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Across-proteome modeling of dimer structures for the bottom-up assembly of protein-protein interaction networks.

ABSTRACT: Deciphering complete networks of interactions between proteins is the key to comprehend cellular regulatory mechanisms. A significant effort has been devoted to expanding the coverage of the proteome-wide interaction space at molecular level. Although a growing body of research shows that protein docking can, in principle, be used to predict biologically relevant interactions, the accuracy of the across-proteome identification of interacting partners and the selection of near-native complex structures still need to be improved.In this study, we developed a new method to discover and model protein interactions employing an exhaustive all-to-all docking strategy. This approach integrates molecular modeling, structural bioinformatics, machine learning, and functional annotation filters in order to provide interaction data for the bottom-up assembly of protein interaction networks. Encouragingly, the success rates for dimer modeling is 57.5 and 48.7% when experimental and computer-generated monomer structures are employed, respectively. Further, our protocol correctly identifies 81% of protein-protein interactions at the expense of only 19% false positive rate. As a proof of concept, 61,913 protein-protein interactions were confidently predicted and modeled for the proteome of E. coli. Finally, we validated our method against the human immune disease pathway.Protein docking supported by evolutionary restraints and machine learning can be used to reliably identify and model biologically relevant protein assemblies at the proteome scale. Moreover, the accuracy of the identification of protein-protein interactions is improved by considering only those protein pairs co-localized in the same cellular compartment and involved in the same biological process. The modeling protocol described in this communication can be applied to detect protein-protein interactions in other organisms and pathways as well as to construct dimer structures and estimate the confidence of protein interactions experimentally identified with high-throughput techniques.

SUBMITTER: Maheshwari S

PROVIDER: S-EPMC5427563 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Across-proteome modeling of dimer structures for the bottom-up assembly of protein-protein interaction networks.

Maheshwari Surabhi S Brylinski Michal M

BMC bioinformatics 20170512 1

<h4>Background</h4>Deciphering complete networks of interactions between proteins is the key to comprehend cellular regulatory mechanisms. A significant effort has been devoted to expanding the coverage of the proteome-wide interaction space at molecular level. Although a growing body of research shows that protein docking can, in principle, be used to predict biologically relevant interactions, the accuracy of the across-proteome identification of interacting partners and the selection of near- ...[more]

PMID: 28499419

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Project description:A substantial proportion of protein interactions relies on small domains binding to short peptides in the partner proteins. Many of these interactions are relatively low affinity and transient, and they impact on signal transduction. However, neither the number of potential interactions mediated by each domain nor the degree of promiscuity at a whole proteome level has been investigated. We have used a combination of phage display and SPOT synthesis to discover all the peptides in the yeast proteome that have the potential to bind to eight SH3 domains. We first identified the peptides that match a relaxed consensus, as deduced from peptides selected by phage display experiments. Next, we synthesized all the matching peptides at high density on a cellulose membrane, and we probed them directly with the SH3 domains. The domains that we have studied were grouped by this approach into five classes with partially overlapping specificity. Within the classes, however, the domains display a high promiscuity and bind to a large number of common targets with comparable affinity. We estimate that the yeast proteome contains as few as six peptides that bind to the Abp1 SH3 domain with a dissociation constant lower than 100 microM, while it contains as many as 50-80 peptides with corresponding affinity for the SH3 domain of Yfr024c. All the targets of the Abp1 SH3 domain, identified by this approach, bind to the native protein in vivo, as shown by coimmunoprecipitation experiments. Finally, we demonstrate that this strategy can be extended to the analysis of the entire human proteome. We have developed an approach, named WISE (whole interactome scanning experiment), that permits rapid and reliable identification of the partners of any peptide recognition module by peptide scanning of a proteome. Since the SPOT synthesis approach is semiquantitative and provides an approximation of the dissociation constants of the several thousands of interactions that are simultaneously analyzed in an array format, the likelihood of each interaction occurring in any given physiological settings can be evaluated. WISE can be easily extended to a variety of protein interaction domains, including those binding to modified peptides, thereby offering a powerful proteomic tool to help completing a full description of the cell interactome.

Dataset Information

Across-proteome modeling of dimer structures for the bottom-up assembly of protein-protein interaction networks.

Publications

Across-proteome modeling of dimer structures for the bottom-up assembly of protein-protein interaction networks.

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