Why Do Hubs in the Yeast Protein Interaction Network Tend To Be Essential: Reexamining the Connection between the Network Topology and Essentiality

Top Cited Papers
Open Access
Publisher Website
Google Scholar
Abstract
The centrality-lethality rule, which notes that high-degree nodes in a protein interaction network tend to correspond to proteins that are essential, suggests that the topological prominence of a protein in a protein interaction network may be a good predictor of its biological importance. Even though the correlation between degree and essentiality was confirmed by many independent studies, the reason for this correlation remains illusive. Several hypotheses about putative connections between essentiality of hubs and the topology of protein–protein interaction networks have been proposed, but as we demonstrate, these explanations are not supported by the properties of protein interaction networks. To identify the main topological determinant of essentiality and to provide a biological explanation for the connection between the network topology and essentiality, we performed a rigorous analysis of six variants of the genomewide protein interaction network for Saccharomyces cerevisiae obtained using different techniques. We demonstrated that the majority of hubs are essential due to their involvement in Essential Complex Biological Modules, a group of densely connected proteins with shared biological function that are enriched in essential proteins. Moreover, we rejected two previously proposed explanations for the centrality-lethality rule, one relating the essentiality of hubs to their role in the overall network connectivity and another relying on the recently published essential protein interactions model. Analysis of protein interaction networks in the budding yeast Saccharomyces cerevisiae has revealed that a small number of proteins, the so-called hubs, interact with a disproportionately large number of other proteins. Furthermore, many hub proteins have been shown to be essential for survival of the cell—that is, in optimal conditions, yeast cannot grow and multiply without them. This relation between essentiality and the number of neighbors in the protein–protein interaction network has been termed the centrality-lethality rule. However, why are such hubs essential? Jeong and colleagues [1] suggested that overrepresentation of essential proteins among high-degree nodes can be attributed to the central role that hubs play in mediating interactions among numerous, less connected proteins. Another view, proposed by He and Zhang, suggested that that the majority of proteins are essential due to their involvement in one or more essential protein–protein interactions that are distributed uniformly at random along the network edges [2]. We find that none of the above reasons determines essentiality. Instead, the majority of hubs are essential due to their involvement in Essential Complex Biological Modules, a group of densely connected proteins with shared biological function that are enriched in essential proteins. This study sheds new light on the topological complexity of protein interaction networks.