The role of 3\'UTR-protein complexes in the regulation of protein multifunctionality and subcellular localization

Multifunctional proteins often perform their different functions when localized in different subcellular compartments. However, the mechanisms leading to their localization are largely unknown. Recently, 39UTRs were found to regulate the cellular localization of newly synthesized proteins through the co-translational formation of 39UTR-protein complexes. Here, we investigate the formation of 39UTR-protein complexes involving multifunctional proteins by exploiting large-scale protein-protein and protein-RNA interaction networks. Focusing on 238 human 9extreme multifunctional9 (EMF) proteins, we predicted 1411 39UTR-protein complexes involving 128 EMF proteins and evaluated their role in regulating protein cellular localization and multifunctionality. Notably, we find that EMF proteins lacking localization addressing signals, yet present at both the nucleus and cell surface, often form 39UTR-protein complexes. In addition, they provide EMF proteins with the diversity of interaction partners necessary to their multifunctionality. Archetypal moonlighting proteins are also predicted to form 39UTR-protein complexes thereby reinforcing our findings. Finally, our results indicate that the formation of 39UTR-protein complex may be a common phenomenon in human cells, affecting up to 20% of the proteins in the human interactome.