Chromatin Recognition Protein Modules: The PHD Finger


The structure of chromatin controls the accessibility to deoxyribonucleic acid (DNA) information. Posttranslational modifications (PTMs) of histones modify the architecture of chromatin and provide docking platforms for proteins that control many DNA‐templated processes. The plant homeodomain (PHD) fingers are small protein domains found in nuclear factors that interact with chromatin. Recent studies have characterised two classes among the PHD fingers, which specifically bind to either unmodified or trimethylated K4 histone H3. A number of PHD finger structures in complex with histone peptides reveal the recognition mechanisms. The combination of multiple histone PTMs, the cooperation between different PHD fingers or between PHD fingers and other histone recognition proteins illustrate the plurality and versatility of this protein module. Mutations or translocations in PHD fingers that affect their interaction with histones have been related to immunological diseases, cancer or mental retardation.

Key Concepts:

  • Histone modifications form part of the chromatin control of DNA‐templated processes.

  • PHD fingers are small nuclear protein domains that bind two zinc ions in an interlaced topology.

  • Several PHD fingers specifically recognise the di‐ and trimethylated K4 histone H3 tail, and others bind specifically to unmethylated K4 histone H3.

  • Aromatic cages are cavities formed by the side chains of 2–4 aromatic residues used by PHD fingers and by other protein modules for binding to methylated lysines.

  • Alterations of the histone recognition by PHD fingers are related to immunological diseases, cancer and mental retardation.

Keywords: PHD finger; chromatin; nucleosome; epigenetics; histone; posttranslational modification; methylation; protein structure

Figure 1.

The nucleosome and histone covalent modifications. (a) The nucleosome is formed by two copies of each histone (H2A, H2B, H3 and H4) and 147 bp of DNA that wrap the histone octamer forming a left‐handed superhelix. The coordinates of the model are taken from the (PDB) accession number 1KX5. The histone globular regions are shown in cartoon with helices illustrated as cylinders, and the DNA is shown in greyish surface representation. The histone tails, depicted in ball‐and‐stick, protrude outside the nucleosome core. (b) Representation of possible histone posttranslational covalent modifications. The histone cores are represented as ellipsoids and the amino acid sequences of the tails are shown. Modification sites were taken from (Allis et al., ; Kouzarides, ) and These modifications might not occur in every organism or simultaneously in the same histone tail.

Figure 2.

(PTM)‐binding modules. Gallery of histone PTM‐binding proteins showing the overall protein fold in cartoon and a detailed view of the interaction with the histone substrate (coloured in magenta). (a) Bromodomains recognise acetylated lysine (Kac). The bromodomain of Gcn5 (PDB 1E6I) bound to H4K16ac is shown. (b) Chromodomains bind di‐ and tri‐methylated lysines. The chromodomain of polycomb bound to H3K27me3 is represented (PDB 1PDQ). The methylated lysine binds in an aromatic cage. (c) Tudor domains recognise mono‐ and di‐methylated lysines. The tandem tudor domain of 53BP1 bound to H4K20me2 is represented (PDB 2IG0). (d) Malignant brain tumor (MBT) repeats recognise mono‐ and dimethylated lysines. Protein L3MBTL1 presents three MBT repeats (PDB 2RHI), and one of them (in yellow) binds dimethylated lysine in an aromatic cage. (e) and (f) WD40‐repeats from two different proteins show different specificity. (e) WD40‐repeat of protein EED with H3K27me3 binding in the central cavity (PDB 3JZG). (f) WD40‐repeat of WDR5 inserts the unmodified H3R2 side chain into the central cavity and exposes the side chain of H3Kme2 to the solvent (PDB 2H6N). (g) and (h) 14‐3‐3 protein and tandem BRCT repeats bind phospho‐serine (PDB 2C1J and 2AZM).

Figure 3.

The PHD finger structure. (a) Cartoon representation of the ING2 PHD finger fold (PDB ID 2G6Q). The protein core is formed by a central antiparallel two‐stranded β sheet that separates the two zinc‐binding sites. Zinc atoms are represented as orange spheres. The Zn‐coordinating side chains and a conserved aromatic residue preceding the last two cysteines are shown. The bound histone tail is shown in yellow. (b) The superposition of the PHD fingers of ING2, BPTF and AIRE shows that, despite important sequence and substrate differences among them, the protein fold is well conserved (PDB IDs 2G6Q, 2F6J, 2KE1).

Figure 4.

Structural bases of histone recognition by PHD fingers. (a) Multiple sequence alignment of different structurally characterised PHD fingers. The sequences are grouped into two classes based on their preference for binding histone H3 with unmethylated (H3K4) or methylated lysine K4 (H3K4me). The cysteines and histidines coordinating the two zinc atoms are highlighted in red and their interlaced arrangement is indicated with lines at the bottom of the alignment. An invariant aromatic residue preceding the last two cysteines is highlighted in dark blue. Residues forming the aromatic cage and the conserved residue neutralising the side chain of unmethylated K4 are highlighted in yellow and green, respectively. Most PHD fingers have an aspartate (in light blue) that interacts with histone R2. RAG2 and Pygo present a residue (highlighted in magenta) that blocks the R2 binding site. On top of the sequences, two arrows indicate the position of the central β‐strands. (b) and (d) Electrostatic surface representation and detailed cartoon interaction of the PHD finger of BPTF bound to H3K4me3 (shown in ball‐and‐stick) (PDB 2F6J). In (d) the surface contour of the residues interacting with K4me3 is drawn to illustrate the features of the aromatic cage. Similar representations of the PHD finger of AIRE bound to H3K4me0 (PDB 2KE1) are shown in (c) and (e). The dashed lines indicate hydrogen bond and ionic interactions between the proteins and the histone tail.



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Further Reading

Baker LA, Allis CD and Wang GG (2008) PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks. Mutation Research 647: 3–12.

Bhaumik SR, Smith E and Shilatifard A (2007) Covalent modifications of histones during development and disease pathogenesis. Nature Structural and Molecular Biology 14: 1008–1016.

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Shilatifard A (2006) Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu Rev Biochem 75: 243–269.

Wang GG, Allis CD and Chi P (2007) Chromatin remodeling and cancer, Part I: covalent histone modifications. Trends in Molecular Medicine 13: 363–372.

Zlatanova J, Bishop TC, Victor JM, Jackson V and van Holde K (2009) The nucleosome family: dynamic and growing. Structure 17: 160–171.

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Lallous, Nada, and Ramón‐Maiques, Santiago(Feb 2011) Chromatin Recognition Protein Modules: The PHD Finger. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023176]