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INSIGHTS INTO THE SPECIFICITY FOR THE INTERACTION OF THE PROMISCUOUS SARS-COV-2 NUCLEOCAPSID PROTEIN N-TERMINAL DOMAIN WITH DEOXYRIBONUCLEIC ACIDS
SARS-CoV-2
Proteína de ligação de DNA/RNA
Especificidade de ligação
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Abstract
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 Nterminal
domain (N-NTD) and N-NTD plus the SR-rich motif (N-NTD-SR) upon binding to single and doublestranded
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.
Keywords in Portuguese
Proteína do nucleocapsídeo SARS-CoV-2SARS-CoV-2
Proteína de ligação de DNA/RNA
Especificidade de ligação
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