Abstract
Herpesviruses cause severe diseases particularly in immunocompromised patients. Both genome packaging and release from the capsid require a unique portal channel occupying one of the 12 capsid vertices. Here, we report the 2.6 Å crystal structure of the pentameric pORF19 of the γ-herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) resembling the portal cap that seals this portal channel. We also present the structure of its β-herpesviral ortholog, revealing a striking structural similarity to its α- and γ-herpesviral counterparts despite apparent differences in capsid association. We demonstrate pORF19 pentamer formation in solution and provide insights into how pentamerization is triggered in infected cells. Mutagenesis in its lateral interfaces blocked pORF19 pentamerization and severely affected KSHV capsid assembly and production of infectious progeny. Our results pave the way to better understand the role of pORF19 in capsid assembly and identify a potential novel drug target for the treatment of herpesvirus-induced diseases.
Highlights
Herpesviruses are a large group of double-stranded DNA viruses that establish latent, lifelong infections in both vertebrate and nonvertebrate species
Cryo-EM analyses of herpesviral capsids show that the herpes simplex virus (HSV)-1 minor capsid protein pUL25 and its Kaposi’s sarcoma-associated herpesvirus (KSHV) ortholog pORF19 are arranged around the penton as part of the capsid vertex–specific component” (CVSC) (S1 Fig) [4,5,11,12,13,15]
human cytomegalovirus (HCMV) pUL77 is considered the ortholog of pUL25 [28], but despite biochemical evidence indicating its association with capsids [28], the analogous positions around the penton vertices are occupied by a dense layer of the β-herpesvirus–specific phosphoprotein pp150 [19,36]
Summary
Herpesviruses are a large group of double-stranded DNA viruses that establish latent, lifelong infections in both vertebrate and nonvertebrate species. All prospective CVSC binding sites near the pentonal vertices on triplexes of the human herpesvirus 6B are occupied by a tetramer of the β-herpesvirus–specific pU11 protein [20], indicating that the spatial organization of the CVSC around the pentons is not conserved across herpesvirus subfamilies In spite of this apparent difference in capsid association, the α-herpesviral CVSC components (pUL17 and pUL25) and their β-herpesviral orthologs (pUL93 and pUL77) serve similar functions. The portal is a dodecamer [8,9] and capped by a star-shaped pentameric density in line with the tail-like structure previously identified at the portal vertex [35] This density was proposed to consist of pentameric layers of the CTD of pUL25 or pORF19 in HSV-1 and KSHV, respectively [4,5,6], in agreement with its role to prevent leakage of encapsidated viral genomes from capsids (for a schematic comparison of penton and portal vertex, see S1 Fig). We thereby identify a novel promising target allowing for the structure-based design of antiherpesviral inhibitors
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