University of North Carolina (UNC) at Chapel Hill - Department of Biology; University of North Carolina (UNC) at Chapel Hill - Lineberger Comprehensive Cancer Center
We report that the SARS-CoV-2 nucleocapsid protein (N-protein) undergoes liquid-liquid phase separation (LLPS) with the viral genome and propose a model of viral packaging through LLPS. N-protein condenses with specific RNA sequences in the first 1000 nts (5'-End) under physiological conditions and condensation is enhanced at human body temperatures. Other regions of gRNA promote dissolution, counteracting aggregation of the large genome. This combination of elements ensures condensates of both specific molecular and physical identity, leading to exclusion of non-packaged RNA sequences. N-protein binds single-stranded RNA flanked by stable structured elements and these features specify the number and location 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 sequence and structure specific, sensitive to human body temperature, and manipulatable with small molecules thus presenting screenable processes for identifying antiviral compounds effective against SARS-CoV-2.
Iserman, Christiane and Roden, Christine Anne and Boerneke, Mark A. and Sealfon, Rachel and McLaughlin, Grace A. and Jungreis, Irwin and Park, Chris and Boppana, Avinash and Fritch, Ethan and Hou, Yixuan and Theesfeld, Chandra and Troyanskaya, Olga G. and Baric, Ralph S. and Sheahan, Timothy P. and Weeks, Kevin M. and Gladfelter, Amy S., Genomic RNA Elements Drive Phase Separation of the SARS-CoV-2 Nucleocapsid (July 2020). Available at SSRN: https://ssrn.com/abstract=3641948 or http://dx.doi.org/10.2139/ssrn.3641948
This version of the paper has not been formally peer reviewed.
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