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Hepatitis C virus (HCV) entry is dependent on host cell molecules tetraspanin CD81, scavenger receptor BI and tight junction proteins claudin-1 and occludin. We previously reported a role for CD81/claudin-1 receptor complexes in HCV entry; however, the molecular mechanism(s) driving association between the receptors is unknown. We explored the molecular interface between CD81 and claudin-1 using a combination of bioinformatic sequence-based modelling, site-directed mutagenesis and Fluorescent Resonance Energy Transfer (FRET) imaging methodologies. Structural modelling predicts the first extracellular loop of claudin-1 to have a flexible beta conformation and identifies a motif between amino acids 62-66 that interacts with CD81 residues T149, E152 and T153. FRET studies confirm a role for these CD81 residues in claudin-1 association and HCV infection. Importantly, mutation of these CD81 residues has minimal impact on protein conformation or HCV glycoprotein binding, highlighting a new functional domain of CD81 that is essential for virus entry.

Original publication

DOI

10.1111/cmi.12008

Type

Journal article

Journal

Cell Microbiol

Publication Date

12/2012

Volume

14

Pages

1892 - 1903

Keywords

Animals, Cell Line, Claudin-1, Computational Biology, Computer Simulation, Fluorescence Resonance Energy Transfer, Hepacivirus, Humans, Models, Molecular, Mutagenesis, Site-Directed, Receptors, Virus, Tetraspanin 28, Virus Internalization