Regulation of translation through the human translation initiation factor eIF5B

描述(申请人提供)：蛋白质合成的控制(翻译)对细胞的增殖、分化或死亡至关重要。我们发现，人类真核翻译启动因子Elf1 A和ELF5竞争G蛋白elF5B的同一表面，并且elF5B可能从ELF5转移到Elf1 A，这将允许相应步骤的开关型控制。ElFSB和Elf1 A是仅有的两个在所有王国中保守的翻译启动因子。ELF5是另一种G蛋白elF2的GTP酶激活蛋白(GAP)。核糖体亚基的连接需要elF2在起始位置识别时的GTP水解，这是由elFSB推动的。因此，elF5B：ELF5/elF1A的相互作用可能协调翻译起始过程中的两个GTP水解点。 ELF5和Elf1A之间对elFSB的竞争使我们能够研究翻译启动调控的空间和时间方面。此外，将抑制elFSB的相互作用用于抗癌治疗的潜力仍有待探索。这项研究将追求以下具体目标： 1.用核方法确定人elF5B-CTD与ELF5 C末端尾部的络合物的结构 磁共振(核磁共振)；建立结合亲和力和特异性的基础。 2.确定elF5B：ELF5/Elf1 A相互作用在翻译起始中的作用，哪些类型的mRNAs受到影响，以及在翻译起始的哪些阶段。测试elFSB是否以及何时从ELF5转移到ElF1A。 3.筛选elFSB与Elf1 A/ELF5相互作用的小分子抑制剂。探索将这些抑制剂用作癌症治疗候选药物的潜力。 这个项目的预期结果将回答翻译启动中的重要问题。它们还将使我能够在新的方向上扩展我的研究，并为在癌症研究领域建立一个成功的职业生涯奠定基础。 与癌症研究相关：积极分裂细胞，如癌细胞，需要增加蛋白质合成的速度。调节蛋白质合成用于癌症治疗的潜力直到最近才开始引起人们的注意。这项提案中概述的工作将有助于建立新的目标，并探索利用蛋白质合成速率调节癌症治疗的新方法，例如阻止氨基酸供应的增加，以应对快速分裂细胞的高需求。

DESCRIPTION (provided by applicant): Control of protein synthesis (translation) is vital for cell proliferation, differentiation or death. We found that human eukaryotic translation initiation factors elF1 A and elF5 compete for the same surface of the G-protein elF5B, and that elF5B may be transferred from elF5 to elF1 A, which would allow for a switch-type control of the corresponding step. elFSB and elF1 A are the only two translation initiation factors conserved among all kingdoms. elF5 is the GTPase-activating protein (GAP) for the other G-protein, elF2. GTP hydrolysis by elF2 upon start site recognition is required for ribosomal subunit joining, which is promoted by elFSB. Thus, the elF5B:elF5/elF1A interactions may coordinate the two GTP hydrolysis checkpoints in translation initiation. The competition between elF5 and elF1 A for elFSB allows to study both the spatial and the temporal aspects of the regulation of translation initiation. Furthermore, the potential of using inhibition of the interactions of elFSB for anti-cancer therapy remains to be explored. The research will pursue the following specific aims: 1. Determine the structure of the complex of human elF5B-CTD with the elF5 C-terminal tail by Nuclear Magnetic Resonance (NMR); establish the basis for binding affinity and specificity. 2. Identify the roles of the elF5B:elF5/elF1 A interactions in translation initiation, what types of mRNAs are affected and at which stages of initiation. Test whether and when elFSB is transferred from elF5 to elF1 A. 3. Screen for small-molecule inhibitors of the interactions of elFSB with elF1 A/elF5. Explore the potential of using these inhibitors as drug candidates for cancer therapy. The results anticipated from this project will answer important questions in translation initiation. They will also allow me to expand my research in new directions, and serve as a foundation for building a successful career in cancer research. Relevance to cancer research: Actively dividing cells, such as cancer cells, require increased rates of protein synthesis. The potential of the regulation of protein synthesis for cancer therapy has only recently started to attract attention. The work outlined in this proposal will help establish new targets and explore new approaches in using modulation of the rates of protein synthesis for cancer therapy, such as blocking the increase in the supply of amino acids in response to the high demands in rapidly dividing cells.