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Soluble oligomers are sufficient for transmission of a yeast prion but do not confer phenotype.

ABSTRACT: Amyloidogenic proteins aggregate through a self-templating mechanism that likely involves oligomeric or prefibrillar intermediates. For disease-associated amyloidogenic proteins, such intermediates have been suggested to be the primary cause of cellular toxicity. However, isolation and characterization of these oligomeric intermediates has proven difficult, sparking controversy over their biological relevance in disease pathology. Here, we describe an oligomeric species of a yeast prion protein in cells that is sufficient for prion transmission and infectivity. These oligomers differ from the classic prion aggregates in that they are soluble and less resistant to SDS. We found that large, SDS-resistant aggregates were required for the prion phenotype but that soluble, more SDS-sensitive oligomers contained all the information necessary to transmit the prion conformation. Thus, we identified distinct functional requirements of two types of prion species for this endogenous epigenetic element. Furthermore, the nontoxic, self-replicating amyloid conformers of yeast prion proteins have again provided valuable insight into the mechanisms of amyloid formation and propagation in cells.

SUBMITTER: Dulle JE

PROVIDER: S-EPMC3812976 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Soluble oligomers are sufficient for transmission of a yeast prion but do not confer phenotype.

Dulle Jennifer E JE Bouttenot Rachel E RE Underwood Lisa A LA True Heather L HL

The Journal of cell biology 20131021 2

Amyloidogenic proteins aggregate through a self-templating mechanism that likely involves oligomeric or prefibrillar intermediates. For disease-associated amyloidogenic proteins, such intermediates have been suggested to be the primary cause of cellular toxicity. However, isolation and characterization of these oligomeric intermediates has proven difficult, sparking controversy over their biological relevance in disease pathology. Here, we describe an oligomeric species of a yeast prion protein ...[more]

PMID: 24145167

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Project description:BackgroundPrions are transmissible, propagating alternative states of proteins, and are usually made from the fibrillar, beta-sheet-rich assemblies termed amyloid. Prions in the budding yeast Saccharomyces cerevisiae propagate heritable phenotypes, uncover hidden genetic variation, function in large-scale gene regulation, and can act like diseases. Almost all these amyloid prions have asparagine/glutamine-rich (N/Q-rich) domains. Other proteins, that we term here 'prionogenic amyloid formers' (PAFs), have been shown to form amyloid in vivo, and to have N/Q-rich domains that can propagate heritable states in yeast cells. Also, there are >200 other S.cerevisiae proteins with prion-like N/Q-rich sequence composition. Furthermore, human proteins with such N/Q-rich composition have been linked to the pathomechanisms of neurodegenerative amyloid diseases.ResultsHere, we exploit the increasing abundance of complete fungal genomes to examine the ancestry of prions/PAFs and other N/Q-rich proteins across the fungal kingdom. We find distinct evolutionary behavior for Q-rich and N-rich prions/PAFs; those of ancient ancestry (outside the budding yeasts, Saccharomycetes) are Q-rich, whereas N-rich cases arose early in Saccharomycetes evolution. This emergence of N-rich prion/PAFs is linked to a large-scale emergence of N-rich proteins during Saccharomycetes evolution, with Saccharomycetes showing a distinctive trend for population sizes of prion-like proteins that sets them apart from all the other fungi. Conversely, some clades, e.g. Eurotiales, have much fewer N/Q-rich proteins, and in some cases likely lose them en masse, perhaps due to greater amyloid intolerance, although they contain relatively more non-N/Q-rich predicted prions. We find that recent mutational tendencies arising during Saccharomycetes evolution (i.e., increased numbers of N residues and a tendency to form more poly-N tracts), contributed to the expansion/development of the prion phenomenon. Variation in these mutational tendencies in Saccharomycetes is correlated with the population sizes of prion-like proteins, thus implying that selection pressures on N/Q-rich protein sequences against amyloidogenesis are not generally maintained in budding yeasts.ConclusionsThese results help to delineate further the limits and origins of N/Q-rich prions, and provide insight as a case study of the evolution of compositionally-defined protein domains.

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Soluble oligomers are sufficient for transmission of a yeast prion but do not confer phenotype.

Publications

Soluble oligomers are sufficient for transmission of a yeast prion but do not confer phenotype.

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