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.

• PMID: 31803017
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Danilov LG, Matveenko AG, Ryzhkova VE, Belousov MV, Poleshchuk OI, Likholetova DV, Sokolov PA, Kasyanenko NA, Kajava AV, Zhouravleva GA, ... Show all

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