FADD self-association is required for stable interaction with an activated death receptor.
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.
Sandu
C
C
Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY 10021, USA.
Morisawa
G
G
Wegorzewska
I
I
Huang
T
T
Arechiga
A F
AF
Hill
J M
JM
Kim
T
T
Walsh
C M
CM
Werner
M H
MH
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*
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