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Disassociation of β1-α1-β2 from the α2-α3 domain of prion protein (PrP) is a prerequisite for the conformational conversion of PrPC into PrPSc: Driven by the free energy landscape.
- Source :
-
International Journal of Biological Macromolecules . Sep2019, Vol. 136, p368-376. 9p. - Publication Year :
- 2019
-
Abstract
- Misfolding of the cellular prion protein (PrPC) into β-sheet-rich scrapie form (PrPSc) is associated with transmissible spongiform encephalopathies. A point mutation F198S is responsible for the development of a rare inherited Gerstmann-Straussler-Scheinker disease caused by the aggregation of PrPC. Thus, identification and the structural characterization of aggregation-prone regions are essential to delineate the conversion of PrPC to the disease-associated PrPSc upon F198S mutation. In the present study, molecular dynamics simulations on the wild-type PrP (WT-PrP) and its mutant were performed to explore the structural basis responsible for aggregation driven by the mutation. Secondary structure analysis revealed that the mutant exhibited a partial unfolding on α2 and the complete distortion in the 3 10 -helix of the β2-α2 loop. Remarkably, the β2-α2 loop is in proximity to α3 attributed by the long-range hydrophobic interactions and such structural intimacy is not observed in the WT-PrP. Owing to this, the β1-α1-β2 regions have separated from α2-α3 domain resulting in the impairment on the hydrogen bond between α1 and α3. Thus, the present study provides a detailed structural description of the F198S mutant in line with previous experimental results and delivers insights into the structural basis responsible for the conversion of PrPC to the disease-associated PrPSc. • The mutant F198S endured a partial unfolding on α2 • The β2-α2 and α2-α3 loops are completely distorted in the single mutant • The long-range hydrophobic interactions are favored in proximity of the β2-α2 loop and α3 • Domain disassociations are occurred by breaking a hydrogen bond between α1 and α3 could be the basis for the conformational conversion of PrPC into PrPSc [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 01418130
- Volume :
- 136
- Database :
- Academic Search Index
- Journal :
- International Journal of Biological Macromolecules
- Publication Type :
- Academic Journal
- Accession number :
- 137851032
- Full Text :
- https://doi.org/10.1016/j.ijbiomac.2019.06.099