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

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.

Posttranslational regulation impacts the fate of duplicated genes

“…Furthermore, to account for gene dosage imbalances (22, 23), we also removed (i) all of the ribosomal proteins or (ii) all known protein complexes and found that our conclusions are still robust (S1.7 and test 6, P < 2.2e −9 , Wilcoxon's test; and S1.7 and test 7, P < 9.8 e −7 , Wilcoxon's test, respectively). We also controlled for potential biases arising from (i) differences in protein abundance (24) (S1.8 and test 8; P < 3.3 e −5 , Wilcoxon's test), (ii) coverage (S1.8 and test 9; P = 0.009, Wilcoxon's test) in the various experiments, (iii) essentiality of genes (25-29) (S1.8 and test 10; P < 2.3e −6 , Wilcoxon's test), or (iv) protein interaction network centrality (27,29,30) (S1.8 and test 11; P < 3e −7 , Wilcoxon's test) and still found that WGD proteins contained more p-sites. The importance of taking into consideration protein function in evolutionary analyses as performed here has been highlighted previously (31).…”

Generalized walks-based centrality measures for complex biological networks

“…The subgraph centrality has been previously applied to the identification of essential proteins in proteomic maps (Estrada, 2006a;2006b;Zotenko et al, 2008;Lin et al, 2008;Gursoy et al, 2008) and the characterization of malignant tissues (Platzer et al, 2007). It has also been applied to the study of weighted graphs to account for the degree of folding of protein chains (see for instance Estrada, 2002;2004) as well as to describe the molecular structure of drug-like and environmentally relevant organic compounds (for a review see Estrada and Uriarte, 2001).…”

Controllability in protein interaction networks

“…For instance, the so-called centrality-lethality rule was first suggested by Jeong et al (3) and Yu et al (4), stating that highly connected proteins tend to be essential. Furthermore, such hubs are also involved in a rising number of protein complexes (5), suggesting that their essentiality is a consequence of their complex involvement (6,7). In humans, human viruses and parasites target certain proteins to seize control of a host cell (8,9) whereas such proteins play a decisive role in different cancer types (10,11).…”