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Evolutionary pressure on the topology of protein interface interaction networks.

ABSTRACT: The densely connected structure of protein-protein interaction (PPI) networks reflects the functional need of proteins to cooperate in cellular processes. However, PPI networks do not adequately capture the competition in protein binding. By contrast, the interface interaction network (IIN) studied here resolves the modular character of protein-protein binding and distinguishes between simultaneous and exclusive interactions that underlie both cooperation and competition. We show that the topology of the IIN is under evolutionary pressure, and we connect topological features of the IIN to specific biological functions. To reveal the forces shaping the network topology, we use a sequence-based computational model of interface binding along with network analysis. We find that the more fragmented structure of IINs, in contrast to the dense PPI networks, arises in large part from the competition between specific and nonspecific binding. The need to minimize nonspecific binding favors specific network motifs, including a minimal number of cliques (i.e., fully connected subgraphs) and many disconnected fragments. Validating the model, we find that these network characteristics are closely mirrored in the IIN of clathrin-mediated endocytosis. Features unexpected on the basis of our motif analysis are found to indicate either exceptional binding selectivity or important regulatory functions.

SUBMITTER: Johnson ME

PROVIDER: S-EPMC3808520 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Evolutionary pressure on the topology of protein interface interaction networks.

Johnson Margaret E ME Hummer Gerhard G

The journal of physical chemistry. B 20130614 42

The densely connected structure of protein-protein interaction (PPI) networks reflects the functional need of proteins to cooperate in cellular processes. However, PPI networks do not adequately capture the competition in protein binding. By contrast, the interface interaction network (IIN) studied here resolves the modular character of protein-protein binding and distinguishes between simultaneous and exclusive interactions that underlie both cooperation and competition. We show that the topolo ...[more]

PMID: 23701316

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Project description:Proteins involved in interactions throughout the course of evolution tend to co-evolve and compensatory changes may occur in interacting proteins to maintain or refine such interactions. However, certain residue pair alterations may prove to be detrimental for functional interactions. Hence, determining co-evolutionary pairings that could be structurally or functionally relevant for maintaining the conservation of an inter-protein interaction is important. Inter-protein co-evolution analysis in several complexes utilizing multiple existing methodologies suggested that co-evolutionary pairings can occur in spatially proximal and distant regions in inter-protein interactions. Subsequently, the Co-Var (Correlated Variation) method based on mutual information and Bhattacharyya coefficient was developed, validated, and found to perform relatively better than CAPS and EV-complex. Interestingly, while applying the Co-Var measure and EV-complex program on a set of protein-protein interaction complexes, co-evolutionary pairings were obtained in interface and non-interface regions in protein complexes. The Co-Var approach involves determining high degree co-evolutionary pairings that include multiple co-evolutionary connections between particular co-evolved residue positions in one protein with multiple residue positions in the binding partner. Detailed analyses of high degree co-evolutionary pairings in protein-protein complexes involved in cancer metastasis suggested that most of the residue positions forming such co-evolutionary connections mainly occurred within functional domains of constituent proteins and substitution mutations were also common among these positions. The physiological relevance of these predictions suggested that Co-Var can predict residues that could be crucial for preserving functional protein-protein interactions. Finally, Co-Var web server (http://www.hpppi.iicb.res.in/ishi/covar/index.html) that implements this methodology identifies co-evolutionary pairings in intra and inter-protein interactions.

Dataset Information

Evolutionary pressure on the topology of protein interface interaction networks.

Publications

Evolutionary pressure on the topology of protein interface interaction networks.

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