acid. The fact that some of the disease-related amino acid exchanges cause no measurable change of the PrP(C) structure indicates that their influence on the conformational transition to the scrapie form of PrP may be due to modified intermolecular interactions during the aggregation process.
Insights
Familial prion diseases are linked to changes in the prion protein (PrP). Molecular dynamics simulations show some mutations alter PrP(C) structure, while others suggest disease arises from modified aggregation interactions.
Area of Science:
- Biochemistry and Molecular Biology
- Neuroscience
- Structural Biology
Background:
- Familial transmissible spongiform encephalopathies (prion diseases) are associated with specific amino acid substitutions in the prion protein (PrP).
- Understanding how these mutations affect the structure and function of PrP is crucial for elucidating disease mechanisms.
Purpose of the Study:
- To investigate the structural impact of disease-associated amino acid mutations in the cellular prion protein (PrP(C)) using molecular dynamics (MD) simulations.
- To explore how structural changes, or lack thereof, relate to the conformational transition to the scrapie form of PrP.
Main Methods:
- Utilized the NMR structure of the globular domain of mouse PrP(C) as a basis for simulations.
- Performed long-time molecular dynamics (MD) simulations at ambient temperature.
- Introduced species-related and disease-related amino acid substitutions into the PrP structure.
Main Results:
- MD simulations revealed varied effects of amino acid substitutions on PrP(C) structure.
- Some mutations resulted in altered packing of secondary structure elements.
- Other mutations showed no significant structural changes or only localized alterations near the mutation site.
Conclusions:
- The lack of measurable structural changes in PrP(C) for some disease-related mutations suggests their pathogenic role may stem from altered intermolecular interactions during aggregation.
- This highlights the complex relationship between PrP structure, mutation, and the pathogenesis of prion diseases.