دورية أكاديمية
Intermolecular Complementation between Two Varicella-Zoster Virus pORF30 Terminase Domains Essential for DNA Encapsidation.
| العنوان: | Intermolecular Complementation between Two Varicella-Zoster Virus pORF30 Terminase Domains Essential for DNA Encapsidation. |
|---|---|
| المؤلفون: | Visalli MA; Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA., House BL; Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA., Lahrman FJ; Department of Biology, Indiana University-Purdue University Fort Wayne, Fort Wayne, Indiana, USA., Visalli RJ; Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA visalli_rj@mercer.edu. |
| المصدر: | Journal of virology [J Virol] 2015 Oct; Vol. 89 (19), pp. 10010-22. Date of Electronic Publication: 2015 Jul 22. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0113724 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-5514 (Electronic) Linking ISSN: 0022538X NLM ISO Abbreviation: J Virol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Society For Microbiology Original Publication: Baltimore, American Society for Microbiology. |
| مواضيع طبية MeSH: | DNA, Viral/*genetics , DNA, Viral/*physiology , Endodeoxyribonucleases/*genetics , Endodeoxyribonucleases/*physiology , Herpesvirus 3, Human/*genetics , Herpesvirus 3, Human/*physiology , Viral Proteins/*genetics , Viral Proteins/*physiology, Amino Acid Substitution ; Cell Line ; Chromosomes, Artificial, Bacterial ; Endodeoxyribonucleases/chemistry ; Genetic Complementation Test ; Humans ; Mutagenesis, Site-Directed ; Open Reading Frames ; Protein Interaction Domains and Motifs ; Sequence Deletion ; Viral Proteins/chemistry ; Virus Assembly/genetics ; Virus Assembly/physiology ; Virus Replication/genetics ; Virus Replication/physiology ; Zinc Fingers |
| مستخلص: | Unlabelled: The herpesviral terminase complex is part of the intricate machinery that delivers a single viral genome into empty preformed capsids (encapsidation). The varicella-zoster virus (VZV) terminase components (pORF25, pORF30, and pORF45/42) have not been studied as extensively as those of herpes simplex virus 1 and human cytomegalovirus (HCMV). In this study, VZV bacterial artificial chromosomes (BACs) were generated with small (Δ30S), medium (Δ30M), and large (Δ30L) ORF30 internal deletions. In addition, we isolated recombinant viruses with specific alanine substitutions in the putative zinc finger motif (30-ZF3A) or in a conserved region (region IX) with predicted structural similarity to the human topoisomerase I core subdomains I and II (30-IXAla, 30-620A, and 30-622A). Recombinant viruses replicated in an ORF30-complementing cell line (ARPE30) but failed to replicate in noncomplementing ARPE19 and MeWo cells. Transmission electron microscopy of 30-IXAla-, 30-620A-, and 30-622A-infected ARPE19 cells revealed only empty VZV capsids. Southern analysis showed that cells infected with parental VZV (VZVLUC) or a repaired virus (30R) contained DNA termini, whereas cells infected with Δ30L, 30-IXAla, 30-620A, or 30-622A contained little or no processed viral DNA. These results demonstrated that pORF30, specifically amino acids 619 to 624 (region IX), was required for DNA encapsidation. A luciferase-based assay was employed to assess potential intermolecular complementation between the zinc finger domain and conserved region IX. Complementation between 30-ZF3A and 30-IXAla provided evidence that distinct pORF30 domains can function independently. The results suggest that pORF30 may exist as a multimer or participate in higher-order assemblies during viral DNA encapsidation. Importance: Antivirals with novel mechanisms of action are sought as additional therapeutic options to treat human herpesvirus infections. Proteins involved in the viral DNA encapsidation process have become promising antiviral targets. For example, letermovir is a small-molecule drug targeting HCMV terminase that is currently in phase III clinical trials. It is important to define the structural and functional characteristics of proteins that make up viral terminase complexes to identify or design additional terminase-specific compounds. The VZV ORF30 mutants described in this study represent the first VZV terminase mutants reported to date. Targeted mutations confirmed the importance of a conserved zinc finger domain found in all herpesvirus ORF30 terminase homologs but also identified a novel, highly conserved region (region IX) essential for terminase function. Homology modeling suggested that the structure of region IX is present in all human herpesviruses and thus represents a potential structurally conserved antiviral target. (Copyright © 2015, American Society for Microbiology. All Rights Reserved.) |
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| معلومات مُعتمدة: | R15 AI062713 United States AI NIAID NIH HHS; 7R15AI062713-03 United States AI NIAID NIH HHS |
| المشرفين على المادة: | 0 (DNA, Viral) 0 (Viral Proteins) EC 3.1.- (Endodeoxyribonucleases) |
| تواريخ الأحداث: | Date Created: 20150724 Date Completed: 20151204 Latest Revision: 20181113 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC4577918 |
| DOI: | 10.1128/JVI.01313-15 |
| PMID: | 26202238 |
| قاعدة البيانات: | MEDLINE |
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