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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
50
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pubmed:dateCreated |
2001-12-12
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pubmed:abstractText |
Death-associated protein kinase is a calcium/calmodulin serine/threonine kinase, which positively mediates programmed cell death in a variety of systems. Here we addressed its mode of regulation and identified a mechanism that restrains its apoptotic function in growing cells and enables its activation during cell death. It involves autophosphorylation of Ser(308) within the calmodulin (CaM)-regulatory domain, which occurs at basal state, in the absence of Ca(2+)/CaM, and is inversely correlated with substrate phosphorylation. This type of phosphorylation takes place in growing cells and is strongly reduced upon their exposure to the apoptotic stimulus of C(6)-ceramide. The substitution of Ser(308) to alanine, which mimics the ceramide-induced dephosphorylation at this site, increases Ca(2+)/CaM-independent substrate phosphorylation as well as binding and overall sensitivity of the kinase to CaM. At the cellular level, it strongly enhances the death-promoting activity of the kinase. Conversely, mutation to aspartic acid reduces the binding of the protein to CaM and abrogates almost completely the death-promoting function of the protein. These results are consistent with a molecular model in which phosphorylation on Ser(308) stabilizes a locked conformation of the CaM-regulatory domain within the catalytic cleft and simultaneously also interferes with CaM binding. We propose that this unique mechanism of auto-inhibition evolved to impose a locking device, which keeps death-associated protein kinase silent in healthy cells and ensures its activation only in response to apoptotic signals.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
14
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pubmed:volume |
276
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
47460-7
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:11579085-Amino Acid Motifs,
pubmed-meshheading:11579085-Amino Acid Sequence,
pubmed-meshheading:11579085-Animals,
pubmed-meshheading:11579085-Apoptosis,
pubmed-meshheading:11579085-Apoptosis Regulatory Proteins,
pubmed-meshheading:11579085-Aspartic Acid,
pubmed-meshheading:11579085-Binding Sites,
pubmed-meshheading:11579085-Blotting, Western,
pubmed-meshheading:11579085-Calcium,
pubmed-meshheading:11579085-Calcium-Calmodulin-Dependent Protein Kinases,
pubmed-meshheading:11579085-Calmodulin,
pubmed-meshheading:11579085-Catalysis,
pubmed-meshheading:11579085-Catalytic Domain,
pubmed-meshheading:11579085-Cell Death,
pubmed-meshheading:11579085-Cell Line,
pubmed-meshheading:11579085-Ceramides,
pubmed-meshheading:11579085-Electrophoresis, Polyacrylamide Gel,
pubmed-meshheading:11579085-Green Fluorescent Proteins,
pubmed-meshheading:11579085-HeLa Cells,
pubmed-meshheading:11579085-Humans,
pubmed-meshheading:11579085-Immunoblotting,
pubmed-meshheading:11579085-Luminescent Proteins,
pubmed-meshheading:11579085-Models, Molecular,
pubmed-meshheading:11579085-Molecular Sequence Data,
pubmed-meshheading:11579085-Mutation,
pubmed-meshheading:11579085-Phosphorylation,
pubmed-meshheading:11579085-Plasmids,
pubmed-meshheading:11579085-Precipitin Tests,
pubmed-meshheading:11579085-Protein Binding,
pubmed-meshheading:11579085-Protein Structure, Tertiary,
pubmed-meshheading:11579085-Sequence Homology, Amino Acid,
pubmed-meshheading:11579085-Serine,
pubmed-meshheading:11579085-Transfection
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pubmed:year |
2001
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pubmed:articleTitle |
The pro-apoptotic function of death-associated protein kinase is controlled by a unique inhibitory autophosphorylation-based mechanism.
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pubmed:affiliation |
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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