Structural basis for molecular recognition and presentation of histone H3 by WDR5.
Histone methylation at specific lysine residues brings about various downstream events that are mediated by different effector proteins. The WD40 domain of WDR5 represents a new class of histone methyl-lysine recognition domains that is important for recruiting H3K4 methyltransferases to K4-dimethylated histone H3 tail as well as for global and gene-specific K4 trimethylation. Here we report the crystal structures of full-length WDR5, WDR5Delta23 and its complexes with unmodified, mono-, di- and trimethylated histone H3K4 peptides. The structures reveal that WDR5 is able to bind all of these histone H3 peptides, but only H3K4me2 peptide forms extra interactions with WDR5 by use of both water-mediated hydrogen bonding and the altered hydrophilicity of the modified lysine 4. We propose a mechanism for the involvement of WDR5 in binding and presenting histone H3K4 for further methylation as a component of MLL complexes.
Schuetz
Anja
A
Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
Allali-Hassani
Abdellah
A
Martín
Fernando
F
Loppnau
Peter
P
Vedadi
Masoud
M
Bochkarev
Alexey
A
Plotnikov
Alexander N
AN
Arrowsmith
Cheryl H
CH
Min
Jinrong
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; D006657:Histones / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008239:Lysine / Q000737:chemistry; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D011994:Recombinant Proteins; C502547:WDR5 protein, human; D011495:Histone-Lysine N-Methyltransferase; D020962:Heterotrimeric GTP-Binding Proteins; D008239:Lysine