致死信号复合体的组装和激活

IF 9.1 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-06-04 DOI:10.1073/pnas.2504819122

Elizabeth Fosuah, Zhangfei Shen, Jiale Xie, Chen Wang, Qingpeng Lin, Tian-Min Fu

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引用次数: 0

摘要

死亡诱导信号复合体（DISC），包括Fas、Fas相关死亡结构域（FADD）和caspase-8，启动外源性细胞凋亡。利用低温电子显微镜（cryo-EM），我们发现Fas和FADD死亡结构域（dd）形成不对称的7:5寡聚物，促进FADD死亡效应结构域（DED）细丝的形成。结构分析表明，FADD DED纤维与caspase-8串联DED纤维非常相似，表明FADD DED可作为caspase-8组装的成核支架。这些发现为DISC组装如何启动细胞凋亡和通过高阶寡聚化放大信号提供了机制框架。

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Assembly and activation of the death-inducing signaling complex

The death-inducing signaling complex (DISC), comprising Fas, Fas-associated death domain (FADD), and caspase-8, initiates extrinsic apoptosis. Using cryogenic electron microscopy (cryo-EM), we show that Fas and FADD death domains (DDs) form an asymmetric 7:5 oligomer, which promotes FADD death effector domain (DED) filament formation. Structural analysis reveals that FADD DED filaments closely resemble caspase-8 tandem DED filaments, suggesting that FADD DED serves as a nucleation scaffold for caspase-8 assembly. These findings provide a mechanistic framework for how DISC assembly initiates apoptosis and amplifies signaling via higher-order oligomerization.

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来源期刊

Proceedings of the National Academy of Sciences of the United States of America 综合性期刊-综合性期刊

CiteScore

19.00

自引率

0.90%

发文量

3575

审稿时长

2.5 months

期刊介绍： The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.