期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 35, 期 10, 页码 1788-1804出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01457-14
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资金
- Wellcome Trust [086688]
- BBSRC [BB/I004483/1] Funding Source: UKRI
- MRC [MC_U117533887] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/I004483/1] Funding Source: researchfish
- Medical Research Council [MC_U117533887] Funding Source: researchfish
- The Francis Crick Institute [10029] Funding Source: researchfish
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 alpha-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.
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