1. Center for Cancer Systems Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA
3. Present address: Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA

Correspondence to: Marc Vidal¹ Email: marc_vidal@dfci.harvard.edu

Abstract

In apparently scale-free protein–protein interaction networks, or 'interactome' networks^{1, 2}, most proteins interact with few partners, whereas a small but significant proportion of proteins, the 'hubs', interact with many partners. Both biological and non-biological scale-free networks are particularly resistant to random node removal but are extremely sensitive to the targeted removal of hubs¹. A link between the potential scale-free topology of interactome networks and genetic robustness^{3, 4} seems to exist, because knockouts of yeast genes^{5, 6} encoding hubs are approximately threefold more likely to confer lethality than those of non-hubs¹. Here we investigate how hubs might contribute to robustness and other cellular properties for protein–protein interactions dynamically regulated both in time and in space. We uncovered two types of hub: 'party' hubs, which interact with most of their partners simultaneously, and 'date' hubs, which bind their different partners at different times or locations. Both in silico studies of network connectivity and genetic interactions described in vivo support a model of organized modularity in which date hubs organize the proteome, connecting biological processes—or modules⁷ —to each other, whereas party hubs function inside modules.

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