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Structural basis for cooperative transcription factor binding to the CBP coactivator
Roberto N De Guzman1, Natalie K Goto, H Jane Dyson
1Department of Molecular Biology MB2, The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Journal of Molecular Biology
|October 29, 2005
Summary
The KIX domain of CREB binding protein (CBP) binds c-Myb and mixed lineage leukemia (MLL) transcription factors. This cooperative binding induces structural changes in KIX, enhancing transcriptional regulation.
Area of Science:
- Molecular Biology
- Structural Biology
- Biochemistry
Background:
- Transcriptional regulation involves interactions between activators and co-activators like CREB binding protein (CBP).
- The KIX domain of CBP exhibits the unique ability to bind multiple proteins simultaneously, facilitating complex transcriptional regulation.
- Understanding these interactions is crucial for deciphering gene expression control mechanisms.
Purpose of the Study:
- To elucidate the structural basis of cooperative binding between the KIX domain and activation domains of c-Myb and mixed lineage leukemia (MLL) transcription factors.
- To investigate the structural rearrangements within the KIX domain upon ternary complex formation.
- To provide insights into the mechanism of enhanced transcriptional regulation mediated by the KIX domain.
Main Methods:
- Solution structure determination of the ternary complex using techniques like Nuclear Magnetic Resonance (NMR) spectroscopy.
- Structural analysis and comparison of the ternary complex with the binary KIX:c-Myb complex.
- Identification of specific molecular interactions and conformational changes.
Main Results:
- The ternary complex structure reveals that MLL and c-Myb activation domains bind to distinct hydrophobic grooves on the KIX domain, forming helical structures.
- Significant structural alterations in KIX are observed at the MLL binding interface in the ternary complex compared to the binary complex.
- Two previously disordered regions in KIX become structured upon MLL binding, forming new interactions with MLL and stabilizing the C-terminal helix, which in turn enhances interactions with c-Myb.
Conclusions:
- Cooperative binding of MLL and c-Myb to the KIX domain induces significant structural changes in KIX, leading to enhanced electrostatic and polar interactions.
- These structural rearrangements provide a molecular basis for the observed cooperativity in transcriptional regulation mediated by the KIX domain.
- The findings offer a deeper understanding of the intricate mechanisms governing transcription factor interactions and gene expression control.