De novo design of synthetic prion domains

Toombs, James A.; Petri, Michelina; Paul, Kacy R.; Kan, Grace Y.; Ben‐Hur, Asa; Ross, Eric D.

doi:10.1073/pnas.1119366109

Cited by 135 publications

(192 citation statements)

References 45 publications

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“…Given that amyloid formation is a site-specific, recognition-based process (23)(24)(25)(26)(27), such steric and/or electrostatic alterations likely hinder aggregation; however, resulting aggregates are characterized by higher order and more rigid structure. Apparently, the more robust amyloids form due to a selection pressure requiring a higher stringency of intermolecular interactions to overcome the anti-aggregation effect of chaotropic ions.…”

Section: Discussionmentioning

confidence: 99%

“…The high primary sequence specificity of amyloid propagation has been clearly demonstrated through mutational studies, construction of synthetic prion, and species barrier studies (23)(24)(25)(26)(27)(28). However, the mechanism of a curious phenomenon in prion biology where a given peptide can misfold into a variety of distinct amyloid structures, each leading to a distinct transmissible or inheritable phenotype (29 -31), remains unclear.…”

mentioning

confidence: 99%

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Ion-specific Effects on Prion Nucleation and Strain Formation

Rubin

Khosravi

Bruce

et al. 2013

Journal of Biological Chemistry

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Background: Prion proteins may adopt multiple aggregate conformations, known as strains. Results: Kosmotropic and chaotropic anions exhibit opposite effects on aggregation kinetics and favor different strains. Conclusion: Both prion nucleation kinetics and prevailing strain patterns strongly depend on ionic composition of the aggregation mixture. Significance: Ionic composition is shown to be a critical determinant in the generation of prion strains.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Ion-specific Effects on Prion Nucleation and Strain Formation

Rubin

Khosravi

Bruce

et al. 2013

Journal of Biological Chemistry

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“…126 Recently synthetic prions have been made de novo enabled by the development of computer algorithms like PAPA (Prion Aggregation Prediction Algorithm) that uses amino acid composition to predict prion propensities of intrinsically disordered protein domains. 127 However, these analyses likely underestimate functional prion domains in the genome because several known prions are not enriched in Q/N residues. For instance, the yeast prion protein Mod5 lacks Q/N rich domains although it forms amyloid like fibers.…”

Section: Characterization Of Prions and Prion Domainsmentioning

confidence: 99%

Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

Sudhakaran

Ramaswami

2016

RNA Biology

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Long-term and short-term memories differ primarily in the duration of their retention. At a molecular level, long-term memory (LTM) is distinguished from short-term memory (STM) by its requirement for new gene expression. In addition to transcription (nuclear gene expression) the translation of stored mRNAs is necessary for LTM formation. The mechanisms and functions for temporal and spatial regulation of mRNAs required for LTM is a major contemporary problem, of interest from molecular, cell biological, neurobiological and clinical perspectives. This review discusses primary evidence in support for translational regulatory events involved in LTM and a model in which different phases of translation underlie distinct phases of consolidation of memories. However, it focuses largely on mechanisms of memory persistence and the role of prion-like domains in this defining aspect of long-term memory. We consider primary evidence for the concept that Cytoplasmic Polyadenylation Element Binding (CPEB) protein enables the persistence of formed memories by transforming in prion-like manner from a soluble monomeric state to a self-perpetuating and persistent polymeric translationally active state required for maintaining persistent synaptic plasticity. We further discuss prion-like domains prevalent on several other RNA-binding proteins involved in neuronal translational control underlying LTM. Growing evidence indicates that such RNA regulatory proteins are components of mRNP (RiboNucleoProtein) granules. In these proteins, prion-like domains, being intrinsically disordered, could mediate weak transient interactions that allow the assembly of RNP granules, a source of silenced mRNAs whose translation is necessary for LTM. We consider the structural bases for RNA granules formation as well as functions of disordered domains and discuss how these complicate the interpretation of existing experimental data relevant to general mechanisms by which prion-domain containing RBPs function in synapse specific plasticity underlying LTM.

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“…Unlike many amyloid-forming proteins that contain short, highly aggregation-prone segments, prion activity in the yeast PFDs appears to be more diffuse, with the prion-promoting residues distributed across larger, intrinsically disordered segments (15). Based on these data, we developed a prion aggregation prediction algorithm (PAPA) (17,18), which is able to discriminate with reasonable accuracy between Q/N-rich domains with and without prion activity.…”

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confidence: 99%

Generating new prions by targeted mutation or segment duplication

Paul

Hendrich

Waechter

et al. 2015

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

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Yeasts contain various protein-based genetic elements, termed prions, that result from the structural conversion of proteins into self-propagating amyloid forms. Most yeast prion proteins contain glutamine/asparagine (Q/N)-rich prion domains that drive prion activity. Here, we explore two mechanisms by which new prion domains could evolve. First, it has been proposed that mutation and natural selection will tend to result in proteins with aggregation propensities just low enough to function under physiological conditions and thus that a small number of mutations are often sufficient to cause aggregation. We hypothesized that if the ability to form prion aggregates was a sufficiently generic feature of Q/N-rich domains, many nonprion Q/N-rich domains might similarly have aggregation propensities on the edge of prion formation. Indeed, we tested four yeast Q/N-rich domains that had no detectable aggregation activity; in each case, a small number of rationally designed mutations were sufficient to cause the proteins to aggregate and, for two of the domains, to create prion activity. Second, oligopeptide repeats are found in multiple prion proteins, and expansion of these repeats increases prion activity. However, it is unclear whether the effects of repeat expansion are unique to these specific sequences or are a generic result of adding additional aggregation-prone segments into a protein domain. We found that within nonprion Q/N-rich domains, repeating aggregation-prone segments in tandem was sufficient to create prion activity. Duplication of DNA elements is a common source of genetic variation and may provide a simple mechanism to rapidly evolve prion activity.

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De novo design of synthetic prion domains

Cited by 135 publications

References 45 publications

Ion-specific Effects on Prion Nucleation and Strain Formation

Ion-specific Effects on Prion Nucleation and Strain Formation

Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains

Generating new prions by targeted mutation or segment duplication

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