An Atlas of Protein-Protein Interactions Across Mouse Tissues

Cellular processes arise from the dynamic organization of proteins in networks of physical interactions. Mapping the complete interactome, has therefore been a central objective of high-throughput biology. However, interaction dynamics across physiological contexts remain poorly understood. Here, we combine protein correlation profiling with stable isotope labelling of mammals to map the interactomes of seven mouse tissues. The resulting maps provide the first proteome-scale survey of interactome dynamics across mammalian tissues, revealing over 125,000 unique interactions with an accuracy comparable to the highest-quality human screens. We identify systematic suppression of cross-talk between the evolutionarily ancient housekeeping interactome and younger, tissue-specific modules. Rewiring of protein interactions across tissues is widespread, and rewired proteins are tightly regulated by multiple cellular mechanisms and implicated in disease. Our study opens up new avenues to uncover regulatory mechanisms that shape in vivo interactome responses to physiological and pathophysiological stimuli in mammalian systems.