Repeated use of interacting domain-pairs in PPI networks. For each organism, the number of occurrences of each DDI in the PPI network was counted. The histogram shows the frequency of PPIs that were attributed to DDIs used only once, twice, and so on. The frequency is computed out of all the PPI-DDI mappings. DDI, domain-domain interaction; PPI, protein-protein interaction.

Interacting domain pairs shared by several organisms. The histogram shows the number of DDIs shared by three, four, and all five organisms. White bars represent DDIs that are used also in E. coli and black bars represent DDIs common only to the eukaryotes in our study. Twenty-seven DDIs were shared by all five organisms. E: E. coli. Y: yeast (S. cerevisae). W: worm (C. elegans). F: fly (D. melanogaster). H: human. DDI, domain-domain interaction.

Interacting domain pairs are abundant in protein complexes. The frequency of DDIs in S. cerevisiae complexes is statistically significantly higher than their fraction in the whole interactome (P values were determined by χ² test). The fraction of PPIs attributed to DDIs increases with the reliability of the interaction and is highest in the cores of the complexes. DDI, domain-domain interaction; PPI, protein-protein interaction.

A schematic description of the analysis. (a) A list of experimentally determined PPIs is compiled for each of the five organisms (E. coli, S. cerevisiae, C. elegans, D. melanogaster, and H. sapiens) from INTACT [32], DIP [19], and BIOGRID [33]. (b) A list of structurally derived DDIs is compiled from 3DID [12] and iPfam [13] databases. (c) The appropriate domains are assigned to each of the interacting proteins according to the definitions of the InterPro database [34]. (d) Based on the data complied in panels b and c, DDIs are mapped onto PPIs. (e) A list of PPIs with DDI assignments is compiled. (f) A list of the DDIs mapped onto PPIs is compiled. DDI, domain-domain interaction; PPI, protein-protein interaction.

The same DDIs are used in different cellular contexts and in different organisms. The interacting domains (demonstrated and labeled in the left-most column) were mapped onto the interacting proteins (demonstrated and labeled in the two right columns). Edges connect between interacting domains/proteins. The proteins may be multidomain proteins, but only the relevant domain is demonstrated. (a) An example of the same DDI mapped onto two pairs of interacting proteins in yeast, which are involved in different processes, namely RNA export and RNA splicing. (b) An example of a subnetwork of four proteins whose interactions are attributed to the same DDIs in S. cerevisiae and in human. In yeast, the interacting proteins are involved in DNA mismatch repair and in human they are involved in meiotic recombination. The proteins MSH4 and MSH5 are not considered homologs of the proteins MSH2, MSH3, or MSH6 (based on the report by Altschul and coworkers [40] and on sequence comparison). (c) An example of two PPIs attributed to the same DDI in different processes in D. melanogaster and human; in fly it is involved in phospholipid biosynthesis and in human in vesicular trafficking. These examples emphasize the modularity of DDIs and their possible role as the 'building blocks' of the PPI networks. The Swiss-Prot accessions of the proteins are as follows: PABP: [P04147]; MEX67: [Q99257]; MSL1: [P40567]; RU2A: [Q08963]; MSH2: [P25847]; MSH3: [P25336]; MSH6: [Q03834]; MSH5: [O43196]; MSH4: [O15457]; SDCB1: [O00560]; and PIPA: [P13217]. DDI, domain-domain interaction; PPI, protein-protein interaction;. fly, D. melanogaster; yeast, S. cerevisiae.