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| Title | Deciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 15, Issue 1, Page 3791, Year 2024 |
| Publish date | May 6, 2024 |
 Authors | Chao-Yu Yang / Chia-I Lien / Yi-Chun Tseng / Yi-Fan Tu / Arkadiusz W Kulczyk / Yen-Chen Lu / Yin-Ting Wang / Tsung-Wei Su / Li-Chung Hsu / Yu-Chih Lo / Su-Chang Lin /   |
| PubMed Abstract | Fas-associated protein with death domain (FADD), procaspase-8, and cellular FLICE-inhibitory proteins (cFLIP) assemble through death-effector domains (DEDs), directing death receptor signaling ...Fas-associated protein with death domain (FADD), procaspase-8, and cellular FLICE-inhibitory proteins (cFLIP) assemble through death-effector domains (DEDs), directing death receptor signaling towards cell survival or apoptosis. Understanding their three-dimensional regulatory mechanism has been limited by the absence of atomic coordinates for their ternary DED complex. By employing X-ray crystallography and cryogenic electron microscopy (cryo-EM), we present the atomic coordinates of human FADD-procaspase-8-cFLIP complexes, revealing structural insights into these critical interactions. These structures illustrate how FADD and cFLIP orchestrate the assembly of caspase-8-containing complexes and offer mechanistic explanations for their role in promoting or inhibiting apoptotic and necroptotic signaling. A helical procaspase-8-cFLIP hetero-double layer in the complex appears to promote limited caspase-8 activation for cell survival. Our structure-guided mutagenesis supports the role of the triple-FADD complex in caspase-8 activation and in regulating receptor-interacting protein kinase 1 (RIPK1). These results propose a unified mechanism for DED assembly and procaspase-8 activation in the regulation of apoptotic and necroptotic signaling across various cellular pathways involved in development, innate immunity, and disease. |
 External links | Nat Commun / PubMed:38710704 / PubMed Central |
| Methods | EM (single particle) / X-ray diffraction |
| Resolution | 3.11 - 7.56 Å |
| Structure data | EMDB-39126, PDB-8ybx:  EMDB-39127: Structure of the FADD/Caspase-8/cFLIP death effector domain assembly  PDB-8yd7:  PDB-8yd8: |
| Chemicals |  ChemComp-SE: |
| Source |
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 Keywords |  APOPTOSIS / FADD / caspase-8 / cellular FLICE-like inhibitory protein / Death effector domain / cFLIP |
