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Context-specific interactions in literature-curated protein interaction databases.

ABSTRACT: BACKGROUND:Databases of literature-curated protein-protein interactions (PPIs) are often used to interpret high-throughput interactome mapping studies and estimate error rates. These databases combine interactions across thousands of published studies and experimental techniques. Because the tendency for two proteins to interact depends on the local conditions, this heterogeneity of conditions means that only a subset of database PPIs are interacting during any given experiment. A typical use of these databases as gold standards in interactome mapping projects, however, assumes that PPIs included in the database are indeed interacting under the experimental conditions of the study. RESULTS:Using raw data from 20 co-fractionation experiments and six published interactomes, we demonstrate that this assumption is often false, with up to 55% of purported gold standard interactions showing no evidence of interaction, on average. We identify a subset of CORUM database complexes that do show consistent evidence of interaction in co-fractionation studies, and we use this subset as gold standards to dramatically improve interactome mapping as judged by the number of predicted interactions at a given error rate. CONCLUSIONS:We recommend using this CORUM subset as the gold standard set in future co-fractionation studies. More generally, we recommend using the subset of literature-curated PPIs that are specific to the experimental context whenever possible.

SUBMITTER: Stacey RG

PROVIDER: S-EPMC6194712 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Project description:Interactions of proteins regulate signaling, catalysis, gene expression and many other cellular functions. Therefore, characterizing the entire human interactome is a key effort in current proteomics research. This challenge is complicated by the dynamic nature of protein-protein interactions (PPIs), which are conditional on the cellular context: both interacting proteins must be expressed in the same cell and localized in the same organelle to meet. Additionally, interactions underlie a delicate control of signaling pathways, e.g. by post-translational modifications of the protein partners - hence, many diseases are caused by the perturbation of these mechanisms. Despite the high degree of cell-state specificity of PPIs, many interactions are measured under artificial conditions (e.g. yeast cells are transfected with human genes in yeast two-hybrid assays) or even if detected in a physiological context, this information is missing from the common PPI databases. To overcome these problems, we developed a method that assigns context information to PPIs inferred from various attributes of the interacting proteins: gene expression, functional and disease annotations, and inferred pathways. We demonstrate that context consistency correlates with the experimental reliability of PPIs, which allows us to generate high-confidence tissue- and function-specific subnetworks. We illustrate how these context-filtered networks are enriched in bona fide pathways and disease proteins to prove the ability of context-filters to highlight meaningful interactions with respect to various biological questions. We use this approach to study the lung-specific pathways used by the influenza virus, pointing to IRAK1, BHLHE40 and TOLLIP as potential regulators of influenza virus pathogenicity, and to study the signalling pathways that play a role in Alzheimer's disease, identifying a pathway involving the altered phosphorylation of the Tau protein. Finally, we provide the annotated human PPI network via a web frontend that allows the construction of context-specific networks in several ways.

Project description:BACKGROUND:Understanding living systems is crucial for curing diseases. To achieve this task we have to understand biological networks based on protein-protein interactions. Bioinformatics has come up with a great amount of databases and tools that support analysts in exploring protein-protein interactions on an integrated level for knowledge discovery. They provide predictions and correlations, indicate possibilities for future experimental research and fill the gaps to complete the picture of biochemical processes. There are numerous and huge databases of protein-protein interactions used to gain insights into answering some of the many questions of systems biology. Many computational resources integrate interaction data with additional information on molecular background. However, the vast number of diverse Bioinformatics resources poses an obstacle to the goal of understanding. We present a survey of databases that enable the visual analysis of protein networks. RESULTS:We selected M=10 out of N=53 resources supporting visualization, and we tested against the following set of criteria: interoperability, data integration, quantity of possible interactions, data visualization quality and data coverage. The study reveals differences in usability, visualization features and quality as well as the quantity of interactions. StringDB is the recommended first choice. CPDB presents a comprehensive dataset and IntAct lets the user change the network layout. A comprehensive comparison table is available via web. The supplementary table can be accessed on http://tinyurl.com/PPI-DB-Comparison-2015. CONCLUSIONS:Only some web resources featuring graph visualization can be successfully applied to interactive visual analysis of protein-protein interaction. Study results underline the necessity for further enhancements of visualization integration in biochemical analysis tools. Identified challenges are data comprehensiveness, confidence, interactive feature and visualization maturing.

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Context-specific interactions in literature-curated protein interaction databases.

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