From Hub Proteins to Hub Modules: The Relationship Between Essentiality and Centrality in the Yeast Interactome at Different Scales of Organization

Numerous studies have suggested that hub proteins in the S. cerevisiae physical interaction network are more likely to be essential than other proteins. The proposed reasons underlying this observed relationship between topology and functioning have been subject to some controversy, with recent work suggesting that it arises due to the participation of hub proteins in essential complexes and processes. However, do these essential modules themselves have distinct network characteristics, and how do their essential proteins differ in their topological properties from their non-essential proteins? We aimed to advance our understanding of protein essentiality by analyzing proteins, complexes and processes within their broader functional context and by considering physical interactions both within and across complexes and biological processes. In agreement with the view that essentiality is a modular property, we found that the number of intracomplex or intraprocess interactions that a protein has is a better indicator of its essentiality than its overall number of interactions. Moreover, we found that within an essential complex, its essential proteins have on average more interactions, especially intracomplex interactions, than its non-essential proteins. Finally, we built a module-level interaction network and found that essential complexes and processes tend to have higher interaction degrees in this network than non-essential complexes and processes; that is, they exhibit a larger amount of functional cross-talk than their non-essential counterparts. Network analyses of large-scale interactomes have been a great aid in advancing our understanding of cellular functioning and organization. Here, we examine one of the most basic and intensely-studied structure-to-function relationships observed in cellular networks: that between the number of interactions a protein has and its tendency to be essential. We develop a new computational framework to systematically analyze essential proteins within their cellular context by explicitly incorporating functional information. We apply this framework to the yeast interactome and demonstrate that the previously observed positive relationship between interaction degree and essentiality is largely due to intramodular interactions. Further, essentiality appears to be a modular property of protein complexes and not more broadly of biological processes. Within an essential complex, its essential proteins tend to have more interactions, especially intra-complex interactions, than its non-essential proteins. Finally, in a computationally inferred module-level interaction network, essential complexes and processes tend to have higher interaction degrees than their non-essential counterparts. In summary, we show a relationship between connectivity and essentiality not only at the protein level, but also within modules and at the module level, with complexes and processes that are essential tending to interact with many functional groups.