Direct binding of Fas-associated death domain (FADD) to the tumor necrosis factor-related apoptosis-inducing ligand receptor DR5 is regulated by the death effector domain of FADD
Direct binding of Fas-associated death domain (FADD) to the tumor necrosis factor-related apoptosis-inducing ligand receptor DR5 is regulated by the death effector domain of FADD
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DOI：
10.1074/jbc.m401680200
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发表时间：
2004-07-30
影响因子：
4.8
通讯作者：
Thorburn, A
中科院分区：
文献类型：
--
作者：
Thomas, LR;Henson, A;Thorburn, A
肿瘤坏死因子受体超家族成员通过死亡结构域相互作用募集受体分子诱导细胞凋亡。这些受体的中心接头分子是含死亡结构域蛋白fas相关死亡结构域（FADD）。FADD结合受体或附加接头上的死亡结构域，将半胱天冬酶招募到活化的受体上。肿瘤坏死因子相关凋亡诱导配体（Tumor necrosis factor-related apoptosis-inducing ligand， TRAIL）通过DR4和DR5两种受体信号细胞凋亡。尽管人们对TRAIL很感兴趣，但FADD被TRAIL受体募集的机制尚不清楚。使用反向双杂交系统，我们之前在FADD的死亡效应域发现了阻止与Fas/CD95结合的突变。在这里，我们发现这些突变也阻止了与DR5的结合。稳定表达这些FADD突变的FADD缺陷Jurkat细胞不转导TRAIL或Fas/CD95信号。第二位点补偿突变恢复Fas/CD95和DR5的结合和信号传导，也在死亡效应域。我们得出结论，与目前FADD的死亡结构域独立于死亡效应结构域起作用的模型相反，FADD的死亡效应结构域与TRAIL和Fas/CD95受体直接接触。
Members of the tumor necrosis factor superfamily of receptors induce apoptosis by recruiting adaptor molecules through death domain interactions. The central adaptor molecule for these receptors is the death domain-containing protein Fas-associated death domain ( FADD). FADD binds a death domain on a receptor or additional adaptor and recruits caspases to the activated receptor. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signals apoptosis through two receptors, DR4 and DR5. Although there is much interest in TRAIL, the mechanism by which FADD is recruited to the TRAIL receptors is not clear. Using a reverse two-hybrid system we previously identified mutations in the death effector domain of FADD that prevented binding to Fas/CD95. Here we show that these mutations also prevent binding to DR5. FADD-deficient Jurkat cells stably expressing these FADD mutations did not transduce TRAIL or Fas/CD95 signaling. Second site compensating mutations that restore binding to and signaling through Fas/CD95 and DR5 were also in the death effector domain. We conclude that in contrast to current models where the death domain of FADD functions independently of the death effector domain, the death effector domain of FADD comes into direct contact with both TRAIL and Fas/CD95 receptors.