Structure of the Fas/FADD complex: A conditional death domain complex mediating signaling by receptor clustering

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.

Caspase-8 isoform 6 promotes death effector filament formation independent of microtubules

“…The sequence can be favorably modeled as a helix. If this model is accurate and the residues do form an extended helix, it is possible that this may act to stabilize prodomain aggregation and filament formation via 'Stem Helix Stabilization' [14].…”

A mechanism underlying the neurotoxicity induced by sodium fluoride and its reversal by epigallocatechin gallate in the rat hippocampus: involvement of NrF2/Keap-1 signaling pathway

“…Fas is a type I membrane protein belonging to the tumor necrosis factor receptor family. The combination of Fas and FasL leads to the multimerization of Fas which Fas-associated protein with death domain (FADD) via interactions between the death domain of Fas and FADD (Salvesen & Riedl, 2009). Subsequently, procaspase-8 binds to Fas-bound FADD via interactions between the death effector domains of FADD and procaspase-8, leading to the activation of cas-8 and cas-9 (Strasser, Jost, & Nagata, 2009), which in turn activates caspase-3, then leading cell to apoptosis (Tsuruta, Oh-hashi, Kiuchi, & Hirata, 2008).…”

Structural analyses of death domains and their interactions

“…Biochemical and structural studies of DD have been explored over the past decade to enable a better understanding of apoptotic and innate immunue signaling. As a result, several DD structures have been elucidated, including four DD:DD complex structures [1,[31][32][33][34][35][36][37][38][39][40]. The molecular structure of DDs and their interactions with partners have revealed the underlying molecular basis for the assembly of DD mediated complexes and for the regulation of apoptosis and the innate immune signaling pathway (Table 1).…”