Histone acetyltransferase (HAT1 family)

 

Hat1, isolated from Saccharomyces cerevisiae, is a type B histone acetyltransferase. It catalyses the sequential acetylation of Lys12 and then Lys5 of newly synthesised histone H4 using acetyl-CoA as the source of the acetyl group. Hat1 associates with the accessory protein Hat2 before binding and acetylating H4. The complex is thought to also bind histone H3. The complex is then imported into the nucleus where the histones are deposited onto DNA with the aid of Hif1. Hat1 is unable to acetylate DNA-associated histones.

 

Reference Protein and Structure

Sequence
Q12341 UniProt (2.3.1.48) IPR017380 (Sequence Homologues) (PDB Homologues)
Biological species
Saccharomyces cerevisiae S288c (Baker's yeast) Uniprot
PDB
1bob - HISTONE ACETYLTRANSFERASE HAT1 FROM SACCHAROMYCES CEREVISIAE IN COMPLEX WITH ACETYL COENZYME A (2.3 Å) PDBe PDBsum 1bob
Catalytic CATH Domains
3.40.630.30 CATHdb (see all for 1bob)
Click To Show Structure

Enzyme Reaction (EC:2.3.1.48)

acetyl-CoA(4-)
CHEBI:57288ChEBI
+
L-lysinium residue
CHEBI:29969ChEBI
→
coenzyme A(4-)
CHEBI:57287ChEBI
+
hydron
CHEBI:15378ChEBI
+
N(6)-acetyl-L-lysine residue
CHEBI:61930ChEBI
Alternative enzyme names: Histone acetokinase, Histone acetylase, Histone transacetylase, Nucleosome-histone acetyltransferase, Lysine acetyltransferase, Protein lysine acetyltransferase, Acetyl-CoA:histone acetyltransferase,

Enzyme Mechanism

Introduction

Glu255 deprotonates Lys12 of H4 and the neutral amine is the nucleophile for attack on the carbonyl of acetyl-CoA. The resulting tetrahedral intermediate collapses back and eliminates CoAS-, which is protonated by an as yet unknown acid. The process is then repeated with Lys5 of H4.

After the acetylation of Lys12 of histone H4 the substrate reorientates in the active site and Lys5 of the histone is acetylated using the same residues.

Catalytic Residues Roles

UniProt PDB* (1bob)
Glu255 Glu255A Glu255 removes a proton from Lys12/Lys5 of H4 to produce the neutral amine, which is a better nucleophile for attack on acetyl CoA. hydrogen bond acceptor, hydrogen bond donor, proton acceptor, proton donor
Phe220 (main-N) Phe220A (main-N) The main chain amide of Phe220 stabilises the oxyanion intermediate. hydrogen bond donor, electrostatic stabiliser
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

proton transfer, intermediate formation, bimolecular nucleophilic addition, unimolecular elimination by the conjugate base, overall product formed, intermediate collapse, intermediate terminated, inferred reaction step, native state of enzyme regenerated

References

  1. Trievel RC et al. (1999), Proc Natl Acad Sci U S A, 96, 8931-8936. Crystal structure and mechanism of histone acetylation of the yeast GCN5 transcriptional coactivator. DOI:10.1073/pnas.96.16.8931. PMID:10430873.
  2. Poveda A et al. (2008), FEBS J, 275, 2122-2136. Site specificity of yeast histone acetyltransferase B complex in vivo. DOI:10.1111/j.1742-4658.2008.06367.x. PMID:18373695.
  3. Parthun MR (2007), Oncogene, 26, 5319-5328. Hat1: the emerging cellular roles of a type B histone acetyltransferase. DOI:10.1038/sj.onc.1210602. PMID:17694075.
  4. Dutnall RN et al. (1998), Cell, 94, 427-438. Structure of the histone acetyltransferase Hat1: a paradigm for the GCN5-related N-acetyltransferase superfamily. PMID:9727486.

Step 1. Glu255 deprotonates the Lys12 of the histone substrate, activating it.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Glu255A hydrogen bond acceptor
Phe220A (main-N) hydrogen bond donor
Glu255A proton acceptor

Chemical Components

proton transfer, intermediate formation

Step 2. The activated lysine of the histone substrate initiates a nucleophilic addition on acetylCoA.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Glu255A hydrogen bond donor
Phe220A (main-N) electrostatic stabiliser

Chemical Components

ingold: bimolecular nucleophilic addition, intermediate formation

Step 3. The tetrahedral intermediate collapses to form the acetylated histone and activated CoA.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Glu255A hydrogen bond donor
Phe220A (main-N) electrostatic stabiliser

Chemical Components

ingold: unimolecular elimination by the conjugate base, overall product formed, intermediate collapse, intermediate formation

Step 4. CoA deprotonates Glu255.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Glu255A hydrogen bond donor
Glu255A proton donor

Chemical Components

proton transfer, intermediate terminated, inferred reaction step, native state of enzyme regenerated, overall product formed
Download: Image, Marvin File

Step 1. Glu255 deprotonates the Lys12 of the histone substrate, activating it.

Step 2. The activated lysine of the histone substrate initiates a nucleophilic addition on acetylCoA.

Step 3. The tetrahedral intermediate collapses to form the acetylated histone and activated CoA.

Step 4. CoA deprotonates Glu255.

Products.

Contributors

Judith A. Reeks, Gemma L. Holliday