tetano
Editor, Senior Moderator
Sci Adv
. 2023 Apr 5;9(14):eadg6473.
doi: 10.1126/sciadv.adg6473. Epub 2023 Apr 5.
A conserved oligomerization domain in the disordered linker of coronavirus nucleocapsid proteins
Huaying Zhao[SUP] 1 [/SUP], Di Wu[SUP] 2 [/SUP], Sergio A Hassan[SUP] 3 [/SUP], Ai Nguyen[SUP] 1 [/SUP], Jiji Chen[SUP] 4 [/SUP], Grzegorz Piszczek[SUP] 2 [/SUP], Peter Schuck[SUP] 1 [/SUP]
Affiliations
Abstract
The nucleocapsid (N-)protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a key role in viral assembly and scaffolding of the viral RNA. It promotes liquid-liquid phase separation (LLPS), forming dense droplets that support the assembly of ribonucleoprotein particles with as-of-yet unknown macromolecular architecture. Combining biophysical experiments, molecular dynamics simulations, and analysis of the mutational landscape, we describe a heretofore unknown oligomerization site that contributes to LLPS, is required for the assembly of higher-order protein-nucleic acid complexes, and is coupled to large-scale conformational changes of N-protein upon nucleic acid binding. The self-association interface is located in a leucine-rich sequence of the intrinsically disordered linker between N-protein folded domains and formed by transient helices assembling into trimeric coiled-coils. Critical residues stabilizing hydrophobic and electrostatic interactions between adjacent helices are highly protected against mutations in viable SARS-CoV-2 genomes, and the oligomerization motif is conserved across related coronaviruses, thus presenting a target for antiviral therapeutics.
. 2023 Apr 5;9(14):eadg6473.
doi: 10.1126/sciadv.adg6473. Epub 2023 Apr 5.
A conserved oligomerization domain in the disordered linker of coronavirus nucleocapsid proteins
Huaying Zhao[SUP] 1 [/SUP], Di Wu[SUP] 2 [/SUP], Sergio A Hassan[SUP] 3 [/SUP], Ai Nguyen[SUP] 1 [/SUP], Jiji Chen[SUP] 4 [/SUP], Grzegorz Piszczek[SUP] 2 [/SUP], Peter Schuck[SUP] 1 [/SUP]
Affiliations
- PMID: 37018390
- DOI: 10.1126/sciadv.adg6473
Abstract
The nucleocapsid (N-)protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a key role in viral assembly and scaffolding of the viral RNA. It promotes liquid-liquid phase separation (LLPS), forming dense droplets that support the assembly of ribonucleoprotein particles with as-of-yet unknown macromolecular architecture. Combining biophysical experiments, molecular dynamics simulations, and analysis of the mutational landscape, we describe a heretofore unknown oligomerization site that contributes to LLPS, is required for the assembly of higher-order protein-nucleic acid complexes, and is coupled to large-scale conformational changes of N-protein upon nucleic acid binding. The self-association interface is located in a leucine-rich sequence of the intrinsically disordered linker between N-protein folded domains and formed by transient helices assembling into trimeric coiled-coils. Critical residues stabilizing hydrophobic and electrostatic interactions between adjacent helices are highly protected against mutations in viable SARS-CoV-2 genomes, and the oligomerization motif is conserved across related coronaviruses, thus presenting a target for antiviral therapeutics.