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; David S. Eisenberg

doi:10.1038/s41467-023-37865-3

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. AndersonKevin A. Murray, Genesis Falcon, Duilio Cascio, Lorena Saelices, Robert Damoiseaux, Vaithilingaraja Arumugaswami, Feng Guo, David S. Eisenberg

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English (US)
Article number	2379
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-37865-3
State	Published - Dec 2023
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Tayeb-Fligelman, E., Bowler, J. T., Tai, C. E., Sawaya, M. R., Jiang, Y. X., Garcia, G., Griner, S. L., Cheng, X., Salwinski, L., Lutter, L., Seidler, P. M., Lu, J., Rosenberg, G. M., Hou, K., Abskharon, R., Pan, H., Zee, C. T., Boyer, D. R., Li, Y., ... Eisenberg, D. S. (2023). Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils. Nature communications, 14(1), Article 2379. https://doi.org/10.1038/s41467-023-37865-3

Tayeb-Fligelman, E, Bowler, JT, Tai, CE, Sawaya, MR, Jiang, YX, Garcia, G, Griner, SL, Cheng, X, Salwinski, L, Lutter, L, Seidler, PM, Lu, J, Rosenberg, GM, Hou, K, Abskharon, R, Pan, H, Zee, CT, Boyer, DR, Li, Y, Anderson, DH, Murray, KA, Falcon, G, Cascio, D, Saelices, L, Damoiseaux, R, Arumugaswami, V, Guo, F & Eisenberg, DS 2023, 'Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils', Nature communications, vol. 14, no. 1, 2379. https://doi.org/10.1038/s41467-023-37865-3

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title = "Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils",

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{\textquoteright}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.",

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

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doi = "10.1038/s41467-023-37865-3",

language = "English (US)",

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AU - Tayeb-Fligelman, Einav

AU - Bowler, Jeannette T.

AU - Tai, Christen E.

AU - Sawaya, Michael R.

AU - Jiang, Yi Xiao

AU - Garcia, Gustavo

AU - Griner, Sarah L.

AU - Cheng, Xinyi

AU - Salwinski, Lukasz

AU - Lutter, Liisa

AU - Seidler, Paul M.

AU - Lu, Jiahui

AU - Rosenberg, Gregory M.

AU - Hou, Ke

AU - Abskharon, Romany

AU - Pan, Hope

AU - Zee, Chih Te

AU - Boyer, David R.

AU - Li, Yan

AU - Anderson, Daniel H.

AU - Murray, Kevin A.

AU - Falcon, Genesis

AU - Cascio, Duilio

AU - Saelices, Lorena

AU - Damoiseaux, Robert

AU - Arumugaswami, Vaithilingaraja

AU - Guo, Feng

AU - Eisenberg, David S.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

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

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