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Structure of the SET domain histone lysine methyltransferase Clr4

Nature Structural Biology volume 9, pages 828–832 (2002)Cite this article

Abstract

Methylation of histone H3 lysine 9 is an important component of the 'histone code' for heterochromatic gene silencing. The SET domain-containing Clr4 protein, a close relative of Su(var)3-9 proteins in higher eukaryotes, specifically methylates lysine 9 of histone H3 and is essential for silencing in Schizosaccharomyces pombe. Here we report the 2.3 Å resolution crystal structure of the catalytic domain of Clr4. The structure reveals an overall fold rich in β-strands, a potential active site consisting of a SAM-binding pocket, and a connected groove that could accommodate the binding of the N-terminal tail of histone H3. The pre-SET motif contains a triangular zinc cluster coordinated by nine cysteines distant from the active site, whereas the post-SET region is largely flexible but proximal to the active site. The structure provides insights into the architecture of SET domain histone methyltransferases and establishes a paradigm for further characterization of the Clr4 family of epigenetic regulators.

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Figure 1: Sequence conservation and structure determination of the catalytic domain of Clr4.
Figure 2: The structure of the HMTase domain of Clr4.
Figure 3: The active site.
Figure 4: Potential cofactor-binding cleft in the HMTase domain of Clr4.

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Acknowledgements

We thank A. Saxena, A. Heroux, D. Schneider and M. Becker for technical assistance, J.-I. Nakayama for help in protein expression, N. Tolia and L. Henry for comments on the manuscript. The work is supported by NIH grants to X.Z., X.C., S.I.G and R.M.X, by a grant from the Ellison Foundation to S.I.G., and by a grant from the W. M. Keck foundation to R.M.X.

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Authors and Affiliations

  1. W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, 11724, New York, USA

    Jinrong Min & Rui-Ming Xu

  2. Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, 30322, Georgia, USA

    Xing Zhang & Xiaodong Cheng

  3. Cold Spring Harbor Laboratory, Cold Spring Harbor, 11724, New York, USA

    Shiv I.S. Grewal

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Correspondence to Rui-Ming Xu.

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Min, J., Zhang, X., Cheng, X. et al. Structure of the SET domain histone lysine methyltransferase Clr4. Nat Struct Mol Biol 9, 828–832 (2002). https://doi.org/10.1038/nsb860

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