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

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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. Infectious viral hepatitis is a major disease in both developing and developed countries. Hepatitis E virus (HEV) is one of the major causes of severe inflammation of the liver, which is characterized by jaundice, fever, liver enlargement, and abdominal pain in humans and non-human primates. The hepatitis E virus capsid is made up of individual subunits consisting of homodimers of a single structural 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. This article reports the crystal structure of the HEV capsid protein domain E2s (protruding domain), along with functional studies, which illustrate the tight homodimeric state of E2s and that dimerization is essential for both HEV–host interactions and disease progression. We also show that the neutralizing antibody recognition site of HEV is located on the E2s domain. The present findings will aid the development of vaccines and novel inhibitors for HEV.