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Structure. 2008 Sep 10;16(9):1407-16. doi: 10.1016/j.str.2008.06.013.

Structural basis for DNA recognition by FoxO1 and its regulation by posttranslational modification.

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The Wistar Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; The Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.


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.

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