Probing the depth of protein subcellular localization regulation

蛋白质亚细胞定位调控深度探讨 细胞被分隔，以容纳许多负责特定细胞活动的不同结构。在这些隔室中，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和存在正确的相互作用的情况下发挥作用至关重要。在过去的40年里，已经发现了大量的信号和定位机制，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，蛋白质定位调控也是多层次的和动态的，最近的大规模显微镜和蛋白质组学项目证明了大量的蛋白质定位在多个细胞隔室中。这种双重本地化可以是周期性的，也可以是有条件的，通常是为了响应不断变化的条件而采用的。蛋白质双重定位的程度以及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可变性。我们的理论基础是，我们的系统风格方法使用尖端的方法和思想，将允许对整个蛋白质组进行更高质量和更高覆盖率的定位注释，以及更好地理解定位调控机制以及靶向基序的组合使用和进化。拟议的研究还应增加对脑室间细胞通讯以及细胞过程的动态调节和对不断变化的条件的反应机制的了解。

Probing the depth of protein subcellular localization regulation Cells 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.