UCLA

Herpesviruses are a large group of double-stranded DNA viruses of animals. Nine species of herpesvirus take human as their primary host and cause diseases ranging from mild lesions to serious malignancies. Herpesviruses are grouped into three subfamilies, namely alpha-, beta-, and gammaherpesviruses. The herpesvirus smallest capsid protein (SCP) and capsid-associated tegument proteins are structurally and/or functionally divergent across the three subfamilies, but the mechanisms are not well understood due to the lack of detailed structures. Combining high-resolution cryo electron microscopy (cryoEM) with structure-guided mutagenesis, we compared virion structures of representative members of the three herpesvirus subfamilies, with a focus on the structure and function of the SCP and tegument proteins. Our main findings are summarized as following: 1. The SCP of betaherpesvirus human cytomegalovirus (HCMV) mediates the capsid-association of tegument protein pp150; 2. The SCP of gammaherpesvirus Kaposi’s sarcoma-associated herpesvirus (KSHV) bridges neighboring MCP molecules in the capsid hexons; 3. All herpesvirus SCPs are acting, alone or in coalition with tegument proteins, as cementing proteins like those in dsDNA bacteriophages to stabilize the capsid for genome packaging; 4. Gammaherpesvirus KSHV has capsid-associated tegument densities that are similar to those in alphaherpesviruses but different from those in betaherpesviruses, and the organization of the two components of these alpha- and gammaherpesvirus tegument is re-established. Our results provide new insights into the understanding of herpesvirus capsid and virion assembly, and are informative to searching for new antiviral targets.