STRING 8--a global view on proteins and their functional interactions in 630 organisms

Abstract

Functional partnerships between proteins are at the core of complex cellular phenotypes, and the networks formed by interacting proteins provide researchers with crucial scaffolds for modeling, data reduction and annotation. STRING is a database and web resource dedicated to protein-protein interactions, including both physical and functional interactions. It weights and integrates information from numerous sources, including experimental repositories, computational prediction methods and public text collections, thus acting as a meta-database that maps all interaction evidence onto a common set of genomes and proteins. The most important new developments in STRING 8 over previous releases include a URL-based programming interface, which can be used to query STRING from other resources, improved interaction prediction via genomic neighborhood in prokaryotes, and the inclusion of protein structures. Version 8.0 of STRING covers about 2.5 million proteins from 630 organisms, providing the most comprehensive view on protein-protein interactions currently available. STRING can be reached at http://string-db.org/.

Figure 1.

Protein association network in STRING. An example of the network view in STRING, centered on the query protein ‘hisB’ from Escherichia coli. The inset shows the annotations and options that are available for each protein, including references to other databases. Three ‘functional modules’ can readily be seen in the network, forming tightly connected clusters. These encompass histidine biosynthesis, branched-chain amino acid biosynthesis, and—less strongly connected—a part of fatty acid biosynthesis. Line color indicates the type of the supporting evidence; all underlying evidence can be inspected in dedicated viewers that are accessible from the network.

Figure 2.

Extended definition of genomic neighborhood. (A) Illustration of a conserved gene neighborhood, containing genes related to the biosynthesis and consumption of tryptophan (simplified from a STRING screenshot). Genes connected by lines are direct neighbors on the chromosome, and genes with similar colors are orthologs across the various organisms. The arrow marks a switch in gene orientation, leading to a head-to-head orientation of two presumptive operons. (B) Divergently oriented genes predict functional linkage in prokaryotes. Each dot summarizes a group (bin) of gene pairs with similar intergenic distances. The fraction of such pairs where both genes are annotated in the same KEGG pathway is indicated, implying functional partnership. Note that divergent gene pairs are slightly shifted towards larger intergenic distances, presumably to accommodate promoters and regulatory sequences.

Figure 3.

The new Application Programming Interface, and how it connects to Cytoscape. Specific items of interest can be retrieved from STRING by constructing URLs accordingly (see Table). Unless STRING's internal identifiers are known, an initial call with the ‘resolve’-request is recommended, to map query items to nodes in the STRING network. TSV, tab-separated values; JSON, JavaScript Object Notation; PSI-MI 2.5, Proteomics Standards Initiative Molecular Interaction (XML and tab-delimited format). *Requests ending on ‘List’ accept more than one input item, but are otherwise identical (multiple query items must be separated by URL-encoded ‘new-line’ characters).