title: Bivalent interaction of the PZP domain of BRPF1 with the nucleosome impacts chromatin dynamics and acetylation.
abstract: BRPF1 (bromodomain PHD finger 1) is a core subunit of the MOZ histone acetyltransferase (HAT) complex, critical for normal developmental programs and implicated in acute leukemias. BRPF1 contains a unique assembly of zinc fingers, termed a PZP domain, the physiological role of which remains unclear. Here, we elucidate the structure-function relationship of this novel epigenetic reader and detail the biological and mechanistic consequences of its interaction with nucleosomes. PZP has a globular architecture and forms a 2:1 stoichiometry complex with the nucleosome, bivalently interacting with histone H3 and DNA. This binding impacts the nucleosome dynamics, shifting the DNA unwrapping/rewrapping equilibrium toward the unwrapped state and increasing DNA accessibility. We demonstrate that the DNA-binding function of the BRPF1 PZP domain is required for the MOZ-BRPF1-ING5-hEaf6 HAT complex to be recruited to chromatin and to acetylate nucleosomal histones. Our findings reveal a novel link between chromatin dynamics and MOZ-mediated acetylation.
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Brianna J
authors.initials: BJ
authors.lastname: Klein
authors.affiliation: Department of Chemistry and Biochemistry and Howard Hughes Medical Institute, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Uma M
authors.initials: UM
authors.lastname: Muthurajan
authors.affiliation: St-Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, CHU de Québec Research Center-Oncology Axis, Quebec City, Québec G1R 2J6, Canada.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Lalonde
authors.affiliation: Department of Physics, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Gibson
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Forest H
authors.initials: FH
authors.lastname: Andrews
authors.affiliation: Department of Chemistry and Biochemistry and Howard Hughes Medical Institute, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Maggie
authors.initials: M
authors.lastname: Hepler
authors.affiliation: Graduate School of Advanced Science & Engineering, Waseda University, Tokyo 162-8480, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Machida
authors.affiliation: Goodman Cancer Research Center & Department of Medicine, McGill University, Montreal, Québec H3A 1A1, Canada.
authors.forename: Kezhi
authors.initials: K
authors.lastname: Yan
authors.affiliation: Graduate School of Advanced Science & Engineering, Waseda University, Tokyo 162-8480, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kurumizaka
authors.affiliation: Department of Physics, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Poirier
authors.affiliation: St-Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, CHU de Québec Research Center-Oncology Axis, Quebec City, Québec G1R 2J6, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Côté
authors.affiliation: Department of Chemistry and Biochemistry and Howard Hughes Medical Institute, University of Colorado, Boulder, CO 80309, USA Karolin.Luger@Colorado.edu.
authors.forename: Karolin
authors.initials: K
authors.lastname: Luger
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA tatiana.kutateladze@ucdenver.edu.
authors.forename: Tatiana G
authors.initials: TG
authors.lastname: Kutateladze
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins; D006657:Histones / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D016415:Sequence Alignment; D000092468:Bromodomain Containing Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002843:Chromatin; D004247:DNA; D004268:DNA-Binding Proteins; D006657:Histones; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D009707:Nucleosomes; C086011:BRPF1 protein, human; D000092468:Bromodomain Containing Proteins