title: Molecular insights into the recognition of N-terminal histone modifications by the BRPF1 bromodomain.
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.
authors: Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA.
authors: Amanda
authors: A
authors: Poplawski
authors: National Magnetic Resonance Facility at Madison and Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Kaifeng
authors: K
authors: Hu
authors: National Magnetic Resonance Facility at Madison and Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Woonghee
authors: W
authors: Lee
authors: Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA.
authors: Senthil
authors: S
authors: Natesan
authors: Department of Biochemistry and Molecular Biology, Division of Basic Science Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Danni
authors: D
authors: Peng
authors: Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA.
authors: Samuel
authors: S
authors: Carlson
authors: Department of Biochemistry and Molecular Biology, Division of Basic Science Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Xiaobing
authors: X
authors: Shi
authors: Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA.
authors: Stefan
authors: S
authors: Balaz
authors: National Magnetic Resonance Facility at Madison and Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: John L
authors: JL
authors: Markley
authors: Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA. Electronic address: karen.glass@acphs.edu.
authors: Karen C
authors: KC
authors: Glass
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D004268:DNA-Binding Proteins; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008239:Lysine / Q000737:chemistry; D046911:Macromolecular Substances / Q000737:chemistry; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D000092468:Bromodomain Containing Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D006657:Histones; D008239:Lysine; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D011994:Recombinant Proteins; C086011:BRPF1 protein, human; D000092468:Bromodomain Containing Proteins
keywords: bromodomain; epigenetics; histone acetyltransferase; molecular dynamic simulations; nuclear magnetic resonance