Evidence of complex formation between FADD and c-FLIP death effector domains for the death inducing signaling complex
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Adaptor protein FADD forms the death inducing signalingcomplex (DISC) by recruiting the initiating caspases-8 and -10through homotypic death effector domain (DED) interactions. Cellular FLICE-inhibitory protein (c-FLIP) is an inhibitor ofdeath ligand-induced apoptosis downstream of deathreceptors, and FADD competes with procaspase-8/10 forrecruitment for DISC. However, the mechanism of action ofFADD and c-FLIP proteins remain poorly understood at themolecular level. In this study, we provide evidence indicatingthat the death effector domain (DED) of FADD interactsdirectly with the death effector domain of human c-FLIP. Inaddition, we use homology modeling to develop a moleculardocking model of FADD and c-FLIP proteins. We also find thatfour structure-based mutants (E80A, L84A, K169A and Y171A)of c-FLIP DEDs disturb the interaction with FADD DED, andthat these mutations lower the stability of the c-FLIP DED.
Abstract
Adaptor protein FADD forms the death inducing signalingcomplex (DISC) by recruiting the initiating caspases-8 and -10through homotypic death effector domain (DED) interactions. Cellular FLICE-inhibitory protein (c-FLIP) is an inhibitor ofdeath ligand-induced apoptosis downstream of deathreceptors, and FADD competes with procaspase-8/10 forrecruitment for DISC. However, the mechanism of action ofFADD and c-FLIP proteins remain poorly understood at themolecular level. In this study, we provide evidence indicatingthat the death effector domain (DED) of FADD interactsdirectly with the death effector domain of human c-FLIP. Inaddition, we use homology modeling to develop a moleculardocking model of FADD and c-FLIP proteins. We also find thatfour structure-based mutants (E80A, L84A, K169A and Y171A)of c-FLIP DEDs disturb the interaction with FADD DED, andthat these mutations lower the stability of the c-FLIP DED.
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