Assembly and activation of the death-inducing signaling complex.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40465623.
- Also identified by DOI 10.1073/pnas.2504819122 and PMC identifier 12168016.
- Licence recorded as CC BY-NC-ND.
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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.
Medical subject headings
- Fas-Associated Death Domain Protein
- Caspase 8
- Death Domain Receptor Signaling Adaptor Proteins