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Methionine Sulfoxide Reductases Suppress the Formation of the [PSI(+)] Prion and Protein Aggregation in Yeast

Prions are self-propagating, misfolded forms of proteins associated with various neurodegenerative diseases in mammals and heritable traits in yeast. How prions form spontaneously into infectious amyloid-like structures without underlying genetic changes is poorly understood. Previous studies have s...

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Autores principales: Schepers, Jana, Carter, Zorana, Kritsiligkou, Paraskevi, Grant, Chris M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9952077/
https://www.ncbi.nlm.nih.gov/pubmed/36829961
http://dx.doi.org/10.3390/antiox12020401
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author Schepers, Jana
Carter, Zorana
Kritsiligkou, Paraskevi
Grant, Chris M.
author_facet Schepers, Jana
Carter, Zorana
Kritsiligkou, Paraskevi
Grant, Chris M.
author_sort Schepers, Jana
collection PubMed
description Prions are self-propagating, misfolded forms of proteins associated with various neurodegenerative diseases in mammals and heritable traits in yeast. How prions form spontaneously into infectious amyloid-like structures without underlying genetic changes is poorly understood. Previous studies have suggested that methionine oxidation may underlie the switch from a soluble protein to the prion form. In this current study, we have examined the role of methionine sulfoxide reductases (MXRs) in protecting against de novo formation of the yeast [PSI(+)] prion, which is the amyloid form of the Sup35 translation termination factor. We show that [PSI(+)] formation is increased during normal and oxidative stress conditions in mutants lacking either one of the yeast MXRs (Mxr1, Mxr2), which protect against methionine oxidation by reducing the two epimers of methionine-S-sulfoxide. We have identified a methionine residue (Met124) in Sup35 that is important for prion formation, confirming that direct Sup35 oxidation causes [PSI(+)] prion formation. [PSI(+)] formation was less pronounced in mutants simultaneously lacking both MXR isoenzymes, and we show that the morphology and biophysical properties of protein aggregates are altered in this mutant. Taken together, our data indicate that methionine oxidation triggers spontaneous [PSI(+)] prion formation, which can be alleviated by methionine sulfoxide reductases.
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spelling pubmed-99520772023-02-25 Methionine Sulfoxide Reductases Suppress the Formation of the [PSI(+)] Prion and Protein Aggregation in Yeast Schepers, Jana Carter, Zorana Kritsiligkou, Paraskevi Grant, Chris M. Antioxidants (Basel) Article Prions are self-propagating, misfolded forms of proteins associated with various neurodegenerative diseases in mammals and heritable traits in yeast. How prions form spontaneously into infectious amyloid-like structures without underlying genetic changes is poorly understood. Previous studies have suggested that methionine oxidation may underlie the switch from a soluble protein to the prion form. In this current study, we have examined the role of methionine sulfoxide reductases (MXRs) in protecting against de novo formation of the yeast [PSI(+)] prion, which is the amyloid form of the Sup35 translation termination factor. We show that [PSI(+)] formation is increased during normal and oxidative stress conditions in mutants lacking either one of the yeast MXRs (Mxr1, Mxr2), which protect against methionine oxidation by reducing the two epimers of methionine-S-sulfoxide. We have identified a methionine residue (Met124) in Sup35 that is important for prion formation, confirming that direct Sup35 oxidation causes [PSI(+)] prion formation. [PSI(+)] formation was less pronounced in mutants simultaneously lacking both MXR isoenzymes, and we show that the morphology and biophysical properties of protein aggregates are altered in this mutant. Taken together, our data indicate that methionine oxidation triggers spontaneous [PSI(+)] prion formation, which can be alleviated by methionine sulfoxide reductases. MDPI 2023-02-07 /pmc/articles/PMC9952077/ /pubmed/36829961 http://dx.doi.org/10.3390/antiox12020401 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Schepers, Jana
Carter, Zorana
Kritsiligkou, Paraskevi
Grant, Chris M.
Methionine Sulfoxide Reductases Suppress the Formation of the [PSI(+)] Prion and Protein Aggregation in Yeast
title Methionine Sulfoxide Reductases Suppress the Formation of the [PSI(+)] Prion and Protein Aggregation in Yeast
title_full Methionine Sulfoxide Reductases Suppress the Formation of the [PSI(+)] Prion and Protein Aggregation in Yeast
title_fullStr Methionine Sulfoxide Reductases Suppress the Formation of the [PSI(+)] Prion and Protein Aggregation in Yeast
title_full_unstemmed Methionine Sulfoxide Reductases Suppress the Formation of the [PSI(+)] Prion and Protein Aggregation in Yeast
title_short Methionine Sulfoxide Reductases Suppress the Formation of the [PSI(+)] Prion and Protein Aggregation in Yeast
title_sort methionine sulfoxide reductases suppress the formation of the [psi(+)] prion and protein aggregation in yeast
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9952077/
https://www.ncbi.nlm.nih.gov/pubmed/36829961
http://dx.doi.org/10.3390/antiox12020401
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