Linear motifs: lost in (pre)translation

Pretranslational modification by alternative splicing, alternative promoter usage and RNA editing enables the production of multiple protein isoforms from a single gene. A large quantity of data now supports the notion that short linear motifs (SLiMs), which are protein interaction modules enriched within intrinsically disordered regions, are key for the functional diversification of these isoforms. The inclusion or removal of these SLiMs can switch the subcellular localisation of an isoform, promote cooperative associations, refine the affinity of an interaction, coordinate phase transitions within the cell, and even create isoforms of opposing function. This article discusses the novel functionality enabled by the addition or removal of SLiM-containing exons by pretranslational modifications, such as alternative splicing and alternative promoter usage, and how these alterations enable the creation and modulation of complex regulatory and signalling pathways.