EMD-39428
Structure of the Caspase-8/cFLIP death effector domain assembly
EMD-39428
Single-particle3.97 Å
Deposition: 11/03/2024
Map released: 30/10/2024
Last modified: 30/10/2024
Sample Organism:
Homo sapiens
Sample: Caspase-8/cFLIP death effector domain assembly
Fitted models: 8ynn (Avg. Q-score: 0.321)
Deposition Authors: Lin S-C, Yang C-Y
Sample: Caspase-8/cFLIP death effector domain assembly
Fitted models: 8ynn (Avg. Q-score: 0.321)
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
(2024) Nat Commun , 15 , 8974 - 8974
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.
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.