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Abstract:
The \emph{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.
