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CryoEM structures of the multimeric secreted NS1, a major factor for dengue hemorrhagic fever

Author

Listed:
  • Bo Shu

    (Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School
    National University of Singapore)

  • Justin S. G. Ooi

    (Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School
    National University of Singapore)

  • Aaron W. K. Tan

    (Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School
    National University of Singapore)

  • Thiam-Seng Ng

    (Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School
    National University of Singapore)

  • Wanwisa Dejnirattisai

    (University of Oxford)

  • Juthathip Mongkolsapaya

    (University of Oxford)

  • Guntur Fibriansah

    (Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School
    National University of Singapore)

  • Jian Shi

    (National University of Singapore)

  • Victor A. Kostyuchenko

    (Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School
    National University of Singapore)

  • Gavin R. Screaton

    (University of Oxford)

  • Shee-Mei Lok

    (Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School
    National University of Singapore)

Abstract

Dengue virus infection can cause dengue hemorrhagic fever (DHF). Dengue NS1 is multifunctional. The intracellular dimeric NS1 (iNS1) forms part of the viral replication complex. Previous studies suggest the extracellular secreted NS1 (sNS1), which is a major factor contributing to DHF, exists as hexamers. The structure of the iNS1 is well-characterised but not that of sNS1. Here we show by cryoEM that the recombinant sNS1 exists in multiple oligomeric states: the tetrameric (stable and loose conformation) and hexameric structures. Stability of the stable and loose tetramers is determined by the conformation of their N-terminal domain – elongated β-sheet or β-roll. Binding of an anti-NS1 Fab breaks the loose tetrameric and hexameric sNS1 into dimers, whereas the stable tetramer remains largely unbound. Our results show detailed quaternary organization of different oligomeric states of sNS1 and will contribute towards the design of dengue therapeutics.

Suggested Citation

  • Bo Shu & Justin S. G. Ooi & Aaron W. K. Tan & Thiam-Seng Ng & Wanwisa Dejnirattisai & Juthathip Mongkolsapaya & Guntur Fibriansah & Jian Shi & Victor A. Kostyuchenko & Gavin R. Screaton & Shee-Mei Lok, 2022. "CryoEM structures of the multimeric secreted NS1, a major factor for dengue hemorrhagic fever," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34415-1
    DOI: 10.1038/s41467-022-34415-1
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