A core network in the SARS-CoV-2 nucleocapsid NTD mediates structural integrity and selective RNA-binding

Karthikeyan Dhamotharan, Sophie M. Korn (), Anna Wacker, Matthias A. Becker, Sebastian Günther, Harald Schwalbe and Andreas Schlundt ()
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Karthikeyan Dhamotharan: Goethe University
Sophie M. Korn: Goethe University
Anna Wacker: Goethe University
Matthias A. Becker: Goethe University
Sebastian Günther: Notkestr. 85
Harald Schwalbe: Goethe University
Andreas Schlundt: Goethe University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract The SARS-CoV-2 nucleocapsid protein is indispensable for viral RNA genome processing. Although the N-terminal domain (NTD) is suggested to mediate specific RNA-interactions, high-resolution structures with viral RNA are still lacking. Available hybrid structures of the NTD with ssRNA and dsRNA provide valuable insights; however, the precise mechanism of complex formation remains elusive. Similarly, the molecular impact of nucleocapsid NTD mutations that have emerged since 2019 has not yet been fully explored. Using crystallography and solution NMR, we investigate how NTD mutations influence structural integrity and RNA-binding. We find that both features rely on a core network of residues conserved in Betacoronaviruses, crucial for protein stability and communication among flexible loop-regions that facilitate RNA-recognition. Our comprehensive structural analysis demonstrates that contacts within this network guide selective RNA-interactions. We propose that the core network renders the NTD evolutionarily robust in stability and plasticity for its versatile RNA processing roles.

Date: 2024
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DOI: 10.1038/s41467-024-55024-0

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