School of Biochemistry and Immunology, Trinity College, Dublin, Dublin 2, Ireland.
Structure. 2009 Nov 11;17(11):1528-37. doi: 10.1016/j.str.2009.09.005.
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.
痘病毒是表达众多蛋白来颠覆宿主免疫反应的 DNA 病毒。牛痘病毒蛋白 K7 采用 Bcl-2 折叠结构，与 Toll 样受体拮抗剂 A52 具有结构和功能上的相似性。这两种蛋白都与 IRAK2 和 TRAF6 相互作用，并抑制 TLR 依赖的 NF-κB 激活。然而，与 A52 不同的是，K7 还与 RNA 解旋酶 DDX3 形成复合物，并拮抗干扰素-β启动子的诱导。我们已经将 K7 的结合位点缩小到 DDX3 的核心 RNA 解旋酶结构域之前的 N 端肽基序。全长 K7 与 DDX3 肽的晶体结构揭示了 DDX3 的串联苯丙氨酸残基像拇指一样突入一个深的疏水性裂缝中。这些苯丙氨酸的突变消除了 DDX3 对干扰素-β启动子诱导的影响。K7-DDX3 的结构揭示了一种新型的病毒 Bcl-2 蛋白结合模式，该模式拮抗先天免疫中的关键途径。
