Hepatitis C Virus E1E2 co-evolving networks unveil their functional dialogs and highlight original therapeutic strategies

Hepatitis C Virus (HCV) infects more than 170 million people worldwide but no vaccine is available yet. HCV entry may represent a promising target for therapies and is mediated by two envelope glycoproteins, E1 and E2, assembled as heterodimer onto the virus surface. However, how E1 and E2 dialog, s...

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Main Author: Douam, Florian
Language:ENG
Published: Ecole normale supérieure de lyon - ENS LYON 2013
Subjects:
Online Access:http://tel.archives-ouvertes.fr/tel-00946592
http://tel.archives-ouvertes.fr/docs/00/94/65/92/PDF/DOUAM_Florian_2013_These_VD.pdf
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spelling ndltd-CCSD-oai-tel.archives-ouvertes.fr-tel-009465922014-02-20T03:25:28Z http://tel.archives-ouvertes.fr/tel-00946592 2013ENSL0869 http://tel.archives-ouvertes.fr/docs/00/94/65/92/PDF/DOUAM_Florian_2013_These_VD.pdf Hepatitis C Virus E1E2 co-evolving networks unveil their functional dialogs and highlight original therapeutic strategies Douam, Florian [SDV:SA] Life Sciences/Agricultural sciences [SDV:SA] Sciences du Vivant/Sciences agricoles Envelope glycoproteins Hepatitis C Virus Virus entry Co-evolving networks Hepatitis C Virus (HCV) infects more than 170 million people worldwide but no vaccine is available yet. HCV entry may represent a promising target for therapies and is mediated by two envelope glycoproteins, E1 and E2, assembled as heterodimer onto the virus surface. However, how E1 and E2 dialog, structurally rearrange and act together during these steps remain poorly defined. In this work, we aimed to clarify the interrelation of E1E2 during virus entry, thus opening ways to potential new therapeutic strategies. We first investigated whether a strong genetic divergence between E1E2 heterodimers may highlight distinct functions. We observed that B-cell derived E1E2 were specialized for B-cell infection, suggesting that new functions can emerge from the E1E2 conformational plasticity. In a second approach, we identified a conserved dialog between E1 and the domain III of E2 that was critical for virus binding and fusion. Moreover, a computational model predicted a strong co-evolution between E1 and E2 as well as potential structural rearrangements, suggesting that HCV E2 is likely a fusion protein able to fold over via its domain III through the mediation of E1. Altogether, these different works highlight that E1 and E2 are involved in complex dialogs that regulate the heterodimer folding and functions, suggesting that E1E2 heterodimer is more likely a single functional protein entity than an association of two proteins with specific functions. 2013-12-12 ENG PhD thesis Ecole normale supérieure de lyon - ENS LYON
collection NDLTD
language ENG
sources NDLTD
topic [SDV:SA] Life Sciences/Agricultural sciences
[SDV:SA] Sciences du Vivant/Sciences agricoles
Envelope glycoproteins
Hepatitis C Virus
Virus entry
Co-evolving networks
spellingShingle [SDV:SA] Life Sciences/Agricultural sciences
[SDV:SA] Sciences du Vivant/Sciences agricoles
Envelope glycoproteins
Hepatitis C Virus
Virus entry
Co-evolving networks
Douam, Florian
Hepatitis C Virus E1E2 co-evolving networks unveil their functional dialogs and highlight original therapeutic strategies
description Hepatitis C Virus (HCV) infects more than 170 million people worldwide but no vaccine is available yet. HCV entry may represent a promising target for therapies and is mediated by two envelope glycoproteins, E1 and E2, assembled as heterodimer onto the virus surface. However, how E1 and E2 dialog, structurally rearrange and act together during these steps remain poorly defined. In this work, we aimed to clarify the interrelation of E1E2 during virus entry, thus opening ways to potential new therapeutic strategies. We first investigated whether a strong genetic divergence between E1E2 heterodimers may highlight distinct functions. We observed that B-cell derived E1E2 were specialized for B-cell infection, suggesting that new functions can emerge from the E1E2 conformational plasticity. In a second approach, we identified a conserved dialog between E1 and the domain III of E2 that was critical for virus binding and fusion. Moreover, a computational model predicted a strong co-evolution between E1 and E2 as well as potential structural rearrangements, suggesting that HCV E2 is likely a fusion protein able to fold over via its domain III through the mediation of E1. Altogether, these different works highlight that E1 and E2 are involved in complex dialogs that regulate the heterodimer folding and functions, suggesting that E1E2 heterodimer is more likely a single functional protein entity than an association of two proteins with specific functions.
author Douam, Florian
author_facet Douam, Florian
author_sort Douam, Florian
title Hepatitis C Virus E1E2 co-evolving networks unveil their functional dialogs and highlight original therapeutic strategies
title_short Hepatitis C Virus E1E2 co-evolving networks unveil their functional dialogs and highlight original therapeutic strategies
title_full Hepatitis C Virus E1E2 co-evolving networks unveil their functional dialogs and highlight original therapeutic strategies
title_fullStr Hepatitis C Virus E1E2 co-evolving networks unveil their functional dialogs and highlight original therapeutic strategies
title_full_unstemmed Hepatitis C Virus E1E2 co-evolving networks unveil their functional dialogs and highlight original therapeutic strategies
title_sort hepatitis c virus e1e2 co-evolving networks unveil their functional dialogs and highlight original therapeutic strategies
publisher Ecole normale supérieure de lyon - ENS LYON
publishDate 2013
url http://tel.archives-ouvertes.fr/tel-00946592
http://tel.archives-ouvertes.fr/docs/00/94/65/92/PDF/DOUAM_Florian_2013_These_VD.pdf
work_keys_str_mv AT douamflorian hepatitiscviruse1e2coevolvingnetworksunveiltheirfunctionaldialogsandhighlightoriginaltherapeuticstrategies
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