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. 2009 Sep 1;8(17):2723-7.
doi: 10.4161/cc.8.17.9399. Epub 2009 Sep 30.

Structure of the Fas/FADD Complex: A Conditional Death Domain Complex Mediating Signaling by Receptor Clustering

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Free PMC article

Structure of the Fas/FADD Complex: A Conditional Death Domain Complex Mediating Signaling by Receptor Clustering

Guy S Salvesen et al. Cell Cycle. .
Free PMC article

Abstract

Death domain complexes are key protein arrangements in the regulation of various cellular signaling events. One of the most prominent death domain complexes first described in the initiation of apoptosis is formed by the transmembrane receptor Fas, the cytosolic adaptor protein FADD, and caspase-8 and is referred to as the Fas/FADD/caspase-8 death inducing signaling complex (DISC). The recent structure of the Fas/FADD death domain complex reveals how formation of this signaling platform can be stringently regulated utilizing only Fas receptor clustering to form a death domain network. This work reveals that an opening mechanism of Fas is needed to expose binding sites for the FADD death domain and sets the stage for a conditional interaction, which is characterized by weak interactions adapted for a regulatory function. The overall crystal structure reveals a tetrameric arrangement of four primary Fas/FADD complexes. Intriguingly all contacts mediating the tetramer are solely provided through Fas/Fas interactions and are entirely dependent on the open form. These findings are instrumental in depicting a mechanism for DISC regulation where Fas receptor clustering leads to the stabilization of the open Fas death domains which are then capable of binding FADD in a weak interaction. At the same time this mechanism ensures that in the absence of a sufficient stimulus no interaction between Fas and FADD is possible. Therefore the conformation dependent, conditional Fas/FADD death domain interaction represents the regulatory element per se. This interaction contrasts the classic constitutive interactions of adaptor domains, which cannot provide regulatory function themselves. This model portrays how sole death domains are able to mediate signaling upon receptor clustering in the complete absence of enzyme activity.

Figures

Figure 1
Figure 1
Schematic of DISC formation—Fas exists in prearranged trimers but no binding occurs between Fas, FADD and Caspase-8. The death domain binding network present in the DISC only forms upon close clustering of Fas receptor trimers which leads to a clustering of its DDs, rendering them competent to bind FADD and initiating DISC formation. The interaction between the Fas DD and FADD is hereby at the heart of the network forming the DISC. Thus the Fas/FADD DD complex is at the center of the signaling regulation switch.
Figure 2
Figure 2
Structure of the primary Fas/FADD DD complex: Fas opening is the central switch revealing the binding sites for FADD. Comparison of the Fas DD in its unbound structure (left) and the Fas/FADD DD complex structure (right). The solution structure of the unbound Fas DD shows the typical death domain fold with a globular arrangement consisting of six helices (left) and a typical hydrophilic surface for a soluble domain (below/rotated). The complex structure shows that in order to form the primary Fas/FADD DD complex Fas has to undergo an opening, where helix six shifts dramatically and fuses with helix five, resulting in the formation of a long helix (stem helix)—in addition a new helix (C-helix) is also formed. The change in helices five and six exposes parts of the hydrophobic core of Fas (below/rotated to visualize the surface), which serves as the main binding site to accommodate the DD of FADD. Right, the primary Fas/FADD DD complex is shown as seen in the structure. (rendering and electrostatic surfaces in pymol/www.pymol.org; pdb accessions: 1DDF/unbound Fas; 3EZQ).
Figure 3
Figure 3
The Fas/FADD DD tetramer. The Fas/FADD DD complex adopts a tetrameric arrangement of four primary Fas/FADD DD complexes in the crystal structure reflecting the oligomerisation state in solution as verified by biochemical and biophysical characterization., All contacts building the tetramer are built by Fas (square) and strictly dependent on the open form (all FADD DDs are displayed in light blue).
Figure 4
Figure 4
Mechanism of DISC formation by receptor clustering: Fas opening and conditional Fas/FADD interaction. Top: Fas receptors and thus DDs exist in preformed timers prior to sufficient clustering. The closed forms represent the stable form of the Fas DDs, the open forms with partial exposure of core are unstable. Close linkage of Fas receptors/DDs by intense clustering of the trimers brings Fas DDs in close proximity, open forms can interact via Fas/Fas interactions leading to their stabilization (schematically illustrated for two sides of the trimers). Consequentially FADD binding sites are formed and stabilized, FADD can bind. Additionally FADD can further contribute to the network through its DD and DED enhancing processivity (not shown).

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