1. ¹Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY, USA
2. ²Center for Immunology and Department of Molecular Biology & Biochemistry, University of California, Irvine, USA
3. ³Wegorzewska and Kim are medical students and their current addresses are not known

Correspondence: MH Werner, Laboratory of Molecular Biophysics, The Rockefeller University, 1230 York Avenue, Box 42, New York, NY 10021, USA. Tel: 212 327 7221; Fax: 212 327 7222; E-mail: mwerner@portugal.rockefeller.edu

Received 29 December 2005; Revised 20 March 2006; Accepted 18 April 2006; Published online 19 May 2006.

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.