Design of a new [PSI+]-no-more mutation in SUP35 with strong inhibitory effect on the [PSI+] prion propagation

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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 vitro and 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.
Язык оригиналаанглийский
Номер статьи274
ЖурналFrontiers in Molecular Neuroscience
Том12
DOI
СостояниеОпубликовано - 19 ноя 2019

Отпечаток

Prions
Mutation
Amino Acid Substitution
Computer Simulation
Proteins
Alleles

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@article{27ccca351d764e25a9287d6d032bec5d,
title = "Design of a new [PSI+]-no-more mutation in SUP35 with strong inhibitory effect on the [PSI+] prion propagation",
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 vitro and 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.",
keywords = "Amyloid, ArchCandy, Prion, Saccharomyces cerevisiae, SUP35 mutation, superpleated-β-structure",
author = "Danilov, {Lavrentii G.} and Matveenko, {Andrew G.} and Ryzhkova, {Varvara E.} and Belousov, {Mikhail V.} and Poleshuk, {Olga I.} and Likholetova, {Daria V.} and Sokolov, {Petr A.} and Kasyanenko, {Nina A.} and Kajava, {Andrey V.} and Zhouravleva, {Galina A.} and Bondarev, {Stanislav A.}",
note = "Danilov LG, Matveenko AG, Ryzhkova VE, Belousov MV, Poleshchuk OI, Likholetova DV, Sokolov PA, Kasyanenko NA, Kajava AV, Zhouravleva GA and Bondarev SA (2019) Design of a New [PSI+]-No-More Mutation in SUP35 With Strong Inhibitory Effect on the [PSI+] Prion Propagation. Front. Mol. Neurosci. 12:274. doi: 10.3389/fnmol.2019.00274",
year = "2019",
month = "11",
day = "19",
doi = "10.3389/fnmol.2019.00274",
language = "English",
volume = "12",
journal = "Frontiers in Molecular Neuroscience",
issn = "1662-5099",
publisher = "Frontiers Media S.A.",

}

TY - JOUR

T1 - Design of a new [PSI+]-no-more mutation in SUP35 with strong inhibitory effect on the [PSI+] prion propagation

AU - Danilov, Lavrentii G.

AU - Matveenko, Andrew G.

AU - Ryzhkova, Varvara E.

AU - Belousov, Mikhail V.

AU - Poleshuk, Olga I.

AU - Likholetova, Daria V.

AU - Sokolov, Petr A.

AU - Kasyanenko, Nina A.

AU - Kajava, Andrey V.

AU - Zhouravleva, Galina A.

AU - Bondarev, Stanislav A.

N1 - Danilov LG, Matveenko AG, Ryzhkova VE, Belousov MV, Poleshchuk OI, Likholetova DV, Sokolov PA, Kasyanenko NA, Kajava AV, Zhouravleva GA and Bondarev SA (2019) Design of a New [PSI+]-No-More Mutation in SUP35 With Strong Inhibitory Effect on the [PSI+] Prion Propagation. Front. Mol. Neurosci. 12:274. doi: 10.3389/fnmol.2019.00274

PY - 2019/11/19

Y1 - 2019/11/19

N2 - 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 vitro and 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.

AB - 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 vitro and 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.

KW - Amyloid

KW - ArchCandy

KW - Prion

KW - Saccharomyces cerevisiae

KW - SUP35 mutation

KW - superpleated-β-structure

U2 - 10.3389/fnmol.2019.00274

DO - 10.3389/fnmol.2019.00274

M3 - Article

VL - 12

JO - Frontiers in Molecular Neuroscience

JF - Frontiers in Molecular Neuroscience

SN - 1662-5099

M1 - 274

ER -