The sensitive [<i>SWI</i><sup>+</sup>] prion

Hines, Justin K.; Craig, Elizabeth A.

doi:10.4161/pri.5.3.16895

Cited by 18 publications

(23 citation statements)

References 31 publications

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“…[ URE3 ] has been repeatedly characterized by relatively large intracellular aggregates and low propagon numbers, likely making it difficult for the prion to be fragmented and passed into progeny relative to other prions like [ PSI + ]. This idea is also consistent with numerous observations that [ URE3 ] is highly sensitive to reductions in chaperone activity, particularly with regard to Sis1 and Hsp104 16 , 27 , 62 , 63 …”

Section: Future Directions and Current Limitationssupporting

confidence: 92%

Prion-specific Hsp40 function: The role of the auxilin homolog Swa2

Oliver

Troisi

Hines

2017

Prion

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Yeast prions are protein-based genetic elements that propagate through cell populations via cytosolic transfer from mother to daughter cell. Molecular chaperone proteins including Hsp70, the Hsp40/J-protein Sis1, and Hsp104 are required for continued prion propagation, however the specific requirements of chaperone proteins differ for various prions. We recently reported that Swa2, the yeast homolog of the mammalian protein auxilin, is specifically required for the propagation of the prion [URE3].1 [URE3] propagation requires both a functional J-domain and the tetratricopeptide repeat (TPR) domain of Swa2, but does not require Swa2 clathrin binding. We concluded that the TPR domain determines the specificity of the genetic interaction between Swa2 and [URE3], and that this domain likely interacts with one or more proteins with a C-terminal EEVD motif. Here we extend that analysis to incorporate additional data that supports this hypothesis. We also present new data eliminating Hsp104 as the relevant Swa2 binding partner and discuss our findings in the context of other recent work involving Hsp90. Based on these findings, we propose a new model for Swa2's involvement in [URE3] propagation in which Swa2 and Hsp90 mediate the formation of a multi-protein complex that increases the number of sites available for Hsp104 disaggregation.

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Section: Future Directions and Current Limitationssupporting

confidence: 92%

Prion-specific Hsp40 function: The role of the auxilin homolog Swa2

Oliver

Troisi

Hines

2017

Prion

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“…Hence, even when a high [ RNQ +] variant is available to facilitate the formation of [ PSI +], the de novo formation of [ RNQ +] under our growth conditions occurs about 5 times more frequently. This places Rnq1 alongside other yeast prion proteins that all have a higher rate of formation than [ PSI +], and are thought to have a functional role in the cell [69]. Moreover, while the ability to induce [ PSI +] was not a requirement for isolation, every [ RNQ +] variant analyzed in this study was shown to facilitate [ PSI +] formation to some degree.…”

Section: Discussionmentioning

confidence: 84%

Spontaneous Variants of the [RNQ+] Prion in Yeast Demonstrate the Extensive Conformational Diversity Possible with Prion Proteins

2013

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Prion strains (or variants) are structurally distinct amyloid conformations arising from a single polypeptide sequence. The existence of prion strains has been well documented in mammalian prion diseases. In many cases, prion strains manifest as variation in disease progression and pathology, and in some cases, these prion strains also show distinct biochemical properties. Yet, the underlying basis of prion propagation and the extent of conformational possibilities available to amyloidogenic proteins remain largely undefined. Prion proteins in yeast that are also capable of maintaining multiple self-propagating structures have provided much insight into prion biology. Here, we explore the vast structural diversity of the yeast prion [RNQ+] in Saccharomyces cerevisiae. We screened for the formation of [RNQ+] in vivo, allowing us to calculate the rate of spontaneous formation as ~2.96x10-6, and successfully isolate several different [RNQ+] variants. Through a comprehensive set of biochemical and biological analyses, we show that these prion variants are indeed novel. No individual property or set of properties, including aggregate stability and size, was sufficient to explain the physical basis and range of prion variants and their resulting cellular phenotypes. Furthermore, all of the [RNQ+] variants that we isolated were able to facilitate the de novo formation of the yeast prion [PSI+], an epigenetic determinant of translation termination. This supports the hypothesis that [RNQ+] acts as a functional amyloid in regulating the formation of [PSI+] to produce phenotypic diversity within a yeast population and promote adaptation. Collectively, this work shows the broad spectrum of available amyloid conformations, and thereby expands the foundation for studying the complex factors that interact to regulate the propagation of distinct aggregate structures.

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“…Because yeast prions are formed of aggregates of normally functional proteins, the sequestration of the prion-forming protein within these aggregates typically results in a loss-of-function phenotype as the result of prion infection. Interestingly, in many cases, this loss of protein function causes complex pleiotropic effects as a consequence because the prion-forming protein is often a regulator of transcription or translation [4, 6, 7]. One particularly striking example is the prion-forming protein Swi1, which normally functions as part of the canonical Swi / Snf chromatin remodeling complex, responsible for regulating the expression of ~6% of all yeast genes [8, 9].…”

Section: Introductionmentioning

confidence: 99%

Determination of growth-phase dependent influences exerted by prions on yeast lipid content using HPTLC—densitometry

Sherma

Fried

Hines

2016

Acta Chromatographica

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Summary Prions of the baker’s yeast Saccharomyces cerevisiae allow for the inheritance of complex traits based solely on the acquisition of cytoplasmic protein aggregates and confer distinctive phenotypes to the cells which harbor them, creating heterogeneity within an otherwise clonal cell population. These phenotypes typically arise from a loss-of-function of the prion-forming protein that is unable to perform its normal cellular function(s) while sequestered in prion amyloid aggregates, but the specific biochemical consequences of prion infection are poorly understood. To begin to address this issue, we initiated a direct investigation into the potential control that yeast prions exert over fungal lipid content by utilizing the prions [URE3] and [PSI+], the first two prions discovered in yeast. We utilized silica gel high-performance thin-layer chromatography (HPTLC)–densitometry to conduct pair-wise quantifications of the relative levels of free sterols, free fatty acids, and triacylglycerols [petroleum ether–diethyl ether–acetic acid (80:20:1) mobile phase, phosphomolybdic acid (PMA) detection reagent]; steryl esters and squalene (hexane–petroleum ether–diethyl ether–acetic acid (50:20;5:1), PMA]; and phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol (chloroform–diethyl ether–acetic acid (65:25:4.5), cupric sulfate–phosphoric acid) in otherwise clonal prion-infected ([PSI+] or [URE3]) and prion-free ([psi−] or [ure-o]) cells in two growth phases: log-phase and stationary phase. Our analysis revealed multiple statistically significant differences (p < 0.00625) between prion-infected and prion-free cells. Interestingly, prion-induced changes varied dramatically by growth phase, indicating that prions exert differential influences on cell physiology between log and stationary growth. Further experimental replication and extension of the analysis to other prions is expected to resolve additional physiological effects of prion infection. This investigation demonstrates that HPTLC–densitometry is an effective method for studying prion-induced alterations in lipid content in yeast.

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The sensitive [SWI⁺] prion

Cited by 18 publications

References 31 publications

Prion-specific Hsp40 function: The role of the auxilin homolog Swa2

Prion-specific Hsp40 function: The role of the auxilin homolog Swa2

Spontaneous Variants of the [RNQ+] Prion in Yeast Demonstrate the Extensive Conformational Diversity Possible with Prion Proteins

Determination of growth-phase dependent influences exerted by prions on yeast lipid content using HPTLC—densitometry

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The sensitive [SWI+] prion

Cited by 18 publications

References 31 publications

Prion-specific Hsp40 function: The role of the auxilin homolog Swa2

Prion-specific Hsp40 function: The role of the auxilin homolog Swa2

Spontaneous Variants of the [RNQ+] Prion in Yeast Demonstrate the Extensive Conformational Diversity Possible with Prion Proteins

Determination of growth-phase dependent influences exerted by prions on yeast lipid content using HPTLC—densitometry

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The sensitive [SWI⁺] prion