title: Structural basis for DNA recognition by FoxO1 and its regulation by posttranslational modification.
abstract: FoxO transcription factors regulate the transcription of genes that control metabolism, cellular proliferation, stress tolerance, and possibly life span. A number of posttranslational modifications within the forkhead DNA-binding domain regulate FoxO-mediated transcription. We describe the crystal structures of FoxO1 bound to three different DNA elements and measure the change in FoxO1-DNA affinity with acetylation and phosphorylation. The structures reveal additional contacts and increased DNA distortion for the highest affinity DNA site. The flexible wing 2 region of the forkhead domain was not observed in the structures but is necessary for DNA binding, and we show that p300 acetylation in wing 2 reduces DNA affinity. We also show that MST1 phosphorylation of FoxO1 prevents high-affinity DNA binding. The observation that FoxO-DNA affinity varies between response elements and with posttranslational modifications suggests that modulation of FoxO-DNA affinity is an important component of FoxO regulation in health and misregulation in disease.
authors.affiliation: The Wistar Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; The Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Brent
authors.forename: Ruchi
authors.initials: R
authors.lastname: Anand
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D004247:DNA / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017433:Protein Structure, Secondary / Q000502:physiology; D017434:Protein Structure, Tertiary; D020218:Response Elements; D017386:Sequence Homology, Amino Acid; D000099317:Hippo Kinases
chemical_list: D004247:DNA; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; C085126:FOXO1 protein, human; C095566:STK4 protein, human; D000099317:Hippo Kinases
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