The protein interaction network of the epithelial junctional complex: a system-level analysis

To acquire system-level understanding of the intercellular junctional complex, protein–protein interactions occurring at the junctions of simple epithelial cells have been examined by network analysis. Although proper hubs (i.e., very rare proteins with exceedingly high connectivity) were absent from the junctional network, the most connected (albeit nonhub) proteins displayed a significant association with essential genes and contributed to the “small world” properties of the network (as shown by in vivo and in silico deletion, respectively). In addition, compared with a random network, the junctional network had greater tendency to form modules and subnets of densely interconnected proteins. Module analysis highlighted general organizing principles of the junctional complex. In particular, two major modules (corresponding to the tight junctions and to the adherens junctions/desmosomes) were linked preferentially to two other modules that acted as structural and signaling platforms.     

ModuleSearch: finding functional modules in a protein–protein interaction network

Many biological processes are performed by a group of proteins rather than by individual proteins. Proteins involved in the same biological process often form a densely connected sub-graph in a protein–protein interaction network. Therefore, finding a dense sub-graph provides useful information to predict the function or protein complex of uncharacterised proteins in the sub-graph. We developed a heuristic algorithm that finds functional modules in a protein–protein interaction network and visualises the modules. The algorithm has been implemented in a platform-independent, standalone program called ModuleSearch. In an interaction network of yeast proteins, ModuleSearch found 366 overlapping modules. Of the modules, 71% have a function shared by more than half the proteins in the module and 58% have a function shared by all proteins in the module. Comparison of ModuleSearch with other programs shows that ModuleSearch finds more sub-graphs than most other programs, yet a higher proportion of the sub-graphs correspond to known functional modules. ModuleSearch and sample data are freely available to academics at http://bclab.inha.ac.kr/ModuleSearch.     

Assessing significance of connectivity and conservation in protein interaction networks.

Comparative analyses of cellular interaction networks enable understanding of the cell's modular organization through identification of functional modules and complexes. These techniques often rely on topological features such as connectedness and density, based on the premise that functionally related proteins are likely to interact densely and that these interactions follow similar evolutionary trajectories. Significant recent work has focused on efficient algorithms for identification of such functional modules and their conservation. In spite of algorithmic advances, development of a comprehensive infrastructure for interaction databases is in relative infancy compared to corresponding sequence analysis tools. One critical, and as yet unresolved aspect of this infrastructure is a measure of the statistical significance of a match, or a dense subcomponent. In the absence of analytical measures, conventional methods rely on computationally expensive simulations based on ad-hoc models for quantifying significance. In this paper, we present techniques for analytically quantifying statistical significance of dense components in reference model graphs. We consider two reference models--a G(n, p) model in which each pair of nodes in a graph has an identical likelihood, p, of sharing an edge, and a two-level G(n, p) model, which accounts for high-degree hub nodes generally observed in interaction networks. Experiments performed on a rich collection of protein interaction (PPI) networks show that the proposed model provides a reliable means of evaluating statistical significance of dense patterns in these networks. We also adapt existing state-of-the-art network clustering algorithms by using our statistical significance measure as an optimization criterion. Comparison of the resulting module identification algorithm, SIDES, with existing methods shows that SIDES outperforms existing algorithms in terms of sensitivity and specificity of identified clusters with respect to available GO annotations.     

ModuleSearch: finding functional modules in a protein-protein interaction network

Many biological processes are performed by a group of proteins rather than by individual proteins. Proteins involved in the same biological process often form a densely connected sub-graph in a protein-protein interaction network. Therefore, finding a dense sub-graph provides useful information to predict the function or protein complex of uncharacterised proteins in the sub-graph. We developed a heuristic algorithm that finds functional modules in a protein-protein interaction network and visualises the modules. The algorithm has been implemented in a platform-independent, standalone program called ModuleSearch. In an interaction network of yeast proteins, ModuleSearch found 366 overlapping modules. Of the modules, 71% have a function shared by more than half the proteins in the module and 58% have a function shared by all proteins in the module. Comparison of ModuleSearch with other programs shows that ModuleSearch finds more sub-graphs than most other programs, yet a higher proportion of the sub-graphs correspond to known functional modules. ModuleSearch and sample data are freely available to academics at http://bclab.inha.ac.kr/ModuleSearch.     

Protein Interaction Networks—More Than Mere Modules

It is widely believed that the modular organization of cellular function is reflected in a modular structure of molecular networks. A common view is that a “module” in a network is a cohesively linked group of nodes, densely connected internally and sparsely interacting with the rest of the network. Many algorithms try to identify functional modules in protein-interaction networks (PIN) by searching for such cohesive groups of proteins. Here, we present an alternative approach independent of any prior definition of what actually constitutes a “module”. In a self-consistent manner, proteins are grouped into “functional roles” if they interact in similar ways with other proteins according to their functional roles. Such grouping may well result in cohesive modules again, but only if the network structure actually supports this. We applied our method to the PIN from the Human Protein Reference Database (HPRD) and found that a representation of the network in terms of cohesive modules, at least on a global scale, does not optimally represent the network''s structure because it focuses on finding independent groups of proteins. In contrast, a decomposition into functional roles is able to depict the structure much better as it also takes into account the interdependencies between roles and even allows groupings based on the absence of interactions between proteins in the same functional role. This, for example, is the case for transmembrane proteins, which could never be recognized as a cohesive group of nodes in a PIN. When mapping experimental methods onto the groups, we identified profound differences in the coverage suggesting that our method is able to capture experimental bias in the data, too. For example yeast-two-hybrid data were highly overrepresented in one particular group. Thus, there is more structure in protein-interaction networks than cohesive modules alone and we believe this finding can significantly improve automated function prediction algorithms.     

Detecting functional modules in the yeast protein-protein interaction network

MOTIVATION: Identification of functional modules in protein interaction networks is a first step in understanding the organization and dynamics of cell functions. To ensure that the identified modules are biologically meaningful, network-partitioning algorithms should take into account not only topological features but also functional relationships, and identified modules should be rigorously validated. RESULTS: In this study we first integrate proteomics and microarray datasets and represent the yeast protein-protein interaction network as a weighted graph. We then extend a betweenness-based partition algorithm, and use it to identify 266 functional modules in the yeast proteome network. For validation we show that the functional modules are indeed densely connected subgraphs. In addition, genes in the same functional module confer a similar phenotype. Furthermore, known protein complexes are largely contained in the functional modules in their entirety. We also analyze an example of a functional module and show that functional modules can be useful for gene annotation. CONTACT: yuan.33@osu.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.     

Comparing protein interaction networks via a graph match-and-split algorithm.

We present a method that compares the protein interaction networks of two species to detect functionally similar (conserved) protein modules between them. The method is based on an algorithm we developed to identify matching subgraphs between two graphs. Unlike previous network comparison methods, our algorithm has provable guarantees on correctness and efficiency. Our algorithm framework also admits quite general criteria that define when two subgraphs match and constitute a conserved module. We apply our method to pairwise comparisons of the yeast protein network with the human, fruit fly and nematode worm protein networks, using a lenient criterion based on connectedness and matching edges, coupled with a clustering heuristic. In evaluations of the detected conserved modules against reference yeast protein complexes, our method performs competitively with and sometimes better than two previous network comparison methods. Further, under some conditions (proper homolog and species selection), our method performs better than a popular single-species clustering method. Beyond these evaluations, we discuss the biology of a couple of conserved modules detected by our method. We demonstrate the utility of network comparison for transferring annotations from yeast proteins to human ones, and validate the predicted annotations. Supplemental text is available at www.cs.berkeley.edu/ approximately nmani/M-and-S/supplement.pdf.     

Combining functional and topological properties to identify core modules in protein interaction networks

Advances in large-scale technologies in proteomics, such as yeast two-hybrid screening and mass spectrometry, have made it possible to generate large Protein Interaction Networks (PINs). Recent methods for identifying dense sub-graphs in such networks have been based solely on graph theoretic properties. Therefore, there is a need for an approach that will allow us to combine domain-specific knowledge with topological properties to generate functionally relevant sub-graphs from large networks. This article describes two alternative network measures for analysis of PINs, which combine functional information with topological properties of the networks. These measures, called weighted clustering coefficient and weighted average nearest-neighbors degree, use weights representing the strengths of interactions between the proteins, calculated according to their semantic similarity, which is based on the Gene Ontology terms of the proteins. We perform a global analysis of the yeast PIN by systematically comparing the weighted measures with their topological counterparts. To show the usefulness of the weighted measures, we develop an algorithm for identification of functional modules, called SWEMODE (Semantic WEights for MODule Elucidation), that identifies dense sub-graphs containing functionally similar proteins. The proposed method is based on the ranking of nodes, i.e., proteins, according to their weighted neighborhood cohesiveness. The highest ranked nodes are considered as seeds for candidate modules. The algorithm then iterates through the neighborhood of each seed protein, to identify densely connected proteins with high functional similarity, according to the chosen parameters. Using a yeast two-hybrid data set of experimentally determined protein-protein interactions, we demonstrate that SWEMODE is able to identify dense clusters containing proteins that are functionally similar. Many of the identified modules correspond to known complexes or subunits of these complexes.     

Analyzing protein lists with large networks: edge-count probabilities in random graphs with given expected degrees.

We present an analytical framework to analyze lists of proteins with large undirected graphs representing their known functional relationships. We consider edge-count variables such as the number of interactions between a protein and a list, the size of a subgraph induced by a list, and the number of interactions bridging two lists. We derive approximate analytical expressions for the probability distributions of these variables in a model of a random graph with given expected degrees. Probabilities obtained with the analytical expressions are used to mine a protein interaction network for functional modules, characterize the connectedness of protein functional categories, and measure the strength of relations between modules.     

Oligomeric protein structure networks: insights into protein-protein interactions

Background  

Protein-protein association is essential for a variety of cellular processes and hence a large number of investigations are being carried out to understand the principles of protein-protein interactions. In this study, oligomeric protein structures are viewed from a network perspective to obtain new insights into protein association. Structure graphs of proteins have been constructed from a non-redundant set of protein oligomer crystal structures by considering amino acid residues as nodes and the edges are based on the strength of the non-covalent interactions between the residues. The analysis of such networks has been carried out in terms of amino acid clusters and hubs (highly connected residues) with special emphasis to protein interfaces.     

In search of the biological significance of modular structures in protein networks

Many complex networks such as computer and social networks exhibit modular structures, where links between nodes are much denser within modules than between modules. It is widely believed that cellular networks are also modular, reflecting the relative independence and coherence of different functional units in a cell. While many authors have claimed that observations from the yeast protein–protein interaction (PPI) network support the above hypothesis, the observed structural modularity may be an artifact because the current PPI data include interactions inferred from protein complexes through approaches that create modules (e.g., assigning pairwise interactions among all proteins in a complex). Here we analyze the yeast PPI network including protein complexes (PIC network) and excluding complexes (PEC network). We find that both PIC and PEC networks show a significantly greater structural modularity than that of randomly rewired networks. Nonetheless, there is little evidence that the structural modules correspond to functional units, particularly in the PEC network. More disturbingly, there is no evolutionary conservation among yeast, fly, and nematode modules at either the whole-module or protein-pair level. Neither is there a correlation between the evolutionary or phylogenetic conservation of a protein and the extent of its participation in various modules. Using computer simulation, we demonstrate that a higher-than-expected modularity can arise during network growth through a simple model of gene duplication, without natural selection for modularity. Taken together, our results suggest the intriguing possibility that the structural modules in the PPI network originated as an evolutionary byproduct without biological significance.     

Modularity in the evolution of yeast protein interaction network

Protein interaction networks are known to exhibit remarkable structures: scale-free and small-world and modular structures. To explain the evolutionary processes of protein interaction networks possessing scale-free and small-world structures, preferential attachment and duplication-divergence models have been proposed as mathematical models. Protein interaction networks are also known to exhibit another remarkable structural characteristic, modular structure. How the protein interaction networks became to exhibit modularity in their evolution? Here, we propose a hypothesis of modularity in the evolution of yeast protein interaction network based on molecular evolutionary evidence. We assigned yeast proteins into six evolutionary ages by constructing a phylogenetic profile. We found that all the almost half of hub proteins are evolutionarily new. Examining the evolutionary processes of protein complexes, functional modules and topological modules, we also found that member proteins of these modules tend to appear in one or two evolutionary ages. Moreover, proteins in protein complexes and topological modules show significantly low evolutionary rates than those not in these modules. Our results suggest a hypothesis of modularity in the evolution of yeast protein interaction network as systems evolution.     

A fast layout algorithm for protein interaction networks

MOTIVATION: Graph drawing algorithms are often used for visualizing relational information, but a naive implementation of a graph drawing algorithm encounters real difficulties when drawing large-scale graphs such as protein interaction networks. RESULTS: We have developed a new, extremely fast layout algorithm for visualizing large-scale protein interaction networks in the three-dimensional space. The algorithm (1) first finds a layout of connected components of an entire network, (2) finds a global layout of nodes with respect to pivot nodes within a connected component and (3) refines the local layout of each connected component by first relocating midnodes with respect to their cutvertices and direct neighbors of the cutvertices and then by relocating all nodes with respect to their neighbors within distance 2. Advantages of this algorithm over classical graph drawing methods include: (1) it is an order of magnitude faster, (2) it can directly visualize data from protein interaction databases and (3) it provides several abstraction and comparison operations for effectively analyzing large-scale protein interaction networks. AVAILABILITY: http://wilab.inha.ac.kr/interviewer/     

Phase transitions in the neuropercolation model of neural populations with mixed local and non-local interactions

We model the dynamical behavior of the neuropil, the densely interconnected neural tissue in the cortex, using neuropercolation approach. Neuropercolation generalizes phase transitions modeled by percolation theory of random graphs, motivated by properties of neurons and neural populations. The generalization includes (1) a noisy component in the percolation rule, (2) a novel depression function in addition to the usual arousal function, (3) non-local interactions among nodes arranged on a multi-dimensional lattice. This paper investigates the role of non-local (axonal) connections in generating and modulating phase transitions of collective activity in the neuropil. We derived a relationship between critical values of the noise level and non-locality parameter to control the onset of phase transitions. Finally, we propose a potential interpretation of ontogenetic development of the neuropil maintaining a dynamical state at the edge of criticality.     

Peeling the yeast protein network

A set of highly connected proteins (or hubs) plays an important role for the integrity of the protein interaction network of Saccharomyces cerevisae by connecting the network's intrinsic modules. The importance of the hubs' central placement is further confirmed by their propensity to be lethal. However, although highly emphasized, little is known about the topological coherence among the hubs. Applying a core decomposition method which allows us to identify the inherent layer structure of the protein interaction network, we find that the probability of nodes both being essential and evolutionary conserved successively increases toward the innermost cores. While connectivity alone is often not a sufficient criterion to assess a protein's functional, evolutionary and topological relevance, we classify nodes as globally and locally central depending on their appearance in the inner or outer cores. The observation that globally central proteins participate in a substantial number of protein complexes which display an elevated degree of evolutionary conservation allows us to hypothesize that globally central proteins serve as the evolutionary backbone of the proteome. Even though protein interaction data are extensively flawed, we find that our results are very robust against inaccurately determined protein interactions.     

BinTree seeking: a novel approach to mine both bi-sparse and cohesive modules in protein interaction networks

Modern science of networks has brought significant advances to our understanding of complex systems biology. As a representative model of systems biology, Protein Interaction Networks (PINs) are characterized by a remarkable modular structures, reflecting functional associations between their components. Many methods were proposed to capture cohesive modules so that there is a higher density of edges within modules than those across them. Recent studies reveal that cohesively interacting modules of proteins is not a universal organizing principle in PINs, which has opened up new avenues for revisiting functional modules in PINs. In this paper, functional clusters in PINs are found to be able to form unorthodox structures defined as bi-sparse module. In contrast to the traditional cohesive module, the nodes in the bi-sparse module are sparsely connected internally and densely connected with other bi-sparse or cohesive modules. We present a novel protocol called the BinTree Seeking (BTS) for mining both bi-sparse and cohesive modules in PINs based on Edge Density of Module (EDM) and matrix theory. BTS detects modules by depicting links and nodes rather than nodes alone and its derivation procedure is totally performed on adjacency matrix of networks. The number of modules in a PIN can be automatically determined in the proposed BTS approach. BTS is tested on three real PINs and the results demonstrate that functional modules in PINs are not dominantly cohesive but can be sparse. BTS software and the supporting information are available at: www.csbio.sjtu.edu.cn/bioinf/BTS/.     

Clustering by common friends finds locally significant proteins mediating modules

MOTIVATION: Much research has been dedicated to large-scale protein interaction networks including the analysis of scale-free topologies, network modules and the relation of domain-domain to protein-protein interaction networks. Identifying locally significant proteins that mediate the function of modules is still an open problem. Method: We use a layered clustering algorithm for interaction networks, which groups proteins by the similarity of their direct neighborhoods. We identify locally significant proteins, called mediators, which link different clusters. We apply the algorithm to a yeast network. RESULTS: Clusters and mediators are organized in hierarchies, where clusters are mediated by and act as mediators for other clusters. We compare the clusters and mediators to known yeast complexes and find agreement with precision of 71% and recall of 61%. We analyzed the functions, processes and locations of mediators and clusters. We found that 55% of mediators to a cluster are enriched with a set of diverse processes and locations, often related to translocation of biomolecules. Additionally, 82% of clusters are enriched with one or more functions. The important role of mediators is further corroborated by a comparatively higher degree of conservation across genomes. We illustrate the above findings with an example of membrane protein translocation from the cytoplasm to the inner nuclear membrane. AVAILABILITY: All software is freely available under Supplementary information.