1. Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, New York 10029-6574, USA
2. These authors contributed equally to this work.

Correspondence to: Ming-Ming Zhou Correspondence and requests for materials should be addressed to M.M.Z. (e-mail: Email: zhoum@inka.mssm.edu). Coordinates for the NMR structure of the P/CAF bromodomain have been deposited in the Brookhaven Protein Data Bank under accession code 1B91.

Abstract

Histone acetylation is important in chromatin remodelling and gene activation^{1, 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 proteins^{5, 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.