Research Article: Novel Protein-Protein Interactions Inferred from Literature Context

Date Published: November 18, 2009

Publisher: Public Library of Science

Author(s): Herman H. H. B. M. van Haagen, Peter A. C. ‘t Hoen, Alessandro Botelho Bovo, Antoine de Morrée, Erik M. van Mulligen, Christine Chichester, Jan A. Kors, Johan T. den Dunnen, Gert-Jan B. van Ommen, Silvère M. van der Maarel, Vinícius Medina Kern, Barend Mons, Martijn J. Schuemie, Alan Ruttenberg.

Abstract: We have developed a method that predicts Protein-Protein Interactions (PPIs) based on the similarity of the context in which proteins appear in literature. This method outperforms previously developed PPI prediction algorithms that rely on the conjunction of two protein names in MEDLINE abstracts. We show significant increases in coverage (76% versus 32%) and sensitivity (66% versus 41% at a specificity of 95%) for the prediction of PPIs currently archived in 6 PPI databases. A retrospective analysis shows that PPIs can efficiently be predicted before they enter PPI databases and before their interaction is explicitly described in the literature. The practical value of the method for discovery of novel PPIs is illustrated by the experimental confirmation of the inferred physical interaction between CAPN3 and PARVB, which was based on frequent co-occurrence of both proteins with concepts like Z-disc, dysferlin, and alpha-actinin. The relationships between proteins predicted by our method are broader than PPIs, and include proteins in the same complex or pathway. Dependent on the type of relationships deemed useful, the precision of our method can be as high as 90%. The full set of predicted interactions is available in a downloadable matrix and through the webtool Nermal, which lists the most likely interaction partners for a given protein. Our framework can be used for prioritizing potential interaction partners, hitherto undiscovered, for follow-up studies and to aid the generation of accurate protein interaction maps.

Partial Text: Protein-protein interactions (PPIs), which we define as proteins that physically interact, are crucial in most complex biological processes. Experimental high-throughput methods such as yeast two-hybrid screens have been used to make large inventories of PPIs and to create protein interaction maps [1]–[6]. However, it is well known that these methods merely show physical interaction under experimental condition and not necessarily indicate a common involvement in a biological process. Computational methods for the prediction of PPIs could theoretically aid the discovery of candidate biological interaction partners. There are many different sources of information that can be used in PPI prediction [7], including protein structures, phylogenetic distribution, interactions between homologous proteins in other organisms, genomic neighborhood, and gene fusions. In this article, we will focus on one source of information, which is arguably the most comprehensive, but also the least structured: biomedical literature itself. Until now text mining techniques are mainly used to rediscover PPIs explicitly described in literature. Often, the now 18 million freely available abstract records of MEDLINE are used for this purpose. PPIs extracted this way have been shown to improve the accuracy of predicted biological networks [8], [9]. Structured information on explicit PPIs extracted from MEDLINE and other sources is freely available in the STRING database [10], or can be found by querying the iHOP website [11].

Scientists in general and scientific annotators in particular derive their knowledge on PPIs not directly discovered by their own experiments from the literature. However, as we show here, only 32% of the known PPIs covered by curated PPI databases can be found in MEDLINE abstracts (Table S1), the resource that is most commonly used for concept searches in the biomedical domain. This is despite the use of a sophisticated synonym expansion and homonym disambiguation systems. It is likely that many of these interactions are only mentioned in the full text of articles, or that the interactions have never been explicitly described in literature but were directly submitted to a database. In either case, the applicability of the most commonly used approach for PPI detection – the direct relation method in publicly available literature – appears to be severely limited.



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