Journal
CELLULAR MICROBIOLOGY
Volume 14, Issue 12, Pages 1892-1903Publisher
WILEY
DOI: 10.1111/cmi.12008
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Funding
- MRC [G0400802, G0801976]
- Wellcome Trust [ME027881]
- European Union 'HEPACUTE (FP7)' programme
- Medical Research Council [G1100247, G0400802, G0801976, G9818340B] Funding Source: researchfish
- MRC [G0400802, G0801976, G1100247] Funding Source: UKRI
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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 6266 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 HCVglycoprotein binding, highlighting a new functional domain of CD81 that is essential for virus entry.
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