Ortholog-based protein-protein interaction prediction and its application to inter-species interactions

Abstract

Background: The rapid growth of protein-protein interaction (PPI) data has led to the emergence of PPI network analysis. Despite advances in high-throughput techniques, the interactomes of several model organisms are still far from complete. Therefore, it is desirable to expand these interactomes with ortholog-based and other methods.

Results: Orthologous pairs of 18 eukaryotic species were expanded and merged with experimental PPI datasets. The contributions of interologs from each species were evaluated. The expanded orthologous pairs enable the inference of interologs for various species. For example, more than 32,000 human interactions can be predicted. The same dataset has also been applied to the prediction of host-pathogen interactions. PPIs between P. falciparum calmodulin and several H. sapiens proteins are predicted, and these interactions may contribute to the maintenance of host cell Ca2+ concentration. Using comparisons with Bayesian and structure-based approaches, interactions between putative HSP40 homologs of P. falciparum and the H. sapiens TNF receptor associated factor family are revealed, suggesting a role for these interactions in the interference of the human immune response to P. falciparum.

Conclusion: The PPI datasets are available from POINT http://point.bioinformatics.tw/ and POINeT http://poinet.bioinformatics.tw/. Further development of methods to predict host-pathogen interactions should incorporate multiple approaches in order to improve sensitivity, and should facilitate the identification of targets for drug discovery and design.

Figure 1

Interactions between P. falciparum and H. sapiens are grouped by biological processes from Gene Ontology. Interactions between P. falciparum and H. sapiens are grouped by biological processes from Gene Ontology. Each node represents a GO biological process in either P. falciparum or H. sapiens. The nodes of biological processes for P. falciparum are shaded based on their involvement in the inter-species interaction network; darker color implies larger involvement. For P. falciparum, most of the interactions are related to metabolic and cellular processes.

Figure 2

Illustration of filtered H. sapiens-P. falciparum interactions. P. falciparum calmodulin (PF14_0323) shares 13 interaction partners with human calmodulin (CALM3), suggesting competition between the two proteins, and interference of host cell Ca²⁺ homeostasis. (Red: red blood cell; Green: the parasitophorous vacuole).