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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Catalytic Domain
  • DNA / metabolism*
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / chemistry*
  • Forkhead Transcription Factors / metabolism*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Nucleic Acid Conformation
  • Phosphorylation
  • Protein Binding
  • Protein Processing, Post-Translational / physiology*
  • Protein Structure, Secondary / physiology
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / metabolism
  • Response Elements
  • Sequence Homology, Amino Acid

Substances

  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • DNA
  • STK4 protein, human
  • Protein-Serine-Threonine Kinases