PLoS pathogens, 2019-01, Vol.15 (1), p.e1007515
2019
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- Autor(en) / Beteiligte
- Titel
- Probing the impact of nairovirus genomic diversity on viral ovarian tumor domain protease (vOTU) structure and deubiquitinase activity
- Ist Teil von
- PLoS pathogens, 2019-01, Vol.15 (1), p.e1007515
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2019
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Post-translational modification of host and viral proteins by ubiquitin (Ub) and Ub-like proteins, such as interferon stimulated gene product 15 (ISG15), plays a key role in response to infection. Viruses have been increasingly identified that contain proteases possessing deubiquitinase (DUB) and/or deISGylase functions. This includes viruses in the Nairoviridae family that encode a viral homologue of the ovarian tumor protease (vOTU). vOTU activity was recently demonstrated to be critical for replication of the often-fatal Crimean-Congo hemorrhagic fever virus, with DUB activity suppressing the type I interferon responses and deISGylase activity broadly removing ISG15 conjugated proteins. There are currently about 40 known nairoviruses classified into fourteen species. Recent genomic characterization has revealed a high degree of diversity, with vOTUs showing less than 25% amino acids identities within the family. Previous investigations have been limited to only a few closely related nairoviruses, leaving it unclear what impact this diversity has on vOTU function. To probe the effects of vOTU diversity on enzyme activity and specificity, we assessed representative vOTUs spanning the Nairoviridae family towards Ub and ISG15 fluorogenic substrates. This revealed great variation in enzymatic activity and specific substrate preferences. A subset of the vOTUs were further assayed against eight biologically relevant di-Ub substrates, uncovering both common trends and distinct preferences of poly-Ub linkages by vOTUs. Four novel X-ray crystal structures were obtained that provide a biochemical rationale for vOTU substrate preferences and elucidate structural features that distinguish the vOTUs, including a motif in the Hughes orthonairovirus species that has not been previously observed in OTU domains. Additionally, structure-informed mutagenesis provided the first direct evidence of a second site involved in di-Ub binding for vOTUs. These results provide new insight into nairovirus evolution and pathogenesis, and further enhances the development of tools for therapeutic purposes.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1553-7374, 1553-7366eISSN: 1553-7374DOI: 10.1371/journal.ppat.1007515Titel-ID: cdi_plos_journals_2251133158
- Format
- –
- Schlagworte
- Amino acids, Arachnids, Backup software, BASIC BIOLOGICAL SCIENCES, Binding sites, Biodiversity, Biological response modifiers, Biology and life sciences, Crimean hemorrhagic fever, Crimean-Congo hemorrhagic fever virus, Crystal structure, Crystallography, X-Ray - methods, Deubiquitinating Enzymes - metabolism, Disease control, Domains, Enzymatic activity, Enzyme activity, Enzymes, Female, Fever, Fluorescence resonance energy transfer, Genetic aspects, Genetic Variation - genetics, Genomics, Hemorrhage, Hemorrhagic fever viruses, Hemorrhagic fevers, Homology, Humans, Identities, Immune response, Infection, Interferon, Investigations, Medicine and health sciences, Mutagenesis, Mutation, Nairovirus - genetics, Nairovirus - pathogenicity, Ovarian cancer, Ovarian Neoplasms - metabolism, Ovarian Neoplasms - virology, Ovary - metabolism, Pathogenesis, Peptide Hydrolases - genetics, Peptide Hydrolases - metabolism, Pharmaceuticals, Phylogenetics, Phylogeny, Physical Sciences, Physiological aspects, Post-translation, Post-translational modifications, Protease, Proteases, Protein Binding, Protein Domains, Protein Processing, Post-Translational - genetics, Proteinase, Proteins, Proteolysis, Research and Analysis Methods, RNA viruses, Sequence Homology, Amino Acid, Sheep, Software, Species classification, Species diversity, Substrate preferences, Substrates, Therapeutic applications, Tumors, Ubiquitin, Ubiquitin - metabolism, Ubiquitination - genetics, Ubiquitins - metabolism, Viral pathogens, Viral proteins, Viral Proteins - metabolism, Viral replication, Viruses