A docking model of key components of the DISC complex: death domain superfamily interactions redefined

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Measuring Composition of CD95 Death-Inducing Signaling Complex and Processing of Procaspase-8 in this Complex
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C H Weber1, C Vincenz

  • 1Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI 48109-0602, USA.

FEBS Letters
|March 21, 2001
PubMed

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.

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