title: 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.
authors: The Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
authors: Guy S
authors: GS
authors: Salvesen
authors: Stefan J
authors: SJ
authors: Riedl
mesh_terms: D017209:Apoptosis; D001665:Binding Sites; D053181:Caspase 8 / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000737:chemistry* / Q000378:metabolism; D008954:Models, Biological; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D019014:fas Receptor / Q000737:chemistry* / Q000378:metabolism
chemical_list: D053200:Fas-Associated Death Domain Protein; D019014:fas Receptor; D053181:Caspase 8