Abstract
Epstein-Barr virus (EBV) is the primary cause of infectious mononucleosis and has been shown to be closely associated with various malignancies. Here, we present a complete atomic model of EBV, including the icosahedral capsid, the dodecameric portal and the capsid-associated tegument complex (CATC). Our in situ portal from the tegumented capsid adopts a closed conformation with its channel valve holding the terminal viral DNA and with its crown region firmly engaged by three layers of ring-like dsDNA, which, together with the penton flexibility, effectively alleviates the capsid inner pressure placed on the portal cap. In contrast, the CATCs, through binding to the flexible penton vertices in a stoichiometric manner, accurately increase the inner capsid pressure to facilitate the pressure-driven genome delivery. Together, our results provide important insights into the mechanism by which the EBV capsid, portal, packaged genome and the CATCs coordinately achieve a pressure balance to simultaneously benefit both viral genome retention and ejection.
Highlights
There are seven known human oncogenic viruses, which account for about 15%–20% of all human cancers.[1]
The asymmetric capsid structure showed the following: (1) the dodecameric portal interacts with five copies of the peripenton hexon (P-hexon) and triplexes of Ta in a 12–5-fold symmetry-mismatch pattern; (2) the terminal viral genome DNA is held by the portal channel valve and is capped by a featureless density called portal cap, named after the counterparts in herpes simplex virus (HSV)-1 and KSHV22,23 (Fig. 1d); and (3) three layers of ring-like viral genome densities tightly wind the portal (Fig. 1d)
The atomic structures of our Epstein-Bar virus (EBV) and other herpesvirus capsids consistently show that their pentons are less strengthened than their hexons, largely due to the variable conformation changes in their penton major capsid proteins (MCP) N-lasso domains, which either adopt an open conformation or are flexible, and lose their lashing functionality.[15,16,17,18,35]
Summary
There are seven known human oncogenic viruses, which account for about 15%–20% of all human cancers.[1] Epstein-Bar virus (EBV), a member of the subfamily gammaherpesviruses that includes the Kaposi Sarcoma-associated herpesvirus (KSHV),[2,3] is the first identified oncovirus.[4,5] EBV infects over 90% of the population worldwide[6] and has been shown to be closely associated with various malignancies, including Hodgkin’s lymphoma,[7] Burkitt’s lymphoma,[3] NK/T cell lymphoma,[8] nasopharyngeal carcinoma[9] and gastric carcinoma.[10]. Genome and the middle pleomorphic tegument compartment fulfilled with 20–40 different viral proteins.[11,12,13,14]. The composition and binding pattern of CATCs vary among different herpesviruses, which is likely in order to cope with the different inner pressures resulted from the packaged genomes that have sizes ranging from 125 to 235 kb.[20]
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