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Molecular recognition of histone H3 by the WD40 protein WDR5

Nature Structural & Molecular Biology volume 13, pages 698–703 (2006)Cite this article

Abstract

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 310-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.

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Figure 1: Crystal structure of WDR5 bound to the N terminus of histone H3.
Figure 2: Recognition of the histone H3 N terminus by WDR5.
Figure 3: Analysis of the affinity of WDR5 for histone H3 peptides bearing different degrees of K4 methylation.

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Acknowledgements

We thank J. Brunzelle for assistance in X-ray data collection, D. Peisach for assistance with rendering figures, D. Peisach for reading the manuscript and providing useful comments, the ESRF for provision of synchrotron radiation facilities and L. Serre and M. Walsh for their assistance in using beamlines FIP BM30A and BM14, respectively. Use of the University of Michigan DNA Sequencing Core was supported by the US National Institutes of Health through the University of Michigan's Cancer Center Support Grant (5 P30 CA46592). J.-F.C. is a Canadian Institutes of Health Research Postdoctoral Fellow. This work was supported by the University of Michigan's Office of the Vice President for Research and US National Institutes of Health grant GM073839 to R.C.T.

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  1. Department of Biological Chemistry, University of Michigan, 1301 Catherine Road, Ann Arbor, 48109-0606, Michigan, USA

    Jean-François Couture, Evys Collazo & Raymond C Trievel

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Correspondence to Raymond C Trievel.

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Supplementary Fig. 1

Sequence alignment of metazoan orthologs of WDR5. (PDF 245 kb)

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Couture, JF., Collazo, E. & Trievel, R. Molecular recognition of histone H3 by the WD40 protein WDR5. Nat Struct Mol Biol 13, 698–703 (2006). https://doi.org/10.1038/nsmb1116

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