The role of the unusual threonine string in the conversion of prion protein

• Published in: Scientific reports 2016-12, Vol.6 (1), p.38877-38877, Article 38877
• Main Authors: Abskharon, Romany, Wang, Fei, Vander Stel, Kayla J., Sinniah, Kumar, Ma, Jiyan
• Format: Article
• Language: English
• Subjects: 631/45; 631/45/470/460; 82; Alanine; Amino Acid Substitution; Amyloid; Animals; Humanities and Social Sciences; Infectivity; Mice; multidisciplinary; Mutation, Missense; Prion protein; Prion Proteins - chemistry; Prion Proteins - genetics; Prion Proteins - metabolism; Proline; Protein folding; Protein Structure, Secondary; Proteins; Science; Threonine; Valine
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep38877

The conversion of normal prion protein (PrP) into pathogenic PrP conformers is central to prion disease, but the mechanism remains unclear. The α-helix 2 of PrP contains a string of four threonines, which is unusual due to the high propensity of threonine to form β-sheets. This structural feature was proposed as the basis for initiating PrP conversion, but experimental results have been conflicting. We studied the role of the threonine string on PrP conversion by analyzing mouse Prnp a and Prnp b polymorphism that contains a polymorphic residue at the beginning of the threonine string, and PrP mutants in which threonine 191 was replaced by valine, alanine, or proline. The PMCA (protein misfolding cyclic amplification) assay was able to recapitulate the in vivo transmission barrier between PrP a and PrP b . Relative to PMCA, the amyloid fibril growth assay is less restrictive, but it did reflect certain properties of in vivo prion transmission. Our results suggest a plausible theory explaining the apparently contradictory results in the role of the threonine string in PrP conversion and provide novel insights into the complicated relationship among PrP stability, seeded conformational change, and prion structure, which is critical for understanding the molecular basis of prion infectivity.