Alternative splicing fine-tunes modular protein interfaces to control protein localization
Year: 2026
Type: article
Abstract: Alternative splicing provides a pervasive means to expand proteome complexity, yet how it reorganizes protein interactions and cellular localization remains unclear. Here, we show that tissue-regulated longer exons preferably reshape local interaction patterns, whereas microexons fine-tune key interfaces linking distinct cellular processes. Integration of subcellular localization data further indicates that such rewiring can redistribute proteins within cells. By using a high-content imaging approach to systematically evaluate the influence of individual exons on protein localization, we show that 38% of the tested isoform pairs alter localization, with microexons, albeit typically shorter than five amino acids, accounting for a substantial proportion of these effects. Bioinformatic and structural analyses demonstrate that microexons can extend secondary structural regions and reposition charged residues, suggesting a potential to modulate local electrostatic environments. Consistent with this, biochemical analysis of a 4-aa microexon in sorting nexin 2, identified in our screen, confirms that residue insertion rather than side-chain chemistry drives key differences in protein localization through repositioning of a flanking, charged residue. Together, these findings suggest that tissue-regulated alternative splicing fine-tunes interface architecture, thus regulating protein assembly, localization and proteome organization.
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
OpenAlex ID: W7221754660