Modular organization of cellular networks

Abstract

We investigated the organization of interacting proteins and protein complexes into networks of modules. A network-clustering method was developed to identify modules. This method of network-structure determination was validated by clustering known signaling-protein modules and by identifying module rudiments in exclusively high-throughput protein-interaction data with high error frequencies and low coverage. The signaling network controlling the yeast developmental transition to a filamentous form was clustered. Abstraction of a modular network-structure model identified module-organizer proteins and module-connector proteins. The functions of these proteins suggest that they are important for module function and intermodule communication.

Figure 1

Clustering of the yeast signaling-protein interaction network. A symmetrical matrix of 64 proteins of the MIPS-database signaling category was clustered identically in both dimensions. The cluster tree is not shown. Each row or column represents a protein. Each feature is the intersection of two proteins and is a grayscale representation of pairwise protein association (see text). Columns to the right of the clustered network represent MIPS-defined signaling pathways [P, polarity-PKC; R, Ras; H, HOG; M, mating/filamentation MAPK (mfMAPK)]. White bars in the MIPS-pathway columns indicate protein members of the pathway.

Figure 2

Clustering of the yeast nuclear-protein network derived from high-throughput interaction and localization data. (A) Examples of clusters representing module rudiments are labeled. The cluster tree is not shown. Arrows indicate high-connectivity hub proteins. (B) Example clusters are shown in detail. Cluster comembers participating in some common structure or function (see text) have large bold labels.

Figure 3

Global protein connectivity versus neighborhood clustering. Each protein in the global protein network (high-throughput data plus validated data) is plotted by its connectivity, k, and its neighborhood clustering, C, the ratio of the number of connections among its k neighbors to the maximum possible number, k(k − 1)/2. Arrows indicate high-connectivity proteins shown in Fig. 2A.

Figure 4

Clustering of the yeast filamentation network. Proteins of the yeast filamentation network were clustered. A tree-depth threshold was set. Tree branches with three or more leaves (clusters with three or more proteins) below the tree threshold are shown. Bullets and large bold labels indicate proteins of highest intracluster connectivity.

Figure 5

Modular model of the yeast filamentation network. Clusters indicated in Fig. 4 are abstracted as modules. All intermodule paths in the filamentation network are indicated as black lines with the interacting proteins at the termini. A gray line connecting the Ras and protein kinase A modules was added to indicate a connection mediated by the small molecule cAMP.