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Structure and ligand of a histone acetyltransferase bromodomain

Abstract

Histone acetylation is important in chromatin remodelling and gene activation1,2,3,4. Nearly all known histone-acetyltransferase (HAT)-associated transcriptional co-activators contain bromodomains, which are 110-amino-acid modules found in many chromatin-associated proteins5,6,7,8,9. Despite the wide occurrence of these bromodomains, their three-dimensional structure and binding partners remain unknown. Here we report the solution structure of the bromodomain of the HAT co-activator P/CAF (p300/CBP-associated factor)10,11. The structure reveals an unusual left-handed up-and-down four-helix bundle. In addition, we showby a combination of structural and site-directed mutagenesis studies that bromodomains can interact specifically with acetylated lysine, making them the first known protein modules to do so. The nature of the recognition of acetyl-lysine by the P/CAF bromodomain is similar to that of acetyl-CoA by histone acetyltransferase. Thus, the bromodomain is functionally linked to the HAT activity of co-activators in the regulation of gene transcription.

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Figure 1: Structure-based sequence alignment of a selected number of bromodomains.
Figure 2: Structure of the P/CAF bromodomain.
Figure 3: Binding of the P/CAF bromodomain to AcK.
Figure 4: The acetyl-lysine binding pocket.

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Acknowledgements

We thank M. Sattler, M. Nilges, M. Rosen, R. P. Meadows, and C. Escalante for technical advice; O. Plotnikova for assistance in the preparation of mutant proteins; I. Wolf for peptide synthesis; and D.Logothetis, H. Weinstein, L. Shapiro, R. Margolskee and A. Farooq for their suggestions and for critical reading of the manuscript. This work was supported by discretionary funds from the Mount Sinai School of Medicine (to M.M.Z.) and NIH grants (to A.A.).

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Correspondence to Ming-Ming Zhou.

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Dhalluin, C., Carlson, J., Zeng, L. et al. Structure and ligand of a histone acetyltransferase bromodomain. Nature 399, 491–496 (1999). https://doi.org/10.1038/20974

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