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Genomic RNA Elements Drive Phase Separation of the SARS-CoV-2 Nucleocapsid

45 Pages Posted: 31 Jul 2020 Publication Status: Published

See all articles by Christiane Iserman

Christiane Iserman

University of North Carolina (UNC) at Chapel Hill - Department of Biology

Christine Anne Roden

University of North Carolina (UNC) at Chapel Hill - Department of Biology

Mark A. Boerneke

University of North Carolina (UNC) at Chapel Hill - Department of Chemistry

Rachel Sealfon

Flatiron Institute - Center for Computational Biology

Grace A. McLaughlin

University of North Carolina (UNC) at Chapel Hill - Department of Biology

Irwin Jungreis

Massachusetts Institute of Technology and Harvard University - Broad Institute

Chris Park

Flatiron Institute

Avinash Boppana

Princeton University - Department of Computer Science

Ethan Fritch

University of North Carolina (UNC) at Chapel Hill - Department of Microbiology and Immunology

Yixuan Hou

University of North Carolina (UNC) at Chapel Hill - Department of Epidemiology

Chandra Theesfeld

Princeton University - Lewis-Sigler Institute for Integrative Genomics

Olga G. Troyanskaya

Princeton University - Lewis-Sigler Institute for Integrative Genomics

Ralph S. Baric

University of North Carolina (UNC) at Chapel Hill - Department of Microbiology and Immunology

Timothy P. Sheahan

University of North Carolina (UNC) at Chapel Hill - Department of Epidemiology

Kevin M. Weeks

University of North Carolina (UNC) at Chapel Hill - Department of Chemistry

Amy S. Gladfelter

University of North Carolina (UNC) at Chapel Hill - Department of Biology; University of North Carolina (UNC) at Chapel Hill - Lineberger Comprehensive Cancer Center

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Abstract

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.

Suggested Citation

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.

Christiane Iserman

University of North Carolina (UNC) at Chapel Hill - Department of Biology ( email )

Coker Hall, CB #3280
120 South Road
Chapel Hill, NC
United States

Christine Anne Roden

University of North Carolina (UNC) at Chapel Hill - Department of Biology ( email )

Coker Hall, CB #3280
120 South Road
Chapel Hill, NC
United States

Mark A. Boerneke

University of North Carolina (UNC) at Chapel Hill - Department of Chemistry ( email )

NC
United States

Rachel Sealfon

Flatiron Institute - Center for Computational Biology ( email )

New York, NY 10010
United States

Grace A. McLaughlin

University of North Carolina (UNC) at Chapel Hill - Department of Biology ( email )

Coker Hall, CB #3280
120 South Road
Chapel Hill, NC
United States

Irwin Jungreis

Massachusetts Institute of Technology and Harvard University - Broad Institute ( email )

415 Main Street
Cambridge, MA 02142
United States

Chris Park

Flatiron Institute ( email )

New York, NY 10010
United States

Avinash Boppana

Princeton University - Department of Computer Science ( email )

35 Olden Street
Princeton, NJ 08540
United States

Ethan Fritch

University of North Carolina (UNC) at Chapel Hill - Department of Microbiology and Immunology ( email )

Chapel Hill, NC
United States

Yixuan Hou

University of North Carolina (UNC) at Chapel Hill - Department of Epidemiology ( email )

United States

Chandra Theesfeld

Princeton University - Lewis-Sigler Institute for Integrative Genomics ( email )

Carl Icahn Laboratory
Princeton, NJ 08544
United States

Olga G. Troyanskaya

Princeton University - Lewis-Sigler Institute for Integrative Genomics ( email )

Carl Icahn Laboratory
Princeton, NJ 08544
United States

Ralph S. Baric

University of North Carolina (UNC) at Chapel Hill - Department of Microbiology and Immunology ( email )

Timothy P. Sheahan

University of North Carolina (UNC) at Chapel Hill - Department of Epidemiology ( email )

United States

Kevin M. Weeks

University of North Carolina (UNC) at Chapel Hill - Department of Chemistry ( email )

NC
United States

Amy S. Gladfelter (Contact Author)

University of North Carolina (UNC) at Chapel Hill - Department of Biology ( email )

Coker Hall, CB #3280
120 South Road
Chapel Hill, NC
United States

University of North Carolina (UNC) at Chapel Hill - Lineberger Comprehensive Cancer Center ( email )

102 Ridge Road
Chapel Hill, NC 27514
United States

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