X-ray structure of a native calicivirus: Structural insights into antigenic diversity and host specificity

Abstract

Caliciviruses, grouped into four genera, are important human and veterinary pathogens with a potential for zoonosis. In these viruses, capsid-related functions such as assembly, antigenicity, and receptor interactions are predominantly encoded in a single protein that forms an icosahedral capsid. Understanding of the immunologic functions and pathogenesis of human caliciviruses in the Norovirus and Sapovirus genera is hampered by the lack of a cell culture system or animal models. Much of our understanding of these viruses, including the structure, has depended on recombinant capsids. Here we report the atomic structure of a native calicivirus from the Vesivirus genus that exhibits a broad host range possibly including humans and map immunological function onto a calicivirus structure. The vesivirus structure, despite a similar architectural design as seen in the recombinant norovirus capsid, exhibits novel features and indicates how the unique modular organization of the capsid protein with interdomain flexibility, similar to an antibody structure with a hinge and an elbow, integrates capsid-related functions and facilitates strain diversity in caliciviruses. The internally located N-terminal arm participates in a novel network of interactions through domain swapping to assist the assembly of the shell domain into an icosahedral scaffold, from which the protruding domain emanates. Neutralization epitopes localize to three hypervariable loops in the distal portion of the protruding domain surrounding a region that exhibits host-specific conservation. These observations suggest a mechanism for antigenic diversity and host specificity in caliciviruses and provide a structural framework for vaccine development.neutralization epitopes ͉ norovirus ͉ vesivirus

Structure of the hepatitis E virus-like particle suggests mechanisms for virus assembly and receptor binding

“…One side of the barrel extensively interacts with the S domain through ␤B, ␤C, and loops CD, EF, and GH. The structure of the HEV-CP P1 domain is related to that of the P2 domain of the calicivirus coat protein (Z score ϭ 2.8) (20). Other top structural homologs are the human UPF1 human helicase core (Z score ϭ 5.1, 1 st ) (21), the ␤-barrel domain of endo-alpha-sialidase (22), the tRNA-binding domain of the translation elongation factor Tu (23), and the receptor-binding domain of the avian reovirus fiber C (24).…”

Cryo-electron microscopy reconstructions of two types of wild rabbit hemorrhagic disease viruses characterized the structural features of Lagovirus

“…The 3.4-Å crystal structure of rNV (Prasad et al, 1999) and 3.2-Å crystal structure of SMSV (Chen et al, 2006) were used to calculate the corresponding density maps by the program "pdb2mrc" from EMAN suite (Ludtke et al, 1999). Both maps are low-pass filtered to the resolution of 11 Å for consensus comparison with cryo-EM map of RHDV (Fig.…”

“…5). The quasi-atomic coordinates of RHDV major capsid protein VP60 were modeled according to crystal structure of SMSV VP60 (Chen et al, 2006) and split into S domain, P1 subdomain and P2 subdomain for cryo-EM map fitting. The fitness between P domain and CC capsomer protrusion density, between S domain and CC capsomer S region density, between P1 subdomain and AB capsomer P1 region density, and between S domain and AB capsomer S region density shows high accuracy under such resolution, and their fittings could be further optimized by automatic local minimization algorithm.…”

“…In addition, higher resolution cryo-EM reconstructions of Feline calicivirus (FCV) VLP (16 Å) (Bhella et al, 2008) and Murine Norovirus (MNV) VLP (12 Å) (Katpally et al, 2008), as well as the interactions between virion and receptor or antibody, fJAM-1-labeled FCV (18 Å) (Bhella et al, 2008), MNV-Fab (22 Å) (Katpally et al, 2008) and RHDV VLP/mAb-E3 (32 Å) (Thouvenin et al, 1997), were reported recently. There are only two available atomic crystal structures of the calicivirus, the recombinant NV VLP (Prasad et al, 1999) and the wild SMSV (Chen et al, 2006). These structures exhibit T = 3 icosahedral symmetry and comprise 180 capsid proteins that are organized into 90 dimeric capsomers.…”

The Feline Calicivirus Leader of the Capsid Protein Is Associated with Cytopathic Effect

“…The 5= end of the viral RNA genome is covalently linked to a VPg protein; the 3= end of the genome is polyadenylated (2,(7)(8)(9). The infectious virion is composed of 180 copies of the major capsid protein VP1 and 1 to 10 copies of the minor structural protein VP2, which together form a capsid around the VPg-linked genome (10)(11)(12)(13)(14)(15). The genomic RNA serves as a template for translation of the ORF1 polyprotein that is proteolytically cleaved by the viral protease to release the nonstructural proteins (16,17), and an ϳ2.2-to 2.6-kb subgenomic bicistronic RNA template is used for the translation of VP1 and VP2 (7,18).…”