Reverse hierarchical DED assembly in the cFLIP-procaspase-8 and cFLIP-procaspase-8-FADD complexes.
CASP8 and FADD-Like Apoptosis Regulating Protein
/ metabolism
Caspase 8
/ metabolism
Humans
Fas-Associated Death Domain Protein
/ metabolism
Cryoelectron Microscopy
Apoptosis
Receptor-Interacting Protein Serine-Threonine Kinases
/ metabolism
Signal Transduction
HEK293 Cells
Crystallography, X-Ray
Models, Molecular
Necroptosis
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 Oct 2024
17 Oct 2024
Historique:
received:
07
06
2024
accepted:
09
10
2024
medline:
18
10
2024
pubmed:
18
10
2024
entrez:
17
10
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39419969
doi: 10.1038/s41467-024-53306-1
pii: 10.1038/s41467-024-53306-1
doi:
Substances chimiques
CASP8 and FADD-Like Apoptosis Regulating Protein
0
Caspase 8
EC 3.4.22.-
Fas-Associated Death Domain Protein
0
FADD protein, human
0
Receptor-Interacting Protein Serine-Threonine Kinases
EC 2.7.11.1
CASP8 protein, human
EC 3.4.22.-
RIPK1 protein, human
EC 2.7.11.1
CFLAR protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8974Subventions
Organisme : Academia Sinica
ID : AS-TP-107-L16
Organisme : Academia Sinica
ID : AS-102-TP-B14-2
Organisme : Academia Sinica
ID : AS-TP-107-L16-1
Organisme : Academia Sinica
ID : AS-102-TP-B14
Organisme : Academia Sinica
ID : AS-TP-107-L16-2
Organisme : Academia Sinica
ID : AS-102-TP-B14-1
Organisme : Academia Sinica
ID : AS-TP-107-L16-3
Organisme : Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
ID : 110-2311-B-001-015-
Organisme : Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
ID : 109-2311-B-001-016-
Organisme : Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
ID : 108-2311-B-001-018-
Organisme : Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
ID : 107-2320-B-001-018-
Organisme : Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
ID : 107-2320-B-006-062-MY3
Organisme : Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
ID : 111-2311-B-006-005-MY3
Organisme : Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
ID : 111-2311-B-006-005-MY3
Informations de copyright
© 2024. The Author(s).
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