Neighbor Overlap Is Enriched in the Yeast Interaction Network: Analysis and Implications

The yeast protein-protein interaction network has been shown to have distinct topological features such as a scale free degree distribution and a high level of clustering. Here we analyze an additional feature which is called Neighbor Overlap. This feature reflects the number of shared neighbors between a pair of proteins. We show that Neighbor Overlap is enriched in the yeast protein-protein interaction network compared with control networks carefully designed to match the characteristics of the yeast network in terms of degree distribution and clustering coefficient. Our analysis also reveals that pairs of proteins with high Neighbor Overlap have higher sequence similarity, more similar GO annotations and stronger genetic interactions than pairs with low ones. Finally, we demonstrate that pairs of proteins with redundant functions tend to have high Neighbor Overlap. We suggest that a combination of three mechanisms is the basis for this feature: The abundance of protein complexes, selection for backup of function, and the need to allow functional variation

Co-expression and co-localization of hub proteins and their partners are encoded in protein sequence

Spatiotemporal coordination is a critical factor in biological processes. Some hubs in protein–protein interaction networks tend to be co-expressed and co-localized with their partners more strongly than others, a difference which is arguably related to functional differences between the hubs. Based on numerous analyses of yeast hubs, it has been suggested that differences in co-expression and co-localization are reflected in the structural and molecular characteristics of the hubs. We hypothesized that if indeed differences in co-expression and co-localization are encoded in the molecular characteristics of the protein, it may be possible to predict the tendency for co-expression and co-localization of human hubs based on features learned from systematically characterized yeast hubs. Thus, we trained a prediction algorithm on hubs from yeast that were classified as either strongly or weakly co-expressed and co-localized with their partners, and applied the trained model to 800 human hub proteins. We found that the algorithm significantly distinguishes between human hubs that are co-expressed and co-localized with their partners and hubs that are not. The prediction is based on sequence derived features such as “stickiness”, i.e. the existence of multiple putative binding sites that enable multiple simultaneous interactions, “plasticity”, i.e. the existence of predicted structural disorder which conjecturally allows for multiple consecutive interactions with the same binding site and predicted subcellular localization. These results suggest that spatiotemporal dynamics is encoded, at least in part, in the amino acid sequence of the protein and that this encoding is similar in yeast and in human

Neighbor Overlap in redundant gene pairs for Non-zero Neighbor Overlap pairs.

<p>Neighbor Overlap in redundant gene pairs for Non-zero Neighbor Overlap pairs.</p

GO annotation similarity for high and low Neighbor Overlap groups.

<p>The distributions in each panel represent the GO annotation similarity of 1000 subsets each of size 100) from the high (blue bars) and low (red bars) Neighbor Overlap groups. The distributions for the three ontologies: Biological Process (top), Molecular Function (middle) and Cellular Component (bottom) show a marked separation between their GO similarities for pairs with high and low NO values.</p

High Neighbor Overlap pairs have stronger genetic interactions than low ones.

<p>The distributions represent the average ε values of 1000 subsets (each of size 100) from the high (blue bars) and low (red bars) Neighbor Overlap groups. Clearly, the ε values are higher for the high than for the low group.</p

Schematic view of Neighbor Overlap.

<p>In the depicted example nodes A (degree = 7) and B (degree = 5) have 3 common neighbors. According to the definitions in the text, NOcount  = 3, NOnorm = 3/5 and NOjaccard  = 1/3.</p

Non-zero Neighbor Overlap in redundant gene pairs.

<p>Non-zero Neighbor Overlap in redundant gene pairs.</p

Enrichment of Neighbor Overlap in the yeast protein-protein interaction network – with and without complexes.

<p>Panel A shows the distribution of Neighbor Overlap using the NOnorm measure, for yeast (blue bars) versus control (red bars). Assessing the contribution of protein complexes to Neighbor Overlap was implemented by removing protein pairs that belong to the same complex from the original analysis (green bars). Panel B shows the yeast (blue bars) and control (red bars) NOnorm distributions on a collapsed version of the yeast interaction network. This was achieved by collapsing all proteins that are part of the same complex to a unified node and computing NOnorm values for the new network. To overcome difference in scale, the higher NOnorm bins are presented in the enlarged inserts. The figure shows that complexes contribute considerably to the NO enrichment, but even when complexes are removed the NO signal is strongly evident.</p