Conformational Flexibility in the Immunoglobulin-Like Domain of the Hepatitis C Virus Glycoprotein E2

MBio
Ieva VasiliauskaiteThomas Krey

Abstract

The hepatitis C virus (HCV) glycoprotein E2 is the major target of neutralizing antibodies and is therefore highly relevant for vaccine design. Its structure features a central immunoglobulin (Ig)-like β-sandwich that contributes to the binding site for the cellular receptor CD81. We show that a synthetic peptide corresponding to a β-strand of this Ig-like domain forms an α-helix in complex with the anti-E2 antibody DAO5, demonstrating an inside-out flip of hydrophobic residues and a secondary structure change in the composite CD81 binding site. A detailed interaction analysis of DAO5 and cross-competing neutralizing antibodies with soluble E2 revealed that the Ig-like domain is trapped by different antibodies in at least two distinct conformations. DAO5 specifically captures retrovirus particles bearing HCV glycoproteins (HCVpp) and infectious cell culture-derived HCV particles (HCVcc). Infection of cells by DAO5-captured HCVpp can be blocked by a cross-competing neutralizing antibody, indicating that a single virus particle simultaneously displays E2 molecules in more than one conformation on its surface. Such conformational plasticity of the HCV E2 receptor binding site has important implications for immunogen design.IMPORTA...Continue Reading

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Citations

Dec 20, 2017·Proceedings of the National Academy of Sciences of the United States of America·Madeleine C MankowskiJustin R Bailey
Feb 29, 2020·PLoS Computational Biology·Lenka StejskalJoe Grove
Jul 14, 2018·Frontiers in Immunology·Naglaa H Shoukry
Jul 4, 2018·Frontiers in Immunology·Luisa J StröhThomas Krey
Sep 11, 2018·Frontiers in Immunology·Samantha A YostJoseph Marcotrigiano
Jun 13, 2018·Frontiers in Immunology·Johnathan D Guest, Brian G Pierce
Jan 28, 2020·Journal of Peptide Science : an Official Publication of the European Peptide Society·Theodorus J MeulemanRob M J Liskamp
Jan 31, 2018·Frontiers in Microbiology·Thomas R FuerstSteven K H Foung
Jun 29, 2018·Frontiers in Immunology·Netanel TzarumMansun Law
Jul 8, 2020·Journal of Biomedical Science·Daniel Sepulveda-CrespoIsidoro Martinez
Sep 20, 2020·International Journal of Molecular Sciences·Luisa J Ströh, Thomas Krey
Nov 5, 2020·The Journal of General Virology·Mphatso D KalemeraJoe Grove
Jan 13, 2021·Proceedings of the National Academy of Sciences of the United States of America·Johnathan D GuestThomas R Fuerst
Feb 14, 2021·Biology·Umberto OresteMaria Rosaria Coscia
Jun 3, 2021·Viruses·Itai YechezkelNetanel Tzarum
Sep 17, 2021·Nature·Ashish KumarJoseph Marcotrigiano

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Methods Mentioned

BETA
glycosylation
PISA
electron microscopy
enzyme-linked immunosorbent assay
ELISA
pulldown
size exclusion chromatography
pulled down
surface plasmon resonance
flow cytometry

Software Mentioned

Chimera
PISA

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