Interaction paths promote module integration and network-level robustness of spliceosome to cascading effects

Abstract

The functionality of distinct types of protein networks depends on the patterns of protein-protein interactions. A problem to solve is understanding the fragility of protein networks to predict system malfunctioning due to mutations and other errors. Spectral graph theory provides tools to understand the structural and dynamical properties of a system based on the mathematical properties of matrices associated with the networks. We combined two of such tools to explore the fragility to cascading effects of the network describing protein interactions within a key macromolecular complex, the spliceosome. Using S. cerevisiae as a model system we show that the spliceosome network has more indirect paths connecting proteins than random networks. Such multiplicity of paths may promote routes to cascading effects to propagate across the network. However, the modular network structure concentrates paths within modules, thus constraining the propagation of such cascading effects, as indicated by analytical results from the spectral graph theory and by numerical simulations of a minimal mathematical model parameterized with the spliceosome network. We hypothesize that the concentration of paths within modules favors robustness of the spliceosome against failure, but may lead to a higher vulnerability of functional subunits, which may affect the temporal assembly of the spliceosome. Our results illustrate the utility of spectral graph theory for identifying fragile spots in biological systems and predicting their implications.