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The catalytic mechanism of the ESA1 histone acetyltransferase involves a self-acetylated intermediate

Nature Structural Biology volume 9, pages 862–869 (2002)Cite this article

Abstract

Yeast ESA1 is a member of the MYST subfamily of histone acetyltransferases (HATs), which use acetyl-coenzyme A (CoA) to acetylate specific Lys residues within histones to regulate gene expression. The structure of an ESA1–CoA complex reveals structural similarity to the catalytic core of the GCN5/PCAF subfamily of HAT proteins. Here we report additional structural and functional studies on ESA1 that demonstrate that histone acetylation proceeds through an acetyl-cysteine enzyme intermediate. This Cys residue is strictly conserved within the MYST members, suggesting a common mode of catalysis by this HAT subfamily. However, this mode of catalysis differs dramatically from the GCN5/PCAF subfamily, which mediate direct nucleophilic attack of the acetyl-CoA cofactor by the enzyme-deprotonated substrate lysine of the histone. These results demonstrate that different HAT subfamilies can use distinct catalytic mechanisms, which have implications for their distinct biological roles and for the development of HAT-specific inhibitors.

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Figure 1: Overall structures of the histone acetyltransferases ESA1 and GCN5 highlighting residues implicated in catalysis.
Figure 2: Structure at the active site of wild type and mutant ESA1 proteins.
Figure 3: Histone acetylation by ESA1 in solution.
Figure 4: Proposed catalytic mechanism for histone acetylation by ESA1.

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Acknowledgements

We thank S. Berger, N. Barlev and W. Lo for help with the HAT assay and valuable discussions; N. DiFlorio in the Wistar Microchemistry facility for help with the mass spectrometry analysis; A. Weaver for help on beamline F2 at CHESS; T. Penning and V. Heredia for help with the Cleland program; K. Zhao for PCAF HAT domain recombinant protein; and D. Christianson, A. Clements, R. Venkataramani and A. Poux for useful discussions.

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Authors and Affiliations

  1. The Wistar Institute, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Yuan Yan, Sandy Harper, David W. Speicher & Ronen Marmorstein

  2. Department of Chemistry, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Yuan Yan & Ronen Marmorstein

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Correspondence to Ronen Marmorstein.

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Yan, Y., Harper, S., Speicher, D. et al. The catalytic mechanism of the ESA1 histone acetyltransferase involves a self-acetylated intermediate. Nat Struct Mol Biol 9, 862–869 (2002). https://doi.org/10.1038/nsb849

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