The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex.
Data(s) |
2002
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Resumo |
Death receptors, such as Fas and tumor necrosis factor-related apoptosis-inducing ligand receptors, recruit Fas-associated death domain and pro-caspase-8 homodimers, which are then autoproteolytically activated. Active caspase-8 is released into the cytoplasm, where it cleaves various proteins including pro-caspase-3, resulting in apoptosis. The cellular Fas-associated death domain-like interleukin-1-beta-converting enzyme-inhibitory protein long form (FLIP(L)), a structural homologue of caspase-8 lacking caspase activity because of several mutations in the active site, is a potent inhibitor of death receptor-induced apoptosis. FLIP(L) is proposed to block caspase-8 activity by forming a proteolytically inactive heterodimer with caspase-8. In contrast, we propose that FLIP(L)-bound caspase-8 is an active protease. Upon heterocomplex formation, a limited caspase-8 autoprocessing occurs resulting in the generation of the p43/41 and the p12 subunits. This partially processed form but also the non-cleaved FLIP(L)-caspase-8 heterocomplex are proteolytically active because they both bind synthetic substrates efficiently. Moreover, FLIP(L) expression favors receptor-interacting kinase (RIP) processing within the Fas-signaling complex. We propose that FLIP(L) inhibits caspase-8 release-dependent pro-apoptotic signals, whereas the single, membrane-restricted active site of the FLIP(L)-caspase-8 heterocomplex is proteolytically active and acts on local substrates such as RIP. |
Identificador |
http://serval.unil.ch/?id=serval:BIB_5A5C5C71FE16 isbn:0021-9258 (Print) pmid:12215447 doi:10.1074/jbc.M206882200 isiid:000179404800074 |
Idioma(s) |
en |
Fonte |
Journal of Biological Chemistry, vol. 277, no. 47, pp. 45162-45171 |
Palavras-Chave | #Amino Acid Sequence; Antigens, CD95/metabolism; Apoptosis/physiology; Binding Sites; CASP8 and FADD-Like Apoptosis Regulating Protein; Carrier Proteins/chemistry; Carrier Proteins/genetics; Caspase 3; Caspase 8; Caspase 9; Caspases/antagonists & inhibitors; Caspases/chemistry; Cell Line; Cell Size; Dimerization; Enzyme Activation; Enzyme Inhibitors/chemistry; Enzyme Inhibitors/metabolism; Fas Ligand Protein; Humans; Intracellular Signaling Peptides and Proteins; Ligands; Macromolecular Substances; Membrane Glycoproteins/genetics; Membrane Glycoproteins/metabolism; Models, Molecular; Molecular Sequence Data; Protein Structure, Tertiary; Sequence Alignment; Signal Transduction/physiology |
Tipo |
info:eu-repo/semantics/article article |