Forkhead followed by disordered tail: The intrinsically disordered regions of FOXO3a.

Forkhead box Class O is one of 19 subfamilies of the Forkhead box family, comprising 4 human transcription factors: FOXO1, FOXO3a, FOXO4, and FOXO6, which are involved in many crucial cellular processes. FOXO3a is a tumor suppressor involved in multiple physiological and pathological processes, and plays essential roles in metabolism, cell cycle arrest, DNA repair, and apoptosis. In its role as a transcription factor, the FOXO3a binds a consensus Forkhead response element DNA sequence, and recruits transcriptional coactivators to activate gene transcription. FOXO3a has additional functions, such as regulating p53-mediated apoptosis and activating kinase ATM. With the exception of the structured DNA-binding forkhead domain, most of the FOXO3a sequence comprises intrinsically disordered regions (IDRs), including 3 regions (CR1-3) that are conserved within the FOXO subfamily. Numerous studies have demonstrated that these IDRs directly mediate many of the diverse functions of FOXO3a. These regions contain post-translational modification and protein-protein interaction sites that integrate upstream signals to maintain homeostasis. Thus, the FOXO3a IDRs are emerging as key mediators of diverse regulatory processes, and represent an important target for the future development of therapeutics for FOXO3a-related diseases.