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Production, Crystallization, and Structure Determination of the IKK-binding Domain of NEMO
Published on: December 28, 2019
Crystal Structures of Ternary Complexes of MEF2 and NKX2-5 Bound to DNA Reveal a Disease Related Protein-Protein
Xiao Lei1, Jun Zhao2, Jared M Sagendorf3
1Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
Abstract:
MEF2 and NKX2-5 transcription factors interact with each other in cardiogenesis and are necessary for normal heart formation. Despite evidence suggesting that these two transcription factors function synergistically and possibly through direct physical interactions, molecular mechanisms by which they interact are not clear. Here we determined the crystal structures of ternary complexes of MEF2 and NKX2-5 bound to myocardin enhancer DNA in two crystal forms. These crystal structures are the first example of human MADS-box/homeobox ternary complex structures involved in cardiogenesis. Our structures reveal two possible modes of interactions between MEF2 and NKX2-5: MEF2 and NKX bind to adjacent DNA sites to recognize DNA in cis; and MEF2 and NKX bind to different DNA strands to interact with each other in trans via a conserved protein-protein interface observed in both crystal forms. Disease-related mutations are mapped to the observed protein-protein interface. Our structural studies provide a starting point to understand and further study the molecular mechanisms of the interactions between MEF2 and NKX2.5 and their roles in cardiogenesis.
Insights
The study reveals how MEF2 and NKX2-5 (transcription factors) interact during heart development. Structural analysis identified two interaction modes, offering insights into cardiogenesis and disease mutations.
Area of Science:
- Molecular biology
- Structural biology
- Developmental biology
Background:
- MEF2 and NKX2-5 are crucial transcription factors for cardiogenesis.
- Their synergistic interaction is vital for normal heart formation, but the molecular mechanisms remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms of MEF2 and NKX2-5 interaction in cardiogenesis.
- To determine the structural basis of their synergistic function.
Main Methods:
- Determined crystal structures of MEF2-NKX2-5-DNA ternary complexes.
- Analyzed two distinct crystal forms of the complexes.
- Mapped disease-related mutations onto the structural interface.
Main Results:
- First structures of human MADS-box/homeobox ternary complexes in cardiogenesis.
- Revealed two interaction modes: cis (adjacent DNA sites) and trans (different DNA strands).
- Identified a conserved protein-protein interface, with disease mutations localized to it.
Conclusions:
- Structural insights into MEF2-NKX2-5 interactions provide a foundation for understanding their roles in heart development.
- The identified interaction modes and interface are key to cardiogenesis and may explain disease mechanisms.
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