Abstract
Control of the activation of apoptosis is important both in development and in protection against cancer. In the classic genetic model Caenorhabditis elegans, the pro-apoptotic protein CED-4 activates the CED-3 caspase and is inhibited by the Bcl-2-like protein CED-9. Both processes are mediated by protein-protein interaction. Facilitating the proximity of CED-3 zymogen molecules was found to induce caspase activation and cell death. CED-4 protein oligomerized in cells and in vitro. This oligomerization induced CED-3 proximity and competed with CED-4:CED-9 interaction. Mutations that abolished CED-4 oligomerization inactivated its ability to activate CED-3. Thus, the mechanism of control is that CED-3 in CED-3:CED-4 complexes is activated by CED-4 oligomerization, which is inhibited by binding of CED-9 to CED-4.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis Regulatory Proteins
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Apoptosis*
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Biopolymers
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Caenorhabditis elegans Proteins*
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Calcium-Binding Proteins / chemistry*
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism*
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Caspases*
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Cell Line
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Chemical Phenomena
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Chemistry, Physical
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Cysteine Endopeptidases / metabolism*
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Cysteine Proteinase Inhibitors / pharmacology
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Enzyme Activation
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Enzyme Precursors / metabolism
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HeLa Cells
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Helminth Proteins / chemistry*
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Helminth Proteins / genetics
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Helminth Proteins / metabolism*
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Humans
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Mutation
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Oligopeptides / pharmacology
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Recombinant Fusion Proteins / metabolism
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Tacrolimus / pharmacology
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Transfection
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bcl-X Protein
Substances
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Apoptosis Regulatory Proteins
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BCL2L1 protein, human
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Biopolymers
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Caenorhabditis elegans Proteins
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Calcium-Binding Proteins
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Ced-4 protein, C elegans
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Ced-9 protein, C elegans
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Cysteine Proteinase Inhibitors
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Enzyme Precursors
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Helminth Proteins
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Oligopeptides
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Fusion Proteins
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bcl-X Protein
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Caspases
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Cysteine Endopeptidases
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ced-3 protein, C elegans
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Tacrolimus