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An atomic model of the interferon-beta enhanceosome
Daniel Panne1, Tom Maniatis, Stephen C Harrison
1The Jack and Eileen Connors Structural Biology Laboratory, Harvard Medical School, Department of Biological Chemistry and Molecular Pharmacology, Howard Hughes Medical Institute, 250 Longwood Avenue, Boston, MA 02115, USA.
Cell
|June 19, 2007
Summary
The interferon-beta (IFN-beta) gene
Area of Science:
- Molecular Biology
- Structural Biology
- Immunology
Background:
- Transcriptional activation of the interferon-beta (IFN-beta) gene depends on the assembly of a protein complex called the enhanceosome.
- The enhanceosome comprises transcription factors ATF-2/c-Jun, Interferon Regulatory Factor 3 (IRF-3)/IRF-7, and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NFkappaB).
- These factors bind cooperatively to the IFN-beta enhancer, recruiting coactivators and chromatin-remodeling proteins to the promoter.
Purpose of the Study:
- To elucidate the structural basis of enhanceosome assembly and DNA binding.
- To understand how cooperative binding of transcription factors is achieved.
- To explain the evolutionary conservation of the IFN-beta enhancer sequence.
Main Methods:
- Determined the crystal structure of the DNA-binding domains of IRF-3, IRF-7, and NFkappaB bound to half of the IFN-beta enhancer.
- Integrated this structure with a previously solved structure of the other half of the enhancer.
- Assembled a complete model of the enhanceosome architecture at the IFN-beta enhancer.
Main Results:
- The association of eight proteins creates a continuous surface for binding the composite DNA element of the IFN-beta enhancer.
- Limited direct protein-protein contacts within the enhanceosome suggest DNA conformation changes and interactions with coactivators (e.g., CBP) mediate cooperative binding.
- Extensive contacts between the protein complex and nearly all DNA nucleotide pairs explain the enhancer's sequence invariance.
Conclusions:
- The study provides a detailed structural model of the IFN-beta enhanceosome.
- Cooperative binding is facilitated by DNA bending and interactions with coactivators, rather than extensive protein-protein interfaces.
- The comprehensive interaction with DNA underscores the functional importance and evolutionary conservation of the IFN-beta enhancer.
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