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Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
Published on: September 20, 2018
Variable control of Ets-1 DNA binding by multiple phosphates in an unstructured region
Miles A Pufall1, Gregory M Lee, Mary L Nelson
1Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112-5550, USA.
Science (New York, N.Y.)
|July 5, 2005
Summary
Multiple phosphorylation sites on the Ets-1 transcription activator act like a rheostat, fine-tuning DNA binding affinity through graded cell signaling. This posttranslational modification alters protein conformation, impacting gene transcription.
Area of Science:
- Molecular Biology
- Biochemistry
- Cell Signaling
Background:
- Posttranslational modifications, such as phosphorylation, are crucial for regulating protein activity.
- Transcription factors like Ets-1 play key roles in gene expression, but their regulation is complex.
Purpose of the Study:
- To investigate how calcium-dependent phosphorylation sites on the Ets-1 protein affect its DNA binding affinity.
- To elucidate the structural and functional consequences of Ets-1 phosphorylation in cell signaling.
Main Methods:
- Nuclear magnetic resonance (NMR) spectroscopy was employed to analyze the structural changes in Ets-1 upon phosphorylation.
- The study focused on Ca2+-dependent phosphorylation sites within the Ets-1 protein.
Main Results:
- Multiple phosphorylation sites on Ets-1 were found to act additively, resulting in graded changes in DNA binding affinity.
- NMR analysis revealed that phosphorylation induces a shift from a dynamic, DNA-binding-ready conformation to a well-folded, inhibited state.
- The phosphorylated sites are located in a flexible region that acts as an allosteric effector, mediating autoinhibition.
Conclusions:
- Variable phosphorylation of Ets-1 functions as a molecular rheostat, providing a mechanism for fine-tuning transcription.
- This study reveals a novel regulatory mechanism for transcription factors at the level of DNA binding through allosteric control by phosphorylation.
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