title: Structural basis for the specific recognition of methylated histone H3 lysine 4 by the WD-40 protein WDR5.
abstract: The WD40 repeat protein WDR5 specifically associates with the K4-methylated histone H3 in human cells. To investigate the structural basis for this specific recognition, we have determined the structure of WDR5 in complex with a dimethylated H3-K4 peptide at 1.9 A resolution. Unlike the chromodomain that recognizes the methylated H3-K4 through a hydrophobic cage, the specificity of WDR5 for methylated H3-K4 is conferred by the nonconventional hydrogen bonds between the two zeta-methyl groups of the dimethylated Lys4 and the carboxylate oxygen of Glu322 in WDR5. The three amino acids Ala-Arg-Thr preceding Lys4 form most of the specific contacts with WDR5, with Ala1 forming intermolecular hydrogen bonds and salt bridges, and the side chain of Arg2 inserting into the central channel of WDR5. Both structural and biochemical studies presented here suggest another mode of recognition for the methylated histone tail.
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Han
authors.forename: Lan
authors.initials: L
authors.lastname: Guo
authors.forename: Huayi
authors.initials: H
authors.lastname: Wang
authors.forename: Yue
authors.initials: Y
authors.lastname: Shen
authors.forename: Xing Wang
authors.initials: XW
authors.lastname: Deng
authors.forename: Jijie
authors.initials: J
authors.lastname: Chai
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D047908:Intracellular Signaling Peptides and Proteins; D008239:Lysine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
chemical_list: D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; C502547:WDR5 protein, human; D011495:Histone-Lysine N-Methyltransferase; D020962:Heterotrimeric GTP-Binding Proteins; D008239:Lysine