Systematic analysis of the effects of splicing on the diversity of post-translational modifications in protein...

Post-translational modifications (PTMs) and splicing are both important regulatory processes controlling protein function; therefore, we developed PTM-POSE (PTM projection onto splice events) to explore the interplay between them. PTM-POSE identifies potential PTM sites associated with alternative isoforms or splice events, enabling comprehensive analysis of how PTMs affect isoform function, protein interactions, and enzymatic regulation. Through systematic analysis of Ensembl transcripts with PTM-POSE, we highlighted two key mechanisms by which splicing diversifies PTMs across isoforms-exclusion of a PTM site (32%) or alteration of the flanking sequences surrounding the PTM (2%). In experiment-specific analysis of PTM-associated splicing events, we identified the potential rewiring of protein-interaction and kinase-substrate networks, suggesting coordinated connections between PTM signaling. We provide our tool and associated data publicly to enable further exploration of splicing-PTM relationships. A record of this paper's transparent peer review process is included in the supplemental information.