Abstract
In apparently scale-free protein–protein interaction networks, or ‘interactome’ networks1,2, 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 robustness3,4 seems to exist, because knockouts of yeast genes5,6 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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Acknowledgements
We thank DFCI Research Computing, especially L. Cai and M. Temple, for technical support and computation resources; members of the Vidal laboratory and J. Dekker for suggestions; T. Clingingsmith for administrative assistance; and H. Ge, C. Armstrong, D. Hill, M. Boxem and P.-O. Vidalain for reading the manuscript. F.P.R., G.F.B., L.V.Z. and D.S.G. were supported in part by an institutional grant from the HHMI Biomedical Research Support Program for Medical Schools. L.V.Z. and D.S.G. were supported by a Fu Fellowship and an NSF Postdoctoral Fellowship in Interdisciplinary Informatics, respectively. This work was supported by grants from the NHGRI, NIGMS and NCI awarded to M.V.
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Supplementary Information
Includes supplementary notes, supplementary methods, supplementary figure legends and references. (DOC 82 kb)
Supplementary Figures
Supplementary figure 1: High-confidence filtered yeast interactome (FYI) dataset; supplementary figure 2: Quality assessment of yeast interaction datasets; supplementary figure 3: Scale-free organization of the FYI network; supplementary figure 4: Titration of AvgPCC distribution according to degree distribution; supplementary figure 5: Impact of date or party hubs removals on the network topology. (PDF 1100 kb)
Supplementary Table 1
The identities of date and party hubs analysed in this study are listed together with their overall and condition-specific AvgPCCs and the number of interactions they mediate. (PDF 181 kb)
Supplementary Table 2
All interactions in FYI dataset. (PDF 323 kb)
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Han, JD., Bertin, N., Hao, T. et al. Evidence for dynamically organized modularity in the yeast protein–protein interaction network. Nature 430, 88–93 (2004). https://doi.org/10.1038/nature02555
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DOI: https://doi.org/10.1038/nature02555
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