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The hepatitis C virus envelope protein complex is a dimer of heterodimers

Augestad, Elias Honerød ; Holmboe Olesen, Christina ; Grønberg, Christina ; Soerensen, Andreas ; Velázquez-Moctezuma, Rodrigo ; Fanalista, Margherita ; Bukh, Jens ; Wang, Kaituo ; Gourdon, Pontus LU and Prentoe, Jannick (2024) In Nature 633(8030). p.704-709
Abstract

Fifty-eight million individuals worldwide are affected by chronic hepatitis C virus (HCV) infection, a primary driver of liver cancer for which no vaccine is available1. The HCV envelope proteins E1 and E2 form a heterodimer (E1/E2), which is the target for neutralizing antibodies2. However, the higher-order organization of these E1/E2 heterodimers, as well as that of any Hepacivirus envelope protein complex, remains unknown. Here we determined the cryo-electron microscopy structure of two E1/E2 heterodimers in a homodimeric arrangement. We reveal how the homodimer is established at the molecular level and provide insights into neutralizing antibody evasion and membrane fusion by HCV, as orchestrated by E2 motifs... (More)

Fifty-eight million individuals worldwide are affected by chronic hepatitis C virus (HCV) infection, a primary driver of liver cancer for which no vaccine is available1. The HCV envelope proteins E1 and E2 form a heterodimer (E1/E2), which is the target for neutralizing antibodies2. However, the higher-order organization of these E1/E2 heterodimers, as well as that of any Hepacivirus envelope protein complex, remains unknown. Here we determined the cryo-electron microscopy structure of two E1/E2 heterodimers in a homodimeric arrangement. We reveal how the homodimer is established at the molecular level and provide insights into neutralizing antibody evasion and membrane fusion by HCV, as orchestrated by E2 motifs such as hypervariable region 1 and antigenic site 412, as well as the organization of the transmembrane helices, including two internal to E1. This study addresses long-standing questions on the higher-order oligomeric arrangement of Hepacivirus envelope proteins and provides a critical framework in the design of novel HCV vaccine antigens.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature
volume
633
issue
8030
pages
6 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:39232163
  • scopus:85200413744
ISSN
0028-0836
DOI
10.1038/s41586-024-07783-5
language
English
LU publication?
yes
id
4482ec3b-3fe5-4591-a669-088f93bb4ee5
date added to LUP
2025-01-09 12:02:41
date last changed
2025-07-11 16:46:10
@article{4482ec3b-3fe5-4591-a669-088f93bb4ee5,
  abstract     = {{<p>Fifty-eight million individuals worldwide are affected by chronic hepatitis C virus (HCV) infection, a primary driver of liver cancer for which no vaccine is available<sup>1</sup>. The HCV envelope proteins E1 and E2 form a heterodimer (E1/E2), which is the target for neutralizing antibodies<sup>2</sup>. However, the higher-order organization of these E1/E2 heterodimers, as well as that of any Hepacivirus envelope protein complex, remains unknown. Here we determined the cryo-electron microscopy structure of two E1/E2 heterodimers in a homodimeric arrangement. We reveal how the homodimer is established at the molecular level and provide insights into neutralizing antibody evasion and membrane fusion by HCV, as orchestrated by E2 motifs such as hypervariable region 1 and antigenic site 412, as well as the organization of the transmembrane helices, including two internal to E1. This study addresses long-standing questions on the higher-order oligomeric arrangement of Hepacivirus envelope proteins and provides a critical framework in the design of novel HCV vaccine antigens.</p>}},
  author       = {{Augestad, Elias Honerød and Holmboe Olesen, Christina and Grønberg, Christina and Soerensen, Andreas and Velázquez-Moctezuma, Rodrigo and Fanalista, Margherita and Bukh, Jens and Wang, Kaituo and Gourdon, Pontus and Prentoe, Jannick}},
  issn         = {{0028-0836}},
  language     = {{eng}},
  number       = {{8030}},
  pages        = {{704--709}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature}},
  title        = {{The hepatitis C virus envelope protein complex is a dimer of heterodimers}},
  url          = {{http://dx.doi.org/10.1038/s41586-024-07783-5}},
  doi          = {{10.1038/s41586-024-07783-5}},
  volume       = {{633}},
  year         = {{2024}},
}