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bioRxiv · 10.1101/2025.03.05.641708

IsoformMapper: A Web Application for Protein-Level Comparison of Splice Variants through Structural Community Analysis

Vergara, A.·Hernandez-Verdeja, T.·Ojeda-May, P.·Ramirez, L.·Edler, D.·Rosvall, M.·Strand, A.
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Abstract

Alternative splicing (AS) plays a key role in numerous cellular processes by enabling the existence of different protein isoforms with potentially different functions and fine-tuning isoform abundance. However, despite its biological importance, tools to compare the domain composition of AS-derived protein isoforms have lagged as they require both structural data and an appropriate methodology for isoform comparison. Recent advances in AI-driven protein structure prediction, particularly AlphaFold2, have made accurate structural determination of splicing isoforms easily accessible, paving the way for new tools to compare their structures and asses the functional consequences of AS at the protein structure level. Here, we present IsoformMapper, a web resource that enables researchers to study alternative splicing at the protein structural level using protein network community analysis, which captures 3D physical interactions between protein regions often missed by traditional domain analysis, allowing comparisons of isoforms across any biological system. As a proof of concept, we used our tool to a case study, in which we studied how GENOMES UNCOUPLED1 (GUN1) dependent retrograde signaling regulates plant de-etiolation through alternative splicing in Arabidopsis. In response to light, we demonstrate that GUN1 regulates the expression of specific spliceosome components, consequently modifying alternative splicing of key genes encoding components essential for establishing of photosynthesis. Additionally, the gun1 mutant showed altered splice variant ratios for PNSL2, CHAOS, and SIG5. Our tool revealed that these isoforms have significantly different protein community structures, illustrating the impact of AS on protein function and demonstrating the practical value of the tool. (247 words) O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/641708v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@c006dcorg.highwire.dtl.DTLVardef@1025b07org.highwire.dtl.DTLVardef@1a64bf6org.highwire.dtl.DTLVardef@c512af_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO IsoformMapper enables structural comparison of protein isoforms through a multi-step analysis pipeline. Starting with AlphaFold2 protein structure predictions of splice variants, the method generates weighted network representations for each isoform. The web application processes multiple AlphaFold predictions per isoform, with the conformational variability between predictions represented as weighted edges in the network representation. These networks are then analyzed using the InfoMap community detection algorithm to identify structural communities, ultimately allowing visualization and comparison of protein isoform structures through interactive network displays and alluvial diagrams. The method is applicable to protein isoforms from any biological system, providing comprehensive analysis of alternative splicing consequences at the protein level by examining structural domains as integrated units. This holistic approach enables users to evaluate potential functional differences between isoforms based on their structural organization. C_FIG

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Vergara, A., Hernandez-Verdeja, T., Ojeda-May, P., Ramirez, L., Edler, D., Rosvall, M., Strand, A.. 2025-03-10. IsoformMapper: A Web Application for Protein-Level Comparison of Splice Variants through Structural Community Analysis. https://doi.org/10.1101/2025.03.05.641708

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