The structure-function paradigm reshaped by intrinsically disordered regions

The classic structure-function paradigm has long been considered a cornerstone of protein biology, as it posits that the specific functionality of a protein is determined by its unique three-dimensional (3D) structure. However, the recognition of intrinsically disordered region (IDR) challenges the notion that a well-defined structure is necessary for protein function and has redefined the traditional structure-function relationship. In this thesis, we first depicted the interaction profiling between transcription factor FOXO4 with co-factor β-catenin, facilitated by the FOXO’s IDR, which highlights the role of IDR as a signaling hub. IDR can also direct biomolecular condensates which play a prominent role in biology. Leveraging the interaction profiling between FOXO4 and β-catenin, a FOXO4-derived short peptide was designed to inhibit IDR-mediated β-catenin condensation. Furthermore, we propose a "monomer saturation" model to elucidate the mechanism through which co-factor derived peptides can perturb condensates, which can be helpful for the potential drug discovery. Lastly, we demonstrate another function of IDRs in regulating the mobility of FOXO proteins within the nucleus, which might contribute to the isoform specificity of FOXO proteins. Future work is required to fully comprehend this intriguing observation mediated by IDRs. Finally, the functional versatility of IDRs highlights the significance of IDRs in biological processes, which reshape the classic structure-function paradigm.