A dominant-negative mutant inhibits multiple prion variants through a common mechanism
AffiliationUniv Arizona, Dept Mol & Cellular Biol
MetadataShow full item record
PublisherPUBLIC LIBRARY SCIENCE
CitationA dominant-negative mutant inhibits multiple prion variants through a common mechanism 2017, 13 (10):e1007085 PLOS Genetics
Rights© 2017 Pei et al. This is an open access article distributed under the terms of the Creative Commons Attribution License.
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AbstractPrions 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.
NoteOpen access journal.
VersionFinal published version
SponsorsNational Institute of General Medical Sciences [R01 GM1100740, R35 GM118042]
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