Intrinsic disorder in protein interaction networks linking cancer with metabolic diseases

Complex diseases are usually driven by numerous proteins that operate as intricate network systems. Deciphering of their signals is required for more advanced level understanding of the cellular processes driven by protein interactions. Therefore, placing diseases into a framework, where they can be viewed together, represents an important and fruitful approach. The goal of this study was to assess the intrinsic disorder present in the proteins forming PPI networks linking cancer with different human diseases. To this end, we used a set of bioinformatics tools to explore intrinsic disorder and liquid-liquid phase separation predispositions of 340 proteins reported earlier by Hirsch et al. (Cancer Cell (2010) 17(4), 348-361; doi: 10.1016/j.ccr.2010.01.022) as differently expressed in common chronic diseases, such as cancer, obesity, diabetes, and cardiovascular diseases. We further examined selected proteins from this set for their interactability and intrinsic disorder-based functionality. Our analyses demonstrated that intrinsically disordered proteins and proteins with intrinsically disordered regions may act as active network promoters and operate as highly connected hubs, which further enables them to play key roles in the disease pathways. The study also indicated that differently expressed proteins involved in disease progression could be characterized by diverse degrees of intrinsic disorder and LLPS propensity. We hope that our findings in combination with the outputs of the proteomic and functional genomic analyses contain essential clues that can be used in further medical research leading to the design of better therapies.