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.

The Portal Vertex of KSHV Promotes Docking of Capsids at the Nuclear Pores

“…Enriched inner tegument CVSC complexes were detected in the portal vertex of KSHV, and unlike the high occupancy of these complexes in HSV-1 [ 10 , 16 , 21 ] and HSV-2 [ 23 , 25 , 69 ] C-capsids, the 11 other vertices in KSHV C-capsids are partially and flexibly occupied with the CVSC, reaching approximately one-third of the full occupancy [ 8 ]. It was also shown that C-capsids of HSV-2 and VZV have higher CVSC occupancy than A- and B-capsids [ 25 , 28 ].…”

“…Cryo-electron microscopy has recently provided high-resolution atomic structures of the portal vertex and the CVSC of KSHV [ 8 , 21 ], as well as of HSV-1 [ 9 , 10 , 17 , 22 ], HSV-2 [ 23 , 24 , 25 ], EBV [ 26 , 27 ], and VZV [ 28 ]. These models have shown that the KSHV portal vertex is enriched with the CVSC tegument complexes, and unlike the high occupancy of CVSC in all vertices of HSV-1 and HSV-2 capsids, CVSC complexes on the other 11 vertices of the KSHV capsids were only partially and flexibly occupied, reaching an average of approximately 30% occupancy.…”

“…These models have shown that the KSHV portal vertex is enriched with the CVSC tegument complexes, and unlike the high occupancy of CVSC in all vertices of HSV-1 and HSV-2 capsids, CVSC complexes on the other 11 vertices of the KSHV capsids were only partially and flexibly occupied, reaching an average of approximately 30% occupancy. It was also shown in HSV-1 and HSV-2, that C-capsids have higher CVSC occupancy, probably due to higher affinity of the CVSC complex to the C-capsid vertices than to A- and B-capsids [ 17 , 23 , 25 , 28 ]. In addition to the CVSC proteins, the KSHV portal vertex has an outward protruding cap on the end of the genomic DNA.…”

Structures and Divergent Mechanisms in Capsid Maturation and Stabilization Following Genome Packaging of Human Cytomegalovirus and Herpesviruses

“…The capsid structure of herpesviruses was resolved by cryo-electron microscopy, which confirmed that the HCMV three-dimensional capsid structure is similar to the alpha- and gamma-herpesviruses’ capsid structure in overall organization [ 7 , 8 ]. The HCMV genome is twice the size of the VZV genome and >50% larger than the HSV-1 genome [ 9 ].…”

New Look of EBV LMP1 Signaling Landscape

“…Further, it will be of great interest to employ the CryoEM technique to study the structure of LMP1 signalosome. This technique has been recently applied to the capsids of EBV and other herpesviruses [236][237][238][239].…”