The structure of FADD has been solved in solution, revealing that the death effector domain (DED) and death domain (DD) are aligned with one another in an orthogonal, tail-to-tail fashion. Mutagenesis of FADD and functional reconstitution with its binding partners define the interaction with the intracellular domain of CD95 and the prodomain of procaspase-8 and reveal a self-association surface necessary to form a productive complex with an activated "death receptor." The identification of a procaspase-specific binding surface on the FADD DED suggests a preferential interaction with one, but not both, of the DEDs of procaspase-8 in a perpendicular arrangement. FADD self-association is mediated by a "hydrophobic patch" in the vicinity of F25 in the DED. The structure of FADD and its functional characterization, therefore, illustrate the architecture of key components in the death-inducing signaling complex.

Self- and hetero-association of the pro-apoptotic proteins Reaper, Hid, and Grim is required for efficient induction of the cell death program.

The gram-positive soil bacterium Arthrobacter nicotinovorans (formerly known as Arthrobacter oxidans and reclassified by Kodama et al. [22]) has the ability to use nicotine as its sole carbon and energy source (8,10,15,17). Nicotine, the alkaloid of the tobacco plant, is synthesized as the L-isomer, and the first enzyme to attack L-nicotine is a trimeric, molybdopterin cofactor (MoCo) (most probably in its dinucleotide form [18])-, flavin adenine dinucleotide (FAD)-, and [Fe-S] clustercontaining nicotine dehydrogenase (NDH), which hydroxylates the pyridine ring at position 6 (Fig.

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.