title: Structural modeling and analysis of dengue-mediated inhibition of interferon signaling pathway.
abstract: Dengue virus (DENV) belongs to the family Flaviviridae and can cause major health problems worldwide, including dengue fever and dengue shock syndrome. DENV replicon in human cells inhibits interferon α and β with the help of its non-structural proteins. Non-structural protein 5 (NS5) of DENV is responsible for the proteasome-mediated degradation of signal transducer and activator of transcription (STAT) 2 protein, which has been implicated in the development of resistance against interferon-mediated antiviral effect. This degradation of STAT2 primarily occurs with the help of E3 ubiquitin ligases. Seven in absentia homologue (SIAH) 2 is a host protein that can mediate the ubiquitination of proteins and is known for its interaction with NS5. In this study, comprehensive computational analysis was performed to characterize the protein-protein interactions between NS5, SIAH2, and STAT2 to gain insight into the residues and sites of interaction between these proteins. The objective of the study was to structurally characterize the NS5-STAT2, SIAH2-STAT2, and NS5-SIAH2 interactions along with the determination of the possible reaction pattern for the degradation of STAT2. Docking and physicochemical studies indicated that DENV NS5 may first interact with the host SIAH2, which can then proceed towards binding with STAT2 from the side of SIAH2. These implications are reported for the first time and require validation by wet-lab studies.
authors.affiliation: Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan.
authors.forename: B
authors.initials: B
authors.lastname: Aslam
authors.affiliation: Research Center for Modeling & Simulation, National University of Sciences and Technology, Islamabad, Pakistan dr.ahmad.jamil@gmail.com.
authors.forename: J
authors.initials: J
authors.lastname: Ahmad
authors.forename: A
authors.initials: A
authors.lastname: Ali
authors.affiliation: Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan.
authors.forename: R Z
authors.initials: RZ
authors.lastname: Paracha
authors.affiliation: Research Center for Modeling & Simulation, National University of Sciences and Technology, Islamabad, Pakistan.
authors.forename: S H K
authors.initials: SH
authors.lastname: Tareen
authors.affiliation: Department of Computer Science, University of Peshawar, Peshawar, Pakistan.
authors.forename: S
authors.initials: S
authors.lastname: Khusro
authors.affiliation: Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan.
authors.forename: T
authors.initials: T
authors.lastname: Ahmad
authors.affiliation: Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University Multan, Pakistan.
authors.forename: S A
authors.initials: SA
authors.lastname: Muhammad
authors.forename: U
authors.initials: U
authors.lastname: Niazi
authors.affiliation: Laboratório de Genética Celular e Molecular, Departamento de Biologia Geral, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.
authors.forename: V
authors.initials: V
authors.lastname: Azevedo
mesh_terms: D000595:Amino Acid Sequence; D003715:Dengue / Q000276:immunology / Q000473:pathology*; D003716:Dengue Virus / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000276:immunology; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009687:Nuclear Proteins / Q000378:metabolism* / Q000648:ultrastructure; D060066:Protein Interaction Maps; D017433:Protein Structure, Secondary; D050794:STAT1 Transcription Factor / Q000378:metabolism / Q000648:ultrastructure; D050795:STAT2 Transcription Factor / Q000378:metabolism* / Q000648:ultrastructure; D016415:Sequence Alignment; D015398:Signal Transduction / Q000276:immunology; D055672:Static Electricity; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism* / Q000648:ultrastructure; D054875:Ubiquitination; D017361:Viral Nonstructural Proteins / Q000378:metabolism* / Q000648:ultrastructure; D000098563:Seven in Absentia Proteins
chemical_list: D007370:Interferon Type I; C582223:NS5 protein, dengue virus; D009687:Nuclear Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D017361:Viral Nonstructural Proteins; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins