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Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification

Kuang-Lei Tsai1, Yuh-Ju Sun, Cheng-Yang Huang

  • 1Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.

Nucleic Acids Research
|October 18, 2007
PubMed

Insights

The crystal structure of FOXO3a-DNA-binding domain reveals how post-translational modifications, like phosphorylation and acetylation, affect DNA binding. This structural insight explains how FOXO3a protein activity is regulated, impacting gene transcription.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Genetics

Background:

  • FOXO3a is a transcription factor regulating gene expression.
  • Its activity is modulated by post-translational modifications (PTMs) such as phosphorylation and acetylation.
  • PTMs occur in the DNA-binding domain (DBD), potentially altering DNA binding.

Purpose of the Study:

  • To elucidate the structural basis of FOXO3a DNA binding.
  • To understand how PTMs influence FOXO3a's transcriptional activity.

Main Methods:

  • X-ray crystallography of FOXO3a-DBD bound to a consensus DNA sequence.
  • Biochemical assays.
  • Mutational studies.

Main Results:

  • Determined the 2.7 Å crystal structure of FOXO3a-DBD bound to DNA.
  • Identified a unique structural feature in the C-terminal region.
  • Demonstrated that phosphorylation (by PKB) and acetylation (by CBP) attenuate DNA binding.
  • Showed that thymine methyl groups in the DNA sequence are crucial for binding recognition.

Conclusions:

  • The structure provides a mechanism for how PTMs regulate FOXO3a DNA-binding activity.
  • Phosphorylation and acetylation reduce FOXO3a transcriptional activity by impairing DNA binding.
  • Specific DNA base recognition by FOXO3a-DBD is critical.

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