title: Evidence of complex formation between FADD and c-FLIP death effector domains for the death inducing signaling complex.
abstract: Adaptor protein FADD forms the death inducing signaling complex (DISC) by recruiting the initiating caspases-8 and -10 through homotypic death effector domain (DED) interactions. Cellular FLICE-inhibitory protein (c-FLIP) is an inhibitor of death ligand-induced apoptosis downstream of death receptors, and FADD competes with procaspase-8/10 for recruitment for DISC. However, the mechanism of action of FADD and c-FLIP proteins remain poorly understood at the molecular level. In this study, we provide evidence indicating that the death effector domain (DED) of FADD interacts directly with the death effector domain of human c-FLIP. In addition, we use homology modeling to develop a molecular docking model of FADD and c-FLIP proteins. We also find that four structure-based mutants (E80A, L84A, K169A and Y171A) of c-FLIP DEDs disturb the interaction with FADD DED, and that these mutations lower the stability of the c-FLIP DED.
authors.affiliation: Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 609-735, Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Hwang
authors.affiliation: Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 609-735, Korea.
authors.forename: Mi Suk
authors.initials: MS
authors.lastname: Jeong
authors.affiliation: Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 609-735, Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 609-735, Korea.
authors.forename: Se Bok
authors.initials: SB
authors.lastname: Jang
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008969:Molecular Sequence Data; D011485:Protein Binding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D053200:Fas-Associated Death Domain Protein