The SARS-CoV-2 nucleocapsid protein is dynamic, disordered, and phase separates with RNA

Nat Commun. 2021 Mar 29;12(1):1936. doi: 10.1038/s41467-021-21953-3.

Abstract

The SARS-CoV-2 nucleocapsid (N) protein is an abundant RNA-binding protein critical for viral genome packaging, yet the molecular details that underlie this process are poorly understood. Here we combine single-molecule spectroscopy with all-atom simulations to uncover the molecular details that contribute to N protein function. N protein contains three dynamic disordered regions that house putative transiently-helical binding motifs. The two folded domains interact minimally such that full-length N protein is a flexible and multivalent RNA-binding protein. N protein also undergoes liquid-liquid phase separation when mixed with RNA, and polymer theory predicts that the same multivalent interactions that drive phase separation also engender RNA compaction. We offer a simple symmetry-breaking model that provides a plausible route through which single-genome condensation preferentially occurs over phase separation, suggesting that phase separation offers a convenient macroscopic readout of a key nanoscopic interaction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites
  • COVID-19 / virology
  • Coronavirus Nucleocapsid Proteins / chemistry*
  • Coronavirus Nucleocapsid Proteins / metabolism*
  • Dimerization
  • Molecular Dynamics Simulation
  • Phosphoproteins / chemistry
  • Phosphoproteins / metabolism
  • Protein Conformation
  • Protein Domains
  • RNA, Viral / chemistry*
  • RNA, Viral / metabolism*
  • SARS-CoV-2 / chemistry*
  • SARS-CoV-2 / metabolism*

Substances

  • Coronavirus Nucleocapsid Proteins
  • Phosphoproteins
  • RNA, Viral
  • nucleocapsid phosphoprotein, SARS-CoV-2