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

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

Global Impacts of a Bilateral Trade Policy on Ballast Water-Mediated Species Spread Risk: A Case Study of Sino-US Trade

A trade policy could generate both economic and environmental impacts. This work is focused on the impacts of a bilateral trade policy on ballast water-mediated nonindigenous species (NIS) spread risk. Taking the hypothetical Sino-US trade restriction as an example, we integrate a computable general equilibrium model and a higher-order NIS spread risk assessment model to examine the impacts of bilateral trade policy on both the economy and NIS spread risks. We have two important findings. First, the Sino-US trade restriction would cause decreases in NIS spread risks to China and the US, as well as to three quarters of worldwide countries/regions. However, the rest one fourth would experience increased NIS spread risks. Second, the relationship between changes in exports and changes in NIS spread risks might not be directly proportional. This is observed with 46% of countries and regions that would see their exports increase but their NIS spread risks drop, with positive impacts on both their economies and environment under the Sino-US trade restriction. These results reveal both broader global impacts as well as the decoupled economic and ecological impacts of a bilateral trade policy. These broader impacts demonstrate the necessity for national governments, which are parties to bilateral agreements to give due consideration to the economic and environmental impacts on countries and regions outside of the agreement

Global Impacts of a Bilateral Trade Policy on Ballast Water-Mediated Species Spread Risk: A Case Study of Sino-US Trade

A trade policy could generate both economic and environmental impacts. This work is focused on the impacts of a bilateral trade policy on ballast water-mediated nonindigenous species (NIS) spread risk. Taking the hypothetical Sino-US trade restriction as an example, we integrate a computable general equilibrium model and a higher-order NIS spread risk assessment model to examine the impacts of bilateral trade policy on both the economy and NIS spread risks. We have two important findings. First, the Sino-US trade restriction would cause decreases in NIS spread risks to China and the US, as well as to three quarters of worldwide countries/regions. However, the rest one fourth would experience increased NIS spread risks. Second, the relationship between changes in exports and changes in NIS spread risks might not be directly proportional. This is observed with 46% of countries and regions that would see their exports increase but their NIS spread risks drop, with positive impacts on both their economies and environment under the Sino-US trade restriction. These results reveal both broader global impacts as well as the decoupled economic and ecological impacts of a bilateral trade policy. These broader impacts demonstrate the necessity for national governments, which are parties to bilateral agreements to give due consideration to the economic and environmental impacts on countries and regions outside of the agreement

Global Impacts of a Bilateral Trade Policy on Ballast Water-Mediated Species Spread Risk: A Case Study of Sino-US Trade

A trade policy could generate both economic and environmental impacts. This work is focused on the impacts of a bilateral trade policy on ballast water-mediated nonindigenous species (NIS) spread risk. Taking the hypothetical Sino-US trade restriction as an example, we integrate a computable general equilibrium model and a higher-order NIS spread risk assessment model to examine the impacts of bilateral trade policy on both the economy and NIS spread risks. We have two important findings. First, the Sino-US trade restriction would cause decreases in NIS spread risks to China and the US, as well as to three quarters of worldwide countries/regions. However, the rest one fourth would experience increased NIS spread risks. Second, the relationship between changes in exports and changes in NIS spread risks might not be directly proportional. This is observed with 46% of countries and regions that would see their exports increase but their NIS spread risks drop, with positive impacts on both their economies and environment under the Sino-US trade restriction. These results reveal both broader global impacts as well as the decoupled economic and ecological impacts of a bilateral trade policy. These broader impacts demonstrate the necessity for national governments, which are parties to bilateral agreements to give due consideration to the economic and environmental impacts on countries and regions outside of the agreement

Homology model and potential virus-capsid binding site of a putative HEV receptor Grp78

National Natural Science Foundation [30925030, 30600106, 30870514, 30972826]; Project 863 [2006AA020905, 2006AA02A209]; great project on infectious diseases and new drug, People's Republic of China [2009ZX09102-230, 2009ZX10004-704, 2008ZX10404]P239, a truncated construct of the hepatitis E virus (HEV) ORF2 protein, has been proven able to bind with a chaperone, Grp78, in both an in vitro co-immune precipitation test and an in vivo cell model. We previously solved the crystal structure of E2s-the C-terminal domain of p239 involved in host interactions. In the present study, we built a 3D structure of Grp78 using homology modeling methods, and docked this molecule with E2s using the Zdockpro module of the InsightII software package. The modeled Grp78 structure was deemed feasible by profile 3D evaluation and molecular dynamic simulations. The docking result consists of six clusters of distinct complexes and C035 was selected as the most reasonable. The interacting interface of the predicted complex is comprised of the Grp78 linker region and nucleotide binding domain along with the E2s groove region and surrounding loops. Using energy, hydrogen bond and solvent accessible surface analyses, we identified a series of key residues that may be involved in the Grp78:E2s interaction. By comparing with the known structure of the Hsp70:J complex, we further concluded that the interaction of Grp78 and E2s could interrupt binding of Grp78 with the J domain, and in turn diminish or even eliminate the binding ability of the Grp78 substrate binding domain. The predicted series of key residues also provides clues for further research that should improve our understanding of the fundamental molecular mechanisms of HEV infection

Hepatitis E virus capsid protein assembles in 4M urea in the presence of salts

The hepatitis E virus (HEV) capsid protein has been demonstrated to be able to assemble into particles in vitro. However, this process and the mechanism of proteinprotein interactions during particle assembly remain unclear. In this study, we investigated the assembly mechanism of HEV structural protein subunits, the capsid protein p239 (aa368606), using analytical ultracentrifugation. It was the first to observe that the p239 can form particles in 4M urea as a result of supplementation with salt, including ammonium sulfate [(NH4)2SO4], sodium sulfate (Na2SO4), sodium chloride (NaCl), and ammonium chloride (NH4Cl). Interestingly, it is the ionic strength that determines the efficiency of promoting particle assembly. The assembly rate was affected by temperature and salt concentration. When (NH4)2SO4 was used, assembling intermediates of p239 with sedimentation coefficient values of approximately 5 S, which were mostly dodecamers, were identified for the first time. A highly conserved 28-aa region (aa368395) of p239 was found to be critical for particle assembly, and the hydrophobic residues Leu372, Leu375, and Leu395of p239 was found to be critical for particle assembly, which was revealed by site-directed mutagenesis. This study provides new insights into the assembly mechanism of native HEV, and contributes a valuable basis for further investigations of protein assembly by hydrophobic interactions under denaturing conditions