Structural basis for the specific recognition of methylated histone H3 lysine 4 by the WD-40 protein WDR5.
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.
Han
Zhifu
Z
National Institute of Biological Sciences, Beijing 102206, China.
Guo
Lan
L
Wang
Huayi
H
Shen
Yue
Y
Deng
Xing Wang
XW
Chai
Jijie
J
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
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