Protein interaction networks structurally integrated

结构整合的蛋白质相互作用网络

• 批准号: 386397-2010
• 负责人: Gsponer, Joerg
• 金额: $ 2.55万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=528856
• 关键词: Protein; interaction; networks; structurally; integrated

As protein-protein interactions are central to all biological processes, a comprehensive determination of all interactions between proteins that take place in an organism provides a fundamental framework for understanding biology as an integrated system. Significant efforts by the research community in recent years have provided first maps of cellular protein-protein interaction (PPI) networks. These maps are major sources of information for discovering new drug targets and for identifying signaling circuits that can be rewired to generate new cellular behavior. However, in order to fully understand (a) cellular processes such as signal transduction (b) the emergence of phenotype from cellular complexity (c) to decipher the complex molecular mechanisms that underlie pathologies like cancer or neurodegeneration and (d) ultimately use this knowledge effectively in drug design and synthetic biology, we have to not only dissect the interactome, but also elucidate how the structure and dynamics of the constituent proteins affect their network function. The broad objectives of this research program are to develop new computational tools to determine the structures of protein complexes with a view to curate PPI maps and provide a solid framework that allows investigating communication in cellular systems and designing drugs that intervene in specific signaling pathways. Under this general theme, we will first pursue two avenues of research that aim at (i) predicting the structure of protein complexes in which one or several members undergo induced folding upon binding, i.e., are intrinsically disordered proteins (IDPs) and (ii) predicting structure and affinities of linear motif-domain complexes in order to evaluate the in vivo likelihood of PPIs that are mediated by this type of interactions and were seen in high-throughput screens.

由于蛋白质-蛋白质相互作用是所有生物过程的核心，因此全面确定生物体中发生的蛋白质之间的所有相互作用为将生物学理解为一个集成系统提供了基本框架。近年来，研究界的重大努力提供了细胞蛋白质-蛋白质相互作用（PPI）网络的第一张地图。这些图谱是发现新的药物靶点和识别可以重新连接以产生新的细胞行为的信号通路的主要信息来源。然而，为了充分理解（a）细胞过程，如信号转导（B）从细胞复杂性中出现表型（c）破译癌症或神经变性等病理学背后的复杂分子机制，以及（d）最终将这些知识有效地用于药物设计和合成生物学，我们不仅要解剖相互作用组，而且阐明了组成蛋白质的结构和动力学如何影响它们的网络功能。该研究计划的广泛目标是开发新的计算工具来确定蛋白质复合物的结构，以期策划PPI地图，并提供一个坚实的框架，允许研究细胞系统中的通信和设计干预特定信号通路的药物。在这个总的主题下，我们将首先追求两种研究途径，旨在（i）预测蛋白质复合物的结构，其中一个或几个成员在结合时发生诱导折叠，即，是内在无序的蛋白质（IDPs）和（ii）预测线性基序结构域复合物的结构和亲和力，以评估在体内的PPI的可能性，介导的这种类型的相互作用，并在高通量屏幕上看到。