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Review
. 2015 Mar 25;115(6):2419-52.
doi: 10.1021/cr500452k. Epub 2015 Jan 16.

Protein lysine acetylation by p300/CBP

Beverley M Dancy  1 , Philip A Cole  1
Affiliations
Review

Protein lysine acetylation by p300/CBP

Beverley M Dancy et al. Chem Rev. .

Erratum in

No abstract available

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Figures

Figure 1
Figure 1
Reversible acetylation of the epsilon amine group of lysine side chains.
Figure 2
Figure 2
Major metabolic processes that produce or consume acetyl-CoA. Processes occurring in the cytoplasm are indicated using purple font, and processes occurring in the mitochondrion are indicated using orange font. Note that PDH can also be nuclear. This figure was adapted in part from Albaugh et al.
Figure 3
Figure 3
Domain structure of p300/CBP. Exon–intron gene diagrams are shown for p300 and CBP (top). Below are example protein structures for the bromodomain (PDB 3I3J, 2.33 Å), catalytic HAT domain (PDB 3BIY, 1.7 Å), ZZ zinc finger (PDB 1TOT), and TAZ2 domain (PDB 3IO2, 2.5 Å). All structures were produced using purified p300, except the ZZ zinc finger, which used purified CBP. p300/CBP proteins are colored with a rainbow, with blue at the N-terminus and red at the C-terminus, and residues included in the structure are listed below each. Zinc ions are black spheres. All structures are based on X-ray crystallography, except the ZZ zinc finger structures from solution NMR. The p300 bromodomain structure shown here is remarkably similar to an independently generated CBP bromodomain structure (not shown, PDB 3DWY, 1.98 Å). Below is a model for full-length p300/CBP with all domains shown, and is a compilation based on several recent analyses.:, three cysteine/histidine-rich (C/H) domains are shown in turquoise, three zinc fingers are shown in yellow, and the catalytic acetyltransferase domain is shown in orange, with its autoacetylated regulatory loop drawn above, which corresponds to residues 1523–1554. A few examples of proteins that bind p300/CBP are listed below the protein model, with the particular domain involved in binding indicated with a black line. Below that, amino acid similarity is indicated, for comparing p300 and CBP sequences within either the catalytic BHC region (from the bromodomain to the C/H3 domain) or the entire protein. At the bottom, commonly purified active p300 variants are indicated, including p300 acetyltransferase/HAT domain, BHC enzyme (bromodomain-HAT-C/H3), and full-length protein. It should be noted that p300 HAT has a deletion in residues 1529–1560.
Figure 4
Figure 4
p300/CBP is central to many important signaling pathways. These include pathways that respond to intracellular signals (turquoise), extracellular signals (purple), and intercellular signals (blue). These pathways control the key cellular functions via altering expression of target genes, through the action of p300/CBP in the nucleus.
Figure 5
Figure 5
p300/CBP functions as a scaffold, bridge, and acetyltransferase. The acetyltransferase reactions are illustrated by turquoise arrows, indicating acetylation of histone and nonhistone substrates (in yellow), as well as autoacetylation of the p300/CBP acetyltransferase domain. The bridge function is illustrated by turquoise squares, representing DNA-binding proteins that bring DNA elements into proximity with p300/CBP through their interactions. The scaffold function is illustrated by orange squares, representing a protein complex being recruited by p300/CBP. These functions together allow for gene expression.
Figure 6
Figure 6
p300 acetyltransferase domain structure bound to Lys-CoA. (A) Secondary structures of p300 acetyltransferase domain. (B) L1 loop and an acidic surface. (C) Parts of Lys-CoA bisubstrate analog (gray) and four p300 residues of interest (green). Generated in PyMol based on Protein Databank entry 3BIY, published by Liu et al.
Figure 7
Figure 7
Acetyl transfer catalysis by p300. (A) The p300 active site is drawn in green, and histone H4 substrate in blue, with important residues indicated. CoA is drawn in black, and binds in a specific tunnel. (B) Four steps in a proposed p300 mechanism. acetyl-CoA binds, then peptidyl-lysine binds. The hydrophobic indole of W1436 promotes an uncharged lysine and positions it for attack. The lysine attacks the carbonyl of acetyl-CoA, while Y1467 acts as a general acid to protonate the leaving group. Acetyl-lysine-containing product leaves quickly, then CoASH departs slowly.
Figure 8
Figure 8
Bisubstrate inhibitors of acetyltransferases.
Figure 9
Figure 9
Natural products implicated as modulators of acetyltransferases.
Figure 10
Figure 10
Synthetic inhibitors of acetyltransferases.
Figure 11
Figure 11
C646 modeled in the acetyltransferase active site. (A) C646 is shown in magenta, computationally docked in the crystal structure of the acetyltransferase active site, which was generated as a cocrystal with Lys-CoA. Several residues that coordinate CoA binding are predicted to similarly coordinate C646 binding, as shown in aqua stick representations of the side chains. (B) The structure of C646, shown in an orientation similar to that in the docked model above.
Figure 12
Figure 12
Structures of CBP bromodomain bound to ligands. The purified CBP bromodomain (residues 1081–1197, shown in a rainbow blue to red) is shown bound to (A) histone H4 residues 14–28 acetylated at K20 (PDB 2RNY); (B) p53 residues 367–386 acetylated at K382 (PDB 1JSP); (C) the compound ischemin (PDB 2L84); and (D) the compound dimethylisoxazole (PDB 3SVH). Peptide ligands are shown in gray (A,B) or stick models colored by atom (C,D and acetyl-lysines in A,B). All structures are based on solution NMR except for (D), which is from X-ray crystallography (1.8 Å).
Figure 13
Figure 13
Structures of p300/CBP TAZ2 domain bound to ligands. The TAZ2 domain is shown colored in a rainbow (blue to red, residues included listed below each) bound to various ligands: STAT1 (A, PDB 2KA6); E1A (B, PDB 2KJE); p53 (C, PDB 2K8F); MEF2-DNA complex (D, PDB 3P57), and C/EBPε (PDB 3T92). All structures are based on solution NMR except for two from X-ray crystallography: that in (D) (2.192 Å) and that in (E) (1.5 Å). All structures were produced using purified p300, except the (A) and (B), which used purified CBP. Zinc ions are black spheres, protein ligands are gray, and DNA is yellow. The crystal structure with MEF2 revealed binding in three possible conformations with TAZ2, and one example is shown here.
Figure 14
Figure 14
Models for targeting influenced by p300-ligand binding. In these models, p300 is shown in green, the histone octamer is shown in yellow, DNA is shown with a red strand, and p300 ligands are indicated with an “L”. In (A), a ligand targets p300 to a gene or other DNA element due to the DNA binding affinity of the ligand. In (B), a ligand targets p300 to a protein complex due to the protein binding affinity of the ligand. In (C), two ligands bridged by p300 allow for chromatin (bound by the purple ligand) to come into proximity with a chromatin-modifying enzyme (the orange ligand). In (D), two ligands compete for the same site within p300, and the one ligand could be seen as a competitive inhibitor for the p300 association with the other.
Figure 15
Figure 15
Mastermind-Notch-CSL-DNA core complex. The complex formed by DNA, CSL, Notch (ANK repeats and RAM region purified separately), and Mastermind N-terminal helix is shown with two different view angles. The X-ray crystal structure was generated at 3.85 Å, and this figure was produced in PyMol using Protein Databank entry 3V79. Proteins are shown as ribbons, with the surfaces at 70% transparency. DNA is shown as stick models colored by atom.
Figure 16
Figure 16
Model for Mastermind activation of p300. In this model, p300 (green) initially has inhibited acetyltransferase activity due to an autoinhibitory loop (orange, left). This is relieved upon recruitment by the Notch-Mastermind-CSL complex. Mastermind (purple) binds to the p300 C/H3 domain, and also to Notch intracellular domain (magenta) and CSL (red). p300 autoacetylation, Mastermind acetylation, and histone acetylation are then catalyzed by p300 (turquoise ▲).
Figure 17
Figure 17
Inhibitors of the p300/CBP bromodomain.
Figure 18
Figure 18
Inhibitors of the other p300/CBP domains.
Figure 19
Figure 19
Diseases of potential therapeutic application for a p300/CBP inhibitor. No p300/CBP inhibitor has yet made it into clinical trials, but the biology of p300/CBP action and documented effects of p300/CBP disruption lead us to hypothesize a beneficial therapeutic potential for a p300/CBP inhibitor in many diseases.
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