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Splicing regulates NAD metabolite binding to histone macroH2A

Nature Structural & Molecular Biology volume 12, pages 624–625 (2005)Cite this article

Abstract

Histone macroH2A is a hallmark of mammalian heterochromatin. Here we show that human macroH2A1.1 binds the SirT1-metabolite O-acetyl-ADP-ribose (OAADPR) through its macro domain. The 1.6-Å crystal structure and mutants reveal how the metabolite is recognized. Mutually exclusive exon use in the gene H2AFY produces macroH2A1.2, whose tissue distribution differs. MacroH2A1.2 shows only subtle structural changes but cannot bind nucleotides. Alternative splicing may thus regulate the binding of nicotinamide adenine dinucleotide (NAD) metabolites to chromatin.

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Figure 1: The human heterochromatic histone mH2A1.1 binds NAD metabolites.
Figure 2: Alternative splicing regulates NAD metabolite binding to human histone macroH2A1 isoforms.

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Acknowledgements

We thank M. Wilm for mass spectrometry; G. Karras, A. Bianco, G. Stier, H. Buhecha, M. Breitenbach and H. Koller for assorted help; S. Fribourg for beamline data collection; A. Akhtar, E. Conti, E. Izaurralde, C. Margulies, I. Mattaj, J. Müller and C. Schultz for discussion; and the staff at beamline ID14-1/ID14-4 of the ESRF for technical support. M.H. acknowledges financial support from the Peter and Traudl Engelhorn Foundation, Germany.

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Author notes

  1. Georg Kustatscher and Michael Hothorn: These authors contributed equally to this work.

Authors and Affiliations

  1. Gene Expression Unit and Structural & Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, 69117, Germany

    Georg Kustatscher, Michael Hothorn, Céline Pugieux, Klaus Scheffzek & Andreas G Ladurner

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  1. Georg Kustatscher
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  2. Michael Hothorn
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  3. Céline Pugieux
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  4. Klaus Scheffzek
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  5. Andreas G Ladurner
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Corresponding authors

Correspondence to Klaus Scheffzek or Andreas G Ladurner.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Schematic group II intron secondary structure. (PDF 460 kb)

Supplementary Fig. 2

The products of splicing from a D56 molecule containing a single-nucleotide 3′-exon. (PDF 445 kb)

Supplementary Table 1

Data collection and refinement statistics (Molecular Replacement). (PDF 75 kb)

Supplementary Methods (PDF 173 kb)

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Kustatscher, G., Hothorn, M., Pugieux, C. et al. Splicing regulates NAD metabolite binding to histone macroH2A. Nat Struct Mol Biol 12, 624–625 (2005). https://doi.org/10.1038/nsmb956

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