Abstract
Cytomegalovirus (CMV) infection causes birth defects and life-threatening complications in immunosuppressed patients. Lack of vaccine and need for more effective drugs have driven widespread ongoing therapeutic development efforts against human CMV (HCMV), mostly using murine CMV (MCMV) as the model system for preclinical animal tests. The recent publication (Yu et al., 2017, DOI: 10.1126/science.aam6892) of an atomic model for HCMV capsid with associated tegument protein pp150 has infused impetus for rational design of novel vaccines and drugs, but the absence of high-resolution structural data on MCMV remains a significant knowledge gap in such development efforts. Here, by cryoEM with sub-particle reconstruction method, we have obtained the first atomic structure of MCMV capsid with associated pp150. Surprisingly, the capsid-binding patterns of pp150 differ between HCMV and MCMV despite their highly similar capsid structures. In MCMV, pp150 is absent on triplex Tc and exists as a “Λ”-shaped dimer on other triplexes, leading to only 260 groups of two pp150 subunits per capsid in contrast to 320 groups of three pp150 subunits each in a “Δ”-shaped fortifying configuration. Many more amino acids contribute to pp150-pp150 interactions in MCMV than in HCMV, making MCMV pp150 dimer inflexible thus incompatible to instigate triplex Tc-binding as observed in HCMV. While pp150 is essential in HCMV, our pp150-deletion mutant of MCMV remained viable though with attenuated infectivity and exhibiting defects in retaining viral genome. These results thus invalidate targeting pp150, but lend support to targeting capsid proteins, when using MCMV as a model for HCMV pathogenesis and therapeutic studies.
Highlights
Cytomegalovirus (CMV) is a member of the β-herpesvirus subfamily of the herpesvirus family and can establish lifelong subclinical infection among the majority of the human population
The structure reveals that the organization patterns of the capsid-associated tegument protein pp150 are different in murine CMV (MCMV) and human CMV (HCMV), despite their highly similar capsid structures
We show that deleting pp150 did not eliminate MCMV infection in contrast to pp150’s essential role in HCMV infections
Summary
Cytomegalovirus (CMV) is a member of the β-herpesvirus subfamily of the herpesvirus family and can establish lifelong subclinical (latent) infection among the majority of the human population. There is no licensed vaccine against HCMV infection and conventional anti-HCMV drugs have wellknown adverse side effects and are compromised by resistance [1]. Recent high-resolution cryoEM structures of human herpesviruses [12,13,14], the demonstration of inhibitors designed based on the structure of small capsid protein (SCP) [12,13], have opened the door to structure-guided design of new drugs and vaccines targeting HCMV capsid proteins and the β-herpesvirus-specific tegument protein pUL32 [or phosphoprotein pp150, see review 15,16–18]. Rationales for targeting pUL32 are manifold: First, it is essential to HCMV propagation [19,20]; Second, pUL32 is unique to human β-herpesviruses; Third, pp150 has been shown to be the most immunogenic in clinical setting [21]; Fourth, from a general point of view, regulatory functions of protein phosphorylation have been targeted against cancers [22] and viral infections, including HCMV [23]. The functional and structural significance of pM32 remains to be established, in stark contrast to the large body of MCMV-based cell and animal studies concerning CMV infections
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