Structure and mechanism of IFN-γ antagonism by an orthopoxvirus IFN-γ-binding protein

초록

Ectromelia virus (ECTV) encodes an IFN-gamma-bincling protein (IFN-gamma BPECTV) that disrupts IFN-gamma signaling and its ability to induce an antiviral state within cells. IFN-gamma BPECTV is an important virulence factor that is highly conserved (>90%) in all orthopoxviruses, including variola virus, the causative agent of smallpox. The 2.2-angstrom crystal structure of the IFN-gamma BPECTV/IFN-gamma complex reveals IFN-gamma BPECTV consists of an lFN-gamma R1 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 lFN-gamma BPECTV/IFN-gamma complex containing four IFN-gamma BPECTV chains and two IFN-gamma dimers. The structure, combined with biochemical and cell-based assays, demonstrates that IFN-gamma BPECTV tetramers are required for efficient IFN-gamma antagonism.

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