An Integrative Study of Protein-RNA Condensates Identifies Scaffolding RNAs and Reveals Players in Fragile X-Associated Tremor/Ataxia Syndrome

Cid-Samper, Fernando; Gelabert-Baldrich, Mariona; Lang, Benjamin; Lorenzo-Gotor, Nieves; Ponti, Riccardo Delli; Severijnen, Lies‐Anne; Bolognesi, Benedetta; Gelpí, Ellen; Hukema, Renate K.; Botta-Orfila, Teresa; Tartaglia, Gian Gaetano

doi:10.1016/j.celrep.2018.11.076

Cited by 66 publications

(120 citation statements)

References 83 publications

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“…In this way, we ensured enough Pub1 concentration to trigger its accumulation into condensates independently from environmental stresses 19,57 . Based on the multivalence of RBDs 11,12,13 and catGRANULE predictions ( Figure 2C and Figure S4) 20,40 , we expected that deletion of specific domains decrease the PS potential.…”

Section: A Model To Monitor Changes In Phase Separationmentioning

confidence: 99%

“…Since both RBDs and PrLDs have been found significantly enriched in phase-separating proteins 19,20,40 , we hypothesized that the two domains might be present and perhaps cooperate to induce condensation. For that reason, we tested whether their co-occurrence is significant.…”

Section: ; T-test F) Fisher Test Of the Association Between Prldmentioning

confidence: 99%

“…In order to select a suitable protein candidate, we ranked the whole yeast proteome according to the phase separation (predicted by catGRANULE) 20,40 and the prion propensities (predicted by PLAAC; Figure 2A) 46 . We found 94 proteins containing PrLD (PLAAC score > 25) and prone to phase separate (catGRANULE score > 0): the potential to form prions has been previously investigated experimentally for 55 of them 29 , 44 are nucleic-acid binding or have annotated RBDs 56 and 37 phase separate in fluorescent foci 29 .…”

Section: A Model To Monitor Changes In Phase Separationmentioning

confidence: 99%

“…The Pub1 protein binds polyuridilated RNA and is present in SGs under different stresses 19,57 . The Ps peak 20,40 of Pub1 overlaps with the second RBD (RBD2, a structured RNA Recognition Motif, RRM) and the PrLD 58 (Figure 2B, Figure S2 and Figure S3). Thus, in the PS region we have the two domains.…”

Section: A Model To Monitor Changes In Phase Separationmentioning

confidence: 99%

“…Thus, a condensate change the dynamicity (solid-or liquid-like behaviour), depending on the type of contacts established by the components, which, in turn, alter the ability to interact with the surrounding environment and the resulting functionality 5,9,10,18,19 . The disturbance of the contact network can impede the correct function of a ribonucleoprotein complex and trigger disease 18,20,21 . While in physiological conditions interactions between proteins are tightly regulated 22 , aberrant a occurs in pathologies such as Amyotrophic Lateral Sclerosis (ALS) that is characterised by aggregation Fused in Sarcoma Fus and its partners 23 .…”

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: A Model To Monitor Changes In Phase Separationmentioning

confidence: 99%

Section: ; T-test F) Fisher Test Of the Association Between Prldmentioning

confidence: 99%

Section: A Model To Monitor Changes In Phase Separationmentioning

confidence: 99%

Section: A Model To Monitor Changes In Phase Separationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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RNA‐protein interactions: Central players in coordination of regulatory networks

et al. 2020

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Changes in the abundance of protein and RNA molecules can impair the formation of complexes in the cell leading to toxicity and death. Here we exploit the information contained in protein, RNA and DNA interaction networks to provide a comprehensive view of the regulation layers controlling the concentration‐dependent formation of assemblies in the cell. We present the emerging concept that RNAs can act as scaffolds to promote the formation ribonucleoprotein complexes and coordinate the post‐transcriptional layer of gene regulation. We describe the structural and interaction network properties that characterize the ability of protein and RNA molecules to interact and phase separate in liquid‐like compartments. Finally, we show that presence of structurally disordered regions in proteins correlate with the propensity to undergo liquid‐to‐solid phase transitions and cause human diseases. Also see the video abstract here https://youtu.be/kfpqibsNfS0

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Overlapping mechanisms of lncRNA and expanded microsatellite RNA

Johnson

Cooper

2020

WIREs RNA

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RNA has major regulatory roles in a wide range of biological processes and a surge of RNA research has led to the classification of numerous functional RNA species. One example is long noncoding RNAs (lncRNAs) that are structurally complex transcripts >200 nucleotides (nt) in length and lacking a canonical open reading frame (ORF). Despite a general lack of sequence conservation and low expression levels, many lncRNAs have been shown to have functionality in diverse biological processes as well as in mechanisms of disease. In parallel with the growing understanding of lncRNA functions, there is a growing subset of microsatellite expansion disorders in which the primary mechanism of pathogenesis is an RNA gain of function arising from RNA transcripts from the mutant allele. Microsatellite expansion disorders are caused by an expansion of short (3-10 nt) repeats located within coding genes. Expanded repeat-containing RNA mediates toxicity through multiple mechanisms, the details of which remain only partially understood. The purpose of this review is to highlight the links between functional mechanisms of lncRNAs and the potential pathogenic mechanisms of expanded microsatellite RNA. These shared mechanisms include protein sequestration, peptide translation, micro-RNA (miRNA) processing, and miRNA sequestration. Recognizing the parallels between the normal functions of lncRNAs and the negative impact of expanded microsatellite RNA on biological processes can provide reciprocal understanding to the roles of both RNA species.

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An Integrative Study of Protein-RNA Condensates Identifies Scaffolding RNAs and Reveals Players in Fragile X-Associated Tremor/Ataxia Syndrome

Cited by 66 publications

References 83 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

RNA‐protein interactions: Central players in coordination of regulatory networks

Overlapping mechanisms of lncRNA and expanded microsatellite RNA

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