Assembly and activation of the death-inducing signaling complex

Proc Natl Acad Sci U S A. 2025 Jun 10;122(23):e2504819122. doi: 10.1073/pnas.2504819122. Epub 2025 Jun 4.

Abstract

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.

Keywords: FADD; Fas; caspase; cryo-EM; death domain.

MeSH terms

  • Apoptosis
  • Caspase 8* / chemistry
  • Caspase 8* / metabolism
  • Cryoelectron Microscopy
  • Death Domain Receptor Signaling Adaptor Proteins* / chemistry
  • Death Domain Receptor Signaling Adaptor Proteins* / metabolism
  • Fas-Associated Death Domain Protein* / chemistry
  • Fas-Associated Death Domain Protein* / genetics
  • Fas-Associated Death Domain Protein* / metabolism
  • Humans
  • Protein Multimerization
  • Signal Transduction
  • fas Receptor / chemistry
  • fas Receptor / metabolism

Substances

  • Fas-Associated Death Domain Protein
  • Caspase 8
  • Death Domain Receptor Signaling Adaptor Proteins
  • fas Receptor
  • FADD protein, human