Abstract
Death-associated protein kinase (DAPk) was recently suggested by sequence homology to be a member of the ROCO family of proteins. Here, we show that DAPk has a functional ROC (Ras of complex proteins) domain that mediates homo-oligomerization and GTP binding through a defined P-loop motif. Upon binding to GTP, the ROC domain negatively regulates the catalytic activity of DAPk and its cellular effects. Mechanistically, GTP binding enhances an inhibitory autophosphorylation at a distal site that suppresses kinase activity. This study presents a new mechanism of intramolecular signal transduction, by which GTP binding operates in cis to affect the catalytic activity of a distal domain in the protein.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Death-Associated Protein Kinases
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GTP-Binding Proteins / genetics
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GTP-Binding Proteins / metabolism*
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Guanosine Triphosphate / metabolism*
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HEK293 Cells
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Humans
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Oncogene Protein p21(ras) / metabolism
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Phosphorylation
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Protein Binding / genetics
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Protein Multimerization
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Signal Transduction*
Substances
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Apoptosis Regulatory Proteins
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Guanosine Triphosphate
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Death-Associated Protein Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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GTP-Binding Proteins
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Oncogene Protein p21(ras)