PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons

Related Articles
Epigenetics: Getting MAD
December 2013
Epigenetics: HAT1 Makes Its Mark
December 2013
Epigenetics: Tracing Histone Demethylase Inhibitors
December 2013
Methylation of Arginine
December 2013
Methyl maintenance
May 2012

Research Themes Epigenetics

Epigenetics: HAT1 Makes Its Mark

SBKB [doi:10.1038/sbkb.2012.173]
Featured Article - December 2013
Short description: The crystal structure of human histone acetyltransferase 1 in complex with acetyl coenzyme A and a histone H4 peptide reveals the basis for substrate specificity and catalysis.

Close-up view of the substrate-binding site of human HAT1. Electrostatic potential surface of the active site of human HAT1 is shown. Acidic and basic surfaces are colored in red and blue, respectively. The H4 peptide (yellow) and AcCoA (grey) are shown in a ball-and-stick representation. Figure courtesy of Alexander Plotnikov.

Histone acetyltransferase 1 (HAT1) catalyzes acetylation of newly synthesized histone H4 by transferring an acetyl group from acetyl coenzyme A (AcCoA) to the lysine ε-amino group on the N-terminal tail of H4. HAT1 specifically acetylates Lys5 and Lys12 in vitro and is important for chromatin assembly and DNA replication. While the structure of yeast HAT1 in complex with AcCoA had been previously reported, it remained unclear how HAT1 recognizes both substrate and AcCoA at the active site and how the complex facilitates catalysis. Hence, Plotnikov and colleagues (Structural Genomics Consortium and Mount Sinai School of Medicine) determined the crystal structure of human HAT1 in complex with both AcCoA and an H4 peptide at 1.9-Å resolution (PDB 2P0W).

The structure reveals that AcCoA and the side chain of Lys12 of the H4 peptide are placed in a canyon between the central and C-terminal domains of HAT1. AcCoA makes extensive hydrophobic and hydrogen-bonding interactions, and the highly-conserved Leu242 of HAT1 appears crucial in orienting the pantotheine moiety of AcCoA for acetyl transfer. Interestingly, while the overall structure of human HAT1 is similar to that of the yeast ortholog, their respective modes of AcCoA recognition differ, with human HAT1 having stronger binding to AcCoA due to interactions with the adenine and ribose rings.

The H4 peptide adopts a well-defined structure in the complex, which likely requires significant conformational changes upon binding to HAT1. Superposition of the human and yeast HAT1 structures suggests that the enzyme does not undergo conformational changes upon H4 peptide binding. Interactions with the enzyme include the highly conserved Glu64 and Trp199 residues, which are crucial for the substrate-binding specificity of HAT1. Remarkably, Lys5 of the substrate does not make any contacts with HAT1, suggesting that Lys12 of histone H4 is the preferred substrate for HAT1, which is further supported by kinetic analysis.

Finally, structure-guided mutagenesis of active-site residues Glu187, Glu276 and Asp277, combined with kinetic analysis, suggests their cumulative effect on deprotonation of the ε-amino group of Lys12 of histone H4 for direct attack of the acetyl group of AcCoA. Given the emerging link between HAT1 and cancer, the crystal structure of the human HAT1–AcCoA–H4 complex should inform future drug discovery efforts.

Arianne Heinrichs


  1. H. Wu et al. Structural basis for substrate specificity and catalysis of human histone acetyltransferase 1.
    Proc. Natl Acad. Sci. USA. 109, 8925-8930 (2012). doi:10.1073/pnas.1114117109

Structural Biology Knowledgebase ISSN: 1758-1338
Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health