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RAIDD is a new 'death' adaptor molecule
1Department of Pathology, University of Michigan Medical School, Ann Arbor 48109, USA.
Abstract:
The effector arm of the cell-death pathway is composed of cysteine proteases belonging to the ICE/CED-3 family. In metazoan cells these exist as inactive polypeptide precursors (zymogens), each composed of a prodomain, which is cleaved to activate the protease, and a large and small catalytic subunit. The coupling of these 'death' proteases to signalling pathways is probably mediated by adaptor molecules that contain protein-protein interaction motifs such as the death domain. Here we describe such an adaptor molecule, RAIDD, which has an unusual bipartite architecture comprising a carboxy-terminal death domain that binds to the homologous domain in RIP, a serine/threonine kinase component of the death pathway. The amino-terminal domain is surprisingly homologous with the sequence of the prodomain of two ICE/CED-3 family members, human ICH-1 (ref. 5) and Caenorhabditis elegans CED-3 (ref. 6). This similar region mediates the binding of RAIDD to ICH-1 and CED-3, serving as a direct link to the death proteases, indicating that the prodomain may, through homophilic interactions, determine the specificity of binding of ICE/CED-3 zymogens to regulatory adaptor molecules. Finally, alternations in the sequence of the N-terminal domain that are equivalent to inactivating mutations in the C. elegans ced-3 gene prevent homophilic binding, highlighting the potentially primordial nature of this interaction.
Insights
Researchers identified RAIDD, an adaptor molecule linking cell-death proteases to signaling pathways. RAIDD
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- The cell-death pathway's effector arm involves ICE/CED-3 family cysteine proteases.
- These proteases function as inactive zymogens in metazoan cells, requiring prodomain cleavage for activation.
- Adaptor molecules with death domains likely couple these proteases to signaling pathways.
Purpose of the Study:
- To identify and characterize novel adaptor molecules involved in the cell-death pathway.
- To elucidate the mechanism by which death proteases are recruited to signaling complexes.
Main Methods:
- Protein interaction studies using yeast two-hybrid or co-immunoprecipitation assays.
- Analysis of protein domain homology and function.
- Site-directed mutagenesis to investigate the role of specific domains.
Main Results:
- A novel adaptor molecule, RAIDD (a death domain-containing RAIDD), was identified.
- RAIDD possesses a bipartite structure with a death domain and an N-terminal domain homologous to ICE/CED-3 prodomains.
- RAIDD directly binds to RIP, a serine/threonine kinase, via its death domain.
- The N-terminal domain of RAIDD mediates homophilic binding to ICH-1 and CED-3 prodomains, linking them to the death proteases.
- Mutations in RAIDD's N-terminal domain analogous to inactivating ced-3 mutations abolish homophilic binding.
Conclusions:
- RAIDD acts as a crucial adaptor, bridging RIP kinase and ICE/CED-3 family proteases in the cell-death pathway.
- The prodomain homology suggests a conserved mechanism for specific zymogen recruitment via homophilic interactions.
- This interaction highlights a potentially ancient mechanism for regulating protease activation in apoptosis.
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