Dynamic Regulation of the Translation Initiation Helicase Complex by Mitogenic Signal Transduction to Eukaryotic Translation Initiation Factor 4G
Dynamic Regulation of the Translation Initiation Helicase Complex by Mitogenic Signal Transduction to Eukaryotic Translation Initiation Factor 4G
复制标题
DOI：
10.1128/mcb.01441-12
复制
发表时间：
2013-03-01
影响因子：
5.3
通讯作者：
Gromeier, Matthias
中科院分区：
文献类型：
--
作者：
Dobrikov, Mikhail I.;Dobrikova, Elena Y.;Gromeier, Matthias
真核翻译起始因子4F（eIF 4F）由帽结合蛋白eIF 4 E、解旋酶eIF 4A和中心支架eIF 4G组成，是控制蛋白质合成的复杂信号网络的汇聚节点。与eIF 3和eIF 4A/4 B一起，eIF 4G将核糖体亚基募集到mRNA中并促进5'非翻译区解旋。哺乳动物eIF 4G包含三个HEAT结构域和参与蛋白质-蛋白质相互作用的非结构化区域。尽管有详细的eIF 4G结构数据，但控制起始支架形成的机制仍然不清楚。我们在HEAT-1/2结构域间连接子中发现了一个新的高度调节的eIF 4 B/-3结合位点，该位点包含两个磷酸化位点，我们将其鉴定为Erk 1/2和酪蛋白激酶2的底物。佛波酯诱导的两个位点的连续磷酸化使HEAT-2从与eIF 4A/-4B/-3的复合物中分离，并刺激HEAT-3与促分裂原活化蛋白激酶信号整合激酶Mnk 1的结合。我们的研究结果提供了一个机制之间的联系细胞内信号转导和动态起始复合物的形成协调灵活的eIF 4G结构。
Eukaryotic translation initiation factor 4F (eIF4F), comprising the cap-binding protein eIF4E, the helicase eIF4A, and the central scaffold eIF4G, is a convergence node for a complex signaling network that controls protein synthesis. Together with eIF3 and eIF4A/4B, eIF4G recruits ribosomal subunits to mRNAs and facilitates 5' untranslated region unwinding. Mammalian eIF4G contains three HEAT domains and unstructured regions involved in protein-protein interactions. Despite detailed eIF4G structure data, the mechanisms controlling initiation scaffold formation remain obscure. We found a new, highly regulated eIF4B/-3 binding site within the HEAT-1/-2 interdomain linker, harboring two phosphorylation sites that we identified as substrates for Erk1/2 and casein kinase 2. Phorbol ester-induced sequential phosphorylation of both sites detached HEAT-2 from the complex with eIF4A/-4B/-3 and stimulated the association of HEAT-3 with the mitogen-activated protein kinase signal integrating kinase Mnk1. Our results provide a mechanistic link between intracellular signal transduction and dynamic initiation complex formation coordinated by flexible eIF4G structure.