Design of a New [PSI+]-No-More Mutation in SUP35 With Strong Inhibitory Effect on the [PSI+] Prion Propagation

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Abstract

A number of [PSI+]-no-more (PNM) mutations, eliminating [PSI+] prion, were previously described in SUP35. In this study, we designed and analyzed a new PNM mutation based on the parallel in-register β-structure of Sup35 prion fibrils suggested by the known experimental data. In such an arrangement, substitution of non-charged residues by charged ones may destabilize the fibril structure. We introduced Q33K/A34K amino acid substitutions into the Sup35 protein, corresponding allele was called sup35-M0. The mutagenized residues were chosen based on ArchCandy in silico prediction of high inhibitory effect on the amyloidogenic potential of Sup35. The experiments confirmed that Sup35-M0 leads to the elimination of [PSI+] with high efficiency. Our data suggested that the elimination of the [PSI+] prion is associated with the decreased aggregation properties of the protein. The new mutation can induce the prion with very low efficiency and is able to propagate only weak [PSI+] prion variants. We also showed that Sup35-M0 protein co-aggregates with the wild-type Sup35 in vivo. Moreover, our data confirmed the utility of the strategy of substitution of non-charged residues by charged ones to design new mutations to inhibit a prion formation.

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Danilov, L. G., Matveenko, A. G., Ryzhkova, V. E., Belousov, M. V., Poleshchuk, O. I., Likholetova, D. V., … Bondarev, S. A. (2019). Design of a New [PSI+]-No-More Mutation in SUP35 With Strong Inhibitory Effect on the [PSI+] Prion Propagation. Frontiers in Molecular Neuroscience, 12. https://doi.org/10.3389/fnmol.2019.00274

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