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

A number of [ ]-no-more (PNM) mutations, eliminating [ ] prion, were previously described in . 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, substitutio...

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Published in:	Frontiers in molecular neuroscience Vol. 12; p. 274
Main Authors:	Danilov, Lavrentii G, Matveenko, Andrew G, Ryzhkova, Varvara E, Belousov, Mikhail V, Poleshchuk, Olga I, Likholetova, Daria V, Sokolov, Petr A, Kasyanenko, Nina A, Kajava, Andrey V, Zhouravleva, Galina A, Bondarev, Stanislav A
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Research Foundation 19-11-2019 Frontiers Media Frontiers Media S.A
Subjects:	Amino acids amyloid Amyloidogenesis ArchCandy Binding sites Cellular Biology Fibrils Genetics Life Sciences Mammals Mutagenesis Mutation Neuroscience Plasmids prion Prions Propagation Proteins PSI Quantitative Methods Saccharomyces cerevisiae SUP35 mutation Yeast France Russia amyloid PSI prion superpleated-β-structure ArchCandy Saccharomyces cerevisiae SUP35 mutation
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Summary:	A number of [ ]-no-more (PNM) mutations, eliminating [ ] prion, were previously described in . 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 . The mutagenized residues were chosen based on ArchCandy prediction of high inhibitory effect on the amyloidogenic potential of Sup35. The experiments confirmed that Sup35-M0 leads to the elimination of [ ] with high efficiency. Our data suggested that the elimination of the [ ] 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 [ ] prion variants. We also showed that Sup35-M0 protein co-aggregates with the wild-type Sup35 . 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by: Maria Rosário Almeida, University of Porto, Portugal Reviewed by: Heinrich J. G. Matthies, University of Alabama at Birmingham, United States; Ilia V. Baskakov, University of Maryland, Baltimore, United States
ISSN:	1662-5099 1662-5099
DOI:	10.3389/fnmol.2019.00274