The intrinsically disordered SARS-CoV-2 nucleoprotein in dynamic complex with its viral partner nsp3a
Luiza M. Bessa, Serafima Guseva, Aldo R. Camacho‐Zarco, Nicola Salvi, Damien Maurin, Laura Mariño, Maiia Botova, Anas Malki, Max Nanao, Malene Ringkjøbing Jensen, Rob W. H. Ruigrok, Martin Blackledge
Abstract
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.