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COVID19-NMR

COVID19-NMR

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Publications

DOI

Int. J. Biol. Macromol., (2022), 203, 466-480

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

I. P. Caruso, V. dos Santos Almeida, M. J. do Amaral, G. Caldas de Andrade, G. Rocha de Araújo, T. Stelling de Araújo, J. Moreira de Azevedo, G. Moreno Barbosa, L. Bartkevihi, P. Reis Bezerra, K. M. dos Santos Cabral, I. Otênio de Lourenço, C. L.F. Malizia-Motta, A. de Luna Marques, N. C. Mebus-Antunes, T. C. Neves-Martins, J. Maróstica de Sá, K. Sanches, M. Caique Santana-Silva, A. Azevedo Vasconcelos, M. da Silva Almeida, G. Cardoso de Amorim, C. Dinis Anobom, A. T. Da Poian, F. Gomes-Neto, A. S. Pinheiro, F. C.L. Almeida

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.

Funded by


Goethe Corona Fonds

DFG

Volkswagen Stiftung

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Coordination

Prof. Dr. Harald Schwalbe (Coordinator)
Institut für Organische Chemie und Chemische Biologie
Zentrum für Biomolekulare Magnetische Resonanz

Johann Wolfgang Goethe-Universität
N160-3.13
Max-von-Laue-Strasse 7
D-60438 Frankfurt am Main

Contact us

++49 69 798 29737
schwalbe@nmr.uni-frankfurt.de

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