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PreprintCited by 0Mosquito-borne diseases and controlEnzyme Structure and FunctionProtein Structure and Dynamics

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Secreted dengue virus NS1 from infection is predominantly dimeric and in complex with high-density lipoprotein

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Chew, Bing Liang Alvin, Ngoh, An Qi, Phoo, Wint Wint, Chan, Kitti Wing Ki, Ser, Zheng, Tulsian, Nikhil K, Lim, Shiao See, Weng, Mei Jie Grace, Watanabe, Satoru, Choy, Milly M., Low, Jenny G., Ooi, Eng Eong, Ruedl, Christiane, Sobota, Radoslaw M., Vasudevan, Subhash G., Luo, Dahai·2024·eLife
DOI 10.7554/elife.90762.2

Preprint — published as 10.7554/elife.90762.3 · Paper page

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Abstract

Abstract Severe dengue infections are characterized by endothelial dysfunction shown to be associated with the secreted nonstructural protein 1 (sNS1), making it an attractive vaccine antigen and biotherapeutic target. To uncover the biologically relevant structure of sNS1, we obtained infection-derived sNS1 (isNS1) from DENV-infected Vero cells through immunoffinity purification instead of recombinant sNS1 (rsNS1) overexpressed in insect or mammalian cell lines. We found that isNS1 appeared as an approximately 250 kDa complex of NS1 and ApoA1 and further determined the cryoEM structures of isNS1 and its complex with a monoclonal antibody/Fab. Indeed, we found that the major species of isNS1 is a complex of the NS1 dimer partially embedded in a High-Density Lipoprotein (HDL) particle. Cross-linking mass spectrometry (XL-MS) studies confirmed that the isNS1 interacts with the major HDL component ApoA1 through interactions that map to the NS1 wing and hydrophobic domains. Furthermore, our studies demonstrated that the sNS1 in sera from DENV-infected mice and a human patient form a similar complex as isNS1. Our results report the molecular architecture of a biological form of sNS1 which may have implications for the molecular pathogenesis of dengue.

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Metadata

Authors
Chew, B. L. A., Ngoh, A. Q., Phoo, W. W., Chan, K. W. K., Ser, Z., Tulsian, N. K., Lim, S. S., Weng, M. J. G., Watanabe, S., Choy, M. M., Low, J. G., Ooi, E. E., Ruedl, C., Sobota, R. M., Vasudevan, S. G., & Luo, D.
Affiliations
  • Nanyang Technological University (SG)
  • Duke-NUS Medical School (SG)
  • Agency for Science, Technology and Research (SG)
  • National University of Singapore (SG)
  • Singapore General Hospital (SG)
  • Griffith University (AU)
Corresponding author
Luo, Dahai
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2024-02-20
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.90762.2
OpenAlex
W4391982582
Cited by
0
References
1
Type
posted content
Language
en
Open access
Licence
Locations
eLife (acceptedVersion, cc-by)
Funders
  • Ministry of Education - Singapore (T2EP30220-0020)
  • National Medical Research Council (MOH-OFIRG20nov-0002, MOHOFIRG18may-0006)
  • Agency for Science, Technology and Research (Career Development Fund 2021)
  • Lee Kong Chian School of Medicine, Nanyang Technological University (LKCMedicine Dean's Postdoctoral Fellowship)
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
dengue virus NS1, high-density lipoprotein, apolipoprotein A-I, protein-lipid complex, cryo-EM structure, cross-linking mass spectrometry, endothelial dysfunction, severe dengue, molecular pathogenesis, vaccine antigens

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