EMD-39427

Single-particle
3.49 Å
EMD-39427 Deposition: 11/03/2024
Map released: 30/10/2024
Last modified: 30/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-39427

Structure of the Caspase-8/cFLIP death effector domain assembly

EMD-39427

Single-particle
3.49 Å
EMD-39427 Deposition: 11/03/2024
Map released: 30/10/2024
Last modified: 30/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Caspase-8/cFLIP death effector domain assembly
Fitted models: 8ynm (Avg. Q-score: 0.439)

Deposition Authors: Lin S-C, Yang C-Y
Reverse hierarchical DED assembly in the cFLIP-procaspase-8 and cFLIP-procaspase-8-FADD complexes.
Yang CY, Tseng YC, Tu YF, Kuo BJ, Hsu LC, Lien CI, Lin YS, Wang YT, Lu YC, Su TW, Lo YC , Lin SC
(2024) Nat Commun , 15 , 8974 - 8974
PUBMED: 39419969
DOI: doi:10.1038/s41467-024-53306-1
ISSN: 2041-1723
Abstract:
cFLIP, a master anti-apoptotic regulator, targets the FADD-induced DED complexes of procaspase-8 in death receptor and ripoptosome signaling pathways. Several tumor cells maintain relatively high levels of cFLIP in achieving their immortality. However, understanding the three-dimensional regulatory mechanism initiated or mediated by elevated levels of cFLIP has been limited by the absence of the atomic coordinates for cFLIP-induced DED complexes. Here we report the crystal plus cryo-EM structures to uncover an unconventional mechanism where cFLIP and procaspase-8 autonomously form a binary tandem DED complex, independent of FADD. This complex gains the ability to recruit FADD, thereby allosterically modulating cFLIP assembly and partially activating caspase-8 for RIPK1 cleavage. Our structure-guided mutagenesis experiments provide critical insights into these regulatory mechanisms, elucidating the resistance to apoptosis and necroptosis in achieving immortality. Finally, this research offers a unified model for the intricate bidirectional hierarchy-based processes using multiprotein helical assembly to govern cell fate decisions.