eIF5 has GDI activity necessary for translational control by eIF2 phosphorylation.
eIF5 has GDI activity necessary for translational control by eIF2 phosphorylation.
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在蛋白质合成起始中，真核生物翻译起始因子（eIF）2（G蛋白）在其GTP结合状态下发挥功能，将起始剂甲硫氨酰-tRNA（tRNAiMet）递送至小核糖体亚基，并且是所有细胞中蛋白质合成所必需的。eIF 2 [eIF 2（αP）]的磷酸化在多种环境中对翻译控制至关重要，包括营养缺乏、病毒感染和记忆形成。eIF 5在起始位点选择中起作用，作为eIF 2·GTP·tRNAiMet三元复合物（TC）在核糖体结合的前起始复合物内的GTP酶加速蛋白（GAP）。在这里，我们定义了eIF 5在连续几轮翻译起始之间eIF 2从其失活的eIF 2·GDP状态再循环中的新调控功能。首先，我们发现eIF 5稳定了GDP与eIF 2的结合，因此是一种双功能蛋白，作为GDP解离抑制剂（GDI）。我们发现，这种活动是独立差距功能，并确定保守的残基内eIF 5是必要的这一作用。此外，我们还发现eIF 5是eIF 2（αP）调节复合物的一个关键组分，该复合物抑制鸟嘌呤核苷酸交换因子（GEF）eIF 2B的活性。我们的研究共同定义了翻译起始途径中的一个新步骤，这对正常的翻译控制至关重要。
In protein synthesis initiation, the eukaryotic translation initiation factor (eIF) 2 (a G protein) functions in its GTP-bound state to deliver initiator methionyl-tRNA (tRNAiMet) to the small ribosomal subunit and is necessary for protein synthesis in all cells. Phosphorylation of eIF2 [eIF2(αP)] is critical for translational control in diverse settings including nutrient deprivation, viral infection and memory formation. eIF5 functions in start site selection as a GTPase accelerating protein (GAP) for the eIF2•GTP•tRNAiMet ternary complex (TC) within the ribosome bound pre-initiation complex. Here we define new regulatory functions of eIF5 in the recycling of eIF2 from its inactive eIF2•GDP state between successive rounds of translation initiation. Firstly we show that eIF5 stabilizes the binding of GDP to eIF2 and is therefore a bi-functional protein that acts as a GDP dissociation inhibitor (GDI). We find that this activity is independent of the GAP function and identify conserved residues within eIF5 that are necessary for this role. In addition we show that eIF5 is a critical component of the eIF2(αP) regulatory complex that inhibits the activity of the guanine-nucleotide exchange factor (GEF) eIF2B. Together our studies define a new step in the translation initiation pathway, one that is critical for normal translational controls.
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