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Cited by 13Mosquito-borne diseases and controlEnzyme Structure and FunctionSARS-CoV-2 and COVID-19 Research

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Structural basis of Zika virus NS1 multimerization and human antibody recognition

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Chew, Bing Liang Alvin, Ngoh, An Qi, Phoo, Wint Wint, Weng, Mei Jie Grace, Sheng, Ho Jun, Chan, Kitti Wing Ki, Tan, Eddie Yong Jun, Gelbart, Terri, Xu, Chenrui, Tan, Gene S., Vasudevan, Subhash G., Luo, Dahai·2024·npj Viruses
DOI 10.1038/s44298-024-00024-6PMC PMC11721437

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Abstract

Zika virus (ZIKV) belongs to the Flavivirus genus of the Flaviviridae family along with the four serotypes of dengue virus (DENV1–4). The recent global outbreaks of contemporary ZIKV strains demonstrated that infection can lead to neurological sequelae in adults and severe abnormalities in newborns that were previously unreported with ancestral strains. As such, there remains an unmet need for efficacious vaccines and antiviral agents against ZIKV. The non-structural protein 1 (NS1) is secreted from the infected cell and is thought to be associated with disease severity besides its proven usefulness for differential diagnoses. However, its physiologically relevant structure and pathogenesis mechanisms remain unclear. Here, we present high-resolution cryoEM structures of ZIKV recombinant secreted NS1 (rsNS1) and its complexes with three human monoclonal antibodies (AA12, EB9, GB5), as well as evidence for ZIKV infection-derived secreted NS1 (isNS1) binding to High Density Lipoprotein (HDL). We show that ZIKV rsNS1 forms tetramers and filamentous repeats of tetramers. We also observed that antibody binding did not disrupt the ZIKV NS1 tetramers as they bound to the wing and connector subdomain of the β-ladder. Our study reveals new insights into NS1 multimerization, highlights the need to distinguish the polymorphic nature of rsNS1 and isNS1, and expands the mechanistic basis of the protection conferred by antibodies targeting NS1.

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Metadata

Authors
Chew, B. L. A., Ngoh, A. Q., Phoo, W. W., Weng, M. J. G., Sheng, H. J., Chan, K. W. K., Tan, E. Y. J., Gelbart, T., Xu, C., Tan, G. S., Vasudevan, S. G., & Luo, D.
Affiliations
  • Nanyang Technological University (SG)
  • Duke-NUS Medical School (SG)
  • J. Craig Venter Institute (US)
Corresponding author
Vasudevan, Subhash G.
ORCID
Venue
npj Viruses
Publisher
Springer Science and Business Media LLC
Published
2024-04-25
Volume
2
Issue
1
Pages
14-14
ISSN
2948-1767 (ISSN-L)
DOI
10.1038/s44298-024-00024-6
PMC
PMC11721437
OpenAlex
W4395463826
Cited by
13
References
1
Citations by year
2026: 3 · 2025: 3 · 2024: 7
FWCI
5.31
Type
journal article
Language
en
Open access
Licence
Locations
  • npj Viruses (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DR-NTU (Nanyang Technological University) (submittedVersion)
Funders
  • National Medical Research Council of Singapore (MOH-OFIRG18may-0006; MOH-OFIRG20nov-0002)
  • Singapore Ministry of Education Academic Research Fund Tier 2 (T2EP30220-0020)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Keywords
Zika virus, NS1 protein, multimerization, tetramer structure, monoclonal antibodies, antibody binding, high-density lipoprotein, flavivirus, vaccine targets, antiviral agents

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