Biochemical and Structural Characterization of an Intramolecular Interaction in FOXO3a and Its Binding with p53

FOXOs and Sirtuins in Vascular Growth, Maintenance, and Aging

“…FOXO3 can bind to p53 and promote p53 stabilization and activation. 103,104,105 p53, in turn, can inhibit FOXO3 transcriptional activity in conditions of oxidative stress and prompt FOXO3 degradation. 106,107 Together, these considerations suggest that FOXO3 is part of a transcriptional network that has pivotal roles during aging.…”

FOXO factors and breast cancer: outfoxing endocrine resistance

“…FOXOs participate in several known transcriptional complexes, such as: i) ER (Schuur et al 2001, Zhao et al 2001; ii) p53 (Wang et al 2008); and iii) CREB binding protein (CBP)/p300. In the case of CBP/p300, the phospho-Thr32/Ser253-isoform has been shown to have lost the ability to physically associate with these transcriptional co-activator proteins (Wang et al , 2012a, and thus, this modification negates the transcriptionally favorable chromatin remodeling that this protein association generally promotes.…”

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

“…As much as 75% of the sequence is predicted to comprise IDRs, thus FOXO3a is considered to be an intrinsically disordered protein (IDP). [41][42][43][44] Because IDRs do not form a rigid structure, IDPs are remarkably versatile and many can form distinct interactions with other proteins in response to different cellular signals. The IDRs of FOXO3a execute many important functions, such as signal integration and mediating protein-protein interactions.…”

“…50 Much effort has focused on determining structures of FH domain, and many solution and X-ray structures of the FH domains of FOXO proteins alone or in complex with DNA have been determined. 41,[51][52][53][54] The FH domain of FOXO3a possesses 3 stacking major a-helices (H1-H3), an antiparallel b-sheet comprising 3 b-strands, and 2 large unstructured wings (W1, W2). The 5-residue insertion partially overlaps a short fourth helix H4, which is poorly defined in the solution structure, with boundaries that vary among different conformers (Fig.…”

“…2). 41 The FOXO3a FH domain binds the double-stranded FRE DNA motif through extensive contacts involving the perpendicular insertion of helix H3 into the major groove, as well as interactions with the C-terminal region, which forms a coil structure. In addition, Wing 1 interacts with the phosphate backbone of the DNA.…”