Structural Insight for Roles of DR5 Death Domain Mutations on Oligomerization of DR5 Death Domain-FADD Complex in the Death-Inducing Signaling Complex Formation: A Computational Study.
Structural Insight for Roles of DR5 Death Domain Mutations on Oligomerization of DR5 Death Domain-FADD Complex in the Death-Inducing Signaling Complex Formation: A Computational Study.
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DR5 死亡结构域突变对死亡诱导信号复合物形成中 DR5 死亡结构域-FADD 复合物寡聚化作用的结构洞察：计算研究。
DOI：
10.1007/s00894-016-2941-0
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发表时间：
2016
影响因子：
2.2
通讯作者：
Song,Yuhua
中科院分区：
文献类型：
--
作者：
Yang,Hongyi;Song,Yuhua
死亡受体5（DR 5）诱导的细胞凋亡，优先肿瘤细胞的死亡已被提出作为一个有前途的癌症治疗。在此过程中，寡聚化的DR 5死亡结构域（DD）与Fas相关死亡结构域（FADD）结合导致FADD激活半胱天冬酶-8，这标志着启动凋亡的死亡诱导信号复合物（DISC）的形成。在肿瘤细胞中发现的DR 5 DD突变被认为在肿瘤的发生发展中起着重要的病理作用，但其阻止DR 5激活的DISC形成的机制尚不清楚。本研究旨在为四种选定的DR 5 DD突变（E355 K、E367 K、K415 N和L363 F）在DISC形成期间DR 5 DD-FADD复合物寡聚化中的作用提供结构和分子见解。分子动力学模拟的结果表明，模拟突变体诱导DR 5 DD-FADD四聚体复合物的构象、动力学运动和相互作用变化，包括蛋白质骨架柔性的变化、FADD DED的caspase-8结合位点的暴露减少、DR 5 DD-FADD DD结合处的氢键和疏水接触减少、静电势分布和残基相关运动的改变，和降低DR 5DD与FADD结合的结合亲和力。该研究为DR 5 DD突变对DR 5 DD-FADD复合物寡聚化的影响提供了结构和分子见解，预计这将促进对DR 5 DD突变体针对DR 5激活的DISC形成的抗性机制的了解。
Death receptor 5 (DR5)-induced apoptosis that prioritizes the death of tumor cells has been proposed as one of the promising cancer therapies. In this process, oligomerized DR5 death domain (DD) binding to Fas-associated death domain (FADD) leads to FADD activating caspase-8, which marks the formation of the death-inducing signaling complex (DISC) that initiates apoptosis. DR5 DD mutations found in cancer cells have been suggested to play an important pathological role, the mechanism through which those mutants prevent the DR5-activated DISC formation is not clear yet. This study sought to provide structural and molecular insight for the roles of four selected DR5 DD mutations (E355K, E367K, K415N, and L363F) in the oligomerization of DR5 DD–FADD complex during the DISC formation. Results from the molecular dynamics simulations show that the simulated mutants induce conformational, dynamical motions and interactions changes in the DR5 DD–FADD tetramer complex, including changes in a protein’s backbone flexibility, less exposure of FADD DED’s caspase-8 binding site, reduced H-bonding and hydrophobic contacts at the DR5 DD–FADD DD binding, altered distribution of the electrostatic potentials and correlated motions of residues, and reduced binding affinity of DR5 DD binding to FADD. This study provides structural and molecular insight for the influence of DR5 DD mutations on oligomerization of DR5 DD–FADD complex, which is expected to foster understanding of the DR5 DD mutants’ resistance mechanism against DR5-activated DISC formation.