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. 2015;9(4):237-43.
doi: 10.1080/19336896.2015.1062201.

Structural conservation of prion strain specificities in recombinant prion protein fibrils in real-time quaking-induced conversion

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Structural conservation of prion strain specificities in recombinant prion protein fibrils in real-time quaking-induced conversion

Kazunori Sano et al. Prion. 2015.

Abstract

A major unsolved issue of prion biology is the existence of multiple strains with distinct phenotypes and this strain phenomenon is postulated to be associated with the conformational diversity of the abnormal prion protein (PrP(Sc)). Real-time quaking-induced conversion (RT-QUIC) assay that uses Escherichia coli-derived recombinant prion protein (rPrP) for the sensitive detection of PrP(Sc) results in the formation of rPrP-fibrils seeded with various strains. We demonstrated that there are differences in the secondary structures, especially in the β-sheets, and conformational stability between 2 rPrP-fibrils seeded with either Chandler or 22L strains in the first round of RT-QUIC. In particular, the differences in conformational properties of these 2 rPrP-fibrils were common to those of the original PrP(Sc). However, the strain specificities of rPrP-fibrils seen in the first round were lost in subsequent rounds. Instead, our findings suggest that nonspecific fibrils became the major species, probable owing to their selective growth advantage in the RT-QUIC. This study shows that at least some strain-specific conformational properties of the original PrP(Sc) can be transmitted to rPrP-fibrils in vitro, but further conservation appears to require unknown cofactors or environmental conditions or both.

Keywords: fibril; prion; real-time quaking-induced conversion (RT-QUIC); recombinant prion protein (rPrP); strain; transmission.

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Figures

Figure 1.
Figure 1.
Hypothetical models for the formation of rPrP-fibrils in sequential RT-QUIC reactions. (A) The formation of 1st-rPrP-fibSc is induced predominantly in the presence of hypothetical cofactors and brain-derived PrPSc in the first round. However, a small amount of nonspecific rPrP-fibrils may be concomitantly generated. (B) In the second round, the nonspecific rPrP-fibrils become predominant because of the paucity of hypothetical cofactors and/or a selective growth advantage of nonspecific fibrils. (C) The formation of nonspecific rPrP-fibrils occupies almost the whole reaction in the fifth round.

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