Protein disorder, prion propensities, and self-organizing macromolecular collectives

Malinovska, Liliana; Kroschwald, Sonja; Alberti, Simon

doi:10.1016/j.bbapap.2013.01.003

Cited by 172 publications

(195 citation statements)

References 180 publications

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“…The connection of prion-like domains with RRMs seems to be a general feature of these domains, as similar observations have been made for S. cerevisiae (Fig. 1D, Left) and other organisms (13,28). Furthermore, we found specific associations of prion-like proteins with certain groups of gene ontology (GO) terms (Fig.…”

Section: Resultssupporting

confidence: 64%

“…To identify mechanisms controlling the aggregation of prion-like proteins in D. discoideum, we first studied the aggregation behavior of several well-characterized prion-like proteins. These proteins have been studied extensively in other organisms and have been shown to form cytosolic aggregates in S. cerevisiae, C. elegans, and mammalian cells (28,(30)(31)(32). In this study, we used the polyQ-containing exon 1 of human huntingtin with 103 consecutive glutamines (Q103) and a synthetic polyasparagine variant in which the glutamines were replaced by asparagines (N47), to account for the extreme N-richness of D. discoideum.…”

Section: Aggregation-prone Prion-like Proteins Do Not Aggregate In Thementioning

confidence: 99%

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Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

Malinovska

Palm

Gibson

et al. 2015

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

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Many protein-misfolding diseases are caused by proteins carrying prion-like domains. These proteins show sequence similarity to yeast prion proteins, which can interconvert between an intrinsically disordered and an aggregated prion state. The natural presence of prions in yeast has provided important insight into disease mechanisms and cellular proteostasis. However, little is known about prions in other organisms, and it is not yet clear whether the findings in yeast can be generalized. Using bioinformatics tools, we show that Dictyostelium discoideum has the highest content of prion-like proteins of all organisms investigated to date, suggesting that its proteome has a high overall aggregation propensity. To study mechanisms regulating these proteins, we analyze the behavior of several well-characterized prion-like proteins, such as an expanded version of human huntingtin exon 1 (Q103) and the prion domain of the yeast prion protein Sup35 (NM), in D. discoideum. We find that these proteins remain soluble and are innocuous to D. discoideum, in contrast to other organisms, where they form cytotoxic cytosolic aggregates. However, when exposed to conditions that compromise molecular chaperones, these proteins aggregate and become cytotoxic. We show that the disaggregase Hsp101, a molecular chaperone of the Hsp100 family, dissolves heat-induced aggregates and promotes thermotolerance. Furthermore, prion-like proteins accumulate in the nucleus, where they are targeted by the ubiquitin-proteasome system. Our data suggest that D. discoideum has undergone specific adaptations that increase the proteostatic capacity of this organism and allow for an efficient regulation of its prion-like proteome. molecular chaperones | proteostasis | Dictyostelium discoideum | protein aggregation | prion

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Section: Resultssupporting

confidence: 64%

Section: Aggregation-prone Prion-like Proteins Do Not Aggregate In Thementioning

confidence: 99%

Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

Malinovska

Palm

Gibson

et al. 2015

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

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“…5,162,163 Co-operative binding between LC domains can however transform them to stronger and stable interactions. 122 PrDs of prions that exhibit self assembly and aggregation are found to exist in disordered state and are also predicted to be IDRs/LC domains. [164][165][166] The biophysical nature and structural details of interaction between these domains in vivo remains to be clearly identified.…”

Section: Prion Like Domains In Neuronal Rnp Mediated Translationmentioning

confidence: 99%

“…190 Multivalent weak interactions among domains of protein assemblies are capable of promoting phase separation. 122,148,191 Similar multivalent interactions leading to phase separation are also implicated in the formation and of the post synaptic densitiy (PSD). 192 Several studies indicate that LC domains can drive assembly of RNP like aggregates.…”

Section: Prion Like Domains In Neuronal Rnp Mediated Translationmentioning

confidence: 99%

“…Notably, when classified according to cellular functions a statistically startling over-representation was seen for proteins involved in RNA binding, transport and processing in the collection of prion-domain containing proteins. 121,122 The unusual composition of the PrDs enables the ensemble of multiple cross b sheets that act as a nucleation point for aggregation of prion proteins. Short oligopeptide repeat sequences that reside within the PrDs also have role in the conformational plasticity.…”

Section: Characterization Of Prions and Prion Domainsmentioning

confidence: 99%

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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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Prion‐like proteins: from computational approaches to proteome‐wide analysis

et al. 2021

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Prions are self-perpetuating proteins able to switch between a soluble state and an aggregated-and-transmissible conformation. These proteinaceous entities have been widely studied in yeast, where they are involved in hereditable phenotypic adaptations.The notion that such proteins could play functional roles and be positively selected by evolution has triggered the development of computational tools to identify prion-like proteins in different kingdoms of life. These algorithms have succeeded in screening multiple proteomes, allowing the identification of prion-like proteins in a diversity of unrelated organisms, evidencing that the prion phenomenon is well conserved among species. Interestingly enough, prion-like proteins are not only connected with the formation of functional membraneless protein-nucleic acid coacervates, but are also linked to human diseases. This review addresses state-of-the-art computational approaches to identify prion-like proteins, describes proteome-wide analysis efforts, discusses these unique proteins' functional role, and illustrates recently validated examples in different domains of life.

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Protein disorder, prion propensities, and self-organizing macromolecular collectives

Cited by 172 publications

References 180 publications

Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

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

Prion‐like proteins: from computational approaches to proteome‐wide analysis

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