Crystal structure of glycoprotein E2 from bovine viral diarrhea virus

Abstract

Pestiviruses, including bovine viral diarrhea virus, are important animal pathogens and are closely related to hepatitis C virus, which remains a major global health threat. They have an outer lipid envelope bearing two glycoproteins, E1 and E2, required for cell entry. They deliver their genome into the host cell cytoplasm by fusion of their envelope with a cellular membrane. The crystal structure of bovine viral diarrhea virus E2 reveals a unique protein architecture consisting of two Ig-like domains followed by an elongated β-stranded domain with a new fold. E2 forms end-to-end homodimers with a conserved C-terminal motif rich in aromatic residues at the contact. A disulfide bond across the interface explains the acid resistance of pestiviruses and their requirement for a redox activation step to initiate fusion. From the structure of E2, we propose alternative possible membrane fusion mechanisms. We expect the pestivirus fusion apparatus to be conserved in hepatitis C virus.domain swap | family Flaviviridae | genus hepacivirus | pH sensing | fusion motif

Alteration of a Second Putative Fusion Peptide of Structural Glycoprotein E2 of Classical Swine Fever Virus Alters Virus Replication and Virulence in Swine

“…Thus, in a more general sense, our findings here and in our previous work (18) support cumulative evidence indicating that the members of the different genera of the Flaviviridae family do not share a fusion mechanism (35,36). Differences in the crystal structures of the BVDV1 and HCV E2 glycoproteins illustrate that common genome arrangement among members of the Flaviviridae family does not translate to structurally similar fusion glycoproteins (29,30). Conversely, structural comparisons indicate that sequences showing marginal homology can display a common class II fold (e.g., dengue virus E and Semliki Forest virus E1 proteins) (37,38).…”

“…However, CSFV E2 glycoprotein does not adopt a canonical class II fold, and the FPII loop, although exposed, is not located at the tip of the molecule (29,30). Thus, in a more general sense, our findings here and in our previous work (18) support cumulative evidence indicating that the members of the different genera of the Flaviviridae family do not share a fusion mechanism (35,36).…”

“…The CSFV FPII was located consecutive to the previously described E2 FP (FPI in Fig. 1), both in the sequence and in comparison with the tridimensional structure of BVDV E2 glycoprotein (29,30). We surmise that these regions, alone or in combination with other sequences of the E1 subunit, might, upon fusion activation, assemble a membrane-interactive surface (42).…”

“…Thus, WW hydrophobicity, i.e., the tendency for partitioning into membrane interfaces, specifically gathered within the E2 sequence from residues 864 to 881, which was not overall hydrophobic according to the KD scale. Subsequent location in the closely related BVDV1 E2 crystal structure (29,30) confirmed that the region from residues 864 to 881 embodies a turn stabilized through DiS bridge formation and partially exposed to solvent (Fig. 1, top).…”

X-Ray Structure of the Pestivirus NS3 Helicase and Its Conformation in Solution

“…1A (2,5,6). Structural studies are available for nonstructural protein 5B (NS5B) (7), E rns (8), E2 (9,10), and N pro (11,12). N pro and E rns are unique to pestiviruses, while all the others have their counterparts in the other genera.…”