Assembly and activation of the death-inducing signaling complex

• 成果类型: Article
• 署名作者: Fosuah, Elizabeth; Shen, Zhangfei; Xie, Jiale; Wang, Chen; Lin, Qingpeng; Fu, Tian-Min
• 署名单位: University System of Ohio; Ohio State University; University of Massachusetts System; UMass Chan Medical School; University of Massachusetts Worcester
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11715
• DOI: 10.1073/pnas.2504819122
• 发表日期: 2025-06-10
• 关键词: apoptosis; reveals; cd95

摘要

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.