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

Abstract

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][1]). 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 ‘party’ hubs, and those that are not coexpressed with their neighbors and located outside modules as ‘date’ hubs ([Han et al , 2004][2]). Here, we named hubs located in static neighborhoods as ‘family’ hubs (they interact with their neighbors constitutively), as these hubs do not belong to party or date hubs because they are located within modules but are not highly coexpressed with their neighbors owing to their static expression pattern. Therefore, family and party hubs constitute the static and dynamic modules in the cell, respectively, whereas date hubs organize them into a network. Based on the classification of hubs by [Han et al (2004)][2], date hubs have been found to evolve at a faster rate than party hubs, thereby suggesting that modularity imposes a constraint on the evolvability of proteins and that the protein interaction network mainly evolves by ‘re‐wiring’ the connections between modules in the network ([Fraser, 2005][3]). We also find that party hubs evolve much slower than other hubs ([Figure 5A][4]). However, family hubs are the ones that evolve the fastest rather than date hubs ([Figure 5A][4]), suggesting that modularity per se does not impose a constraint on the evolvability of proteins, as family hubs are also modular. Consistent with their evolutionary plasticity, deletions of family hubs in yeast are tolerated significantly more than deletions of party hubs, indicating specific robustness of the cell to dysfunctions in static modules. Moreover, family hubs are significantly ‘noisier’ in their expression ([Figure 5C][4]), meaning that their expression levels vary from cell‐to‐cell considerably more when compared to party or date hubs. These observations argue that family hubs are the most variable components of the cell both genetically during evolution and expressionally between cells in a population. Family hubs, and hence static modules, could therefore serve as buffers of genetic variations as well as of expression noise within the cell that contribute to the robustness of the cell. Mol Syst Biol. 3: 110 [1]: #F1 [2]: #ref-12 [3]: #ref-8 [4]: #F5