Abstract
The death domain and death effector domain are two common motifs that mediate protein-protein interactions between components of cell death signaling complexes. The mechanism by which these domains engage their binding partners has been explored by extensive mutagenesis of two death adaptors, FADD and TRADD, suggesting that a death adaptor can discriminate its intended binding partners from other proteins harboring similar motifs. Death adaptors are found to utilize one of two topologically conserved surfaces for protein-protein interaction, whether that partner is another adaptor or its cognate receptor. These surfaces are topologically related to the interaction between death domains observed in the x-ray crystal structure of the Drosophila adaptor Tube bound to Pelle kinase. Comparing the topology of protein-protein interactions for FADD complexes to TRADD complexes reveals that FADD uses a Tube-like surface in each of its death motifs to engage either CD95 or TRADD. TRADD reverses these roles, employing a Pelle-like surface to interact with either receptor TNFR1 or adaptor FADD. Since death adaptors display a Tube-like or Pelle-like preference for engaging their binding partners, Tube/Pelle-like pairing provides a mechanism for death adaptor discrimination of death receptors.
Highlights
(6 –13), yet no mechanism by which these domains recognize one another among cell death proteins has been described
The TRADD DD is responsible for both interaction with the intracellular domain of TNFR1 and the DD of the Fas-associated death domain protein FADD
To identify the FADD binding surface of TRADD, 28 site-specific mutations were introduced into the TRADD DD and screened by a GST-TRADD DD
Summary
(6 –13), yet no mechanism by which these domains recognize one another among cell death proteins has been described. Biochemical characterization of the death adaptors FADD and the TNFR1-associated death domain protein TRADD [19] and dissection of how these adaptors recognize their binding partners suggests that these adaptors have a preferential binding surface for each other and for their cognate receptors. TRADD operates in a complementary fashion, using its Pelle-like surface to engage FADD or TNFR1. These observations demonstrate that there is an intrinsic specificity for protein partnerships built into the domain fold of a given adaptor. By defining the topology of these relationships, we propose that death adaptors utilize their Tube- and Pelle-like binding surfaces to discriminate one receptor from another to form distinct molecular complexes in cell death signal transduction
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
