Fosuah Elizabeth, Shen Zhangfei, Xie Jiale, Wang Chen, Lin Qingpeng, Fu Tian-Min
Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43210.
Department of Pathology, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605.
Proc Natl Acad Sci U S A. 2025 Jun 10;122(23):e2504819122. doi: 10.1073/pnas.2504819122. Epub 2025 Jun 4.
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.
由Fas、Fas相关死亡结构域（FADD）和半胱天冬酶-8组成的死亡诱导信号复合物（DISC）启动外源性细胞凋亡。我们利用低温电子显微镜（cryo-EM）表明，Fas和FADD死亡结构域（DDs）形成一个不对称的7:5寡聚体，促进FADD死亡效应结构域（DED）丝的形成。结构分析表明，FADD DED丝与半胱天冬酶-8串联DED丝非常相似，这表明FADD DED作为半胱天冬酶-8组装的成核支架。这些发现为DISC组装如何启动细胞凋亡并通过高阶寡聚化放大信号提供了一个机制框架。
