Molecular recognition of histone H3 by the WD40 protein WDR5.
The WD40-repeat protein WDR5 is a conserved subunit of Trithorax (TRX) histone methyltransferase complexes. WDR5 has been reported to selectively bind dimethylated Lys4 (K4me2) in histone H3 to promote K4 trimethylation by TRX. To elucidate the basis of this binding specificity, we have determined the crystal structure of WDR5 bound to a histone H3 peptide bearing K4me2. The structure reveals that the N terminus of histone H3 binds as a 3(10)-helix in the central depression formed by the WD40 repeats. R2 in histone H3 is bound in the acidic channel in the protein's core, whereas K4me2 is solvent exposed and does not engage in direct interactions with WDR5. Functional studies confirm that WDR5 recognizes A1, R2 and T3 in histone H3 but has virtually identical affinities for the unmodified and mono-, di- and trimethylated forms of K4, demonstrating that it does not discriminate among different degrees of methylation of this residue.
Couture
Jean-François
JF
Department of Biological Chemistry, University of Michigan, 1301 Catherine Road, Ann Arbor, Michigan 48109-0606, USA.
Collazo
Evys
E
Trievel
Raymond C
RC
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation
D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D010455:Peptides; C502547:WDR5 protein, human; D011495:Histone-Lysine N-Methyltransferase; D020962:Heterotrimeric GTP-Binding Proteins