DIGGER: Exploring the Functional Role of Alternative Splicing in Protein Interactions

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2020 Sep 25

PMID 32976589

Citations 20

Authors

Zakaria Louadi

Kevin Yuan

Alexander Gress

Olga Tsoy

Olga V Kalinina

Jan Baumbach

Tim Kacprowski

Markus List

Affiliations

Soon will be listed here.

Abstract

Alternative splicing plays a major role in regulating the functional repertoire of the proteome. However, isoform-specific effects to protein-protein interactions (PPIs) are usually overlooked, making it impossible to judge the functional role of individual exons on a systems biology level. We overcome this barrier by integrating protein-protein interactions, domain-domain interactions and residue-level interactions information to lift exon expression analysis to a network level. Our user-friendly database DIGGER is available at https://exbio.wzw.tum.de/digger and allows users to seamlessly switch between isoform and exon-centric views of the interactome and to extract sub-networks of relevant isoforms, making it an essential resource for studying mechanistic consequences of alternative splicing.

Citing Articles

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Toward a comprehensive profiling of alternative splicing proteoform structures, interactions and functions.

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Biosurfer for systematic tracking of regulatory mechanisms leading to protein isoform diversity.

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References

El-Gebali S, Mistry J, Bateman A, Eddy S, Luciani A, Potter S . The Pfam protein families database in 2019. Nucleic Acids Res. 2018; 47(D1):D427-D432. PMC: 6324024. DOI: 10.1093/nar/gky995. View

Meyer M, Das J, Wang X, Yu H . INstruct: a database of high-quality 3D structurally resolved protein interactome networks. Bioinformatics. 2013; 29(12):1577-9. PMC: 3673217. DOI: 10.1093/bioinformatics/btt181. View

Emig D, Salomonis N, Baumbach J, Lengauer T, Conklin B, Albrecht M . AltAnalyze and DomainGraph: analyzing and visualizing exon expression data. Nucleic Acids Res. 2010; 38(Web Server issue):W755-62. PMC: 2896198. DOI: 10.1093/nar/gkq405. View

Ellis J, Barrios-Rodiles M, Colak R, Irimia M, Kim T, Calarco J . Tissue-specific alternative splicing remodels protein-protein interaction networks. Mol Cell. 2012; 46(6):884-92. DOI: 10.1016/j.molcel.2012.05.037. View

Sahni N, Yi S, Taipale M, Fuxman Bass J, Coulombe-Huntington J, Yang F . Widespread macromolecular interaction perturbations in human genetic disorders. Cell. 2015; 161(3):647-660. PMC: 4441215. DOI: 10.1016/j.cell.2015.04.013. View

Li B, Dewey C . RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. 2011; 12:323. PMC: 3163565. DOI: 10.1186/1471-2105-12-323. View

Lobo de Figueiredo-Pontes L, Wong D, Tin V, Chung L, Yasuda H, Yamaguchi N . Identification and characterization of ALK kinase splicing isoforms in non-small-cell lung cancer. J Thorac Oncol. 2014; 9(2):248-53. PMC: 4096850. DOI: 10.1097/JTO.0000000000000050. View

Yeo G, Holste D, Kreiman G, Burge C . Variation in alternative splicing across human tissues. Genome Biol. 2004; 5(10):R74. PMC: 545594. DOI: 10.1186/gb-2004-5-10-r74. View

Ghadie M, Lambourne L, Vidal M, Xia Y . Domain-based prediction of the human isoform interactome provides insights into the functional impact of alternative splicing. PLoS Comput Biol. 2017; 13(8):e1005717. PMC: 5591010. DOI: 10.1371/journal.pcbi.1005717. View

10.

Tress M, Abascal F, Valencia A . Alternative Splicing May Not Be the Key to Proteome Complexity. Trends Biochem Sci. 2016; 42(2):98-110. PMC: 6526280. DOI: 10.1016/j.tibs.2016.08.008. View

11.

Yang X, Coulombe-Huntington J, Kang S, Sheynkman G, Hao T, Richardson A . Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell. 2016; 164(4):805-17. PMC: 4882190. DOI: 10.1016/j.cell.2016.01.029. View

12.

Beqqali A . Alternative splicing in cardiomyopathy. Biophys Rev. 2018; 10(4):1061-1071. PMC: 6082314. DOI: 10.1007/s12551-018-0439-y. View

13.

Wang X, Wei X, Thijssen B, Das J, Lipkin S, Yu H . Three-dimensional reconstruction of protein networks provides insight into human genetic disease. Nat Biotechnol. 2012; 30(2):159-64. PMC: 3708476. DOI: 10.1038/nbt.2106. View

14.

Mosca R, Ceol A, Aloy P . Interactome3D: adding structural details to protein networks. Nat Methods. 2013; 10(1):47-53. DOI: 10.1038/nmeth.2289. View

15.

Cunningham F, Achuthan P, Akanni W, Allen J, Amode M, Armean I . Ensembl 2019. Nucleic Acids Res. 2018; 47(D1):D745-D751. PMC: 6323964. DOI: 10.1093/nar/gky1113. View

16.

Barbosa-Morais N, Irimia M, Pan Q, Xiong H, Gueroussov S, Lee L . The evolutionary landscape of alternative splicing in vertebrate species. Science. 2012; 338(6114):1587-93. DOI: 10.1126/science.1230612. View

17.

Sulakhe D, DSouza M, Wang S, Balasubramanian S, Athri P, Xie B . Exploring the functional impact of alternative splicing on human protein isoforms using available annotation sources. Brief Bioinform. 2018; 20(5):1754-1768. PMC: 6917224. DOI: 10.1093/bib/bby047. View

18.

Denley A, Bonython E, Booker G, Cosgrove L, Forbes B, Ward C . Structural determinants for high-affinity binding of insulin-like growth factor II to insulin receptor (IR)-A, the exon 11 minus isoform of the IR. Mol Endocrinol. 2004; 18(10):2502-12. DOI: 10.1210/me.2004-0183. View

19.

Alcaraz N, List M, Dissing-Hansen M, Rehmsmeier M, Tan Q, Mollenhauer J . Robust de novo pathway enrichment with KeyPathwayMiner 5. F1000Res. 2016; 5:1531. PMC: 4965696. DOI: 10.12688/f1000research.9054.1. View

20.

Malakar P, Chartarifsky L, Hija A, Leibowitz G, Glaser B, Dor Y . Insulin receptor alternative splicing is regulated by insulin signaling and modulates beta cell survival. Sci Rep. 2016; 6:31222. PMC: 4985653. DOI: 10.1038/srep31222. View