The role of disorder in interaction networks: a structural analysis - PubMed (original) (raw)

The role of disorder in interaction networks: a structural analysis

Philip M Kim et al. Mol Syst Biol. 2008.

Abstract

Recent studies have emphasized the value of including structural information into the topological analysis of protein networks. Here, we utilized structural information to investigate the role of intrinsic disorder in these networks. Hub proteins tend to be more disordered than other proteins (i.e. the proteome average); however, we find this only true for those with one or two binding interfaces ('single'-interface hubs). In contrast, the distribution of disordered residues in multi-interface hubs is indistinguishable from the overall proteome. Surprisingly, we find that the binding interfaces in single-interface hubs are highly structured, as is the case for multi-interface hubs. However, the binding partners of single-interface hubs tend to have a higher level of disorder than the proteome average, suggesting that their binding promiscuity is related to the disorder of their binding partners. In turn, the higher level of disorder of single-interface hubs can be partly explained by their tendency to bind to each other in a cascade. A good illustration of this trend can be found in signaling pathways and, more specifically, in kinase cascades. Finally, our findings have implications for the current controversy related to party and date-hubs.

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Figures

Figure 1

Figure 1

(A) Disorder in singlish-interface hubs versus multi-interface hubs. (Wilcoxon ranksum test, _P_=1.0e−8). (B) Distribution of disordered residues in the yeast proteins. As can be seen, most yeast proteins have a relatively low level of disorder; however, almost all have some fraction of disordered residues. (C) Distribution of disorder in multi-interface hubs. The distribution does not significantly deviate from the distribution of the yeast proteome (Kolmogorov-Smirnov test, _P_-value=0.11). In other words, multi-interface hubs do not have different levels of disorder than normal proteins. (D) Distribution of disorder in singlish-interface hubs. Singlish-interface hubs show a different distribution in terms of disorder (Kolmogorov–Smirnov test, _P_=2.0e−6).

Figure 2

Figure 2

dN/dS ratio of ordered and disordered proteins, and hubs. (A) All yeast proteins, split by order/disorder (Wilcoxon rank sum test, _P_-value <2.2e−16); (B) Hubs only (Wilcoxon rank sum test, _P_=1.5e−6).

Figure 3

Figure 3

(A) Disorder in the interface regions of singlish- and multi-interface hubs. (Wilcoxon ranksum test, _P_=0.4). (B) Disorder of the binding partner of singlish- and multi-interface hubs (Wilcoxon ranksum test, _P_=4.5e−5). BIOGRID data are reported in the boxplot. Similar results were found for Kim et al (2006) and Batada et al (2006) data sets (Supplementary Figure S5). (C) Schematic representation of disorder in singlish-interface hubs. Singlish-interface hubs have large portions of disordered regions (painted in gray). However, the interface is itself is highly structured (painted in black). One reason for the disorder in the bulk of the protein is the fact that singlish-interface hubs often are targeted by kinases. On the other hand, they tend to be kinases themselves and target disordered regions in other proteins.

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