Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing

• Published in: Cell Vol. 164; no. 4; pp. 805 - 817
• Main Authors: Yang, Xinping, Coulombe-Huntington, Jasmin, Kang, Shuli, Sheynkman, Gloria M., Hao, Tong, Richardson, Aaron, Sun, Song, Yang, Fan, Shen, Yun A., Murray, Ryan R., Spirohn, Kerstin, Begg, Bridget E., Duran-Frigola, Miquel, MacWilliams, Andrew, Pevzner, Samuel J., Zhong, Quan, Wanamaker, Shelly A., Tam, Stanley, Ghamsari, Lila, Sahni, Nidhi, Yi, Song, Rodriguez, Maria D., Balcha, Dawit, Tan, Guihong, Costanzo, Michael, Andrews, Brenda, Boone, Charles, Zhou, Xianghong J., Salehi-Ashtiani, Kourosh, Charloteaux, Benoit, Chen, Alyce A., Calderwood, Michael A., Aloy, Patrick, Roth, Frederick P., Hill, David E., Iakoucheva, Lilia M., Xia, Yu, Vidal, Marc
• Format: Journal Article Web Resource
• Language: English
• Published: United States Elsevier Inc 11.02.2016; Cell Press
• Subjects: Alternative Splicing; Animals; Cloning, Molecular; Evolution, Molecular; functional properties; genes; Genetics & genetic processes; Génétique & processus génétiques; Humans; Life sciences; Models, Molecular; Open Reading Frames; Protein Interaction Domains and Motifs; Protein Interaction Maps; protein isoforms; Protein Isoforms - metabolism; protein-protein interactions; proteins; Proteome - analysis; Proteome - metabolism; Proteome/analysis/metabolism; proteomics; Sciences du vivant
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2016.01.029

While alternative splicing is known to diversify the functional characteristics of some genes, the extent to which protein isoforms globally contribute to functional complexity on a proteomic scale remains unknown. To address this systematically, we cloned full-length open reading frames of alternatively spliced transcripts for a large number of human genes and used protein-protein interaction profiling to functionally compare hundreds of protein isoform pairs. The majority of isoform pairs share less than 50% of their interactions. In the global context of interactome network maps, alternative isoforms tend to behave like distinct proteins rather than minor variants of each other. Interaction partners specific to alternative isoforms tend to be expressed in a highly tissue-specific manner and belong to distinct functional modules. Our strategy, applicable to other functional characteristics, reveals a widespread expansion of protein interaction capabilities through alternative splicing and suggests that many alternative “isoforms” are functionally divergent (i.e., “functional alloforms”). [Display omitted] •Alternative splicing can produce isoforms with vastly different interaction profiles•These differences can be as great as those between proteins encoded by different genes•Isoform-specific partners exhibit distinct expression and functional characteristics Alternatively spliced isoforms of proteins exhibit strikingly different interaction profiles and thus, in the context of global interactome networks, appear to behave as if encoded by distinct genes rather than as minor variants of each other.