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.
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Abbreviations
- DRs:
-
death receptors
- DED:
-
N-terminal death effector domain
- DD:
-
death domain
- DISC:
-
death-inducing signaling complex
- TNFR1:
-
tumor necrosis factor receptor 1
- IC:
-
intracellular domain
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Acknowledgements
We thank Vishva Dixit, Michael Lenardo and Marcus Peter for cDNAs of human CD95 and FADD, Marcus Peter for MCF7-FAS cells and antibodies. We thank Marcus Peter, Doug Green and Vishva Dixit for many useful discussions. We thank Andrew Thorburn and Lance R. Thomas for TRADD cDNA, pcDNA3.1 Puro vectors, Jurkat A3, I2.1 cell lines and for useful discussions. This work was supported in part by fellowships from the Human Frontier Science Program (LT0537), the NHMRC of Australia (997045) and the Norman and Rosita Winston Foundation to J.M.H., and by the National Science Foundation, the National Institutes of Health and Irma T. Hirschl Trust grants to MHW. M.HW is a Distinguished Young Scholar of the W.M. Keck Foundation.
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I Wegorzewska and T Kim: Wegorzewska and Kim are medical students and their current addresses are not known
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Sandu, C., Morisawa, G., Wegorzewska, I. et al. FADD self-association is required for stable interaction with an activated death receptor. Cell Death Differ 13, 2052–2061 (2006). https://doi.org/10.1038/sj.cdd.4401966
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DOI: https://doi.org/10.1038/sj.cdd.4401966
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