Probing the depth of protein subcellular localization regulation

探索蛋白质亚细胞定位调控的深度细胞被划分为许多不同的结构，负责特定的细胞活动。在这些区室中适当的蛋白质亚细胞定位和分布对于确保蛋白质在正确的环境中和正确的相互作用物存在下发挥功能至关重要。在过去的四十年中，已经发现了许多信号和定位机制，包括蛋白质靶向序列和基序以及蛋白质相互作用结构域和调节定位的翻译后修饰。然而，蛋白质定位调节也是多层次的和动态的，如最近的大规模显微镜和蛋白质组学项目所证实的，这些项目已经确定了大量的蛋白质定位在一个以上的细胞隔室中。这种双重定位可以是周期性的或有条件的，并且通常用于响应不断变化的条件。蛋白质的双重定位的程度和靶向信号的分子调控和组合使用仍然知之甚少。我们的目标是利用新技术和大规模数据集在蛋白质组水平上研究这些机制和靶向信号的变异性。我们的理由是，我们的系统风格的方法，使用尖端的方法和思想，将允许更高的质量和更高的覆盖率的定位注释的整个蛋白质组，以及更好地了解定位调节机制和组合使用和靶向基序的演变。拟议的研究还应导致增加对室间细胞通信以及细胞过程和对变化条件的反应机制的动态调节的理解。

Probing the depth of protein subcellular localization regulationCells are compartmentalized to house many different structures responsible for specific cellular activities. Appropriate protein subcellular localization and distribution in these compartments is critical to ensure proteins function in the right environment and in presence of the right interactors. Over the past forty years, numerous signals and localization mechanisms have been uncovered including protein targeting sequences and motifs as well as protein interaction domains and post-translational modifications regulating localization. However, protein localization regulation is also multi-layered and dynamic as witnessed by recent large-scale microscopy and proteomics projects which have identified large numbers of proteins localizing in more than one cellular compartment. Such dual localization can be cyclical or conditional and is often employed in response to changing conditions. The extent of dual localization of proteins and the molecular regulation and combinatorial usage of targeting signals remain poorly understood. Our goal is to make use of new technologies and large-scale datasets to study these mechanisms and the variability of targeting signals on proteome-wide level. Our rationale is that our systems style approach using cutting-edge methods and ideas will allow both a higher quality and higher coverage of localization annotation for whole proteomes as well as a better understanding of localization regulation mechanisms and the combinatorial usage and evolution of targeting motifs. The proposed research should also result in the increased understanding of inter-compartmental cellular communication as well as of the dynamic regulation of cellular processes and response mechanisms to changing conditions.