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Prion protein NMR structure and familial human spongiform encephalopathies
1Institut für Molekularbiologie und Biophysik, Eidgenössische Technische Hochschule-Hönggerberg, CH-8093 Zurich, Switzerland.
Abstract:
The refined NMR structure of the mouse prion protein domain mPrP(121-231) and the recently reported NMR structure of the complete 208-residue polypeptide chain of mPrP are used to investigate the structural basis of inherited human transmissible spongiform encephalopathies. In the cellular form of mPrP no spatial clustering of mutation sites is observed that would indicate the existence of disease-specific subdomains. A hydrogen bond between residues 128 and 178 provides a structural basis for the observed highly specific influence of a polymorphism in position 129 in human PrP on the disease phenotype that segregates with the mutation Asp-178-Asn. Overall, the NMR structure implies that only part of the disease-related amino acid replacements lead to reduced stability of the cellular form of PrP, indicating that subtle structural differences in the mutant proteins may affect intermolecular signaling in a variety of different ways.
Insights
Structural analysis of mouse prion protein reveals insights into inherited human prion diseases. Subtle structural changes in mutant proteins may influence disease pathways.
Area of Science:
- Structural Biology
- Neuroscience
- Biochemistry
Background:
- Inherited human transmissible spongiform encephalopathies (TSEs) are linked to mutations in the prion protein (PrP).
- Understanding the structural basis of these mutations is crucial for disease mechanism elucidation.
Purpose of the Study:
- To investigate the structural underpinnings of inherited human TSEs using mouse prion protein (mPrP) structures.
- To explore how specific mutations and polymorphisms affect PrP structure and function.
Main Methods:
- Utilized refined Nuclear Magnetic Resonance (NMR) structures of mouse prion protein domains (mPrP(121-231)) and full-length mPrP.
- Analyzed the spatial distribution of mutation sites within the cellular form of mPrP.
- Investigated the role of specific hydrogen bonds, such as between residues 128 and 178, in disease phenotype.
Main Results:
- No evidence of disease-specific subdomains was found in the cellular form of mPrP based on mutation site clustering.
- A hydrogen bond between residues 128 and 178 explains the significant impact of the position 129 polymorphism on human PrP disease phenotype, particularly with the Asp-178-Asn mutation.
- NMR structures suggest that not all disease-related amino acid substitutions result in reduced cellular PrP stability.
Conclusions:
- Subtle structural variations in mutant prion proteins, rather than just reduced stability, likely contribute to disease pathogenesis.
- These structural differences may influence intermolecular signaling in diverse ways, impacting disease progression.
- The findings provide a structural framework for understanding the complex relationship between PrP mutations, polymorphisms, and inherited TSEs.