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A docking model of key components of the DISC complex: death domain superfamily interactions redefined
1Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI 48109-0602, USA.
Abstract:
Apoptosis is mediated by a highly regulated signal transduction cascade that eventually leads to precisely directed cell death. The death-inducing signaling complex (DISC), composed of Fas, FADD, and caspase-8, is an apical signaling complex that mediates receptor-induced apoptosis. We have docked the experimentally determined structures of the Fas and FADD death domains into a model of a partial DISC signaling complex. The arrangement of Fas and FADD was determined using the interaction modes of the two heterodimer crystal structures determined to date, Pelle/Tube and Apaf-1/procaspase-9. The proposed model reveals that both interactions can be accommodated in a single multimeric complex. Importantly, the model is consistent with reported site-directed mutagenesis data indicating residues throughout the domain are critical for function. These results imply that members of the death domain superfamily have the potential for multivalent interactions, offering novel possibilities for regulation of apoptotic signaling.
Insights
This study models the Fas and FADD death domains within the death-inducing signaling complex (DISC). The model suggests multivalent interactions within the death domain superfamily, offering new insights into apoptosis regulation.
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- Apoptosis is a crucial cellular process regulated by complex signaling pathways.
- The death-inducing signaling complex (DISC), comprising Fas, FADD, and caspase-8, is central to receptor-mediated apoptosis.
Purpose of the Study:
- To model the structural arrangement of Fas and FADD death domains within a partial DISC.
- To explore the potential for multivalent interactions within the death domain superfamily.
Main Methods:
- Docking experimentally determined structures of Fas and FADD death domains.
- Utilizing interaction modes from Pelle/Tube and Apaf-1/procaspase-9 heterodimer crystal structures.
- Validating the model against site-directed mutagenesis data.
Main Results:
- A proposed model for the arrangement of Fas and FADD within a partial DISC was developed.
- The model accommodates interaction modes from known heterodimer structures, suggesting a single multimeric complex.
- The model aligns with mutagenesis data, highlighting the functional importance of various residues.
Conclusions:
- Members of the death domain superfamily possess the capacity for multivalent interactions.
- These multivalent interactions present novel mechanisms for regulating apoptotic signaling pathways.