Structural insight for the roles of fas death domain binding to FADD and oligomerization degree of the Fas-FADD complex in the death-inducing signaling complex formation: a computational study.
Structural insight for the roles of fas death domain binding to FADD and oligomerization degree of the Fas-FADD complex in the death-inducing signaling complex formation: a computational study.
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fas 死亡结构域与 FADD 结合的结构洞察以及 Fas-FADD 复合物寡聚化程度在死亡诱导信号复合物形成中的作用：一项计算研究。
作者：
Yan,Qi;McDonald,JayM;Zhou,Tong;Song,Yuhua
Fas与Fas相关死亡结构域（FADD）的结合激活FADD-caspase-8结合，形成死亡诱导信号复合物（DISC），触发细胞凋亡。Fas-Fas缔合物主要以二聚体形式存在于Fas-FADD复合物中，而Fas-FADD四聚体复合物有形成更高级寡聚体的趋势。低聚化的Fas-FADD复合物在DISC形成中的重要性已经得到证实。本研究试图从结构上了解Fas死亡结构域（Fas DD）与FADD的结合以及Fas DD-FADD复合物的寡聚化在激活FADD-procaspase-8结合中的作用。结果显示Fas DD与FADD的结合稳定了FADD构象，包括FADD死亡效应结构域（FADD DED）中FADD-半胱氨酸天冬氨酸蛋白酶原-8结合的关键残基的稳定性增加。Fas DD与FADD的结合导致FADD残基的相关运动和非相关运动的程度降低，并导致FADD DED和FADD死亡结构域（FADD DD）之间的反向相关运动。在Fas DD与FADD结合的情况下，观察到FADD中允许FADD与半胱天冬酶原-8相互作用的半胱天冬酶原-8结合残基的暴露。我们还观察到不同程度的FADD的构象和运动变化的Fas DD-FADD复合物的寡聚化程度不同。与Fas DD FADD二聚体复合物相比，Fas DD FADD四聚体复合物中FADD残基的构象稳定性增加，相关运动程度降低。本研究为Fas DD与FADD的结合以及Fas DD-FADD复合物在DISC形成中的寡聚化程度对凋亡信号的作用提供了结构证据。Proteins 2013.© 2012 Wiley Periodicals，Inc.
Fas binding to Fas‐associated death domain (FADD) activates FADD–caspase‐8 binding to form death‐inducing signaling complex (DISC) that triggers apoptosis. The Fas–Fas association exists primarily as dimer in the Fas–FADD complex, and the Fas–FADD tetramer complexes have the tendency to form higher order oligomer. The importance of the oligomerized Fas–FADD complex in DISC formation has been confirmed. This study sought to provide structural insight for the roles of Fas death domain (Fas DD) binding to FADD and the oligomerization of Fas DD–FADD complex in activating FADD–procaspase‐8 binding. Results show Fas DD binding to FADD stabilized the FADD conformation, including the increased stability of the critical residues in FADD death effector domain (FADD DED) for FADD–procaspase‐8 binding. Fas DD binding to FADD resulted in the decreased degree of both correlated and anticorrelated motion of the residues in FADD and caused the reversed correlated motion between FADD DED and FADD death domain (FADD DD). The exposure of procaspase‐8 binding residues in FADD that allows FADD to interact with procaspase‐8 was observed with Fas DD binding to FADD. We also observed different degrees of conformational and motion changes of FADD in the Fas DD–FADD complex with different degrees of oligomerization. The increased conformational stability and the decreased degree of correlated motion of the residues in FADD in Fas DD–FADD tetramer complex were observed compared to those in Fas DD–FADD dimer complex. This study provides structural evidence for the roles of Fas DD binding to FADD and the oligomerization degree of Fas DD–FADD complex in DISC formation to signal apoptosis. Proteins 2013. © 2012 Wiley Periodicals, Inc.