ArticleThe Journal of biological chemistry2024
Phosphorylation in the Ser/Arg-rich region of the nucleocapsid of SARS-CoV-2 regulates phase separation by inhibiting self-association of a distant helix.
Article in The Journal of biological chemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Direct interaction between human DDX1 and SARS-CoV-2 nucleocapsid protein is regulated by phosphorylation.The Journal of biological chemistry · 2026Article
- Peptide ligands to explore interactions with intrinsically disordered multidomain proteins: the case of SARS-CoV-2 nucleocapsid protein.Scientific reports · 2026Article
- Review
- Research progress of nucleocapsid protein of novel coronavirus: structure, function and targeted therapy.Archives of virology · 2026Review
- Overcoming host restrictions to enable continuous passaging of GII.3 human norovirus in human intestinal enteroids.Science advances · 2026Article
- Mapping SARS-CoV-2 Nucleocapsid Function with Nanobodies.bioRxiv : the preprint server for biology · 2026Article
- Mechanism of SARS-CoV-2 Nucleocapsid Protein Phosphorylation-Induced Functional Switch.Viruses · 2026Article
- Intramolecular loops control SARS-CoV-2 nucleocapsid protein self-association and nucleic acid binding dependent on phosphorylation.bioRxiv : the preprint server for biology · 2026Article
- Rewriting the viral script: post-translational modifications orchestrating SARS-CoV-2 pathogenesis and immune evasion.Frontiers in microbiology · 2026Review
- Phosphorylation toggles the SARS-CoV-2 nucleocapsid protein between two membrane-associated condensate states.Nature communications · 2025Article
- SARS-CoV-2 nucleocapsid protein directly prevents cGAS-DNA recognition through competitive binding.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Dynamic interactions of dimeric hub proteins underlie their diverse functions and structures: A comparative analysis of 14-3-3 and LC8.The Journal of biological chemistry · 2025Review
- Revealing the Potential of a Chimaera: a Peptide-Peptide Nucleic Acid Molecule Designed To Interact with the SARS-CoV-2 Nucleocapsid Protein.Angewandte Chemie (International ed. in English) · 2025Article
- Coupling of SARS-CoV-2 to Amyloid Fibrils and Liquid-Liquid Phase Separation.Current protein & peptide science · 2025Review
- Afobazole: a potential drug candidate which can inhibit SARS CoV-2 and mimicry of the human respiratory pacemaker protein.In silico pharmacology · 2025Article
- Intrinsic factors behind long COVID: exploring the role of nucleocapsid protein in thrombosis.PeerJ · 2025Review
- The Nucleocapsid (N) Proteins of Different Human Coronaviruses Demonstrate a Variable Capacity to Induce the Formation of Cytoplasmic Condensates.International journal of molecular sciences · 2024Article
- SARS-CoV-2 Assembly: Gaining Infectivity and Beyond.Viruses · 2024Review
- RNA-Protein Assemblies: A Review of Biophysical Principles and Coarse-Grained Modeling Approaches.Wiley interdisciplinary reviews. RNAReview
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Authors and funding
6 authors.
Funding
Abstract
The nucleocapsid protein (N) of SARS-CoV-2 is essential for virus replication, genome packaging, evading host immunity, and virus maturation. N is a multidomain protein composed of an independently folded monomeric N-terminal domain that is the primary site for RNA binding and a dimeric C-terminal domain that is essential for efficient phase separation and condensate formation with RNA. The domains are separated by a disordered Ser/Arg-rich region preceding a self-associating Leu-rich helix. Phosphorylation in the Ser/Arg region in infected cells decreases the viscosity of N:RNA condensates promoting viral replication and host immune evasion. The molecular level effect of phosphorylation, however, is missing from our current understanding. Using NMR spectroscopy and analytical ultracentrifugation, we show that phosphorylation destabilizes the self-associating Leu-rich helix 30 amino-acids distant from the phosphorylation site. NMR and gel shift assays demonstrate that RNA binding by the linker is dampened by phosphorylation, whereas RNA binding to the full-length protein is not significantly affected presumably due to retained strong interactions with the primary RNA-binding domain. Introducing a switchable self-associating domain to replace the Leu-rich helix confirms the importance of linker self-association to droplet formation and suggests that phosphorylation not only increases solubility of the positively charged elongated Ser/Arg region as observed in other RNA-binding proteins but can also inhibit self-association of the Leu-rich helix. These data highlight the effect of phosphorylation both at local sites and at a distant self-associating hydrophobic helix in regulating liquid-liquid phase separation of the entire protein.
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