Specificity and evolvability in eukaryotic protein interaction networks

Abstract

Progress in uncovering the protein interaction networks of several species has led to questions of what underlying principles might govern their organization. Few studies have tried to determine the impact of protein interaction network evolution on the observed physiological differences between species. Using comparative genomics and structural information, we show here that eukaryotic species have rewired their interactomes at a fast rate of approximately 10(-5) interactions changed per protein pair, per million years of divergence. For Homo sapiens this corresponds to 10(3) interactions changed per million years. Additionally we find that the specificity of binding strongly determines the interaction turnover and that different biological processes show significantly different link dynamics. In particular, human proteins involved in immune response, transport, and establishment of localization show signs of positive selection for change of interactions. Our analysis suggests that a small degree of molecular divergence can give rise to important changes at the network level. We propose that the power law distribution observed in protein interaction networks could be partly explained by the cell's requirement for different degrees of protein binding specificity.

Figure 1. Preferential Interaction Turnover Is Observed in All Eukaryotic Interactomes

We have binned proteins according to their average number of interactions and calculated for each bin the rate of change of interactions. There is a very strong correlation between the degree of connectivity and the interaction turnover.

Figure 2. Protein Binding Domains with Many Structural Interactions Observed Have a Higher Link Turnover

We have grouped proteins containing domains with increasing observed structural interactions with other domain types and calculated for each bin the rate of change of interactions. Proteins containing domains known to interact with many other different domains have a higher rate of change of interactions than proteins containing domains with few known interactions.

Figure 3. Biological Process Can Determine Link Dynamics Independently of the Number of Interaction Partners

We have binned proteins according to the biological processes, defined in Gene Ontology, and calculated for each bin the average number of interactions and average rate of change of interactions (see Materials and Methods). The black line represents the expected rate of change for proteins with increasing numbers of interactions.