Probing the depth of protein subcellular localization regulation

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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.