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Deciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis

Chao-Yu Yang1, Chia-I Lien2, Yi-Chun Tseng1,3

  • 1Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan.

Nature Communications
|May 6, 2024
PubMed

Insights

Structural insights into FADD, procaspase-8, and cFLIP complexes reveal how these proteins regulate cell death pathways. The atomic structures elucidate mechanisms controlling apoptosis and necroptosis signaling for development and disease.

Area of Science:

  • Molecular and Cellular Biology
  • Structural Biology
  • Immunology

Background:

  • Fas-associated protein with death domain (FADD), procaspase-8, and cellular FLICE-inhibitory proteins (cFLIP) are key regulators of cell death signaling.
  • Their assembly via death-effector domains (DEDs) dictates apoptosis or cell survival.
  • Lack of atomic structures for their ternary DED complex limited understanding of regulatory mechanisms.

Purpose of the Study:

  • To determine the atomic coordinates of human FADD-procaspase-8-cFLIP complexes.
  • To gain structural insights into the interactions governing death receptor signaling.
  • To elucidate the mechanisms of apoptotic and necroptotic signaling regulation.

Main Methods:

  • X-ray crystallography
  • Cryogenic electron microscopy (cryo-EM)
  • Structure-guided mutagenesis

Main Results:

  • Atomic coordinates of human FADD-procaspase-8-cFLIP complexes were determined.
  • Structures revealed how FADD and cFLIP orchestrate caspase-8 complex assembly.
  • A helical procaspase-8-cFLIP hetero-double layer was identified, potentially promoting limited caspase-8 activation for cell survival.
  • Mutagenesis supported the role of the triple-FADD complex in caspase-8 activation and RIPK1 regulation.

Conclusions:

  • The study provides a unified mechanism for DED assembly and procaspase-8 activation.
  • These findings offer mechanistic explanations for regulating apoptotic and necroptotic signaling.
  • The results have implications for understanding cell death in development, immunity, and disease.

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