Understanding the link between splicing and mRNA localization by structural biology

mRNA定位对于所有发育程序都是必不可少的，例如细胞运动、细胞特化和不对称细胞分裂。在果蝇中，oskar mRNA定位于卵母细胞的后极决定了腹部和原始生殖细胞的形成。转运需要反式作用因子识别oskar mRNA转录物中的特定序列。然后这些核糖核蛋白颗粒与驱动蛋白马达相互作用，以便沿着微管运输。SOLE RNA是在剪接时形成的特异性oskar mRNA序列，并且位于距离外显子连接复合物（EJC）沉积位点仅几个核苷酸的位置。SOLE RNA和EJC都是mRNA定位不可或缺的蛋白质，PYM（Partner of Y14-Mago）是一种与EJC Y14和Mago的核心成分相关的蛋白质。PYM在EJC稳态和mRNA定位中具有双重作用。最近，我们发现该蛋白直接与SOLE RNA相互作用，这表明mRNA定位和EJC稳态可能是共同调节的。在本研究中，我们的目标是阐明SOLE RNA和PYM在mRNA定位中的作用，以及它们与EJC的相互作用。我们将采取跨学科的方法，结合结构生物学，体内功能测定和生物化学。该项目将有助于对生物发育中最受调控，最复杂和最基本的过程之一的分子理解。

mRNA localization is essential to all developmental programmes, such as cell movement, cell specialization and asymmetric cell division. In Drosophila melanogaster, oskar mRNA localization to the posterior pole of the oocyte determines where the abdomen and primordial germ cells form. The transport requires the recognition of specific sequences in the oskar mRNA transcript by trans acting factors. These ribonucleoprotein particles then interact with the kinesin motor for transport along the microtubules. The SOLE RNA is a specific oskar mRNA sequence that forms upon splicing and is located only a few nucleotides away from the Exon Junction Complex (EJC) deposition site. Both the SOLE RNA and the EJC are indispensable for mRNA localization.PYM (Partner of Y14-Mago) is a protein that was identified because of its association with the core components of the EJC Y14 and Mago. PYM has a dual role in both EJC homeostasis and mRNA localization. Recently we discovered that the protein directly interacts with the SOLE RNA, suggesting that mRNA localization and EJC homeostasis might be co-regulated.In this grant proposal we aim at shedding light on the role of the SOLE RNA and PYM in mRNA localization, as well as their interplay with the EJC. We will take an interdisciplinary approach combining structural biology, functional assays in vivo and biochemistry.This project will contribute to the molecular understanding of one of the most regulated, complex and fundamental processes of organism development.