Open AccessStructure and mechanism of IFN-γ antagonism by an orthopoxvirus IFN-γ-binding protein
Author(s) -
Anthony A. Nuara,
Leigh J. Walter,
Naomi J. Logsdon,
Sungil Yoon,
Brandi C. Jones,
Jill Schriewer,
R. Mark Buller,
Mark R. Walter
Publication year - 2008
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0705753105
Subject(s) - ectromelia virus , interferon gamma , biology , interferon , orthopoxvirus , virology , variola virus , immunology , cytokine , vaccinia , gene , biochemistry , recombinant dna
Ectromelia virus (ECTV) encodes an IFN-γ-binding protein (IFN-γBPECTV ) that disrupts IFN-γ signaling and its ability to induce an antiviral state within cells. IFN-γBPECTV is an important virulence factor that is highly conserved (>90%) in all orthopoxviruses, including variola virus, the causative agent of smallpox. The 2.2-Å crystal structure of the IFN-γBPECTV /IFN-γ complex reveals IFN-γBPECTV consists of an IFN-γR1 ligand-binding domain and a 57-aa helix-turn-helix (HTH) motif that is structurally related to the transcription factor TFIIA. The HTH motif forms a tetramerization domain that results in an IFN-γBPECTV /IFN-γ complex containing four IFN-γBPECTV chains and two IFN-γ dimers. The structure, combined with biochemical and cell-based assays, demonstrates that IFN-γBPECTV tetramers are required for efficient IFN-γ antagonism.