The intrinsically disordered SARS-CoV-2 nucleoprotein in dynamic complex with its viral partner nsp3a

The processes of genome replication and transcription of SARS-CoV-2 represent important targets for viral inhibition. Betacoronaviral nucleoprotein (N) is a highly dynamic cofactor of the replication-transcription complex (RTC), whose function depends on an essential interaction with the amino-terminal ubiquitin-like domain of nsp3 (Ubl1). Here, we describe this complex (dissociation constant - 30 to 200 nM) at atomic resolution. The interaction implicates two linear motifs in the intrinsically disordered linker domain (N3), a hydrophobic helix ((219)LALLLLDRLNQL(230)) and a disordered polar strand ((243)GQTVTKKSAAEAS(255)), that mutually engage to form a bipartite interaction, folding N3 around Ubl1. This results in substantial collapse in the dimensions of dimeric N, forming a highly compact molecular chaperone, that regulates binding to RNA, suggesting a key role of nsp3 in the association of N to the RTC. The identification of distinct linear motifs that mediate an important interaction between essential viral factors provides future targets for development of innovative strategies against COVID-19.

Automated summary

The genome replication and transcription processes of SARS-CoV-2 are important targets for inhibiting the virus. The interaction between the nucleoprotein (N) and the amino-terminal ubiquitin-like domain of nsp3 (Ubl1), which is a cofactor of the replication-transcription complex, has been described at the atomic level. This interaction involves two linear motifs in the linker domain of N, which fold N around Ubl1 to regulate binding to RNA. The identification of these motifs provides future targets for developing innovative strategies against COVID-19.