Tissue-Specific Alternative Splicing Remodels Protein-Protein Interaction Networks

Alternative splicing plays a key role in the expansion of proteomic and regulatory complexity, yet the functions of the vast majority of differentially spliced exons are not known. In this study, we observe that brain and other tissue-regulated exons are significantly enriched in flexible regions of proteins that likely form conserved interaction surfaces. These proteins participate in significantly more interactions in protein-protein interaction (PPI) networks than other proteins. Using LUMIER, an automated PPI assay, we observe that approximately one-third of analyzed neural-regulated exons affect PPIs. Inclusion of these exons stimulated and repressed different partner interactions at comparable frequencies. This assay further revealed functions of individual exons, including a role for a neural-specific exon in promoting an interaction between Bridging Integrator 1 (Bin1)/Amphiphysin II and Dynamin 2 (Dnm2) that facilitates endocytosis. Collectively, our results provide evidence that regulated alternative exons frequently remodel interactions to establish tissue-dependent PPI networks. ⺠Proteins containing tissue-regulated exons have high centrality in PPI networks ⺠Tissue-regulated exons are highly enriched in protein regions that mediate PPIs ⺠LUMIER reveals that one-third of analyzed neural-specific exons modulate PPIs ⺠Exon-resolution functional mapping reveals specific roles for neural AS events