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

Abstract

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.

Simple Topological Features Reflect Dynamics and Modularity in Protein Interaction Networks

“…We also find that essentiality is positively correlated with clustering and functional similarity, while negatively correlated with betweenness and participation (though this correlation is not significant for betweenness in Yeast-all ). This is in agreement with recent evidence of the tight relationship of a protein's essentiality with modularity and its involvement in essential complexes [22], [23], as hubs with high avPCC, clustering, or functional similarity, and correspondingly low betweenness and participation, are likely to play key roles in modules and complexes.…”

Protein-protein Interaction Networks of E. coli and S. cerevisiae are similar

“…For instance, the so-called centrality-lethality rule326 suggests that central proteins with many interactions are more likely to be essential than poorly connected proteins. While highly connected proteins are more often essential in S. cerevisiae they are also involved in an increasing number of protein complexes27, suggesting that their essentiality is a consequence of their involvement in essential complexes282930. To determine essentiality-specific characteristics we utilized a set of 712 essential proteins in E. coli from the DEG database18.…”

Topological properties of robust biological and computational networks

“…This suggests that a gene's essentiality depends on both its module (i.e. its function) and its topological role within the module, and this analysis has also been shown to hold for various definitions of biological module [21]. Interestingly, the feature with the highest correlation using the global network was not the average degree (0.352) but the k-core number of the node (0.367).…”