Disease-associated F198S Mutation Increases the Propensity of the Recombinant Prion Protein for Conformational Conversion to Scrapie-like Form *
Journal of Biological Chemistry, ISSN: 0021-9258, Vol: 277, Issue: 50, Page: 49065-49070
2002
- 69Citations
- 66Captures
- 1Mentions
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Metrics Details
- Citations69
- Citation Indexes69
- 69
- CrossRef55
- Captures66
- Readers66
- 66
- Mentions1
- Blog Mentions1
- Blog1
Article Description
The critical step in the pathogenesis of transmissible spongiform encephalopathies (prion diseases) is the conversion of a cellular prion protein (PrP c ) into a protease-resistant, β-sheet rich form (PrP Sc ). Although the disease transmission normally requires direct interaction between exogenous PrP Sc and endogenous PrP C, the pathogenic process in hereditary prion diseases appears to develop spontaneously ( i.e. not requiring infection with exogenous PrP Sc ). To gain insight into the molecular basis of hereditary spongiform encephalopathies, we have characterized the biophysical properties of the recombinant human prion protein variant containing the mutation (Phe 198 → Ser) associated with familial Gerstmann-Straussler-Scheinker disease. Compared with the wild-type protein, the F198S variant shows a dramatically increased propensity to self-associate into β-sheet-rich oligomers. In a guanidine HCl-containing buffer, the transition of the F198S variant from a normal α-helical conformation into an oligomeric β-sheet structure is about 50 times faster than that of the wild-type protein. Importantly, in contrast to the wild-type PrP, the mutant protein undergoes a spontaneous conversion to oligomeric β-sheet structure even in the absence of guanidine HCl or any other denaturants. In addition to β-sheet structure, the oligomeric form of the protein is characterized by partial resistance to proteinase K digestion, affinity for amyloid-specific dye, thioflavine T, and fibrillar morphology. The increased propensity of the F198S variant to undergo a conversion to a PrP Sc -like form correlates with a markedly decreased thermodynamic stability of the native α-helical conformer of the mutant protein. This correlation supports the notion that partially unfolded intermediates may be involved in conformational conversion of the prion protein.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0021925819331540; http://dx.doi.org/10.1074/jbc.m207511200; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=0037073678&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/12372829; http://www.jbc.org/lookup/doi/10.1074/jbc.M207511200; https://syndication.highwire.org/content/doi/10.1074/jbc.M207511200; https://linkinghub.elsevier.com/retrieve/pii/S0021925819331540; https://dx.doi.org/10.1074/jbc.m207511200
American Society for Biochemistry & Molecular Biology (ASBMB)
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