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

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.