Genomic RNA Elements Drive Phase Separation of the SARS-CoV-2 Nucleocapsid.
Mol Cell, 2020/12/17;80(6):1078-1091.e6.
Iserman C[1], Roden CA[2], Boerneke MA[3], Sealfon RSG[4], McLaughlin GA[1], Jungreis I[5], Fritch EJ[6], Hou YJ[7], Ekena J[1], Weidmann CA[3], Theesfeld CL[8], Kellis M[5], Troyanskaya OG[9], Baric RS[6], Sheahan TP[7], Weeks KM[3], Gladfelter AS[10]
Affiliations
PMID: 33290746DOI: 10.1016/j.molcel.2020.11.041
Impact factor: 19.328
Abstract
We report that the SARS-CoV-2 nucleocapsid protein (N-protein) undergoes liquid-liquid phase separation (LLPS) with viral RNA. N-protein condenses with specific RNA genomic elements under physiological buffer conditions and condensation is enhanced at human body temperatures (33°C and 37°C) and reduced at room temperature (22°C). RNA sequence and structure in specific genomic regions regulate N-protein condensation while other genomic regions promote condensate dissolution, potentially preventing aggregation of the large genome. At low concentrations, N-protein preferentially crosslinks to specific regions characterized by single-stranded RNA flanked by structured elements and these features specify the location, number, and strength of N-protein binding sites (valency). Liquid-like N-protein condensates form in mammalian cells in a concentration-dependent manner and can be altered by small molecules. Condensation of N-protein is RNA sequence and structure specific, sensitive to human body temperature, and manipulatable with small molecules, and therefore presents a screenable process for identifying antiviral compounds effective against SARS-CoV-2.
Keywords: SARS-CoV-2, Condensation, phase separation, packaging, RNP-MaP, RNA structure, nucleocapsid, coronavirus
MeSH terms
Animals; Antiviral Agents; COVID-19; Chlorocebus aethiops; Coronavirus Nucleocapsid Proteins; Drug Evaluation, Preclinical; Genome, Viral; HEK293 Cells; Humans; Nucleocapsid; Phosphoproteins; RNA, Viral; SARS-CoV-2; Vero Cells; COVID-19 Drug Treatment
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