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Type: Journal article
Title: Elongation factor 2 kinase is regulated by proline hydroxylation and protects cells during hypoxia
Author: Moore, C.
Mikolajek, H.
Da Mota, S.
Wang, X.
Kenney, J.
Werner, J.
Proud, C.
Citation: Molecular and Cellular Biology, 2015; 35(10):1788-1804
Publisher: American Society for Microbiology
Issue Date: 2015
ISSN: 0270-7306
Statement of
Claire E. J. Moore, Halina Mikolajek, Sergio Regufe da Mota, Xuemin Wang, Justin W. Kenney, Jörn M. Werner, Christopher G. Proud
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.
Keywords: Neurons; Cells, Cultured; HCT116 Cells; Hela Cells; Animals; Humans; Mice; Peptide Elongation Factor 2; Proline; Calmodulin; Cell Hypoxia; Enzyme Activation; Catalytic Domain; Hydroxylation; Phosphorylation; Elongation Factor 2 Kinase; HEK293 Cells; Prolyl-Hydroxylase Inhibitors; Prolyl Hydroxylases
Rights: © 2015, American Society for Microbiology. All Rights Reserved.
RMID: 0030035721
DOI: 10.1128/MCB.01457-14
Appears in Collections:Medical Sciences publications

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