Intra molecular interactions in the regulation of p53 pathway
The p53 tumor suppressor is highly regulated at the level of protein degradation and transcriptional activity. The key players of the pathway, p53, MDM2, and MDMX are present at multiple conformational states that are responsive to regulation by post-translational modifications and proteinprotein interactions. The structures of major functional domains of these proteins have been determined, but the mechanisms of several intrinsically disordered regions remain unclear despite their critical roles in signaling and regulation. Recent studies suggest that these disordered regions function in part by dynamic intra molecular interactions with the structured domains to regulate p53 DNA binding, MDM2 ubiquitin E3 ligase activity, and MDMX-p53 binding. These findings provide new insight on how p53 is controlled by various stress signals, and suggest potential targets for the search of allosteric regulators of the p53 pathway.