The yeast global transcriptional co-repressor protein Cyc8 can propagate as a prion

Patel, Basant K.; Gavin-Smyth, Jackie; Liebman, Susan W.

doi:10.1038/ncb1843

Cited by 239 publications

(199 citation statements)

References 28 publications

(54 reference statements)

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“…Expression of peptides with a specific Q-rich region, like the QA-repeat of Gts1p or TCERG1/CA150, might present a strategy to interfere with Htt toxicity. However, regions with QA-repeats may themselves tend to aggregate, as reflected by the aggregation propensity of Gts1p (21,62) and Cyc8p, another yeast prion with a QA-repeat (63). Indeed, expansion of the QA-repeat of TCERG1/CA150 can lead to an earlier onset of HD (60), presumably by placing a burden on the cellular proteostasis system (10).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Q-rich prion-like proteins suppresses polyQ cytotoxicity and alters the polyQ interactome

Ripaud¹,

Chumakova²,

Antonin³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Expansion of a poly-glutamine (polyQ) repeat in a group of functionally unrelated proteins is the cause of several inherited neurodegenerative disorders, including Huntington's disease. The polyQ length-dependent aggregation and toxicity of these disease proteins can be reproduced in Saccharomyces cerevisiae. This system allowed us to screen for genes that when overexpressed reduce the toxic effects of an N-terminal fragment of mutant huntingtin with 103 Q. Surprisingly, among the identified suppressors were three proteins with Q-rich, prion-like domains (PrDs): glycine threonine serine repeat protein (Gts1p), nuclear polyadenylated RNA-binding protein 3, and minichromosome maintenance protein 1. Overexpression of the PrD of Gts1p, containing an imperfect 28 residue glutamine-alanine repeat, was sufficient for suppression of toxicity. Association with this discontinuous polyQ domain did not prevent 103Q aggregation, but altered the physical properties of the aggregates, most likely early in the assembly pathway, as reflected in their increased SDS solubility. Molecular simulations suggested that Gts1p arrests the aggregation of polyQ molecules at the level of nonfibrillar species, acting as a cap that destabilizes intermediates on path to form large fibrils. Quantitative proteomic analysis of polyQ interactors showed that expression of Gts1p reduced the interaction between polyQ and other prion-like proteins, and enhanced the association of molecular chaperones with the aggregates. These findings demonstrate that short, Q-rich peptides are able to shield the interactive surfaces of toxic forms of polyQ proteins and direct them into nontoxic aggregates.protein aggregation | protein misfolding | neurodegeneration | prion | polyglutamine proteins

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Section: Discussionmentioning

confidence: 99%

Overexpression of Q-rich prion-like proteins suppresses polyQ cytotoxicity and alters the polyQ interactome

Ripaud¹,

Chumakova²,

Antonin³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Prions (Wickner 1994;Coustou et al 1997;Derkatch et al 2001;Du et al 2008;Alberti et al 2009;Nemecek et al 2009;Patel et al 2009;Rogoza et al 2010). Sup35p is a subunit of the translation termination factor; Rnq1p has no known function; Swi1p, Cyc8p, Mot3p, and Sfp1 are transcription factors; and Mca1p is a metacaspase (putative protease).…”

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confidence: 99%

Prion-Forming Ability of Ure2 of Yeasts Is Not Evolutionarily Conserved

et al. 2011

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ABSTRACT[URE3] is a prion (infectious protein) of the Saccharomyces cerevisiae Ure2p, a regulator of nitrogen catabolism. We show that wild S. paradoxus can be infected with a [URE3] prion, supporting the use of S. cerevisiae as a prion test bed. We find that the Ure2p of Candida albicans and C. glabrata also regulate nitrogen catabolism. Conservation of amino acid sequence within the prion domain of Ure2p has been proposed as evidence that the [URE3] prion helps its host. We show that the C. albicans Ure2p, which does not conserve this sequence, can nonetheless form a [URE3] prion in S. cerevisiae, but the C. glabrata Ure2p, which does have the conserved sequence, cannot form [URE3] as judged by its performance in S. cerevisiae. These results suggest that the sequence is not conserved to preserve prion forming ability.

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“…Rnq1p is rich in Q and N residues (hence its name) and had been shown capable of self-propagating aggregation (Sondheimer and Lindquist 2000). Derkatch et al showed that amyloid of Rnq1p was the basis of [PIN+] by applying the above three genetic criteria (Derkatch et al 2001 (Du et al 2008;Patel et al 2009;Suzuki et al 2012). It is expected that this method will be useful in finding prions of other organisms, particularly because the prion domain of Mod5p is not Q/N rich, unlike those of other yeast prions (Suzuki et al 2012).…”

Section: Phenotype Relationshipmentioning

confidence: 99%

Prions

Kryndushkin

Edskes

Shewmaker

et al. 2017

Cold Spring Harb Protoc

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Infectious proteins (prions) are usually self-templating filamentous protein polymers (amyloids). Yeast prions are genes composed of protein and, like the multiple alleles of DNA-based genes, can have an array of “variants,” each a distinct self-propagating amyloid conformation. Like the lethal mammalian prions and amyloid diseases, yeast prions may be lethal, or only mildly detrimental, and show an array of phenotypes depending on the protein involved and the prion variant. Yeast prions are models for both rare mammalian prion diseases and for several very common amyloidoses such as Alzheimer’s disease, type 2 diabetes, and Parkinson’s disease. Here, we describe their detection and characterization using genetic, cell biological, biochemical, and physical methods.

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The yeast global transcriptional co-repressor protein Cyc8 can propagate as a prion

Cited by 239 publications

References 28 publications

Overexpression of Q-rich prion-like proteins suppresses polyQ cytotoxicity and alters the polyQ interactome

Overexpression of Q-rich prion-like proteins suppresses polyQ cytotoxicity and alters the polyQ interactome

Prion-Forming Ability of Ure2 of Yeasts Is Not Evolutionarily Conserved

Prions

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