View from an mRNP: The Roles of SR Proteins in Assembly, Maturation and Turnover

Wegener, Marius; Müller-McNicoll, Michaela

doi:10.1007/978-3-030-31434-7_3

Cited by 37 publications

(70 citation statements)

References 158 publications

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“…2). SR-regions bind both RNA and proteins 25 . To gain insight into the molecular properties of the SR-region of N SARS-CoV-2 and its interaction with RNA, we combined NMR spectroscopy with molecular dynamics (MD) simulations.…”

Section: Resultsmentioning

confidence: 99%

“…SR-phosphorylation modulates RNA-induced phase separation. Phosphorylation of SR-domains provides functional specificity and adjustability to ribonucleoprotein formation 25 and impairs binding of SR-domains of pre-mRNA splicing factors to protein hydrogel droplets 27 . To gain insight into the impact of phosphorylation of the SR-region of N SARS-CoV-2 on its RNA binding, we performed MD simulations of the high-density SRstretch carrying phosphate groups at different serine residues ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

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Nucleocapsid protein of SARS-CoV-2 phase separates into RNA-rich polymerase-containing condensates

et al. 2020

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The etiologic agent of the Covid-19 pandemic is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The viral membrane of SARS-CoV-2 surrounds a helical nucleocapsid in which the viral genome is encapsulated by the nucleocapsid protein. The nucleocapsid protein of SARS-CoV-2 is produced at high levels within infected cells, enhances the efficiency of viral RNA transcription, and is essential for viral replication. Here, we show that RNA induces cooperative liquid–liquid phase separation of the SARS-CoV-2 nucleocapsid protein. In agreement with its ability to phase separate in vitro, we show that the protein associates in cells with stress granules, cytoplasmic RNA/protein granules that form through liquid-liquid phase separation and are modulated by viruses to maximize replication efficiency. Liquid–liquid phase separation generates high-density protein/RNA condensates that recruit the RNA-dependent RNA polymerase complex of SARS-CoV-2 providing a mechanism for efficient transcription of viral RNA. Inhibition of RNA-induced phase separation of the nucleocapsid protein by small molecules or biologics thus can interfere with a key step in the SARS-CoV-2 replication cycle.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Nucleocapsid protein of SARS-CoV-2 phase separates into RNA-rich polymerase-containing condensates

et al. 2020

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“…Analysis of the corresponding N proteins showed that the mutations are most frequent in the SR-region of N SARS-CoV-2 ( Figure 3A), which is conserved among human coronaviruses ( Figure S2). SR-regions bind both RNA and proteins (Wegener and Muller-McNicoll, 2019). To gain insight into the molecular properties of the SR-region of N SARS-CoV-2 and its interaction with RNA, we combined NMR spectroscopy with molecular dynamics (MD) simulations.…”

Section: Rna-interaction Of the Mutation-prone Sr-regionmentioning

confidence: 99%

“…Phosphorylation of SR-domains provides functional specificity and adjustability to ribonucleoprotein formation (Wegener and Muller-McNicoll, 2019) and impairs binding of SR-domains of pre-mRNA splicing factors to protein hydrogel droplets (Kwon et al, 2014). To gain insight into the impact of phosphorylation of the SRregion of N SARS-CoV-2 on its RNA binding, we performed MD simulations of the highdensity SR-stretch carrying phosphate groups at different serine residues ( Figure S4A).…”

Section: Sr-phosphorylation Modulates Rna-induced Phase Separationmentioning

confidence: 99%

“…To validate the results from MD simulation, we phosphorylated the SRpeptide in vitro using the serine/arginine protein kinase 1 (SRPK1) and performed NMR spectroscopy. SRPK1 phosphorylates SR-motifs and is involved in a wide spectrum of cellular activities including the regulation of viral genome replication (Fukuhara et al, 2006;Wegener and Muller-McNicoll, 2019). SRPK1phosphorylation resulted in two species, a single phosphorylation at S188 (Figure 4B, middle) and a di-phosphorylated state, which is heterogeneously phosphorylated at four different serines ( Figure 4B, bottom).…”

Section: Sr-phosphorylation Modulates Rna-induced Phase Separationmentioning

confidence: 99%

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Nucleocapsid protein of SARS-CoV-2 phase separates into RNA-rich polymerase-containing condensates

Savastano

Opakua

Ranković

et al. 2020

Preprint

136

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The etiologic agent of the Covid-19 pandemic is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The viral membrane of SARS-CoV-2 surrounds a helical nucleocapsid in which the viral genome is encapsulated by the nucleocapsid protein. The nucleocapsid protein of SARS-CoV-2 is produced at high levels within infected cells, enhances the efficiency of viral RNA transcription and is essential for viral replication. Here we show that RNA induces cooperative liquid-liquid phase separation of the SARS-CoV-2 nucleocapsid protein. In agreement with its ability to phase separate in vitro, we show that the protein associates in cells with stress granules, cytoplasmic RNA/protein granules that form through liquid-liquid phase separation and are modulated by viruses to maximize replication efficiency. Liquid-liquid phase separation generates high-density protein/RNA condensates that recruit the RNA-dependent RNA polymerase complex of SARS-CoV-2 providing a mechanism for efficient transcription of viral RNA. Inhibition of RNA-induced phase separation of the nucleocapsid protein by small molecules or biologics thus can interfere with a key step in the SARS-CoV-2 replication cycle.

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The RNA‐binding protein MEX3A is a prognostic factor and regulator of resistance to gemcitabine in pancreatic ductal adenocarcinoma

Panzeri

Manni²,

Capone

et al. 2020

Molecular Oncology

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View from an mRNP: The Roles of SR Proteins in Assembly, Maturation and Turnover

Cited by 37 publications

References 158 publications

Nucleocapsid protein of SARS-CoV-2 phase separates into RNA-rich polymerase-containing condensates

Nucleocapsid protein of SARS-CoV-2 phase separates into RNA-rich polymerase-containing condensates

Nucleocapsid protein of SARS-CoV-2 phase separates into RNA-rich polymerase-containing condensates

The RNA‐binding protein MEX3A is a prognostic factor and regulator of resistance to gemcitabine in pancreatic ductal adenocarcinoma

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