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

Shu B., Ooi JSG., Tan AWK., Ng T-S., Dejnirattisai W., Mongkolsapaya J., Fibriansah G., Shi J., Kostyuchenko VA., Screaton GR., Lok S-M.

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.

DOI

10.1038/s41467-022-34415-1

Type

Journal article

Journal

Nature communications

Publication Date

11/2022

Volume

13

Addresses

Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, 169857, Singapore.

Keywords

Humans, Dengue Virus, Dengue, Noonan Syndrome, Viral Nonstructural Proteins, Severe Dengue

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