Insights into the specificity for the interaction of the promiscuous SARS-CoV-2 nucleocapsid protein N-terminal domain with deoxyribonucleic acids

The SARS-CoV-2 nucleocapsid protein (N) is a multifunctional promiscuous nucleic acid-binding protein, which plays a major role in nucleocapsid assembly and discontinuous RNA transcription, facilitating the template switch of transcriptional regulatory sequences (TRS). Here, we dissect the structura...

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Bibliographic Details
Published in:International journal of biological macromolecules 2022-04, Vol.203, p.466-480
Main Authors: Caruso, Icaro Putinhon, dos Santos Almeida, Vitor, do Amaral, Mariana Juliani, de Andrade, Guilherme Caldas, de Araújo, Gabriela Rocha, de Araújo, Talita Stelling, de Azevedo, Jéssica Moreira, Barbosa, Glauce Moreno, Bartkevihi, Leonardo, Bezerra, Peter Reis, dos Santos Cabral, Katia Maria, de Lourenço, Isabella Otênio, Malizia-Motta, Clara L.F., de Luna Marques, Aline, Mebus-Antunes, Nathane Cunha, Neves-Martins, Thais Cristtina, de Sá, Jéssica Maróstica, Sanches, Karoline, Santana-Silva, Marcos Caique, Vasconcelos, Ariana Azevedo, da Silva Almeida, Marcius, de Amorim, Gisele Cardoso, Anobom, Cristiane Dinis, Da Poian, Andrea T., Gomes-Neto, Francisco, Pinheiro, Anderson S., Almeida, Fabio C.L.
Format: Article
Language:English
Subjects:
Binding Sites
Binding specificity
COVID-19 - virology
DNA - chemistry
DNA - metabolism
DNA/RNA binding protein
Gene Expression Regulation, Viral
Host-Pathogen Interactions
Humans
Hydrogen Bonding
Models, Molecular
Nucleic Acids - chemistry
Nucleic Acids - metabolism
Nucleocapsid Proteins - chemistry
Nucleocapsid Proteins - metabolism
Protein Binding
Protein Interaction Domains and Motifs
RNA - chemistry
RNA - metabolism
SARS-CoV-2 - physiology
SARS-CoV-2 nucleocapsid protein
Spectrum Analysis
Structure-Activity Relationship
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Description
Summary:The SARS-CoV-2 nucleocapsid protein (N) is a multifunctional promiscuous nucleic acid-binding protein, which plays a major role in nucleocapsid assembly and discontinuous RNA transcription, facilitating the template switch of transcriptional regulatory sequences (TRS). Here, we dissect the structural features of the N protein N-terminal domain (N-NTD) and N-NTD plus the SR-rich motif (N-NTD-SR) upon binding to single and double-stranded TRS DNA, as well as their activities for dsTRS melting and TRS-induced liquid-liquid phase separation (LLPS). Our study gives insights on the specificity for N-NTD(-SR) interaction with TRS. We observed an approximation of the triple-thymidine (TTT) motif of the TRS to β-sheet II, giving rise to an orientation difference of ~25° between dsTRS and non-specific sequence (dsNS). It led to a local unfavorable energetic contribution that might trigger the melting activity. The thermodynamic parameters of binding of ssTRSs and dsTRS suggested that the duplex dissociation of the dsTRS in the binding cleft is entropically favorable. We showed a preference for TRS in the formation of liquid condensates when compared to NS. Moreover, our results on DNA binding may serve as a starting point for the design of inhibitors, including aptamers, against N, a possible therapeutic target essential for the virus infectivity.
ISSN:0141-8130
1879-0003
DOI:10.1016/j.ijbiomac.2022.01.121