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 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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature |
| ISSN | 0028-0836 |
| DOI | |
| Status | E-pub ahead of print - 2024 |
Bibliografisk note
Funding Information:The authors thank T. H. Pape for assistance with sample screening and data collection; J. Conrad, K. Wallden, D. Morado and M. Carroni for sample screening and data collection; L. Mikkelsen, A. L. S\u00F8rensen and L. Nielsen for general laboratory support; B. \u00D8. Lindhardt and C. M. Bonefeld for support of the project; and T. Krey, M. Law, A. Patel and C. Rice for providing reagents. This work was supported by the Novo Nordisk BRIDGE grant NNF20SA0064340 (E.H.A.), Lundbeck Foundation Experiment grant R324-2019-1375 (J.P.), Lundbeck Foundation Experiment R346-2020-2019 (P.G.), Lundbeck Foundation Fellowship R335-2019-2052 (J.P.), Lundbeck Foundation Fellowship R133-A12689 (P.G.), Lundbeck Ascending Investigator R313-2019-774 (P.G.), Lundbeck Foundation Experiment R324-2019-1855 (K.W.), Lundbeck Foundation Postdoc R303-2018-3396 (R.V.-M.), Candys Foundation PhD grant 2016-195 (E.H.A., J.B. and J.P.), Candys Foundation PhD grant 2019-317 (C.H.O., J.B. and J.P.), Sapere Aude Advanced grant 0602-02366B (J.B.), Distinguished Investigator Grant from the Novo Nordisk Foundation NNF19OC0054518 (J.B.), The Danish Council for Independent Research 9039-00273 (P.G.), The Swedish Research Council grants 2016-04474 and 2022-01315 (P.G.), Knut and Alice Wallenberg Foundation Prolongation Fellow grant 2020.0194 (P.G.) and Knut and Alice Wallenberg 2015.0131 (P.G.). The Danish Cryo-EM Facility at CFIM, University of Copenhagen, is supported by Novo-Nordisk Foundation grant no. NNF14CC0001. The Cryo-EM Swedish National Facility at SciLifeLab is funded by the Knut and Alice Wallenberg, Family Erling Persson and Kempe Foundations, SciLifeLab, Stockholm University and Ume\u00E5 University.
Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.