title: FADD self-association is required for stable interaction with an activated death receptor.
abstract: Receptor-mediated programmed cell death proceeds through an activated receptor to which the death adaptor FADD and the initiator procaspases 8 and/or 10 are recruited following receptor stimulation. The adaptor FADD is responsible for both receptor binding and recruitment of the procaspases into the death-inducing signaling complex. Biochemical dissection of the FADD death effector domain and functional replacement with a coiled-coil motif demonstrates that there is an obligatory FADD self-association via the DED during assembly of the death-inducing signaling complex. Using engineered oligomerization motifs with defined stoichiometries, the requirement for FADD self-association through the DED can be separated from the caspase-recruitment function of the domain. Disruption of FADD self-association precludes formation of a competent signaling complex. On this basis, we propose an alternative architecture for the FADD signaling complex in which FADD acts as a molecular bridge to stitch together an array of activated death receptors.
authors.affiliation: Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY 10021, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sandu
authors.forename: G
authors.initials: G
authors.lastname: Morisawa
authors.forename: I
authors.initials: I
authors.lastname: Wegorzewska
authors.forename: T
authors.initials: T
authors.lastname: Huang
authors.forename: A F
authors.initials: AF
authors.lastname: Arechiga
authors.forename: J M
authors.initials: JM
authors.lastname: Hill
authors.forename: T
authors.initials: T
authors.lastname: Kim
authors.forename: C M
authors.initials: CM
authors.lastname: Walsh
authors.forename: M H
authors.initials: MH
authors.lastname: Werner
mesh_terms: D053455:Caspase 10 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D019169:Jurkat Cells; D046911:Macromolecular Substances; D009154:Mutation; D011485:Protein Binding; D053218:Receptors, Death Domain / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D046911:Macromolecular Substances; D053218:Receptors, Death Domain; D053455:Caspase 10; D053181:Caspase 8; C506438:CASP10 protein, human