RNA as a key factor in driving or preventing self-assembly of the TAR DNA-binding protein 43

Zacco, Elsa; Graña-Montes, Ricardo; Martin, Stephen R.; Groot, Natalia Sánchez de; Alfano, Caterina; Tartaglia, Gian Gaetano; Pastore, Annalisa

doi:10.1016/j.jmb.2019.01.028

Cited by 76 publications

(108 citation statements)

References 71 publications

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“…Removal of the RBD reduces the liquid-like behaviour of the condensate 22 in favour of interactions that lead to more solid-like aggregation 29,73 . In agreement with this finding, previous studies indicated the importance of RNA in SGs network specificity and organization 74 : RNA-binding proteins can be dragged in the condensates by RNA networks 31,37,75 . Indeed, RNA is a key modulator of the dynamics and material state of ribonucleoprotein complexes 70,76,77,78 and a highly structured RNA can provide the scaffold to allow formation of large assemblies 20,31 .…”

Section: Discussionsupporting

confidence: 83%

“…There is an intense debate on which protein regions contribute to the assembly and dynamics of biomolecular condensates 30,31,37,69,70,71,72 . Our computational analysis of H. sapiens and S. cerevisiae proteomes reveals that the PS propensity is intrinsically linked to occurrence of PrLDs and RBDs.…”

Section: Discussionmentioning

confidence: 99%

“…Specific RNA interactions result in abrogation of aggregation 37 and solubilisation of proteins 31 or, by contrast, increased condensation 20 .…”

Section: Introductionmentioning

confidence: 99%

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RNA-Binding and Prion Domains: The Yin and Yang of Phase Separation

Gotor

Armaos

Calloni

et al. 2020

Preprint

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Biomolecular condensates are membrane-less organelles mainly composed of proteins and RNAs that organize intracellular spaces and regulate biochemical reactions. The ability of proteins and RNAs to phase separate is encoded in their sequences, yet it is still unknown which domains drive the process and what are their specific roles. Here, we systematically investigated the human and yeast proteomes to find regions promoting biomolecular condensation. Using advanced computational models to predict the phase separation propensity of proteins, we designed a set of experiments to investigate the contributions of Prion-Like Domains (PrLDs) and RNA-Binding Domains (RBDs). We found that while just one PrLD is sufficient to drive protein condensation, multiple RBDs are needed to modulate the dynamicity of the assemblies. In the case of stress granule protein Pub1 we show that the PrLD promotes sequestration of protein partners and the RBD confers liquid-like behaviour to the condensate. Our work sheds light on the fine interplay between RBDs and PrLD to regulate formation of membrane-less organelles, opening up the avenue for their manipulation.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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RNA-Binding and Prion Domains: The Yin and Yang of Phase Separation

Gotor

Armaos

Calloni

et al. 2020

Preprint

Self Cite

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“…Furthermore, a recent study using a combination of biophysical approaches showed that both sequence and length of RNA can influence TDP-43 aggregation. Specifically, long UG repeats may help stabilize TDP-43 structure while excess non-specific RNA may promote aggregation (Zacco et al, 2019). Taken together these studies underscore the importance of a thorough characterization of the different TDP-43 conformations in the context of its RNA and protein partners.…”

Section: Rna As a Toxic Factormentioning

confidence: 87%

To Be or Not To Be…Toxic—Is RNA Association With TDP-43 Complexes Deleterious or Protective in Neurodegeneration?

Loganathan

Lehmkuhl

Eck

et al. 2020

Front. Mol. Biosci.

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TAR DNA binding protein (TDP-43) is a nucleic acid binding protein associated with insoluble cytoplasmic aggregates in several neurodegenerative disorders, including 97% of the ALS cases. In healthy individuals, TDP-43 is primarily localized to the nucleus; it can shuttle between the nucleus and the cytoplasm, and is involved in several aspects of RNA processing including transcription, splicing, RNA stability, transport, localization, stress granule (SG) formation, and translation. Upon stress, TDP-43 aggregates in the cytoplasm and associates with several types of RNA and protein assemblies, resulting in nuclear depletion of TDP-43. Under conditions of prolonged stress, cytoplasmic TDP-43 undergoes liquid-liquid phase separation (LLPS) and becomes less mobile. Evidence exists to support a scenario in which insoluble TDP-43 complexes sequester RNA and/or proteins causing disturbances in both ribostasis and proteostasis, which in turn contribute to neurodegeneration. However, the relationship between RNA binding and TDP-43 toxicity remains unclear. Recent studies provide conflicting views on the role of RNA in TDP-43 toxicity, with some finding RNA as a toxic factor whereby RNA binding contributes to TDP-43 toxicity, while others find RNA to be a protective factor that inhibits TDP-43 aggregation. Here we review and discuss these recent reports, which ultimately highlight the importance of understanding the heterogeneity of TDP-43 assemblies and collectively point to solubilizing TDP-43 as a potential therapeutic strategy.

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“…Others have shown that the CTD is not sufficient, but rather that the CTD combined with the RRM2 is required for significant accumulation of aggregates in cellular models (Johnson et al, 2008;Yang et al, 2010;Fallini et al, 2012;Wang et al, 2013). And indeed, as discussed above, the RRM domains contain amylogenic sequence elements that contribute to aggregation (Shodai et al, 2012(Shodai et al, , 2013Chiang et al, 2016;Guenther et al, 2018b) and constructs lacking the CTD have been shown to aggregate as well (Zacco et al, 2019).…”

Section: Liquid-liquid Phase Separation and Aggregationmentioning

confidence: 98%

Structural Insights Into TDP-43 and Effects of Post-translational Modifications

François‐Moutal

Perez‐Miller

Scott

et al. 2019

Front. Mol. Neurosci.

115

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Transactive response DNA binding protein (TDP-43) is a key player in neurodegenerative diseases. In this review, we have gathered and presented structural information on the different regions of TDP-43 with high resolution structures available. A thorough understanding of TDP-43 structure, effect of modifications, aggregation and sites of localization is necessary as we develop therapeutic strategies targeting TDP-43 for neurodegenerative diseases. We discuss how different domains as well as posttranslational modification may influence TDP-43 overall structure, aggregation and droplet formation. The primary aim of the review is to utilize structural insights as we develop an understanding of the deleterious behavior of TDP-43 and highlight locations of established and proposed post-translation modifications. TDP-43 structure and effect on localization is paralleled by many RNA-binding proteins and this review serves as an example of how structure may be modulated by numerous compounding elements.

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RNA as a key factor in driving or preventing self-assembly of the TAR DNA-binding protein 43

Cited by 76 publications

References 71 publications

RNA-Binding and Prion Domains: The Yin and Yang of Phase Separation

RNA-Binding and Prion Domains: The Yin and Yang of Phase Separation

To Be or Not To Be…Toxic—Is RNA Association With TDP-43 Complexes Deleterious or Protective in Neurodegeneration?

Structural Insights Into TDP-43 and Effects of Post-translational Modifications

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