title: Histone demethylase KDM5A is regulated by its reader domain through a positive-feedback mechanism.
abstract: The retinoblastoma binding protein KDM5A removes methyl marks from lysine 4 of histone H3 (H3K4). Misregulation of KDM5A contributes to the pathogenesis of lung and gastric cancers. In addition to its catalytic jumonji C domain, KDM5A contains three PHD reader domains, commonly recognized as chromatin recruitment modules. It is unknown whether any of these domains in KDM5A have functions beyond recruitment and whether they regulate the catalytic activity of the demethylase. Here using biochemical and nuclear magnetic resonance (NMR)-based structural studies, we show that the PHD1 preferentially recognizes unmethylated H3K4 histone tail, product of KDM5A-mediated demethylation of tri-methylated H3K4 (H3K4me3). Binding of unmodified H3 peptide to the PHD1 stimulates catalytic domain-mediated removal of methyl marks from H3K4me3 peptide and nucleosome substrates. This positive-feedback mechanism--enabled by the functional coupling between a reader and a catalytic domain in KDM5A--suggests a model for the spread of demethylation on chromatin.
authors: 1] Department of Cellular and Molecular Pharmacology, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA [2] Chemistry and Chemical Biology Graduate Program, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA.
authors: Idelisse Ortiz
authors: IO
authors: Torres
authors: 1] Department of Biochemistry and Biophysics, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA [2] Biophysics Graduate Program, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA.
authors: Kristopher M
authors: KM
authors: Kuchenbecker
authors: 1] Department of Cellular and Molecular Pharmacology, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA [2] Chemistry and Chemical Biology Graduate Program, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA [3] UCSF Medical Scientist Training Program, University of California, 513 Parnassus Avenue, San Francisco, California 94143, USA.
authors: Chimno I
authors: CI
authors: Nnadi
authors: Department of Biochemistry and Biophysics, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA.
authors: Robert J
authors: RJ
authors: Fletterick
authors: Department of Pharmaceutical Chemistry, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA.
authors: Mark J S
authors: MJ
authors: Kelly
authors: 1] Department of Cellular and Molecular Pharmacology, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA [2] Department of Pharmaceutical Chemistry, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA.
authors: Danica Galonić
authors: DG
authors: Fujimori
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry; D002942:Circular Dichroism; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000737:chemistry; D007313:Insecta; D007700:Kinetics; D008239:Lysine / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009707:Nucleosomes / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry; D056485:Retinoblastoma-Binding Protein 2 / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D002843:Chromatin; D009707:Nucleosomes; D010455:Peptides; D011994:Recombinant Proteins; C070050:KDM5A protein, human; D056485:Retinoblastoma-Binding Protein 2; C447780:EGLN2 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D005982:Glutathione Transferase; D008239:Lysine