A heterotrimeric death domain complex in Toll signaling
A heterotrimeric death domain complex in Toll signaling
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DOI：
10.1073/pnas.202396399
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发表时间：
2002-10-01
影响因子：
11.1
通讯作者：
Wasserman, SA
中科院分区：
文献类型：
--
作者：
Sun, HY;Bristow, BN;Wasserman, SA
从跨膜受体Toll到Rel相关转录因子的信号调节果蝇胚胎的背腹图案以及幼虫和成虫免疫。为了确定其他途径的组成部分，我们已经使用双链RNA干扰来研究调节哺乳动物Rel家族成员NF-κ B的基因的果蝇对应物。在培养细胞中的实验揭示，衔接蛋白MyD 88的果蝇直系同源物对于从Toll到第二衔接蛋白Tube的信号转导是必需的。通过使用免疫共沉淀研究，我们发现了一个异源三聚体的死亡结构域的MyD 88，管，和蛋白激酶Pelle协会。通过晶体学研究定义的相互作用位点的定点突变分析表明，Tube通过Tube死亡结构域上的两个不同的结合表面将MyD 88和Pelle招募到异源三聚体中。此外，功能测定证实，该异源三聚体的形成对于通过Toll途径的信号转导是至关重要的。
Signaling from the transmembrane receptor Toll to Rel-related transcription factors regulates dorsoventral patterning of the Drosophila embryo, as well as larval and adult immunity. To identify additional pathway components, we have used double-stranded RNA interference to investigate Drosophila counterparts of genes that regulate the mammalian Rel family member NF-kappaB. Experiments in cultured cells reveal that the fly orthologue of the adaptor protein MyD88 is essential for signal transduction from Toll to a second adaptor protein, Tube. By using coimmunoprecipitation studies, we find a heterotrimeric association of the death domains of MyD88, Tube, and the protein kinase Pelle. Site-directed mutational analyses of interaction sites defined by crystallographic studies demonstrate that Tube recruits MyD88 and Pelle into the heterotrimer by two distinct binding surfaces on the Tube death domain. Furthermore, functional assays confirm that the formation of this heterotrimer is critical for signal transduction by the Toll pathway.