title: Structural analysis and insight into Zika virus NS5 mediated interferon inhibition.
abstract: The Zika virus outbreak in 2015-2016 is the largest of its kind for which WHO declared a Public Health Emergency of International Concerns. No FDA approved drug is available for the treatment of the viral infection. The interaction of flavivirus NS5 protein with SIAH2 ubiquitin ligase has been previously known. NS5 of Zika virus has been implicated in the degradation of STAT2 protein, which activates interferon-stimulated antiviral activity. Based on our proposition that NS5 utilizes SIAH2-mediated proteasomal degradation of STAT2, an in-silico study was carried out to characterize the protein-protein interactions between NS5, SIAH2 and STAT2 proteins. The aim of our study was to identify the amino acid residues of NS5 involved in IFN antagonism as well as to find the association between NS5, SIAH2 and STAT2 to predict the interaction pattern of these proteins. Analysis proposed that NS5 recruits SIAH2 for the ubiquitination-dependent degradation of STAT2. NS5 residues involved in interaction with SIAH2 and/or STAT2 were found to be mostly conserved across related flaviviruses. These are novel findings regarding the Zika virus and require confirmation through experimental approaches.
authors.affiliation: Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, 44000, Pakistan.
authors.forename: Hamza Arshad
authors.initials: HA
authors.lastname: Dar
authors.affiliation: Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, 44000, Pakistan.
authors.forename: Tahreem
authors.initials: T
authors.lastname: Zaheer
authors.affiliation: Research Center for Modeling and Simulation (RCMS), National University of Sciences and Technology (NUST), Islamabad, 44000, Pakistan.
authors.forename: Rehan Zafar
authors.initials: RZ
authors.lastname: Paracha
authors.affiliation: Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, 44000, Pakistan. Electronic address: amjad.ali@asab.nust.edu.pk.
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015870:Gene Expression; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D007372:Interferons / Q000235:genetics / Q000276:immunology; D062105:Molecular Docking Simulation; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D050795:STAT2 Transcription Factor / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D054875:Ubiquitination; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D000071244:Zika Virus / Q000737:chemistry* / Q000201:enzymology / Q000276:immunology; D000071243:Zika Virus Infection / Q000235:genetics / Q000276:immunology / Q000821:virology; D000098563:Seven in Absentia Proteins
chemical_list: C096041:NS5 protein, flavivirus; D009687:Nuclear Proteins; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D017361:Viral Nonstructural Proteins; D007372:Interferons; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D046988:Proteasome Endopeptidase Complex
keywords: Interferon antagonism; NS5 docking; Phylogenetic analysis; STAT2 degradation; Zika virus