Comparison of protein interaction networks reveals species conservation and divergence

Abstract

Background: Recent progresses in high-throughput proteomics have provided us with a first chance to characterize protein interaction networks (PINs), but also raised new challenges in interpreting the accumulating data.

Results: Motivated by the need of analyzing and interpreting the fast-growing data in the field of proteomics, we propose a comparative strategy to carry out global analysis of PINs. We compare two PINs by combining interaction topology and sequence similarity to identify conserved network substructures (CoNSs). Using this approach we perform twenty-one pairwise comparisons among the seven recently available PINs of E.coli, H.pylori, S.cerevisiae, C.elegans, D.melanogaster, M.musculus and H.sapiens. In spite of the incompleteness of data, PIN comparison discloses species conservation at the network level and the identified CoNSs are also functionally conserved and involve in basic cellular functions. We investigate the yeast CoNSs and find that many of them correspond to known complexes. We also find that different species harbor many conserved interaction regions that are topologically identical and these regions can constitute larger interaction regions that are topologically different but similar in framework. Based on the species-to-species difference in CoNSs, we infer potential species divergence. It seems that different species organize orthologs in similar but not necessarily the same topology to achieve similar or the same function. This attributes much to duplication and divergence of genes and their associated interactions. Finally, as the application of CoNSs, we predict 101 protein-protein interactions (PPIs), annotate 339 new protein functions and deduce 170 pairs of orthologs.

Conclusion: Our result demonstrates that the cross-species comparison strategy we adopt is powerful for the exploration of biological problems from the perspective of networks.

Figure 1

Schematic of pairwise network comparison in NetAlign. The comparison between two PINs is accomplished by a fast subgraph isomorphism algorithm and the resulting s-CoNSs are connected maximal common subgraphs (MCS) and exact matches of the two networks. The s-CoNSs are further merged by a clustering rule to produce c-CoNSs that allow inexact match among homologous regions of interaction in the two networks. The identified s-CoNSs and c-CoNSs are scored on the basis of their interaction topologies and evaluated by statistical significance.

Figure 2

Representative s-CoNSs. Each pair of matched conserved proteins from two different species is shown in one node with their identifiers delimited by a slash; black edges are conserved PPIs existed in both PINs and constitute the s-CoNS, while red/green edges are discrepant PPIs observed only in the species on the left/right of the slash, respectively. a-d. These s-CoNSs corresponds to the RNA polymerase (RNAP) of prokaryotes and are identified from the PIN comparison between E.coli (left) and H.pylori (right) (figure 10). e. This s-CoNS is from the NetAlign analysis between H.sapien and M.musculus. It is a part of the system of fibroblast growth factors (FGF) and FGF receptors (figure 8). Gene duplication present in this system results in great redundancy for the identified s-CoNSs that 151 very similar s-CoNSs are identified. f. This is an s-CoNS harbored by the PINs of S.cerevisiae and C.elegans, and it is a part of E2F/DP transcription factor complex (figure 4). Based on the discrepant red edge, we predict that F11A10.2 interacts with T13H5.4 and this prediction is also present in the interolog database [32]. g-k. These s-CoNSs constitute the complex of replication factor C (figure 3) and are derived from the comparison between the PINs of S.cerevisiae and H.sapien.

Figure 3

Representative c-CoNS: the complex of replication factor C (RFC). Figure 3-10 are representative c-CoNSs. Each c-CoNS is shown in two separate panels each for a species; orthologous and transitively orthologous proteins are shown in the same horizontal level in each panel. Black edges are conserved PPIs existed in both PINs and constitute c-CoNSs, while red/green edges are discrepant PPIs observed only in the species on the left/right panel, respectively.

Figure 4

Representative c-CoNS: E2F/DP transcription factor complex.

Figure 5

Representative c-CoNS: the general transcription and DNA repair factor IIH (TFIIH) complex.

Figure 6

Representative c-CoNS: ATP synthase.

Figure 7

Representative c-CoNS: synaptosomal neurotransmitter release.

Figure 8

Representative c-CoNS: system of fibroblast growth factors (FGFs) and FGF receptors.

Figure 9

Representative c-CoNS: nucleocytoplasmic transport.

Figure 10

Representative c-CoNS: bacterial RNA polymerase (RNAP).

Figure 11

Function distribution of the identified CoNSs. Each pie chart represents the distribution of the ten functional categories of the CoNSs derived from a pairwise PIN comparison. The area of each pie chart is approximately scaled according to the number of conserved proteins involved in the CoNSs.