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

Michael M Brent1, Ruchi Anand, Ronen Marmorstein

  • 1The Wistar Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; The Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.

Structure (London, England : 1993)
|September 13, 2008
PubMed

Insights

FoxO transcription factors regulate key cellular processes. Posttranslational modifications like acetylation and phosphorylation alter FoxO1 DNA binding affinity, impacting gene regulation in health and disease.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • FoxO transcription factors are crucial regulators of cellular functions including metabolism, proliferation, stress response, and longevity.
  • Their activity is modulated by various posttranslational modifications (PTMs) within the forkhead DNA-binding domain.
  • Understanding these modifications is key to comprehending FoxO's role in cellular regulation.

Purpose of the Study:

  • To elucidate the structural basis of FoxO1 binding to different DNA elements.
  • To investigate how specific PTMs, namely acetylation and phosphorylation, affect FoxO1-DNA binding affinity.
  • To explore the implications of altered FoxO-DNA affinity in cellular regulation and disease.

Main Methods:

  • X-ray crystallography was used to determine the structures of FoxO1 bound to three distinct DNA sequences.
  • DNA-binding affinity assays were performed to quantify the impact of p300 acetylation and MST1 phosphorylation on FoxO1-DNA interactions.
  • Biochemical analyses were conducted to assess the role of the wing 2 region in DNA binding.

Main Results:

  • Crystal structures revealed detailed interactions between FoxO1 and DNA, highlighting increased DNA distortion at the highest affinity site.
  • p300-mediated acetylation in the wing 2 region was found to decrease FoxO1-DNA binding affinity.
  • MST1-mediated phosphorylation of FoxO1 was shown to inhibit high-affinity DNA binding.
  • The flexible wing 2 region, though not observed in crystal structures, is essential for DNA binding.

Conclusions:

  • FoxO-DNA binding affinity is sequence-dependent and dynamically regulated by PTMs.
  • Modulation of FoxO-DNA affinity through acetylation and phosphorylation represents a significant mechanism for controlling gene transcription.
  • Dysregulation of FoxO-DNA affinity by PTMs may contribute to various diseases.

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