2k86 | pdb_00002k86
Solution Structure of FOXO3a Forkhead domain
Structural highlights
Disease[FOXO3_HUMAN] Note=A chromosomal aberration involving FOXO3 is found in secondary acute leukemias. Translocation t(6;11)(q21;q23) with MLL/HRX. Function[FOXO3_HUMAN] Transcriptional activator which triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress. Recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3'. Participates in post-transcriptional regulation of MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation.[1] [2] [3] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedFOXO3a, a forkhead transcription factor and member of the forkhead box class O (FOXO) subfamily, has been shown to promote the translocation of p53 to the cytoplasm, thereby inducing the mitochondria-associated apoptotic pathway. However, the binding sites that mediate this interaction between FOXO3a and p53 have not been identified. Here, we show that two regions within FOXO3a, the forkhead (FH) DNA binding domain and a conserved C-terminal transactivation domain (CR3), interact with the DNA binding domain of p53, with affinities in the low millimolar range and low micromolar range, respectively. Our data further suggest that within the FOXO3a molecule, the FH and CR3 domains engage in an intramolecular interaction with low micromolar affinity. Moreover, we used NMR to determine the solution structure of the FH domain. This enabled us to map the binding site for the CR3, which overlaps with the DNA binding site. We demonstrate that an intrinsically disordered linker between the FH and CR3 domains is required for full p53 binding activity. We also show that p53 disrupts the intramolecular interaction between FH and CR3. These results provide evidence for interplay of the FH and CR3 domains in association with p53. Biochemical and structural characterization of an intramolecular interaction in FOXO3a and its binding with p53.,Wang F, Marshall CB, Yamamoto K, Li GY, Plevin MJ, You H, Mak TW, Ikura M J Mol Biol. 2008 Dec 19;384(3):590-603. Epub 2008 Sep 18. PMID:18824006[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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