Identification of an expanded binding surface on the FADD death domain responsible for interaction with CD95/Fas
Identification of an expanded binding surface on the FADD death domain responsible for interaction with CD95/Fas
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DOI：
10.1074/jbc.m304996200
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发表时间：
2004-01-09
影响因子：
4.8
通讯作者：
Werner, MH
中科院分区：
文献类型：
--
作者：
Hill, JM;Morisawa, G;Werner, MH
CD95（Fas、Apo-1）处的程序性细胞死亡是通过在细胞质膜表面形成死亡诱导信号复合物 (DISC) 来实现的。 DISC 的组装被认为是通过 FADD 的死亡结构域 (DD) 和 CD95 的细胞质结构域之间的同型相互作用发生的。先前对 FADD/CD95 相互作用的分析导致鉴定出 FADD DD 内由 α 螺旋 2 和 3 形成的推定 CD95 结合表面。现在对 CD95/FADD DD 相互作用的更详细分析表明，FADD DD 中存在与 CD95 相互作用的双峰表面。该结构域一侧的广阔表面由 α 螺旋 1、2、3、5 和 6 中的元件组成。这个主要表面对于许多带有该基序的蛋白质来说是常见的，无论它们是否与程序性细胞死亡相关。第二表面位于结构域的相对面上，涉及螺旋 3 和 4 中的残基。主表面在拓扑上类似于果蝇管 DD 中鉴定的蛋白质相互作用表面和仓鼠 PEA-15 的死亡效应器结构域，这两种生理上不相关的蛋白质与结构上不相关的结合伙伴相互作用。这些结果表明，DD 内存在结构保守的表面，可以介导同型和异型结合配偶体的蛋白质识别，而第二个表面可能负责稳定 DISC 中的高级复合物。
The initiation of programmed cell death at CD95 (Fas, Apo-1) is achieved by forming a death-inducing signaling complex (DISC) at the cytoplasmic membrane surface. Assembly of the DISC has been proposed to occur via homotypic interactions between the death domain (DD) of FADD and the cytoplasmic domain of CD95. Previous analysis of the FADD/CD95 interaction led to the identification of a putative CD95 binding surface within FADD DD formed by alpha helices 2 and 3. More detailed analysis of the CD95/FADD DD interaction now demonstrates that a bimodal surface exists in the FADD DD for interaction with CD95. An expansive surface on one side of the domain is composed of elements in alpha helices 1, 2, 3, 5, and 6. This major surface is common to many proteins harboring this motif, whether or not they are associated with programmed cell death. A secondary surface resides on the opposite face of the domain and involves residues in helices 3 and 4. The major surface is topologically similar to the protein interaction surface identified in Drosophila Tube DD and the death effector domain of hamster PEA-15, two physiologically unrelated proteins which interact with structurally unrelated binding partners. These results demonstrate the presence of a structurally conserved surface within the DD which can mediate protein recognition with homo- and heterotypic binding partners, whereas a second surface may be responsible for stabilizing the higher order complex in the DISC.