Sequence-specific recruitment of transcriptional co-repressor Cabin1 by myocyte enhancer factor-2

Abstract

The myocyte enhancer factor-2 (MEF2) family of transcription factors has important roles in the development and function of T cells, neuronal cells and muscle cells1,2,3. MEF2 is capable of repressing or activating transcription by association with a variety of co-repressors or co-activators in a calcium-dependent manner1,4,5. Transcriptional repression by MEF2 has attracted particular attention because of its potential role in hypertrophic responses of cardiomyocytes6. Several MEF2 co-repressors, such as Cabin1/Cain and class II histone deacetylases (HDACs), have been identified7,8,9,10,11,12. However, the molecular mechanism of their recruitment to specific promoters by MEF2 remains largely unknown. Here we report a crystal structure of the MADS-box/MEF2S domain of human MEF2B bound to a motif of the transcriptional co-repressor Cabin1 and DNA at 2.2 Å resolution. The crystal structure reveals a stably folded MEF2S domain on the surface of the MADS box. Cabin1 adopts an amphipathic α-helix to bind a hydrophobic groove on the MEF2S domain, forming a triple-helical interaction. Our studies of the ternary Cabin1/MEF2/DNA complex show a general mechanism by which MEF2 recruits transcriptional co-repressor Cabin1 and class II HDACs to specific DNA sites.

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Figure 1: Structure of the Cabin1/MEF2B/DNA complex.
Figure 2: The fully folded structure of the MADS-box/MEF2S domain.
Figure 3: The overall structure of the Cabin1-binding site of MEF2B.
Figure 4: Crystallographic and mutational analyses of the Cabin1/MEF2B interface.

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Acknowledgements

We thank H. Tong from APS beamline 14-BM, M. Giffin and D. Bates for help in data collection, G. Murphy, N. Ahn, J. Goodrich and D. Wuttke for critical reading of the manuscript, and T. Mckinsey for discussion. This research was supported by a scholar award from the Damon Runyon–Walter Winchell Foundation (L.C.) and grants from the W. M. Keck foundation (L.C.) and the NIH (L.C. and J.O.L.).

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Correspondence to Lin Chen.

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Han, A., Pan, F., Stroud, J. et al. Sequence-specific recruitment of transcriptional co-repressor Cabin1 by myocyte enhancer factor-2. Nature 422, 730–734 (2003). https://doi.org/10.1038/nature01555

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