A dominant-negative mutant inhibits multiple prion variants through a common mechanism.
Prions adopt alternative, self-replicating protein conformations and thereby determine novel phenotypes that are often irreversible. Nevertheless, dominant-negative prion mutants can revert phenotypes associated with some conformations. These observations suggest that, while intervention is possible...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-10-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC5679637?pdf=render |
| _version_ | 1818693541357944832 |
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| author | Fen Pei Susanne DiSalvo Suzanne S Sindi Tricia R Serio |
| author_facet | Fen Pei Susanne DiSalvo Suzanne S Sindi Tricia R Serio |
| author_sort | Fen Pei |
| collection | DOAJ |
| description | Prions adopt alternative, self-replicating protein conformations and thereby determine novel phenotypes that are often irreversible. Nevertheless, dominant-negative prion mutants can revert phenotypes associated with some conformations. These observations suggest that, while intervention is possible, distinct inhibitors must be developed to overcome the conformational plasticity of prions. To understand the basis of this specificity, we determined the impact of the G58D mutant of the Sup35 prion on three of its conformational variants, which form amyloids in S. cerevisiae. G58D had been previously proposed to have unique effects on these variants, but our studies suggest a common mechanism. All variants, including those reported to be resistant, are inhibited by G58D but at distinct doses. G58D lowers the kinetic stability of the associated amyloid, enhancing its fragmentation by molecular chaperones, promoting Sup35 resolubilization, and leading to amyloid clearance particularly in daughter cells. Reducing the availability or activity of the chaperone Hsp104, even transiently, reverses curing. Thus, the specificity of inhibition is determined by the sensitivity of variants to the mutant dosage rather than mode of action, challenging the view that a unique inhibitor must be developed to combat each variant. |
| first_indexed | 2024-12-17T13:15:19Z |
| format | Article |
| id | doaj.art-19dc8ec6a21141b0ae5b8611e492c8db |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-17T13:15:19Z |
| publishDate | 2017-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-19dc8ec6a21141b0ae5b8611e492c8db2022-12-21T21:47:01ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042017-10-011310e100708510.1371/journal.pgen.1007085A dominant-negative mutant inhibits multiple prion variants through a common mechanism.Fen PeiSusanne DiSalvoSuzanne S SindiTricia R SerioPrions adopt alternative, self-replicating protein conformations and thereby determine novel phenotypes that are often irreversible. Nevertheless, dominant-negative prion mutants can revert phenotypes associated with some conformations. These observations suggest that, while intervention is possible, distinct inhibitors must be developed to overcome the conformational plasticity of prions. To understand the basis of this specificity, we determined the impact of the G58D mutant of the Sup35 prion on three of its conformational variants, which form amyloids in S. cerevisiae. G58D had been previously proposed to have unique effects on these variants, but our studies suggest a common mechanism. All variants, including those reported to be resistant, are inhibited by G58D but at distinct doses. G58D lowers the kinetic stability of the associated amyloid, enhancing its fragmentation by molecular chaperones, promoting Sup35 resolubilization, and leading to amyloid clearance particularly in daughter cells. Reducing the availability or activity of the chaperone Hsp104, even transiently, reverses curing. Thus, the specificity of inhibition is determined by the sensitivity of variants to the mutant dosage rather than mode of action, challenging the view that a unique inhibitor must be developed to combat each variant.http://europepmc.org/articles/PMC5679637?pdf=render |
| spellingShingle | Fen Pei Susanne DiSalvo Suzanne S Sindi Tricia R Serio A dominant-negative mutant inhibits multiple prion variants through a common mechanism. PLoS Genetics |
| title | A dominant-negative mutant inhibits multiple prion variants through a common mechanism. |
| title_full | A dominant-negative mutant inhibits multiple prion variants through a common mechanism. |
| title_fullStr | A dominant-negative mutant inhibits multiple prion variants through a common mechanism. |
| title_full_unstemmed | A dominant-negative mutant inhibits multiple prion variants through a common mechanism. |
| title_short | A dominant-negative mutant inhibits multiple prion variants through a common mechanism. |
| title_sort | dominant negative mutant inhibits multiple prion variants through a common mechanism |
| url | http://europepmc.org/articles/PMC5679637?pdf=render |
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