Topology and Grb2 interactions of the intrinsically disordered platform protein Gab1

总的来说，细胞通过其许多表面受体接收的众多信号如何在分子水平上有效地处理成一种特定的细胞反应仍然是一个谜。在现代信号转导研究和细胞生物学中，对这些分子信号计算的高阶过程进行更多的研究是一个紧迫的问题。在拟议的项目中，将研究Gab家族的内在无序蛋白质，这些蛋白质是计算细胞内信号的大型多蛋白质复合物的高度动态组装平台。我们结合联合收割机细胞生物学、生物化学和结构生物学研究来表征Grb 2和Gab1的组装，以及随后的其他相关信号蛋白（如PI 3激酶）在磷酸化Gab1上的对接。从这些分子的超分子组织的Gab1和其变化的翻译后修饰的见解，我们希望解开分子信号计算的基本原则，以及提高我们的理解无处不在的Gab蛋白的生理和病理作用。

By and large it remains an enigma how the numerous signals received by cells through their many surface receptors are effectively processed on the molecular level towards one specific cellular response. Shedding more light onto these higher order processes of molecular signal computation is a burning issue in modern signal transduction research and in cell biology in general. In the proposed project, intrinsically disordered proteins of the Gab family will be studied, which are highly dynamic assembly platforms for large multi-protein complexes computing intracellular signals. We combine cell biology, biochemical and structural biology studies to characterize the assembly of Grb2 and Gab1 and, subsequently, the docking of other associating signaling proteins (like PI3 kinase) on phosphorylated Gab1. From these molecular insights into the supramolecular organization of Gab1 and its variation by post-translational modifications, we expect to unravel fundamental principles of molecular signal computation, as well as improving our understanding of the physiological and pathological roles of the ubiquitous Gab proteins.