A dominant-negative mutant inhibits multiple prion variants through a common mechanism

Fen Pei, Susanne DiSalvo, Suzanne S. Sindi, Tricia R. Serio

Research output: Research - peer-reviewArticle

Abstract

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.

LanguageEnglish (US)
Article numbere1007085
JournalPLoS Genetics
Volume13
Issue number10
DOIs
StatePublished - Oct 1 2017

Fingerprint

prions
mutants
mutant
Prions
amyloid
Amyloid
phenotype
inhibitor
dosage
Phenotype
plasticity
fragmentation
kinetics
protein
dose
effect
protein conformation
molecular chaperones
mechanism of action
cells

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

A dominant-negative mutant inhibits multiple prion variants through a common mechanism. / Pei, Fen; DiSalvo, Susanne; Sindi, Suzanne S.; Serio, Tricia R.

In: PLoS Genetics, Vol. 13, No. 10, e1007085, 01.10.2017.

Research output: Research - peer-reviewArticle

Pei, Fen ; DiSalvo, Susanne ; Sindi, Suzanne S. ; Serio, Tricia R./ A dominant-negative mutant inhibits multiple prion variants through a common mechanism. In: PLoS Genetics. 2017 ; Vol. 13, No. 10.
@article{08384704154d4585ba090f3572f29567,
title = "A dominant-negative mutant inhibits multiple prion variants through a common mechanism",
abstract = "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.",
author = "Fen Pei and Susanne DiSalvo and Sindi, {Suzanne S.} and Serio, {Tricia R.}",
year = "2017",
month = "10",
doi = "10.1371/journal.pgen.1007085",
volume = "13",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "10",

}

TY - JOUR

T1 - A dominant-negative mutant inhibits multiple prion variants through a common mechanism

AU - Pei,Fen

AU - DiSalvo,Susanne

AU - Sindi,Suzanne S.

AU - Serio,Tricia R.

PY - 2017/10/1

Y1 - 2017/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85033237088&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85033237088&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1007085

DO - 10.1371/journal.pgen.1007085

M3 - Article

VL - 13

JO - PLoS Genetics

T2 - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 10

M1 - e1007085

ER -