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Review
. 2019 Sep 27;20(5):1754-1768.
doi: 10.1093/bib/bby047.

Exploring the functional impact of alternative splicing on human protein isoforms using available annotation sources

Dinanath Sulakhe  1   2 , Mark D'Souza  1 , Sheng Wang  1   3 , Sandhya Balasubramanian  1   4 , Prashanth Athri  5 , Bingqing Xie  1   6 , Stefan Canzar  3   7 , Gady Agam  6 , T Conrad Gilliam  1   2 , Natalia Maltsev  1   2
Affiliations
Review

Exploring the functional impact of alternative splicing on human protein isoforms using available annotation sources

Dinanath Sulakhe et al. Brief Bioinform. .

Abstract

In recent years, the emphasis of scientific inquiry has shifted from whole-genome analyses to an understanding of cellular responses specific to tissue, developmental stage or environmental conditions. One of the central mechanisms underlying the diversity and adaptability of the contextual responses is alternative splicing (AS). It enables a single gene to encode multiple isoforms with distinct biological functions. However, to date, the functions of the vast majority of differentially spliced protein isoforms are not known. Integration of genomic, proteomic, functional, phenotypic and contextual information is essential for supporting isoform-based modeling and analysis. Such integrative proteogenomics approaches promise to provide insights into the functions of the alternatively spliced protein isoforms and provide high-confidence hypotheses to be validated experimentally. This manuscript provides a survey of the public databases supporting isoform-based biology. It also presents an overview of the potential global impact of AS on the human canonical gene functions, molecular interactions and cellular pathways.

Keywords: alternative splicing; context-specific; interaction; isoform; pathway; protein function.

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Figures

Figure 1.
Figure 1.
(A) Five major patterns of AS; (B) the core splicing signals required for the recognition of the intron–exon boundaries and the accurate removal of introns by the splicing machinery [8]: 5′ splice donor, 3′ splice acceptor, branchpoint and polypyrimidine tract; (C) The splicing regulatory elements (SREs) represented by cis-acting sequence motifs in exons or introns recognized by trans-acting splice factor proteins [9]. SREs are classified as exonic splice enhancers, exonic splice silencers, intronic splice enhancers and intronic splice silencers. The trans-acting splicing factors include (a) splice enhancing SR-proteins that bind splice enhancers to promote exon inclusion and (b) splice silencing proteins such as heterogeneous nuclear ribonucleoproteins (hnRNPs) that bind splicing silencers and inhibit exon recognition.
Figure 2.
Figure 2.
Functional impact of AS of protein isoforms. (A) Splicing events lead to the loss or modification of functional domains and sites (e.g. DNA-binding sites, active sites of enzymes, etc.) and consequently to the modification of function in comparison with the canonical isoform. (B) AS affects protein interactions with substrates and other proteins because of the use of alternative SLIMs and binding interfaces. (C) Changes in the protein functions (A) and protein interactions (B) lead to the rewiring of the molecular networks.
Figure 3.
Figure 3.
Comparison of the complete human proteomes from UniProt, Ensembl and RefSeq that include isoform information. Internal redundancy was removed before the comparison between the databases was performed, and only identical sequences were reported for the overlaps between the databases. This Venn diagram was drawn using InteractiVenn [82].
Figure 4.
Figure 4.
Loss or modifications of the sequence features in the human alternatively spliced isoforms in comparison with the canonical isoforms involved in different biological processes. Total 100% represents all features under consideration that were lost because of AS in a particular functional category. The table contains the absolute numbers of the lost features for each functional category.
Figure 5.
Figure 5.
Modification of sequence features in canonical enzymatic sequences because of AS. Total 100% represents the total number of features under consideration lost because of AS in a particular class of the enzymes. The table contains the absolute numbers of the lost features for each enzyme class.
Figure 6.
Figure 6.
The effect of AS on protein–protein, protein–peptide, protein–ligand and protein–ion interactions.
Figure 7.
Figure 7.
Loss of sequence features by AS isoforms involved in cellular pathways. (100% represents all features lost because of AS in all genes associated with the pathway).
Figure 8.
Figure 8.
Glycolytic pathway. The enzymes subjected to AS are labeled with ‘AS’. The table on the left represents the numbers of AS isoforms for every glycolytic gene (according to the UniProt data). A number of alternatively spliced glycolytic isoforms were confirmed by proteomics studies. These include glycolytic genes involved in the formation of the 6-phosphofructokinase complex (PFKM, PFKL and PFKP), liver and muscle glucokinase (PKLR, PKM), hexokinases 1 and 4 (GCK, HK1), glycogen synthase (GYS1) and liver and muscle glycogen phosphorylases PYGM and PYGL [128].
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