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

Author

Listed:
  • Einav Tayeb-Fligelman

    (UCLA
    UCLA
    UCLA
    Howard Hughes Medical Institute)

  • Jeannette T. Bowler

    (UCLA
    UCLA
    UCLA
    Howard Hughes Medical Institute)

  • Christen E. Tai

    (UCLA
    UCLA)

  • Michael R. Sawaya

    (UCLA
    UCLA
    UCLA
    Howard Hughes Medical Institute)

  • Yi Xiao Jiang

    (UCLA
    UCLA
    UCLA
    Howard Hughes Medical Institute)

  • Gustavo Garcia

    (UCLA)

  • Sarah L. Griner

    (UCLA
    UCLA
    UCLA
    Howard Hughes Medical Institute)

  • Xinyi Cheng

    (UCLA
    UCLA
    UCLA
    Howard Hughes Medical Institute)

  • Lukasz Salwinski

    (UCLA
    UCLA
    UCLA)

  • Liisa Lutter

    (UCLA
    UCLA
    UCLA
    Howard Hughes Medical Institute)

  • Paul M. Seidler

    (UCLA
    UCLA
    University of Southern California School of Pharmacy)

  • Jiahui Lu

    (UCLA
    UCLA
    UCLA
    Howard Hughes Medical Institute)

  • Gregory M. Rosenberg

    (UCLA
    UCLA
    UCLA
    Howard Hughes Medical Institute)

  • Ke Hou

    (UCLA
    UCLA
    UCLA
    Howard Hughes Medical Institute)

  • Romany Abskharon

    (UCLA
    UCLA
    UCLA
    Howard Hughes Medical Institute)

  • Hope Pan

    (UCLA
    UCLA
    UCLA
    Howard Hughes Medical Institute)

  • Chih-Te Zee

    (UCLA)

  • David R. Boyer

    (UCLA
    UCLA
    UCLA
    Howard Hughes Medical Institute)

  • Yan Li

    (UCLA
    UCLA)

  • Daniel H. Anderson

    (UCLA
    UCLA
    UCLA
    Howard Hughes Medical Institute)

  • Kevin A. Murray

    (UCLA
    UCLA
    UCLA
    Howard Hughes Medical Institute)

  • Genesis Falcon

    (UCLA)

  • Duilio Cascio

    (UCLA)

  • Lorena Saelices

    (UCLA
    UCLA
    University of Texas Southwestern Medical Center)

  • Robert Damoiseaux

    (UCLA
    UCLA
    UCLA
    UCLA)

  • Vaithilingaraja Arumugaswami

    (UCLA
    UCLA
    UCLA)

  • Feng Guo

    (UCLA
    UCLA
    UCLA)

  • David S. Eisenberg

    (UCLA
    UCLA
    UCLA
    Howard Hughes Medical Institute)

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.

Suggested Citation

  • 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 &, 2023. "Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37865-3
    DOI: 10.1038/s41467-023-37865-3
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    References listed on IDEAS

    as
    1. Mirren Charnley & Saba Islam & Guneet K. Bindra & Jeremy Engwirda & Julian Ratcliffe & Jiangtao Zhou & Raffaele Mezzenga & Mark D. Hulett & Kyunghoon Han & Joshua T. Berryman & Nicholas P. Reynolds, 2022. "Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Adriana Savastano & Alain Ibáñez de Opakua & Marija Rankovic & Markus Zweckstetter, 2020. "Nucleocapsid protein of SARS-CoV-2 phase separates into RNA-rich polymerase-containing condensates," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    3. Michael R. Sawaya & Shilpa Sambashivan & Rebecca Nelson & Magdalena I. Ivanova & Stuart A. Sievers & Marcin I. Apostol & Michael J. Thompson & Melinda Balbirnie & Jed J. W. Wiltzius & Heather T. McFar, 2007. "Atomic structures of amyloid cross-β spines reveal varied steric zippers," Nature, Nature, vol. 447(7143), pages 453-457, May.
    4. Shan Lu & Qiaozhen Ye & Digvijay Singh & Yong Cao & Jolene K. Diedrich & John R. Yates & Elizabeth Villa & Don W. Cleveland & Kevin D. Corbett, 2021. "The SARS-CoV-2 nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    5. Stuart A. Sievers & John Karanicolas & Howard W. Chang & Anni Zhao & Lin Jiang & Onofrio Zirafi & Jason T. Stevens & Jan Münch & David Baker & David Eisenberg, 2011. "Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation," Nature, Nature, vol. 475(7354), pages 96-100, July.
    6. Jiahui Lu & Qin Cao & Michael P. Hughes & Michael R. Sawaya & David R. Boyer & Duilio Cascio & David S. Eisenberg, 2020. "CryoEM structure of the low-complexity domain of hnRNPA2 and its conversion to pathogenic amyloid," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
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