Influence of prion variant and yeast strain variation on prion-molecular chaperone requirements

Hines, Justin K.; Higurashi, Takashi; Srinivasan, Mathangi; Craig, Elizabeth A.

doi:10.4161/pri.17818

Cited by 25 publications

(67 citation statements)

References 34 publications

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“…Our work now provides a mechanistic explanation of these previous findings, supporting the hypothesis that different chaperone dependencies may be dictated by the exposure or conformation of different regions of the protein [99]. Indeed, these different amyloid-chaperone relationships likely explain why differences in the host environment, due to different genetic backgrounds or environmental conditions, can modulate prion propagation [100], [101]. Moreover, our data support the hypothesis that different host cofactors might interact with different amyloid structures to influence pathology [102].…”

Section: Discussionsupporting

confidence: 78%

Extensive Diversity of Prion Strains Is Defined by Differential Chaperone Interactions and Distinct Amyloidogenic Regions

Stein

True

2014

PLoS Genet

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Amyloidogenic proteins associated with a variety of unrelated diseases are typically capable of forming several distinct self-templating conformers. In prion diseases, these different structures, called prion strains (or variants), confer dramatic variation in disease pathology and transmission. Aggregate stability has been found to be a key determinant of the diverse pathological consequences of different prion strains. Yet, it remains largely unclear what other factors might account for the widespread phenotypic variation seen with aggregation-prone proteins. Here, we examined a set of yeast prion variants of the [RNQ+] prion that differ in their ability to induce the formation of another yeast prion called [PSI+]. Remarkably, we found that the [RNQ+] variants require different, non-contiguous regions of the Rnq1 protein for both prion propagation and [PSI+] induction. This included regions outside of the canonical prion-forming domain of Rnq1. Remarkably, such differences did not result in variation in aggregate stability. Our analysis also revealed a striking difference in the ability of these [RNQ+] variants to interact with the chaperone Sis1. Thus, our work shows that the differential influence of various amyloidogenic regions and interactions with host cofactors are critical determinants of the phenotypic consequences of distinct aggregate structures. This helps reveal the complex interdependent factors that influence how a particular amyloid structure may dictate disease pathology and progression.

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Section: Discussionsupporting

confidence: 78%

Extensive Diversity of Prion Strains Is Defined by Differential Chaperone Interactions and Distinct Amyloidogenic Regions

Stein

True

2014

PLoS Genet

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“…While its specific cellular functions are still unclear, Sis1 is also an essential yeast protein; yeast cells are inviable unless the J-domain of Sis1 is expressed in cis with at least one of these two glycine-rich regions, underscoring their biological importance [40]. However, despite being essential, Sis1's expression can be greatly reduced, or the protein may be truncated, resulting in the support of cell viability but not prion propagation [18] [23], [24], [25], [41], [42], [43]. For example, the C-terminal peptide-binding domain is generally dispensable for both viability and prion propagation [40] [41], [43].…”

Section: Introductionmentioning

confidence: 99%

Functional Diversification of Hsp40: Distinct J-Protein Functional Requirements for Two Prions Allow for Chaperone-Dependent Prion Selection

et al. 2014

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Yeast prions are heritable amyloid aggregates of functional yeast proteins; their propagation to subsequent cell generations is dependent upon fragmentation of prion protein aggregates by molecular chaperone proteins. Mounting evidence indicates the J-protein Sis1 may act as an amyloid specificity factor, recognizing prion and other amyloid aggregates and enabling Ssa and Hsp104 to act in prion fragmentation. Chaperone interactions with prions, however, can be affected by variations in amyloid-core structure resulting in distinct prion variants or ‘strains’. Our genetic analysis revealed that Sis1 domain requirements by distinct variants of [PSI +] are strongly dependent upon overall variant stability. Notably, multiple strong [PSI +] variants can be maintained by a minimal construct of Sis1 consisting of only the J-domain and glycine/phenylalanine-rich (G/F) region that was previously shown to be sufficient for cell viability and [RNQ +] prion propagation. In contrast, weak [PSI +] variants are lost under the same conditions but maintained by the expression of an Sis1 construct that lacks only the G/F region and cannot support [RNQ +] propagation, revealing mutually exclusive requirements for Sis1 function between these two prions. Prion loss is not due to [PSI +]-dependent toxicity or dependent upon a particular yeast genetic background. These observations necessitate that Sis1 must have at least two distinct functional roles that individual prions differentially require for propagation and which are localized to the glycine-rich domains of the Sis1. Based on these distinctions, Sis1 plasmid-shuffling in a [PSI +]/[RNQ +] strain permitted J-protein-dependent prion selection for either prion. We also found that, despite an initial report to the contrary, the human homolog of Sis1, Hdj1, is capable of [PSI +] prion propagation in place of Sis1. This conservation of function is also prion-variant dependent, indicating that only one of the two Sis1-prion functions may have been maintained in eukaryotic chaperone evolution.

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“…However, the ability of ClpB to replace Hsp104 in prion propagation in yeast [112], the requirement of additional cofactors, such as Sis1, a representative of the Hsp40 family, and yeast Hsp70 for the prion severing activity of Hsp104 [113,114], and the finding that binding of Hsp104 to prion aggregates needs Hsp70 activity, as found for ClpB [23,27], suggest that the overall functional mechanism of ClpB and Hsp104 is similar and that both protein disaggregation and prion fiber fragmentation rely on Hsp100-Hsp70 collaboration [21].…”

Section: Allosteric Communication Between the Motor Units Of The Hexamentioning

confidence: 99%

Chaperone-assisted protein aggregate reactivation: Different solutions for the same problem

Aguado

Fernández-Higuero

Moro

et al. 2015

Archives of Biochemistry and Biophysics

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Influence of prion variant and yeast strain variation on prion-molecular chaperone requirements

Cited by 25 publications

References 34 publications

Extensive Diversity of Prion Strains Is Defined by Differential Chaperone Interactions and Distinct Amyloidogenic Regions

Extensive Diversity of Prion Strains Is Defined by Differential Chaperone Interactions and Distinct Amyloidogenic Regions

Functional Diversification of Hsp40: Distinct J-Protein Functional Requirements for Two Prions Allow for Chaperone-Dependent Prion Selection

Chaperone-assisted protein aggregate reactivation: Different solutions for the same problem

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