A protein coevolution method uncovers critical features of the Hepatitis C Virus fusion mechanism.

Details

Ressource 1Download: journal.ppat.1006908.pdf (18180.50 [Ko])
State: Public
Version: Final published version
Serval ID
serval:BIB_EF740A22E54F
Type
Article: article from journal or magazin.
Collection
Publications
Title
A protein coevolution method uncovers critical features of the Hepatitis C Virus fusion mechanism.
Journal
PLoS pathogens
Author(s)
Douam F., Fusil F., Enguehard M., Dib L., Nadalin F., Schwaller L., Hrebikova G., Mancip J., Mailly L., Montserret R., Ding Q., Maisse C., Carlot E., Xu K., Verhoeyen E., Baumert T.F., Ploss A., Carbone A., Cosset F.L., Lavillette D.
ISSN
1553-7374 (Electronic)
ISSN-L
1553-7366
Publication state
Published
Issued date
03/2018
Peer-reviewed
Oui
Volume
14
Number
3
Pages
e1006908
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
Amino-acid coevolution can be referred to mutational compensatory patterns preserving the function of a protein. Viral envelope glycoproteins, which mediate entry of enveloped viruses into their host cells, are shaped by coevolution signals that confer to viruses the plasticity to evade neutralizing antibodies without altering viral entry mechanisms. The functions and structures of the two envelope glycoproteins of the Hepatitis C Virus (HCV), E1 and E2, are poorly described. Especially, how these two proteins mediate the HCV fusion process between the viral and the cell membrane remains elusive. Here, as a proof of concept, we aimed to take advantage of an original coevolution method recently developed to shed light on the HCV fusion mechanism. When first applied to the well-characterized Dengue Virus (DENV) envelope glycoproteins, coevolution analysis was able to predict important structural features and rearrangements of these viral protein complexes. When applied to HCV E1E2, computational coevolution analysis predicted that E1 and E2 refold interdependently during fusion through rearrangements of the E2 Back Layer (BL). Consistently, a soluble BL-derived polypeptide inhibited HCV infection of hepatoma cell lines, primary human hepatocytes and humanized liver mice. We showed that this polypeptide specifically inhibited HCV fusogenic rearrangements, hence supporting the critical role of this domain during HCV fusion. By combining coevolution analysis and in vitro assays, we also uncovered functionally-significant coevolving signals between E1 and E2 BL/Stem regions that govern HCV fusion, demonstrating the accuracy of our coevolution predictions. Altogether, our work shed light on important structural features of the HCV fusion mechanism and contributes to advance our functional understanding of this process. This study also provides an important proof of concept that coevolution can be employed to explore viral protein mediated-processes, and can guide the development of innovative translational strategies against challenging human-tropic viruses.
Keywords
Animals, Carcinoma, Hepatocellular/metabolism, Carcinoma, Hepatocellular/pathology, Carcinoma, Hepatocellular/virology, Evolution, Molecular, Hepacivirus/physiology, Hepatitis C/metabolism, Hepatitis C/pathology, Hepatitis C/virology, Humans, Liver Neoplasms/metabolism, Liver Neoplasms/pathology, Liver Neoplasms/virology, Mice, Mice, Inbred C57BL, Protein Binding, Tumor Cells, Cultured, Viral Envelope Proteins/chemistry, Viral Envelope Proteins/genetics, Viral Envelope Proteins/metabolism, Virus Internalization, Virus Replication
Pubmed
Web of science
Open Access
Yes
Create date
03/05/2018 14:49
Last modification date
20/08/2019 17:17
Usage data