Related Experiment Video
Updated: Jul 1, 2026
10:23
Time-Resolved Fluorescence Anisotropy from Single Molecules for Characterizing Local Flexibility in Biomolecules
Published on: April 25, 2025
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
Summary
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.
More Related Videos
Related Concept Videos
02:04Covalently Linked Protein Regulators
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.
These groups modify specific amino acids in a protein.
02:32Histone Modification
The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
02:32Histone Modification
The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
01:23Regulation of Expression at Multiple Steps
The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the addition of a...
02:04Co-activators and Co-repressors
Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
01:37Epigenetic Regulation
Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
X-chromosome...