Prions are affected by evolution at two levels

Wickner, Reed B.; Kelly, Amy C.

doi:10.1007/s00018-015-2109-6

Cited by 17 publications

(12 citation statements)

References 168 publications

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“…This finding is consistent with the idea that fragmentation efficiency is one of the key features that distinguishes prion from nonprion amyloid (43). However, amyloid of HET-s(218-289), which can induce a functional prion state (49), is stiff and strong. This result suggests that high fragmentation rates of amyloid may not be an absolute necessity for prion behavior and that other ''seeding'' mechanisms, such as secondary nucleation, may be equally important for certain prion amyloids.…”

Section: Discussionsupporting

confidence: 90%

“…S12). It is also interesting to note that multiple strains/variants of sup35 and PrP prions have been identified, and the amyloids they form in vitro showed significant heterogeneity, which is in contrast to the lack of strains and unique amyloid structure found for HET-s (49). sup35 can form strains that propagate strong and weak phenotypes (50).…”

Section: Discussionmentioning

confidence: 99%

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Mapping the Broad Structural and Mechanical Properties of Amyloid Fibrils

Lamour

Nassar

Chan

et al. 2017

Biophysical Journal

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Amyloids are fibrillar nanostructures of proteins that are assembled in several physiological processes in human cells (e.g., hormone storage) but also during the course of infectious (prion) and noninfectious (nonprion) diseases such as Creutzfeldt-Jakob and Alzheimer's diseases, respectively. How the amyloid state, a state accessible to all proteins and peptides, can be exploited for functional purposes but also have detrimental effects remains to be determined. Here, we measure the nanomechanical properties of different amyloids and link them to features found in their structure models. Specifically, we use shape fluctuation analysis and sonication-induced scission in combination with full-atom molecular dynamics simulations to reveal that the amyloid fibrils of the mammalian prion protein PrP are mechanically unstable, most likely due to a very low hydrogen bond density in the fibril structure. Interestingly, amyloid fibrils formed by HET-s, a fungal protein that can confer functional prion behavior, have a much higher Young's modulus and tensile strength than those of PrP, i.e., they are much stiffer and stronger due to a tighter packing in the fibril structure. By contrast, amyloids of the proteins RIP1/RIP3 that have been shown to be of functional use in human cells are significantly stiffer than PrP fibrils but have comparable tensile strength. Our study demonstrates that amyloids are biomaterials with a broad range of nanomechanical properties, and we provide further support for the strong link between nanomechanics and b-sheet characteristics in the amyloid core.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Mapping the Broad Structural and Mechanical Properties of Amyloid Fibrils

Lamour

Nassar

Chan

et al. 2017

Biophysical Journal

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“…The fact that prion function and evolution are affected at 2 levels (DNA and protein) has been recently pointed out by Wickner and Kelly. 64 (Table 2). Moreover, it is applicable to any hereditary prion allele, whenever it is amyloid or non-amyloid.…”

Section: Discussionmentioning

confidence: 99%

“…The first encodes the prion protein sequence, while the second describes the state of this material, and both affect prion functions and evolution. 64 Notably, the presence of a certain [PRION C ] allele in a cell does not mean that all molecules of the corresponding protein are transformed into the prion state: some portion of the native protein is also retained. [65][66][67] So, the symbol [PRION C ] signifies the availability of specific epigenetic mark, which is absent in the [prion ¡ ] cells.…”

Section: The Bimodularity Principle Of Hereditary Prion Allelesmentioning

confidence: 99%

Allelic variants of hereditary prions: The bimodularity principle

Tikhodeyev

Тарасов

Bondarev

2017

Prion

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Modern biology requires modern genetic concepts equally valid for all discovered mechanisms of inheritance, either "canonical" (mediated by DNA sequences) or epigenetic. Applying basic genetic terms such as "gene" and "allele" to protein hereditary factors is one of the necessary steps toward these concepts. The basic idea that different variants of the same prion protein can be considered as alleles has been previously proposed by Chernoff and Tuite. In this paper, the notion of prion allele is further developed. We propose the idea that any prion allele is a bimodular hereditary system that depends on a certain DNA sequence (DNA determinant) and a certain epigenetic mark (epigenetic determinant). Alteration of any of these 2 determinants may lead to establishment of a new prion allele. The bimodularity principle is valid not only for hereditary prions; it seems to be universal for any epigenetic hereditary factor.

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“…The newly formed [PSI+] and [URE3] prions are most often toxic or even lethal (17), and the infrequent occurrence of even their mildest forms (18)(19)(20) in wild strains indicates that they are, on the net, detrimental (19,21; reviewed in ref. 22). One expects that there should be antiprion systems that prevent prion formation or cure them as they arise.…”

mentioning

confidence: 99%

[PSI+] prion propagation is controlled by inositol polyphosphates

Wickner

Kelly

Bezsonov

et al. 2017

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

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The yeast prions [PSI+] and [URE3] are folded in-register parallel β-sheet amyloids of Sup35p and Ure2p, respectively. In a screen for antiprion systems curing [PSI+] without protein overproduction, we detected Siw14p as an antiprion element. An array of genetic tests confirmed that many variants of [PSI+] arising in the absence of Siw14p are cured by restoring normal levels of the protein. Siw14p is a pyrophosphatase specifically cleaving the β phosphate from 5-diphosphoinositol pentakisphosphate (5PP-IP), suggesting that increased levels of this or some other inositol polyphosphate favors [PSI+] propagation. In support of this notion, we found that nearly all variants of [PSI+] isolated in a WT strain were lost upon loss of , which encodes inositol polyphosphate multikinase. Inactivation of the Arg82p kinase by D131A and K133A mutations (preserving Arg82p's nonkinase transcription regulation functions) resulted the loss of its ability to support [PSI+] propagation. The loss of [PSI+] inΔ is independent of Hsp104's antiprion activity. [PSI+] variants requiring Arg82p could propagate in Δ (IP kinase), Δ (IP 5-kinase), Δ (IP 1-kinase), Δ (inositol pyrophosphatase), orΔ Δ mutants but not inΔ Δ orΔ Δ double mutants. Thus, nearly all [PSI+] prion variants require inositol poly-/pyrophosphates for their propagation, and at least IP or 5PP-IP can support [PSI+] propagation.

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Prions are affected by evolution at two levels

Cited by 17 publications

References 168 publications

Mapping the Broad Structural and Mechanical Properties of Amyloid Fibrils

Mapping the Broad Structural and Mechanical Properties of Amyloid Fibrils

Allelic variants of hereditary prions: The bimodularity principle

[PSI+] prion propagation is controlled by inositol polyphosphates

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