Heterologous prion-forming proteins interact to cross-seed aggregation in Saccharomyces cerevisiae

Abstract The early stages of protein misfolding remain incompletely understood, as most mammalian proteinopathies are only detected after irreversible protein aggregates have formed. Cross-seeding, where one aggregated protein templates the misfolding of a heterologous protein, is one mechanism prop...

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Autores principales:	Kathryn M. Keefer, Kevin C. Stein, Heather L. True
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/259adbae8b134b91a3ddc1e372d5a9a2
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spelling	oai:doaj.org-article:259adbae8b134b91a3ddc1e372d5a9a22021-12-02T16:06:52ZHeterologous prion-forming proteins interact to cross-seed aggregation in Saccharomyces cerevisiae10.1038/s41598-017-05829-52045-2322https://doaj.org/article/259adbae8b134b91a3ddc1e372d5a9a22017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05829-5https://doaj.org/toc/2045-2322Abstract The early stages of protein misfolding remain incompletely understood, as most mammalian proteinopathies are only detected after irreversible protein aggregates have formed. Cross-seeding, where one aggregated protein templates the misfolding of a heterologous protein, is one mechanism proposed to stimulate protein aggregation and facilitate disease pathogenesis. Here, we demonstrate the existence of cross-seeding as a crucial step in the formation of the yeast prion [PSI +], formed by the translation termination factor Sup35. We provide evidence for the genetic and physical interaction of the prion protein Rnq1 with Sup35 as a predominant mechanism leading to self-propagating Sup35 aggregation. We identify interacting sites within Rnq1 and Sup35 and determine the effects of breaking and restoring a crucial interaction. Altogether, our results demonstrate that single-residue disruption can drastically reduce the effects of cross-seeding, a finding that has important implications for human protein misfolding disorders.Kathryn M. KeeferKevin C. SteinHeather L. TrueNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kathryn M. Keefer Kevin C. Stein Heather L. True Heterologous prion-forming proteins interact to cross-seed aggregation in Saccharomyces cerevisiae
description	Abstract The early stages of protein misfolding remain incompletely understood, as most mammalian proteinopathies are only detected after irreversible protein aggregates have formed. Cross-seeding, where one aggregated protein templates the misfolding of a heterologous protein, is one mechanism proposed to stimulate protein aggregation and facilitate disease pathogenesis. Here, we demonstrate the existence of cross-seeding as a crucial step in the formation of the yeast prion [PSI +], formed by the translation termination factor Sup35. We provide evidence for the genetic and physical interaction of the prion protein Rnq1 with Sup35 as a predominant mechanism leading to self-propagating Sup35 aggregation. We identify interacting sites within Rnq1 and Sup35 and determine the effects of breaking and restoring a crucial interaction. Altogether, our results demonstrate that single-residue disruption can drastically reduce the effects of cross-seeding, a finding that has important implications for human protein misfolding disorders.
format	article
author	Kathryn M. Keefer Kevin C. Stein Heather L. True
author_facet	Kathryn M. Keefer Kevin C. Stein Heather L. True
author_sort	Kathryn M. Keefer
title	Heterologous prion-forming proteins interact to cross-seed aggregation in Saccharomyces cerevisiae
title_short	Heterologous prion-forming proteins interact to cross-seed aggregation in Saccharomyces cerevisiae
title_full	Heterologous prion-forming proteins interact to cross-seed aggregation in Saccharomyces cerevisiae
title_fullStr	Heterologous prion-forming proteins interact to cross-seed aggregation in Saccharomyces cerevisiae
title_full_unstemmed	Heterologous prion-forming proteins interact to cross-seed aggregation in Saccharomyces cerevisiae
title_sort	heterologous prion-forming proteins interact to cross-seed aggregation in saccharomyces cerevisiae
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/259adbae8b134b91a3ddc1e372d5a9a2
work_keys_str_mv	AT kathrynmkeefer heterologousprionformingproteinsinteracttocrossseedaggregationinsaccharomycescerevisiae AT kevincstein heterologousprionformingproteinsinteracttocrossseedaggregationinsaccharomycescerevisiae AT heatherltrue heterologousprionformingproteinsinteracttocrossseedaggregationinsaccharomycescerevisiae
_version_	1718384830508433408

Heterologous prion-forming proteins interact to cross-seed aggregation in Saccharomyces cerevisiae

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