Dimerization of Hepatitis E Virus Capsid Protein E2s Domain Is Essential for Virus–Host Interaction

Abstract

Hepatitis E virus (HEV), a non-enveloped, positive-stranded RNA virus, is transmitted in a faecal-oral manner, and causes acute liver diseases in humans. The HEV capsid is made up of capsomeres consisting of homodimers of a single structural capsid protein forming the virus shell. These dimers are believed to protrude from the viral surface and to interact with host cells to initiate infection. To date, no structural information is available for any of the HEV proteins. Here, we report for the first time the crystal structure of the HEV capsid protein domain E2s, a protruding domain, together with functional studies to illustrate that this domain forms a tight homodimer and that this dimerization is essential for HEV–host interactions. In addition, we also show that the neutralizing antibody recognition site of HEV is located on the E2s domain. Our study will aid in the development of vaccines and, subsequently, specific inhibitors for HEV.

Structural basis for the neutralization of hepatitis E virus by a cross-genotype antibody

“…The 8G12's epitope is located at the E2s dimerization region ( Figure 3 Table S1 and Figure S4C). Notably, we have shown that E2s dimerization is essential for HEV infection [11], and it is also worth mentioning that the epitope of the genotype 1-preferred neutralizing mAb 8C11 on E2s HEV-1 is located in the groove region, an entirely different site [17] (Figure 3D).…”

“…The virus adsorption region (AR) is defined as the virus surface region that directly interacts with its complementary receptor on host cells. Previously, it was reported that dimerization of the protruding region (E2s domain) is a prerequisite for HEV virulence and plays an important role in the host-virus interaction [9][10][11]17]. Therefore, it seems reasonable to propose that the AR is located, at least in part, near the dimerization region and includes the identified epitope region of these mAbs.…”

“…The capsid protein is responsible for virion assembly, host interaction and immunogenicity and is formed by homodimeric subunits, which comprise a protrusion domain [9,10] (E2s: npg www.cell-research.com | Cell Research aa 455-602 [11] or its N-terminal extension version E2: aa 394-606 [12]). These dimers project from the surface of the virus and initiate infection by interacting with host cells.…”

“…Structural comparisons of the E2s (aa 455-602) of genotype 1 [11] (resolution of 2.0 Å) with that of VLPs (T=1; aa 112-608) for genotype 3 [9] and genotype 4 [10] (3.5 Å) have revealed that the HEV capsid is formed by capsomeres comprising a homodimeric ORF2, and that virus infection is initiated through the interaction of this protruding homodimer with host cells. Cryo-electron microscopy studies [16] have additionally confirmed these structural findings.…”

Role of heat-shock protein 90 in hepatitis E virus capsid trafficking

“…Moreover, the interaction between p239 and the host cells was dependent on the dimeric conformation fit of p239 and the binding significantly inhibited HEV infectivity on HepG2 and Huh7 cells. The three-dimensional crystal structure of HEV VLP further demonstrates that this peptide is on the surface of the viral capsid protein, suggesting that it has an important functional role in cell entry (Guu et al, 2009;Li et al, 2009;Yamashita et al, 2009). …”