Cryo-EM structure of the varicella-zoster virus A-capsid

Abstract

Varicella-zoster virus (VZV), a member of the Alphaherpesvirinae subfamily, causes severe diseases in humans of all ages. The viral capsids play critical roles in herpesvirus infection, making them potential antiviral targets. Here, we present the 3.7-Å-resolution structure of the VZV A-capsid and define the molecular determinants underpinning the assembly of this complicated viral machinery. Overall, the VZV capsid has a similar architecture to that of other known herpesviruses. The major capsid protein (MCP) assembles into pentons and hexons, forming extensive intra- and inter-capsomer interaction networks that are further secured by the small capsid protein (SCP) and the heterotriplex. The structure reveals a pocket beneath the floor of MCP that could potentially be targeted by antiviral inhibitors. In addition, we identified two alphaherpesvirus-specific structural features in SCP and Tri1 proteins. These observations highlight the divergence of different herpesviruses and provide an important basis for developing antiviral drugs.

Fig. 1. Overall architecture of VZV A-capsid.

a Density map of the icosahedral VZV A-capsid, colored by radius with the scheme below. An icosahedral facet is indicated by a triangle. b Organization of the capsid proteins within a facet. The symmetry-related molecules are represented by the same color. There are three types of hexons (P, C, and E) and five heterotriplexes (a–e) with unique molecular contexts in the capsid. The MCP is shown in surface, and the SCP and heterotriplex proteins are shown as cartoon models. c The density map of an ASU, colored by proteins. The MCPs in different capsomers are colored in the same scheme as used in (b). A schematic diagram of the heterotriplex assembly is shown to facilitate visualization of its orientation at different sites. d Atomic structure of each capsid protein, colored by domains. The inset shows the close-up view of the HK97-like fold in the floor of MCP.

Fig. 2. Structures of MCP and SCP in different capsomers.

a Overall structure of a hexon at the side view. Two adjacent MCP–SCP heterodimers are shown as cartoon models and the other four are shown as white surface models. One MCP is colored by domains and the other adjacent protomer is colored in cyan. The SCPs are colored by chains. b Top view of the hexon capsomer, revealing the contacting network of SCPs. c Bottom view of the basal floor interaction network in a hexon. d–f Architecture and inter-protomer interactions of a penton, shown in similar views and color schemes to those of the hexon in (a–c). g Superposition of the MCP conformers in hexon and penton capsomers. The insets show the close-up views of distinguished structural motifs with different conformations. The unresolved regions are represented by dashed lines.

Fig. 3. Inter-capsomer contacting networks at the basal floor.

a Overview of capsomer organization and interaction network within an ASU. The unique MCP conformers involved in inter-capsomer contacts are shown in different colors, and the rest parts are set transparent for clarity. b–f Close-up views of interactions between adjacent capsomers at different sites as indicated in (a). The critical motifs or domains involved in interactions are shown in solid colors, and the rest parts in the background are set transparent for clarity. The unresolved regions are represented by dashed lines.

Fig. 4. Comparison of the interaction networks between penton and hexon capsomers in different herpesviruses.

a Overview of the contacting interface between penton and hexon capsomers as viewed from outside or inside of the capsid. The four MCP conformers involved in interactions are highlighted in different colors. b–g Close-up views of the interactions between penton and hexon MCPs. The motifs involved in contacts are shown in solid colors, and the rest parts of the subunits are set transparent for clarity. The unresolved regions in the structure are represented by dashed lines. The insets show the zoomed-in inside (left panel) and outside (right panel) views of the central interaction details.

Fig. 5. Structure of the glue heterotriplex.

a Overview of the heterotriplex distribution within an ASU in the capsid. The penton and hexon capsomers are set transparent to highlight the locations of the heterotriplex (colored by chains) at different sites. b Enlarged view of the Tri1–Tri2 heterotriplex structure, colored by chains. The internal insertion arm of Tri1 is highlighted in yellow and the disordered N-terminal anchor is represented with dashed lines. c Interactions between the two Tri2 subunits within the heterotriplex. The interchain disulfide bond between the embracing arms is shown as spheres in the enlarged box. d Comparison of the different conformations of the two Tri2 subunits in a heterotriplex. e–g Interactions between the heterotriplex (surface model) and capsomers (cartoon model).

Fig. 6. Group-specific structural features in herpesvirus capsid proteins.

a Comparison of SCP in different herpesviruses and its binding to the MCP. The MCP is colored in gray and the SCP is colored by domains. The disordered regions are represented by dashed lines. b Structures of the heterotriplex in different herpesviruses. The two Tri2 subunits are shown as surface models (colored by chains) and the Tri1 molecule is shown as a cartoon model (colored by domains). The Tri1 N-anchor in VZV and HSV-1 and the insertion arm in HSV-2, which are represented by dashed lines, were not resolved in the structure.