Mapping of neutralization epitopes on the HCV E2 protein sequence. The alignment of the HCV gene sequence is based on the genotype 1a, H77c (GenBank accession no. AF011751). Regions that are associated with CD81 binding (blue square), HVR1 (solid brown square), transmembrane domain (TM) and glycosylation sites (fork) are as indicated. Contact residues broadly neutralizing antibodies to both linear and conformational epitopes are as listed. Residues that participate in CD81 binding are labeled in blue and glycosylation sites that affect antibody neutralization are in dark green. For the conformational epitopes, contact residues are located mainly at two discontinuous regions, aa424–443 and aa523–540.

Putative model of HCV E2 glycoprotein based on a class II fold with the expansion of Domain I and the contact residues recognized by broad neutralization antibody. The linear sequence of HCV H77-E2 ectodomain from aa384–715, is represented as a chain of beads (right) or schematic diagram of the tertiary organization (left), and the expanded DI is shown in the middle. For the model on the right, colored circles are labeled with the corresponding amino acid. Circles in pale and bright colors represent residues in the background and foreground of the domains, respectively labeled in white and black fonts. Residues that participate in CD81 binding are contoured in blue. Disulfide bonds and glycosylation sites are indicated by thick black bars and green circles, respectively, numbered sequentially. Unstructured segments are in white font on a brown background. For the left schematic diagram, DI, DII and DIII are labeled in red, yellow and blue, respectively. The connectivity of the β-strands in DI is indicated, labeled with the standard class II nomenclature. In the middle graph, the conserved epitopes recognized by broadly neutralization antibodies are labeled with yellow circle in the expanded DI. The residues recognized by linear epitope are outlined with bright purple, while conformational epitopes are outlined with dark purple. Residues that participate in CD81 binding are labeled in blue and glycosylation sites in dark green. Some of the residues are numbered as the amino acid position in the E2 glycoprotein. The specific contact residues for the conformational antibodies are located on four β-strands, C₀, D₀, E₀ and F₀, which form the top β-sheet of domain I, overlapping with CD81 binding residues. Figure 2 is adapted with permission from Krey et al. [62].