1. Nucleation seed size determines amyloid clearance and establishes a barrier to prion appearance in yeast
- Author
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Jason Dark, Tricia R. Serio, Janice Villali, Teal M. Brechtel, Fen Pei, and Suzanne Sindi
- Subjects
Amyloid ,Saccharomyces cerevisiae Proteins ,Prions ,1.1 Normal biological development and functioning ,Saccharomyces cerevisiae ,Biophysics ,Nucleation ,Neurodegenerative ,Medical and Health Sciences ,Article ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,Underpinning research ,Structural Biology ,Acquired Cognitive Impairment ,2.1 Biological and endogenous factors ,Aetiology ,Cycloheximide ,Molecular Biology ,Heat-Shock Proteins ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,Extramural ,Neurosciences ,Transmissible Spongiform Encephalopathy (TSE) ,Biological Sciences ,biology.organism_classification ,Yeast ,Brain Disorders ,Emerging Infectious Diseases ,Infectious Diseases ,Chemical Sciences ,Dementia ,030217 neurology & neurosurgery ,Developmental Biology ,Peptide Termination Factors ,Clearance - Abstract
Amyloid appearance is a rare event that is promoted in the presence of other aggregated proteins. These aggregates were thought to act by templating the formation of an assembly-competent nucleation seed, but we find an unanticipated role for them in enhancing the persistence of amyloid after it arises. Specifically, Saccharoymyces cerevisiae Rnq1 amyloid reduces chaperone-mediated disassembly of Sup35 amyloid, promoting its persistence in yeast. Mathematical modeling and corresponding in vivo experiments link amyloid persistence to the conformationally defined size of the Sup35 nucleation seed and suggest that amyloid is actively cleared by disassembly below this threshold to suppress appearance of the [PSI+] prion in vivo. Remarkably, this framework resolves multiple known inconsistencies in the appearance and curing of yeast prions. Thus, our observations establish the size of the nucleation seed as a previously unappreciated characteristic of prion variants that is key to understanding transitions between prion states.
- Published
- 2020
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