Title: Intermodular and intramodular proteins in protein interaction networks

The availability of large-scale protein-protein interaction networks for numerous organisms provides an opportunity to comprehensively analyze the roles proteins play in the functional organization of the cell.

First, we re-examine an influential but controversial characterization of the dynamic modularity of the S. cerevisiae interactome that incorporated gene expression data into network analysis. We analyse the protein-protein interaction networks of five organisms, S. cerevisiae, H. sapiens, D. melanogaster, A. thaliana, and E. coli, and confirm significant and consistent functional and structural differences between hub proteins that are co-expressed with their interacting partners and those that are not, and support the view that the former tend to be intramodular whereas the latter tend to be intermodular. However, we also demonstrate that in each of these organisms, simple topological measures are significantly correlated with the average co-expression of a hub with its partners, and therefore also reflect protein intra- and inter- modularity. Further, cross-interactomic analysis demonstrates that these simple topological characteristics of hub proteins tend to be conserved across organisms. Overall, we give evidence that purely topological features of static interaction networks reflect aspects of the dynamics and modularity of interactomes as well as previous measures incorporating expression data, and are a powerful means for understanding the dynamic roles of hubs in interactomes.

Second, we study the role of multifunctional genes (and proteins they encode) in protein interaction networks. Many genes in a genome have more than one function. However, genome-wide analysis of multifunctional genes and an explanation of the mechanisms underlying multifunctionality are still lacking. We leverage functional annotations of genes to extract a group of genes each of which has at least two completely different functions, and distinguish these, the most multifunctional genes, from the remaining genes that are currently known to have a single function. We find biologically significant differences between multifunctional and all other genes on a large scale. We show that multifunctional genes are intermodular and play a central role in the interactome, bridging different functional modules.