Differential affinity of FLIP and procaspase 8 for FADD's DED binding surfaces regulates DISC assembly.
Nat Commun
; 5: 3350, 2014 Feb 28.
Article
em En
| MEDLINE
| ID: mdl-24577104
ABSTRACT
Death receptor activation triggers recruitment of FADD, which via its death effector domain (DED) engages the DEDs of procaspase 8 and its inhibitor FLIP to form death-inducing signalling complexes (DISCs). The DEDs of FADD, FLIP and procaspase 8 interact with one another using two binding surfaces defined by α1/α4 and α2/α5 helices, respectively. Here we report that FLIP has preferential affinity for the α1/α4 surface of FADD, whereas procaspase 8 has preferential affinity for FADD's α2/α5 surface. These relative affinities contribute to FLIP being recruited to the DISC at comparable levels to procaspase 8 despite lower cellular expression. Additional studies, including assessment of DISC stoichiometry and functional assays, suggest that following death receptor recruitment, the FADD DED preferentially engages FLIP using its α1/α4 surface and procaspase 8 using its α2/α5 surface; these tripartite intermediates then interact via the α1/α4 surface of FLIP DED1 and the α2/α5 surface of procaspase 8 DED2.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Caspase 8
/
Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD
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Proteína de Domínio de Morte Associada a Fas
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article