Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils

Einav Tayeb-Fligelman, Jeannette T. Bowler, Christen E. Tai, Michael R. Sawaya, Yi Xiao Jiang, Gustavo Garcia, Sarah L. Griner, Xinyi Cheng, Lukasz Salwinski, Liisa Lutter, Paul M. Seidler, Jiahui Lu, Gregory M. Rosenberg, Ke Hou, Romany Abskharon, Hope Pan, Chih-Te Zee, David R. Boyer, Yan Li, Daniel H. Anderson, Kevin A. Murray, Genesis Falcon, Duilio Cascio, Lorena Saelices, Robert Damoiseaux, Vaithilingaraja Arumugaswami, Feng Guo and David S. Eisenberg ()
Additional contact information
Einav Tayeb-Fligelman: UCLA
Jeannette T. Bowler: UCLA
Christen E. Tai: UCLA
Michael R. Sawaya: UCLA
Yi Xiao Jiang: UCLA
Gustavo Garcia: UCLA
Sarah L. Griner: UCLA
Xinyi Cheng: UCLA
Lukasz Salwinski: UCLA
Liisa Lutter: UCLA
Paul M. Seidler: UCLA
Jiahui Lu: UCLA
Gregory M. Rosenberg: UCLA
Ke Hou: UCLA
Romany Abskharon: UCLA
Hope Pan: UCLA
Chih-Te Zee: UCLA
David R. Boyer: UCLA
Yan Li: UCLA
Daniel H. Anderson: UCLA
Kevin A. Murray: UCLA
Genesis Falcon: UCLA
Duilio Cascio: UCLA
Lorena Saelices: UCLA
Robert Damoiseaux: UCLA
Vaithilingaraja Arumugaswami: UCLA
Feng Guo: UCLA
David S. Eisenberg: UCLA

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract The self-assembly of the Nucleocapsid protein (NCAP) of SARS-CoV-2 is crucial for its function. Computational analysis of the amino acid sequence of NCAP reveals low-complexity domains (LCDs) akin to LCDs in other proteins known to self-assemble as phase separation droplets and amyloid fibrils. Previous reports have described NCAP’s propensity to phase-separate. Here we show that the central LCD of NCAP is capable of both, phase separation and amyloid formation. Within this central LCD we identified three adhesive segments and determined the atomic structure of the fibrils formed by each. Those structures guided the design of G12, a peptide that interferes with the self-assembly of NCAP and demonstrates antiviral activity in SARS-CoV-2 infected cells. Our work, therefore, demonstrates the amyloid form of the central LCD of NCAP and suggests that amyloidogenic segments of NCAP could be targeted for drug development.

Date: 2023
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DOI: 10.1038/s41467-023-37865-3

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