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

PLoS Genetics
Fen PeiT R Serio

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, chall...Continue Reading

References

Jun 24, 1997·Proceedings of the National Academy of Sciences of the United States of America·C Y KingK Wüthrich
Sep 18, 1997·The Journal of General Virology·R A SomervilleM Jeffrey
Sep 18, 1997·Proceedings of the National Academy of Sciences of the United States of America·K KanekoS B Prusiner
Jun 18, 1998·Annals of Neurology·S ShibuyaT Kitamoto
Oct 15, 1998·Nature Medicine·J SafarS B Prusiner
May 18, 1999·Biophysical Chemistry·J MaselM A Nowak
Jun 18, 2002·APMIS : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica·Michael A Tranulis
Jul 9, 2002·Molecular and Cellular Biology·Frédérique NessMick F Tuite
Sep 25, 2002·Proceedings of the National Academy of Sciences of the United States of America·Véronique PerrierAndrew C Wallace
May 30, 2003·Nature·Fiona HoustonNora Hunter
Dec 12, 2003·The Journal of Biological Chemistry·Valerie GrimmingerStefan Walter
Mar 27, 2004·PLoS Biology·Lev Z OsherovichJonathan S Weissman
Jun 10, 2004·Amyloid : the International Journal of Experimental and Clinical Investigation : the Official Journal of the International Society of Amyloidosis·Hitaru KishidaKiyotoshi Kaneko
Aug 11, 2004·The Journal of General Virology·Anne BuschmannMartin H Groschup
Oct 16, 2004·The Journal of General Virology·J-Y MadecT Baron
Oct 16, 2004·The Journal of General Virology·Leonor OrgeJ Pedro Simas
Oct 21, 2004·Journal of Cell Science·Carole CrozetVéronique Perrier
Dec 3, 2004·The Veterinary Record·H OnnaschH F Bassett
Dec 14, 2004·Journal of Veterinary Diagnostic Investigation : Official Publication of the American Association of Veterinary Laboratory Diagnosticians, Inc·D Gavier-WidénC Hård af Segerstad
Mar 11, 2006·The Journal of General Virology·Olivier AndréolettiFrédéric Lantier
Jul 1, 2006·Nature·Motomasa TanakaJonathan S Weissman
Jul 4, 2006·Brain : a Journal of Neurology·Clare R Trevitt, John Collinge
Jul 29, 2006·Journal of Virology·Ryuichiro AtarashiShigeru Katamine
Oct 20, 2006·Biochemical and Biophysical Research Communications·Frédéric RonzonThierry Baron
Jan 27, 2007·PLoS Biology·Prasanna Satpute-KrishnanTricia R Serio

❮ Previous
Next ❯

Citations

Jun 7, 2019·The Journal of Biological Chemistry·Jeremy J RyanMeredith E Jackrel
May 27, 2020·PLoS Computational Biology·Paul LemarreSuzanne S Sindi
May 23, 2018·FEMS Yeast Research·Amber TariqJames Shorter
Dec 6, 2019·Frontiers in Molecular Neuroscience·Lavrentii G DanilovStanislav A Bondarev
May 6, 2020·Nature Structural & Molecular Biology·Janice VillaliTricia R Serio
May 3, 2018·FEMS Yeast Research·Tricia R Serio

❮ Previous
Next ❯

Methods Mentioned

BETA
electrophoresis
fluorescence-based microscopy
flow cytometry
PCR
FACS
fluorescence microscopy

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.