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PLoS Comput Biol. 2017 Aug 28;13(8):e1005717. doi: 10.1371/journal.pcbi.1005717. eCollection 2017 Aug.

Domain-based prediction of the human isoform interactome provides insights into the functional impact of alternative splicing.

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Department of Bioengineering, McGill University, Montreal, Québec, Canada.
Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.


Alternative splicing is known to remodel protein-protein interaction networks ("interactomes"), yet large-scale determination of isoform-specific interactions remains challenging. We present a domain-based method to predict the isoform interactome from the reference interactome. First, we construct the domain-resolved reference interactome by mapping known domain-domain interactions onto experimentally-determined interactions between reference proteins. Then, we construct the isoform interactome by predicting that an isoform loses an interaction if it loses the domain mediating the interaction. Our prediction framework is of high-quality when assessed by experimental data. The predicted human isoform interactome reveals extensive network remodeling by alternative splicing. Protein pairs interacting with different isoforms of the same gene tend to be more divergent in biological function, tissue expression, and disease phenotype than protein pairs interacting with the same isoforms. Our prediction method complements experimental efforts, and demonstrates that integrating structural domain information with interactomes provides insights into the functional impact of alternative splicing.

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