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首页> 外文期刊>Molecular and Cellular Biology >Elongation Factor 2 Kinase Is Regulated by Proline Hydroxylation and Protects Cells during Hypoxia
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Elongation Factor 2 Kinase Is Regulated by Proline Hydroxylation and Protects Cells during Hypoxia

机译：缺氧过程中脯氨酸羟化调节伸长因子2激酶并保护细胞

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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.
机译：蛋白质合成，特别是翻译延伸，需要大量能量，这通常是由氧化代谢产生的。延伸受真核生物延伸因子2（eEF2）磷酸化的控制，该酶抑制其活性并被钙/钙调蛋白依赖性α激酶eEF2激酶（eEF2K）催化。缺氧导致eEF2K活化并诱导eEF2磷酸化，而与先前已知的eEF2K输入无关。在这里，我们显示eEF2K在脯氨酸98上受到羟基化作用。脯氨酸羟化是由脯氨酸羟化酶催化的，脯氨酸羟化酶是在缺氧过程中失活的氧依赖性酶。脯氨酸羟化酶的药理抑制作用还刺激eEF2磷酸化。 Pro98位于钙调蛋白结合和eEF2K催化域之间的一个普遍保守的接头。其羟基化部分损害钙调蛋白与eEF2K的结合，并显着限制钙调蛋白刺激的eEF2K活性。神经细胞依赖氧气，而eEF2K有助于保护它们免受缺氧的影响。 eEF2K是直接参与主要耗能过程的蛋白质的第一个实例，该过程将通过脯氨酸羟基化来调节。由于eEF2K在缺氧和其他营养不足的情况下具有细胞保护作用，因此它可能是治疗血管化不良实体瘤的重要靶标。

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