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PMID:9651369
| Citation |
Chaudhary, D, O'Rourke, K, Chinnaiyan, AM and Dixit, VM (1998) The death inhibitory molecules CED-9 and CED-4L use a common mechanism to inhibit the CED-3 death protease. J. Biol. Chem. 273:17708-12 |
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| Abstract |
The apoptotic machinery of Caenorhabditis elegans includes three core interacting components: CED-3, CED-4, and CED-9. CED-3 is a death protease composed of a prodomain and a protease domain. CED-4 is a P-loop-containing, nucleotide-binding molecule that complexes with the single polypeptide zymogen form of CED-3, promoting its activation by autoprocessing. CED-9 blocks death by complexing with CED-4 and suppressing its ability to promote CED-3 activation. A naturally occurring alternatively spliced form of CED-4 that contains an insertion within the nucleotide-binding region (CED-4L) functions as a dominant negative inhibitor of CED-3 processing and attenuates cell death. Domain mapping studies revealed that distinct regions within CED-4 bind to the CED-3 prodomain and protease domain. Importantly, the CED-4 P-loop was involved in prodomain binding. Disruption of P-loop geometry because of mutation of a critical lysine (K165R) or insertional inactivation (CED-4L) abolished prodomain binding. Regardless, K165R and CED-4L still retained CED-3 binding through the protease domain but were unable to initiate CED-3 processing. Therefore, the P-loop-prodomain interaction is critical for triggering CED-4-mediated CED-3 processing. Underscoring the importance of this interaction was the finding that CED-9 contacted the P-loop and selectively inhibited its interaction with the CED-3 prodomain. These results provide a simple mechanism for how CED-9 functions to block CED-4-mediated CED-3 processing and cell death. |
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| Keywords |
Apoptosis/physiology; Apoptosis Regulatory Proteins; Caenorhabditis elegans Proteins; Calcium-Binding Proteins/genetics; Calcium-Binding Proteins/physiology; Caspases; Cell Line; Cysteine Endopeptidases/metabolism; Cysteine Proteinase Inhibitors; Helminth Proteins/genetics; Helminth Proteins/physiology; Humans; Mutagenesis; Protein Binding; Protein Processing, Post-Translational; Proto-Oncogene Proteins/physiology; Proto-Oncogene Proteins c-bcl-2; Sequence Deletion |
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Significance
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| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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