Elongation factor 2 kinase is regulated by proline hydroxylation and protects cells during hypoxia

Claire E J Moore, Halina Mikolajek, Sergio Regufe Da Mota, Xuemin Wang, Justin W. Kenney, Jörn M. Werner, Christopher G. Proud

Research output: Contribution to journalArticlepeer-review

57 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1788-1804
Number of pages17
JournalMolecular and Cellular Biology
Issue number10
Publication statusPublished or Issued - 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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