title: A bromodomain-DNA interaction facilitates acetylation-dependent bivalent nucleosome recognition by the BET protein BRDT.
abstract: Bromodomains are critical components of many chromatin modifying/remodelling proteins and are emerging therapeutic targets, yet how they interact with nucleosomes, rather than acetylated peptides, remains unclear. Using BRDT as a model, we characterized how the BET family of bromodomains interacts with site-specifically acetylated nucleosomes. Here we report that BRDT interacts with nucleosomes through its first (BD1), but not second (BD2) bromodomain, and that acetylated histone recognition by BD1 is complemented by a bromodomain-DNA interaction. Simultaneous DNA and histone recognition enhances BRDT's nucleosome binding affinity and specificity, and its ability to localize to acetylated chromatin in cells. Conservation of DNA binding in bromodomains of BRD2, BRD3 and BRD4, indicates that bivalent nucleosome recognition is a key feature of these bromodomains and possibly others. Our results elucidate the molecular mechanism of BRDT association with nucleosomes and identify structural features of the BET bromodomains that may be targeted for therapeutic inhibition.
authors.affiliation: European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany.
authors.forename: Thomas C R
authors.initials: TC
authors.lastname: Miller
authors.affiliation: European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Simon
authors.affiliation: European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Rybin
authors.affiliation: European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany.
authors.forename: Helga
authors.initials: H
authors.lastname: Grötsch
authors.affiliation: CNRS UMR 5309, INSERM, U1209, Université Grenoble Alpes, Institut Albert Bonniot, 38700 Grenoble, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Curtet
authors.affiliation: CNRS UMR 5309, INSERM, U1209, Université Grenoble Alpes, Institut Albert Bonniot, 38700 Grenoble, France.
authors.forename: Saadi
authors.initials: S
authors.lastname: Khochbin
authors.affiliation: European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany.|Leibniz University Hannover, Centre for Biomolecular Drug Research, D-30167 Hannover, Germany.|Helmholtz Centre for Infection Research, Group of Structural Chemistry, D-38124 Braunschweig, Germany.
authors.forename: Teresa
authors.initials: T
authors.lastname: Carlomagno
authors.affiliation: European Molecular Biology Laboratory (EMBL), Structural and Computational Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Müller
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D006657:Histones; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins / Q000737:chemistry*; D009707:Nucleosomes / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D000092468:Bromodomain Containing Proteins
chemical_list: D006657:Histones; D009687:Nuclear Proteins; D009707:Nucleosomes; C109570:BRDT protein, human; D000092468:Bromodomain Containing Proteins