Revealing static and dynamic modular architecture of the eukaryotic protein interaction network

In an effort to understand the dynamic organization of the protein interaction network and its role in the regulation of cell behavior, positioning of proteins into specific network localities was studied with respect to their expression dynamics. First, we find that constitutively expressed and dynamically co‐regulated proteins cluster in distinct functionally specialized network neighborhoods to form static and dynamic functional modules, respectively. Then, we show that whereas dynamic modules are mainly responsible for condition‐dependent regulation of cell behavior, static modules provide robustness to the cell against genetic perturbations or protein expression noise, and therefore may act as buffers of evolutionary as well as population variations in cell behavior. Observations in this study refine the previously proposed model of dynamic modularity in the protein interaction network, and propose a link between the evolution of gene expression regulation and biological robustness. Synopsis In order to test the specific organizational layout of transcriptionally regulated (dynamic) versus nonregulated (static) proteins in the protein interaction network, we integrated high‐confidence protein interaction data from yeast with high‐throughput microarray gene expression data. The extent of transcriptional regulation of a gene (i.e. expression variance, EV) was simply scored by taking the statistical variance of its expression profile across 272 microarray experiments from various conditions. By constructing a global interaction preference matrix of proteins with various EVs, we find that the network is enriched for clusters of static and dynamic proteins (static and dynamic neighborhoods, respectively) (Figure 1B). These neighborhoods are specialized functional modules dedicated to specific cellular processes like mRNA synthesis, protein degradation or vesicle trafficking. Interestingly, some cellular functions seem to be mainly performed by static modules, whereas others are mainly carried out by dynamically expressed modules, pointing to functional distinction between the two types of modules. Our study shows that expression criteria for a protein to be located within a module are that either it has to be highly coexpressed with its neighbors in the network or it must be located within a static neighborhood. An earlier study named hubs (highly connected proteins) that are highly coexpressed with their neighbors and that are therefore in modules as ‘par