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https://hdl.handle.net/2440/115582
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dc.contributor.author | Moore, C.E.J. | - |
dc.contributor.author | Mikolajek, H. | - |
dc.contributor.author | Da Mota, S.R. | - |
dc.contributor.author | Wang, X. | - |
dc.contributor.author | Kenney, J.W. | - |
dc.contributor.author | Werner, J.M. | - |
dc.contributor.author | Proud, C.G. | - |
dc.date.issued | 2015 | - |
dc.identifier.citation | Molecular and Cellular Biology, 2015; 35(10):1788-1804 | - |
dc.identifier.issn | 0270-7306 | - |
dc.identifier.issn | 1098-5549 | - |
dc.identifier.uri | http://hdl.handle.net/2440/115582 | - |
dc.description.abstract | Protein synthesis, especially translation elongation, requires large amounts of energy, which is often generated by oxidative metabolism. Elongation is controlled by phosphorylation of eukaryotic elongation factor 2 (eEF2), which inhibits its activity and is catalyzed by eEF2 kinase (eEF2K), a calcium/calmodulin-dependent α-kinase. Hypoxia causes the activation of eEF2K and induces eEF2 phosphorylation independently of previously known inputs into eEF2K. Here, we show that eEF2K is subject to hydroxylation on proline-98. Proline hydroxylation is catalyzed by proline hydroxylases, oxygen-dependent enzymes which are inactivated during hypoxia. Pharmacological inhibition of proline hydroxylases also stimulates eEF2 phosphorylation. Pro98 lies in a universally conserved linker between the calmodulin-binding and catalytic domains of eEF2K. Its hydroxylation partially impairs the binding of calmodulin to eEF2K and markedly limits the calmodulin-stimulated activity of eEF2K. Neuronal cells depend on oxygen, and eEF2K helps to protect them from hypoxia. eEF2K is the first example of a protein directly involved in a major energy-consuming process to be regulated by proline hydroxylation. Since eEF2K is cytoprotective during hypoxia and other conditions of nutrient insufficiency, it may be a valuable target for therapy of poorly vascularized solid tumors. | - |
dc.description.statementofresponsibility | Claire E. J. Moore, Halina Mikolajek, Sergio Regufe da Mota, Xuemin Wang, Justin W. Kenney, Jörn M. Werner, Christopher G. Proud | - |
dc.language.iso | en | - |
dc.publisher | American Society for Microbiology | - |
dc.rights | © 2015, American Society for Microbiology. All Rights Reserved. | - |
dc.source.uri | http://dx.doi.org/10.1128/mcb.01457-14 | - |
dc.subject | Neurons | - |
dc.subject | Cells, Cultured | - |
dc.subject | HCT116 Cells | - |
dc.subject | Hela Cells | - |
dc.subject | Animals | - |
dc.subject | Humans | - |
dc.subject | Mice | - |
dc.subject | Peptide Elongation Factor 2 | - |
dc.subject | Proline | - |
dc.subject | Calmodulin | - |
dc.subject | Cell Hypoxia | - |
dc.subject | Enzyme Activation | - |
dc.subject | Catalytic Domain | - |
dc.subject | Hydroxylation | - |
dc.subject | Phosphorylation | - |
dc.subject | Elongation Factor 2 Kinase | - |
dc.subject | HEK293 Cells | - |
dc.subject | Prolyl-Hydroxylase Inhibitors | - |
dc.subject | Prolyl Hydroxylases | - |
dc.title | Elongation factor 2 kinase is regulated by proline hydroxylation and protects cells during hypoxia | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1128/MCB.01457-14 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Proud, C.G. [0000-0003-0704-6442] | - |
Appears in Collections: | Aurora harvest 3 Medical Sciences publications |
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