The tumor suppressor protein p53 functions as the guardian of the genome, directing cellular responses to DNA damage through transcriptional regulation of DNA repair and apoptosis pathways. Alternative splicing of the p53 mRNA generates twelve major isoforms, which share the ordered DNA-binding domain but differ in the lengths of the intrinsically disordered N- and C-terminal regulatory regions. These termini serve as key sites for post-translational modifications and protein-protein interactions that modulate activity. However, the structural and dynamic consequences of truncations within these regions remain poorly understood. In this study, we investigate how naturally occurring splice variants with shortened regulatory domains affect conformational dynamics and long-range communication within p53 and selected cancer-associated mutants. Using molecular dynamics simulations and network-based analyses, we explore how changes in the disordered N- and C-terminal domains may influence allosteric coupling to the DNA-binding core, thereby modulating activity. Our study aims to characterize the structural phenomena underlying splice-induced regulatory changes and to identify general principles by which splicing modulate intrinsic dynamics. These results contribute to understanding how structural diversity arising from alternative splicing shapes the function of multi-domain, intrinsically disordered proteins. We also discuss how insights from this work may inform future efforts to design isoform-targeted modulators that restore wild-type behavior in cancer-associated p53 mutants.
Kelly M. Thayer (Sun,) studied this question.