J Biol Chem. 2004 Dec 10;279(50):52479-86. Epub 2004 Sep 27.

The C-terminal tails of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas receptors have opposing functions in Fas-associated death domain (FADD) recruitment and can regulate agonist-specific mechanisms of receptor activation.External

Thomas, L. R., Johnson, R. L., Reed, J. C., Thorburn, A.,
--- - Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Members of the tumor necrosis factor (TNF) superfamily of receptors such as Fas/CD95 and the TNF-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5 induce apoptosis by recruiting adaptor molecules and caspases. The central adaptor molecule for these receptors is a death domain-containing protein, FADD, which binds to the activated receptor via death domain-death domain interactions. Here, we show that in addition to the death domain, the C-terminal tails of DR4 and DR5 positively regulate FADD binding, caspase activation and apoptosis. In contrast, the corresponding region in the Fas receptor has the opposite effect and inhibits binding to the receptor death domain. Replacement of wild-type or mutant DR5 molecules into DR5-deficient BJAB cells indicates that some agonistic antibodies display an absolute requirement for the C-terminal tail for FADD binding and signaling while other antibodies can function in the absence of this mechanism. These data demonstrate that regions outside the death domains of DR4 and DR5 have opposite effects to that of Fas in regulating FADD recruitment and show that different death receptor agonists can use distinct molecular mechanisms to activate signaling from the same receptor.
PMID: 15452120External
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 DR4 Link FADD Yeast two-hybrid Not specified 272-469 Yeast Not specified Full length Yeast 15452120
DD DR5 Link FADD Yeast two-hybrid Not specified 209-412 Yeast Not specified Full length Yeast 15452120
(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
In vivo interaction
  Endogenous
expression
Overexpression DD1 DD2 Reference
Family DD1 DD2 Method Species Region Species Region
DD DR4 Link FADD Co-immunoprecipitation BAJB Not specified 272-469 Not specified Full length 15452120
DD DR5 Link FADD Co-immunoprecipitation BJAB Not specified 209-412 Not specified Full length 15452120
(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
Functional Role
Family DD1 DD2 Method Death-related Death-unrelated Reference
DD DR4 Link FADD Caspase cleaved assay Caspase8 activation 15452120
DD DR5 Link FADD Caspase cleaved assay Caspase8 activation 15452120
(Link: click this icon to show interactions only between the two corresponding DDs)