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J Mol Biol. 2014 Apr 17;426(8):1661-76. doi: 10.1016/j.jmb.2013.12.007. Epub 2013 Dec 12.

Molecular insights into the recognition of N-terminal histone modifications by the BRPF1 bromodomain.

Author information

1
Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA.
2
National Magnetic Resonance Facility at Madison and Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
3
Department of Biochemistry and Molecular Biology, Division of Basic Science Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4
Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA. Electronic address: karen.glass@acphs.edu.

Abstract

The monocytic leukemic zinc finger (MOZ) histone acetyltransferase (HAT) acetylates free histones H3, H4, H2A, and H2B in vitro and is associated with up-regulation of gene transcription. The MOZ HAT functions as a quaternary complex with the bromodomain-PHD finger protein 1 (BRPF1), inhibitor of growth 5 (ING5), and hEaf6 subunits. BRPF1 links the MOZ catalytic subunit to the ING5 and hEaf6 subunits, thereby promoting MOZ HAT activity. Human BRPF1 contains multiple effector domains with known roles in gene transcription, as well as chromatin binding and remodeling. However, the biological function of the BRPF1 bromodomain remains unknown. Our findings reveal novel interactions of the BRPF1 bromodomain with multiple acetyllysine residues on the N-terminus of histones and show that it preferentially selects for H2AK5ac, H4K12ac, and H3K14ac. We used chemical shift perturbation data from NMR titration experiments to map the BRPF1 bromodomain ligand binding pocket and identified key residues responsible for coordination of the post-translationally modified histones. Extensive molecular dynamics simulations were used to generate structural models of bromodomain-histone ligand complexes, to analyze hydrogen bonding and other interactions, and to calculate the binding free energies. Our results outline the molecular mechanism driving binding specificity of the BRPF1 bromodomain for discrete acetyllysine residues on the N-terminal histone tails. Together, these data provide insights into how histone recognition by the bromodomain directs the biological function of BRPF1, ultimately targeting the MOZ HAT complex to chromatin substrates.

KEYWORDS:

bromodomain; epigenetics; histone acetyltransferase; molecular dynamic simulations; nuclear magnetic resonance

PMID:
24333487
PMCID:
PMC3969779
DOI:
10.1016/j.jmb.2013.12.007
[Indexed for MEDLINE]
Free PMC Article

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