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Cysteine residues in a yeast viral A/B toxin crucially control host cell killing via pH-triggered disulfide rearrangements
K28 is a viral A/B protein toxin that intoxicates yeast and fungal cells by endocytosis and retrograde transport to the endoplasmic reticulum (ER). Although toxin translocation into the cytosol occurs on the oxidized α/β heterodimer, the precise mechanism of how the toxin crosses the ER membrane is...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391188/ https://www.ncbi.nlm.nih.gov/pubmed/28228551 http://dx.doi.org/10.1091/mbc.E16-12-0842 |
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author | Suzuki, Yutaka Schwartz, Sara L. Mueller, Nina C. Schmitt, Manfred J. |
author_facet | Suzuki, Yutaka Schwartz, Sara L. Mueller, Nina C. Schmitt, Manfred J. |
author_sort | Suzuki, Yutaka |
collection | PubMed |
description | K28 is a viral A/B protein toxin that intoxicates yeast and fungal cells by endocytosis and retrograde transport to the endoplasmic reticulum (ER). Although toxin translocation into the cytosol occurs on the oxidized α/β heterodimer, the precise mechanism of how the toxin crosses the ER membrane is unknown. Here we identify pH-triggered, toxin-intrinsic thiol rearrangements that crucially control toxin conformation and host cell killing. In the natural habitat and low-pH environment of toxin-secreting killer yeasts, K28 is structurally stable and biologically active as a disulfide-bonded heterodimer, whereas it forms inactive disulfide-bonded oligomers at neutral pH that are caused by activation and thiol deprotonation of β-subunit cysteines. Because such pH increase reflects the pH gradient during compartmental transport within target cells, potential K28 oligomerization in the ER lumen is prevented by protein disulfide isomerase. In addition, we show that pH-triggered thiol rearrangements in K28 can cause the release of cytotoxic α monomers, suggesting a toxin-intrinsic mechanism of disulfide bond reduction and α/β heterodimer dissociation in the cytosol. |
format | Online Article Text |
id | pubmed-5391188 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-53911882017-06-30 Cysteine residues in a yeast viral A/B toxin crucially control host cell killing via pH-triggered disulfide rearrangements Suzuki, Yutaka Schwartz, Sara L. Mueller, Nina C. Schmitt, Manfred J. Mol Biol Cell Articles K28 is a viral A/B protein toxin that intoxicates yeast and fungal cells by endocytosis and retrograde transport to the endoplasmic reticulum (ER). Although toxin translocation into the cytosol occurs on the oxidized α/β heterodimer, the precise mechanism of how the toxin crosses the ER membrane is unknown. Here we identify pH-triggered, toxin-intrinsic thiol rearrangements that crucially control toxin conformation and host cell killing. In the natural habitat and low-pH environment of toxin-secreting killer yeasts, K28 is structurally stable and biologically active as a disulfide-bonded heterodimer, whereas it forms inactive disulfide-bonded oligomers at neutral pH that are caused by activation and thiol deprotonation of β-subunit cysteines. Because such pH increase reflects the pH gradient during compartmental transport within target cells, potential K28 oligomerization in the ER lumen is prevented by protein disulfide isomerase. In addition, we show that pH-triggered thiol rearrangements in K28 can cause the release of cytotoxic α monomers, suggesting a toxin-intrinsic mechanism of disulfide bond reduction and α/β heterodimer dissociation in the cytosol. The American Society for Cell Biology 2017-04-15 /pmc/articles/PMC5391188/ /pubmed/28228551 http://dx.doi.org/10.1091/mbc.E16-12-0842 Text en © 2017 Suzuki et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. |
spellingShingle | Articles Suzuki, Yutaka Schwartz, Sara L. Mueller, Nina C. Schmitt, Manfred J. Cysteine residues in a yeast viral A/B toxin crucially control host cell killing via pH-triggered disulfide rearrangements |
title | Cysteine residues in a yeast viral A/B toxin crucially control host cell killing via pH-triggered disulfide rearrangements |
title_full | Cysteine residues in a yeast viral A/B toxin crucially control host cell killing via pH-triggered disulfide rearrangements |
title_fullStr | Cysteine residues in a yeast viral A/B toxin crucially control host cell killing via pH-triggered disulfide rearrangements |
title_full_unstemmed | Cysteine residues in a yeast viral A/B toxin crucially control host cell killing via pH-triggered disulfide rearrangements |
title_short | Cysteine residues in a yeast viral A/B toxin crucially control host cell killing via pH-triggered disulfide rearrangements |
title_sort | cysteine residues in a yeast viral a/b toxin crucially control host cell killing via ph-triggered disulfide rearrangements |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391188/ https://www.ncbi.nlm.nih.gov/pubmed/28228551 http://dx.doi.org/10.1091/mbc.E16-12-0842 |
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