Dynamics of the cellular interactome

University Of Washington, Seattle WA

Investigators

Linked publications, trials & patents

Abstract

Cellular functional pathways have evolved through selective pressures and fitness benefits conferred through protein intra- and inter-molecular interactions that comprise all protein conformational features and protein- protein interactions, collectively referred to as the interactome. While the interactome is regulated by proteome levels, it is also regulated independently by posttranslational modifications, co-factors and ligand levels, as well as many local protein environmental factors, such as osmolyte concentration, pH, ionic strength, temperature and others. Because fitness selection operates on processes that take place within the crowded intra-cellular environment, our efforts have developed technologies to qualitatively and quantitatively measure highly evolved interactome networks to improve comprehension of molecular functional landscapes in cells. To overcome barriers and gain insight on cellular interactomes, our lab is developing novel in vivo chemical cross-linking molecules referred to as Protein Interaction Reporter (PIR) technologies and new mass spectrometry methods. These developments have provided the initial quantitative in vivo insights on interactomes in live cells. In this project, we propose to further advance and apply Protein Interaction Reporter (PIR) technologies together with advanced informatics, mass spectrometry and ion separation technologies to gain deeper insight on cellular interactome dynamics during stress exposure. The primary goal driving our technology advancement is to better understand how interactome dynamics shape functional landscapes inside cells. Questions we will address include: what interactome changes are common and unique among cells exposed to heat, nutrient, and oxidative stresses, how stress-dependent interactome dynamics are altered by HSP90, HSF1 and other inhibitors or other perturbations and how do emerging mitochondrial therapies like Elamipretide that improve cell survival alter stress-induced interactome dynamics. These efforts will reveal cellular interactome dynamics resultant from multiple stress conditions as well as interactome changes that improve cell survival that can serve as targets for future therapies for cancer, aging, cardiovascular, neurodegeneration, and many other diseases.