Capsids under pressure

Nature doi:10.1038/nature25438 (2018)

Credit: NATURE

Icosahedral capsids of herpesviruses such as Kaposi's sarcoma-associated herpesvirus (KSHV) consist of nearly 3,000 individual proteins, the bulk of which are pentamers and hexamers of the viral protein MCP decorated with the smaller protein SCP and joined by heterotrimeric triplexes consisting of Tri1 and two Tri2 proteins. To begin to understand how the capsid structure is mechanically stabilized under the high pressure imposed by the double-stranded DNA genome and to gain new insights into capsid assembly, Dai et al. solved the cryo-EM structure of KSHV virions. Extensive analysis of the interactions among the four proteins, including validation with mutagenesis, revealed several critical interactions, including those in which the hydrophobic residues of the L-shaped MCP form a groove with SCP, which itself forms a crosslink to a neighboring MCP and also supports π-stacking interactions between MCP and SCP. The authors found the MCP hydrophobic groove to be targetable with a peptide mimic that reduces virion production. Furthermore, β-strands between adjacent MCPs join together to form, via disulfide bonding, a turbine-shaped ring in each hexon. The authors also defined three types of network interactions in MCP that are critical for the mechanical sturdiness of the KSHV capsid, as well as interactions with the Tri proteins critical for capsid assembly. These results highlight a complex assembly mechanism optimized for stability against the pressure imposed by the DNA contained within.