Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013 Feb;99(2):98-111.
doi: 10.1002/bip.22128.

Histone acetyltransferases: Rising ancient counterparts to protein kinases

Hua Yuan  1 , Ronen Marmorstein
Affiliations
Review

Histone acetyltransferases: Rising ancient counterparts to protein kinases

Hua Yuan et al. Biopolymers. 2013 Feb.

Abstract

Protein kinases catalyze phosphorylation, a posttranslational modification widely utilized in cell signaling. Histone acetyltransferases (HATs) catalyze a counterpart posttranslational modification of acetylation which marks histones for epigenetic signaling but in some cases modifies non-histone proteins to mediate other cellular activities. In addition, recent proteomic studies have revealed that thousands of proteins are acetylated throughout the cell to regulate diverse biological processes, thus placing acetyltransferases on the same playing field as kinases. Emerging biochemical and structural data further supports mechanistic and biological links between the two enzyme families. In this article, we will review what is known to date about the structure, catalysis and mode of regulation of HAT enzymes and draw analogies, where relevant, to protein kinases. This comparison reveals that HATs may be rising ancient counterparts to protein kinases.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Overall Structure of HAT Proteins and Kinases
Representative members of the 5 HAT families and kinase are illustrated as cartoons. The structurally conserved core region of HATs are colored in blue and flanking N- and C-terminal regions are colored in aqua. The cofactor is shown in stick figure in yellow (a) Yeast HAT1 (yHAT1, KAT1)/Ac-CoA (PDB 1BOB), (b) Tetrahymena Gcn5 (tGcn5, KAT2)/CoA/histone H3 peptide (PDB 1PUA), (c) Yeast Esa1(yEsas1, KAT5)/H4K16-CoA (PDB 3TO6) (residues flanking K16 in the peptide are disordered in the structure), (d) Human p300 (hp300, KAT3B)/Lys-CoA (PDB 3BIY), (e) Yeast Rtt109(yRtt109, KAT11)/CoA (PDB 3D35) and (f) Human insulin receptor tyrosine kinase (with the N-lobe in green and C-lobe in aqua) in complex with the non-hydrolyzable ATP analogue, AMP-PNP (stick) and substrate-peptide (purple) (PDB 1IR3)
Figure 2
Figure 2. Catalytic Mechanism of HAT Proteins and Kinases
Active sites of representative members of the HAT families (same as Figure 1) and cAMP kinase are illustrated highlighting the relevant side chains on a backbone cartoon of the active site. The cofactors are shown in yellow sticks and catalytic residues in green sticks. (a) tGcn5/CoA/histone H3. Key catalytic residues are labeled and hydrophobic residues of the active site that likely raise the pKa of Glu173 are shown in white sticks. The numbering is for yGcn5. (b) yEsa1/H4K16CoA. Key catalytic residues are labeled and hydrophobic residues of the active site that likely raise the pKa of Glu338 are shown in white sticks. Residues flanking Lys16 in the histone H4 peptide are disordered in the structure. (c) hp300/Lys-CoA. Residues demonstrated to play catalytic roles are labeled with other potential catalytic residues shown in dark green. (d) yRtt109/CoA with potential catalytic residues in the corresponding position of hp300 shown in sticks. (e) hHAT1/AcCoA/histone H4. The three general base candidate residues are represented as green sticks. (f) cAMP-dependent protein kinase in complex with ATP highlighting the P-loop (blue), A-loop (red), catalytic loop (green) and hinge region (orange) (PDB 1ATP).
Figure 3
Figure 3. Substrate Binding by HAT Proteins and kinases
Close-up electrostatic surface view of HAT domains (same as in Figure 1) and cAMP kinase structures with peptide substrates or CoA-peptide bisubstrate inhibitors shown in ball and stick model in cpk color. Electrostatic potential is color coded with red representing negative charge (−4 kT/e) and blue representing positive charge (4 kT/e). (a) Structure of tGcn5 bound to CoA (yellow) and a 19- residue histone H3 peptide (white) centered around K14 (purple). (b) Structure of hHAT1 bound to AcCoA (yellow) and a histone H4 peptide (1–20) (white) centered around K12 (purple). (c) Structure of the hp300/LysCoA complex. The LysCoA inhibitor is shown in yellow for the CoA moiety and purple for the lysine moiety. (d) Structure of the yEsa1/H4K16CoA complex (only the lysine residue of the H4K16 peptide component of the bisubstrate inhibitor is ordered in the crystal structure and shown in purple). (e) Structure of cAMP-dependent protein kinase in complex with a substrate peptide showing the serine residue in purple (PDB 1JBP).
Figure 4
Figure 4. Auto Regulation of HAT Proteins and Kinases
Close-up views of the autoacetylation site of HAT proteins and kinases. (a) Model for hp300 activation by autoacetylation (electrostatic potential maps are contoured at ± 4.0 kT/e, the same as in Figure 3), (b) The Lys290 autoacetylation site of yRtt109 highlighting the environment around acetylated Lys290. (c) Structure of hMOF highlighting the environment around acetylated Lys274 (green stick). The loop harboring Lys274 is highlighted in red for the acetylated conformation and blue for the unacetylated conformation. Superposition of the yEsa1/H4K16CoA structure with hMOF indicates that the unacetylated conformation would clash with binding of the cognate substrate lysine (as represented by the lysine of the H4K16CoA bisubstrate inhibitor shown in purple). (d) Structures of insulin receptor tyrosine kinase showing the autoinhibited conformation (left, PDB 1IRK) and autoactivated conformation (right, PDB 1IR3). The activation loop harboring unphosphorylated Tyr1162 adopts an autoinhibited conformation (blue) that would clash with the binding of both the cofactor (yellow stick) and cognate peptide substrate (purple).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Krebs EG, Fischer EH. J Biol Chem. 1955;216:113–120. - PubMed
    1. Fischer EH, Krebs EG. J Biol Chem. 1955;216:121–132. - PubMed
    1. Walsh DA, Perkins JP, Krebs EG. Journal of Biological Chemistry. 1968;243:3763–3765. - PubMed
    1. Wu H, Moshkina N, Min J, Zeng H, Joshua J, Zhou MM, Plotnikov AN. Proc Natl Acad Sci U S A. 2012;109:8925–8930. - PMC - PubMed
    1. Brownell JE, Zhou J, Ranalli T, Kobayashi R, Edmondson DG, Roth SY, Allis CD. Cell. 1996;84:843–851. - PubMed

LinkOut - more resources