Mutational analyses of c-FLIPR, the only murine short FLIP isoform, reveal requirements for DISC recruitment
| Autor: | Ingo Schmitz, Eric Keil, Nana Ueffing, Klaus Schulze-Osthoff, Ronald Kühne, Christian Freund |
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| Rok vydání: | 2008 |
| Předmět: |
Models
Molecular Gene isoform Death Domain Receptor Signaling Adaptor Proteins Proteasome Endopeptidase Complex Protein Conformation Molecular Sequence Data CASP8 and FADD-Like Apoptosis Regulating Protein Apoptosis Plasma protein binding Transfection Mice Viral Proteins Imaging Three-Dimensional Protein structure Animals Humans Protein Isoforms Amino Acid Sequence FADD Binding site Structural motif Molecular Biology Caspase 8 Binding Sites biology Cell Biology Protein Structure Tertiary Cell biology Flip Mutation Death-inducing signaling complex NIH 3T3 Cells biology.protein Hydrophobic and Hydrophilic Interactions Protein Binding |
| Zdroj: | Cell Death & Differentiation. 15:773-782 |
| ISSN: | 1476-5403 1350-9047 |
| DOI: | 10.1038/sj.cdd.4402314 |
| Popis: | Cellular FLICE-inhibitory protein (c-FLIP) proteins are known as potent inhibitors of death receptor-mediated apoptosis by interfering with caspase-8 activation at the death-inducing signaling complex (DISC). Among the three human isoforms, c-FLIP(long), c-FLIP(short) and c-FLIP(R), the latter isoform is poorly characterized. We report here the characterization of murine c-FLIP(R) and show that it is the only short c-FLIP isoform expressed in mice. By generating several mutants, we demonstrate that both death effector domains (DEDs) are required for DISC binding and the antiapoptotic function of c-FLIP(R). Surprisingly, the C-terminal tail is important for both protein stability and DISC recruitment. Three-dimensional modeling of c-FLIP(R) revealed a substantial similarity of the overall structures and potential interaction motifs with the viral FLIP MC159. We found, however, that c-FLIP(R) uses different structural motifs for its DISC recruitment. Whereas MC159 interferes with interaction and self-oligomerization of the DISC component FADD by its extensive hydrophilic surface, a narrow hydrophobic patch of c-FLIP(R) on the surface of DED2 is crucial for DISC association. Thus, despite the presence of similar tandem DEDs, viral and cellular FLIPs inhibit apoptosis by remarkably divergent mechanisms. |
| Databáze: | OpenAIRE |
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