Polymorphisms at amino acid residues 141 and 154 influence conformational variation in ovine PrP

Area of Science:

• Prion biology
• Molecular genetics
• Structural biology

Background:

• Polymorphisms in the ovine prion protein (PrP) gene are linked to susceptibility to different forms of ovine prion disease, including classical and atypical scrapie.
• Classical scrapie is transmissible between sheep, while atypical scrapie's transmissibility is less clear, suggesting distinct underlying molecular mechanisms.
• Specific amino acid residues within PrP are hypothesized to influence protein structure and conversion, potentially determining scrapie type.

Purpose of the Study:

• To investigate the structural and conformational effects of specific ovine PrP polymorphisms at residues 141 and 154.
• To computationally and experimentally correlate these structural changes with susceptibility to classical and atypical scrapie.

Main Methods:

• Computational analysis, including molecular dynamics simulations, to assess PrP conformational dynamics and interactions.
• Experimental validation using circular dichroism spectroscopy and immunobiochemical studies on ovine recombinant PrP variants.

Main Results:

• Computational models revealed conserved regions in ovine PrP near residues 141 and 154, with genotypic differences in conformational dynamics.
• The Leu141Arg154 PrP variant showed a higher propensity for extended beta-sheet formation in the N-terminal region compared to Phe141Arg154 and Leu141His154 variants.
• Experimental data supported the computational findings, demonstrating that residues 141 and 154 influence PrP secondary structure and conformational changes.

Conclusions:

• Amino acid residues 141 and 154 play a critical role in modulating ovine PrP secondary structure and conformational stability.
• These structural influences are associated with distinct forms of ovine scrapie, providing insights into disease pathogenesis.
• The findings highlight the importance of specific PrP polymorphisms in determining susceptibility and potentially the characteristics of prion diseases.