eIF2B promotes eIF5 dissociation from eIF2*GDP to facilitate guanine nucleotide exchange for translation initiation.
eIF2B promotes eIF5 dissociation from eIF2*GDP to facilitate guanine nucleotide exchange for translation initiation.
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DOI：
10.1101/gad.231514.113
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发表时间：
2013-12-15
影响因子：
10.5
通讯作者：
Pavitt GD
中科院分区：
文献类型：
--
作者：
Jennings MD;Zhou Y;Mohammad-Qureshi SS;Bennett D;Pavitt GD
蛋白质合成因子 eIF2 将起始子 tRNA 递送至核糖体。两种蛋白调节其 G 蛋白循环：eIF5 具有 GTP 酶激活蛋白 (GAP) 和 GDP 解离抑制剂 (GDI) 功能，eIF2B 是鸟嘌呤核苷酸交换因子 (GEF)。詹宁斯等人。现在建立 eIF2B 的第二个活性（作为 GDI 置换因子 [GDF]）并证明该功能独立于其 GEF 活性。这项研究表明 eIF2B 是一种双功能蛋白，并定义了蛋白质合成起始途径中的一个额外步骤。蛋白质合成因子 eIF2 将起始子 tRNA 递送至核糖体。两种蛋白调节其 G 蛋白循环：eIF5 具有 GTP 酶加速蛋白 (GAP) 和 GDP 解离抑制剂 (GDI) 功能，eIF2B 是鸟嘌呤核苷酸交换因子 (GEF)。在本研究中，我们使用蛋白质-蛋白质相互作用和核苷酸交换测定来监测eIF2从eIF2·GDP/eIF5 GDI复合物中释放的动力学，并确定eIF2B对此释放的影响。我们证明，eIF2B 具有第二种活性，即 GDI 置换因子 (GDF)，它可以在 GEF 作用之前从 eIF2·GDP/eIF5 GDI 复合体中招募 eIF2。我们发现 GDF 功能依赖于 eIF2Bɛ 和 eIF2Bγ 亚基，并确定了一种新的 eIF2-eIF2Bγ 相互作用。此外，GDF 和 GEF 的活动是独立的。首先，与 GEF 不同，eIF2B GDF 对 eIF2α 磷酸化不敏感。其次，我们发现已知会破坏 GCN4 翻译控制的 eIF2Bγ 突变会显着损害 GDF 活性，但不会损害 GEF 功能。因此，我们的数据定义了蛋白质合成起始途径中的一个额外步骤，这对于其正确控制非常重要。我们提出了一种新模型，将 eIF2B GDF 功能置于有效 eIF2 回收及其通过 eIF2 磷酸化的调节的背景下。
Protein synthesis factor eIF2 delivers initiator tRNA to the ribosome. Two proteins regulate its G-protein cycle: eIF5 has both GTPase-activating protein (GAP) and GDP dissociation inhibitor (GDI) functions, and eIF2B is the guanine nucleotide exchange factor (GEF). Jennings et al. now establish a second activity for eIF2B (as a GDI displacement factor [GDF]) and demonstrate that this function is independent of its GEF activity. This study suggests that eIF2B is a bifunctional protein and defines an additional step in the protein synthesis initiation pathway. Protein synthesis factor eIF2 delivers initiator tRNA to the ribosome. Two proteins regulate its G-protein cycle: eIF5 has both GTPase-accelerating protein (GAP) and GDP dissociation inhibitor (GDI) functions, and eIF2B is the guanine nucleotide exchange factor (GEF). In this study, we used protein–protein interaction and nucleotide exchange assays to monitor the kinetics of eIF2 release from the eIF2•GDP/eIF5 GDI complex and determine the effect of eIF2B on this release. We demonstrate that eIF2B has a second activity as a GDI displacement factor (GDF) that can recruit eIF2 from the eIF2•GDP/eIF5 GDI complex prior to GEF action. We found that GDF function is dependent on the eIF2Bɛ and eIF2Bγ subunits and identified a novel eIF2–eIF2Bγ interaction. Furthermore, GDF and GEF activities are shown to be independent. First, eIF2B GDF is insensitive to eIF2α phosphorylation, unlike GEF. Second, we found that eIF2Bγ mutations known to disrupt GCN4 translational control significantly impair GDF activity but not GEF function. Our data therefore define an additional step in the protein synthesis initiation pathway that is important for its proper control. We propose a new model to place eIF2B GDF function in the context of efficient eIF2 recycling and its regulation by eIF2 phosphorylation.
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