Nature. 2009 Feb 19;457(7232):1019-22. Epub 2008 Dec 31.

The Fas-FADD death domain complex structure unravels signalling by receptor clustering.External

Scott, F. L., Stec, B., Pop, C., Dobaczewska, M. K., Lee, J. J., Monosov, E., Robinson, H., Salvesen, G. S., Schwarzenbacher, R., Riedl, S. J.,
--- - Program in Apoptosis and Cell Death Research, The Burnham Institute for Medical Research, La Jolla, California 92037, USA.
The death inducing signalling complex (DISC) formed by Fas receptor, FADD (Fas-associated death domain protein) and caspase 8 is a pivotal trigger of apoptosis. The Fas-FADD DISC represents a receptor platform, which once assembled initiates the induction of programmed cell death. A highly oligomeric network of homotypic protein interactions comprised of the death domains of Fas and FADD is at the centre of DISC formation. Thus, characterizing the mechanistic basis for the Fas-FADD interaction is crucial for understanding DISC signalling but has remained unclear largely because of a lack of structural data. We have successfully formed and isolated the human Fas-FADD death domain complex and report the 2.7 A crystal structure. The complex shows a tetrameric arrangement of four FADD death domains bound to four Fas death domains. We show that an opening of the Fas death domain exposes the FADD binding site and simultaneously generates a Fas-Fas bridge. The result is a regulatory Fas-FADD complex bridge governed by weak protein-protein interactions revealing a model where the complex itself functions as a mechanistic switch. This switch prevents accidental DISC assembly, yet allows for highly processive DISC formation and clustering upon a sufficient stimulus. In addition to depicting a previously unknown mode of death domain interactions, these results further uncover a mechanism for receptor signalling solely by oligomerization and clustering events.
PMID: 19118384External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vitro interaction
  DD1 DD2 Reference
Family DD1 DD2 Method Species Region Expression Species Region Expression
DD FADD Link Fas His fusion protein pull-down Human 93-208 E.coli Human 223-335 E.coli 19118384
DD FADD Link Fas In vitro purification protein assembly(Size-exclusion chromatography) Human 93-208 E.coli Human 223-335 E.coli 19118384
(Link: click this icon to show interactions only between the two corresponding DDs)
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
Characterization
  Stoichiometry Affinity Protein-Protein interface Reference
Family DD1 DD2 Method Mutation Complex structure
DD FADD Link Fas Structure 4:4 L172A (FADD) 3EZQ 19118384
(Link: click this icon to show interactions only between the two corresponding DDs)