A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD-TRAF2 interaction

TRAP proteins are major mediators for the cell activation, cell survival, a nd antiapoptotic functions of the TNF receptor superfamily. They can be rec ruited to activated TNF receptors either by direct interactions with the re ceptors or indirectly via the adaptor protein TRADD. We now report the stru cture of the TRADD-TRAF2 complex, which is highly distinct from receptor-TR AF2 interactions. This interaction is significantly stronger and we show by an in vivo signaling assay that TRAF2 signaling is more readily initiated by TRADD than by direct receptor-TRAF2 interactions. TRADD is specific for TRAF1 and TRAF2, which ensures the recruitment of cIAPs for the direct inhi bition of caspase activation in the signaling complex. The stronger affinit y and unique specificity of the TRADD-TRAF2 interaction are crucial for the suppression of apoptosis and provide a mechanistic basis for the perturbat ion of TRAP recruitment in sensitizing cell death induction.