title: Structural basis for targeting of human RNA helicase DDX3 by poxvirus protein K7.
abstract: Poxviruses are DNA viruses that express numerous proteins to subvert the host immune response. Vaccinia virus protein K7 adopts a Bcl-2 fold and displays structural and functional similarities to Toll-like receptor antagonist A52. Both proteins interact with IRAK2 and TRAF6 and suppress TLR-dependent NF-kappaB activation. However, unlike A52, K7 also forms a complex with RNA helicase DDX3 and antagonizes interferon-beta promoter induction. We have narrowed the K7 binding site to an N-terminal peptide motif of DDX3 ahead of its core RNA-helicase domains. The crystal structure of full-length K7 in complex with the DDX3 peptide reveals a thumblike projection of tandem phenalyalanine residues of DDX3 into a deep hydrophobic cleft. Mutagenesis of these phenylalanines abolishes the effects of DDX3 on interferon-beta promoter induction. The structure of K7-DDX3 reveals a novel binding mode by a viral Bcl-2 protein that antagonizes a key pathway in innate immunity.
authors.affiliation: School of Biochemistry and Immunology, Trinity College, Dublin, Dublin 2, Ireland.
authors.forename: Shun-Ichiro
authors.initials: S
authors.lastname: Oda
authors.forename: Martina
authors.initials: M
authors.lastname: Schröder
authors.forename: Amir R
authors.initials: AR
authors.lastname: Khan
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D003460:Crystallization; D053487:DEAD-box RNA Helicases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D016899:Interferon-beta / Q000037:antagonists & inhibitors; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D016415:Sequence Alignment; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D014616:Vaccinia virus / Q000737:chemistry*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048029:TNF Receptor-Associated Factor 6; D014764:Viral Proteins; D016899:Interferon-beta; D053592:Interleukin-1 Receptor-Associated Kinases; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases