Breakthrough study uncovers mechanism to inhibit RNA binding in SARS-CoV-2 nucleocapsid protein
Nikhil Prasad Fact checked by:Thailand Medical News Team Aug 08, 2024 4 months, 2 weeks, 3 days, 5 hours, 32 minutes ago
COVID-19 News: The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has driven extensive research into understanding the virus's structure and replication mechanisms. Among the various components of SARS-CoV-2, the nucleocapsid (N) protein plays a crucial role in encapsulating the viral RNA genome. Recent research has shed light on how specific modifications to this protein can inhibit its ability to bind RNA, a discovery that holds potential for new antiviral strategies.
.jpg)
Breakthrough study uncovers mechanism to inhibit RNA binding in SARS-CoV-2 nucleocapsid protein. SARS-CoV-2 nucleocapsid protein comprises five domains (N1 to N5, top). The construct shown in the zoom comprises three of these domains, N2, the RNA binding domain; N3, the disordered central domain containing two helices H1 (219 to 231) and H2 (248 to 255) and the serine-arginine–rich (SR) region that is hyperphosphorylated in infected cells; and the dimerization domain N4. This construct is referred to as N234. The sequence of the SR region is shown in blue.
Study Overview and Institutional Contributions
Researchers from multiple prestigious institutions contributed to this groundbreaking study. The team included scientists from Université Grenoble Alpes, CNRS, CEA, IBS in France, Evotec (France) SAS, the Department of Biochemistry and Molecular Biophysics at Columbia University, New York, and Sanofi R&D, Integrated Drug Discovery in France. Their collaborative efforts have provided detailed insights into the phosphorylation-dependent conformational changes in the SARS-CoV-2 N protein and how these changes impact its function.
Key Findings on Phosphorylation and RNA Binding
The central focus of this study that is covered in this
COVID-19 News report was the SR (serine-arginine-rich) region within the N protein. This region is known to undergo hyperphosphorylation in infected cells. Phosphorylation is a common post-translational modification where a phosphate group is added to specific amino acids within a protein, often altering its activity and interactions.
Using advanced nuclear magnetic resonance (NMR) spectroscopy, the researchers tracked structural changes in the N protein as it was phosphorylated by three key kinases: serine-arginine protein kinase 1 (SRPK1), glycogen synthase kinase 3 (GSK-3), and casein kinase 1 (CK1). They discovered that phosphorylation at eight specific sites within the SR region resulted in the inhibition of RNA binding. This inhibition occurred because the phosphorylated SR region interacted with the same interface on the N protein that normally binds RNA.
Detailed Mechanism of Inhibition
The study revealed that the interaction between the phosphorylated SR region and the RNA binding interface of the N protein was highly specific. When the SR region was phosphorylated by SRPK1 and GSK-3, i
t prevented the N protein from binding to RNA. However, phosphorylation by protein kinase A (PKA) did not have the same inhibitory effect. This specificity indicates that the particular pattern of phosphorylation by SRPK1, GSK-3, and CK1 is crucial for inhibiting RNA binding.
Phosphorylation of the SR region caused it to bind to the RNA binding domain of the N protein, effectively blocking the binding of RNA. This auto-inhibitory mechanism suggests that the phosphorylation pattern resulting from the activity of these kinases creates a conformational switch in the N protein that inhibits its interaction with RNA.
Implications for Viral Function and Replication
The N protein of SARS-CoV-2 is essential not only for protecting the viral RNA from the host's immune response but also for the assembly of new virus particles. By inhibiting RNA binding, phosphorylation may regulate the transition between different stages of the viral life cycle, such as genome packaging and unpackaging.
In practical terms, this means that phosphorylation could serve as a switch to control the N protein's ability to bind RNA at different stages of the virus's replication cycle. For instance, during the initial stages of infection, preventing RNA binding could help the virus evade the host's immune system. Later, during the assembly of new virus particles, dephosphorylation might restore the N protein's ability to bind RNA, facilitating the packaging of the viral genome.
Potential for Antiviral Strategies
Understanding the molecular details of this inhibitory mechanism opens potential pathways for developing antiviral therapies. Targeting the specific kinases responsible for the phosphorylation pattern that inhibits RNA binding, or developing molecules that can mimic the inhibitory effects of phosphorylation, could provide new strategies to disrupt the SARS-CoV-2 replication process.
Such therapeutic strategies could involve the use of small molecules or peptides that mimic the phosphorylated SR region, binding to the N protein and preventing RNA interaction. Alternatively, inhibitors of SRPK1, GSK-3, and CK1 could be explored as potential antiviral drugs, aiming to prevent the phosphorylation of the N protein and thereby disrupting the virus's ability to replicate and assemble.
Conclusion
This study offers valuable insights into the role of phosphorylation in regulating the function of the SARS-CoV-2 N protein. By elucidating the specific phosphorylation sites and their impact on RNA binding, the researchers have highlighted a potential mechanism that could be exploited for therapeutic purposes. The detailed understanding of how phosphorylation induces conformational changes that inhibit RNA binding provides a unique perspective on the viral life cycle and opens new avenues for antiviral drug development.
The study findings were published in the peer-reviewed journal: Science Advances.
https://www.science.org/doi/10.1126/sciadv.aax2323
For the latest
COVID-19 News, keep on logging to Thailand Medical News.
Read Also:
https://www.thailandmedical.news/news/sars-cov-2-nucleocapsid-protein-prevents-viral-degradation-by-disrupting-nonsense-mediated-mrna-decay
https://www.thailandmedical.news/news/coronavirus-nucleocapsid-protein-suppresses-innate-immune-response-through-disruption-of-nucleocytoplasmic-trafficking
Share
Tweet
Share
