Chromatin Recognition Protein Modules: The PHD Finger

Nada Lallous, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
Santiago Ramón‐Maiques, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

Published online: February 2011

DOI: 10.1002/9780470015902.a0023176

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 Protein Data Bank (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., 2009; Kouzarides, 2007b) http://www.millipore.com/techpublications/tech1/pb1014en00 and http://www.abcam.com. These modifications might not occur in every organism or simultaneously in the same histone tail.
Figure 2. Histone posttranslational modification (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 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 -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.
close
 References
    Aasland R, Gibson TJ and Stewart AF (1995) The PHD finger: implications for chromatin-mediated transcriptional regulation. Trends in Biochemical Science 20: 56–59.
    book Allis CD, Jenuwein T and Reinberg D (ed.) (2009) Epigenetics, 2009 edn. New York: Cold Spring Harbor Laboratory Press.
    Chakravarty S, Zeng L and Zhou MM (2009) Structure and site-specific recognition of histone H3 by the PHD finger of human autoimmune regulator. Structure 17: 670–679.
    Champagne KS and Kutateladze TG (2009) Structural insight into histone recognition by the ING PHD fingers. Current Drug Targets 10: 432–441.
    Champagne KS, Saksouk N and Pena PV (2008) The crystal structure of the ING5 PHD finger in complex with an H3K4me3 histone peptide. Proteins 72: 1371–1376.
    Chang PY, Hom RA, Musselman CA et al. (2010) Binding of the MLL PHD3 finger to histone H3K4me3 is required for MLL-dependent gene transcription. Journal of Molecular Biology 400: 137–144.
    Chignola F, Gaetani M, Rebane A et al. (2009) The solution structure of the first PHD finger of autoimmune regulator in complex with non-modified histone H3 tail reveals the antagonistic role of H3R2 methylation. Nucleic Acids Research 37: 2951–2961.
    Chruscicki A, Macdonald VE, Young BP, Loewen CJ and Howe LJ (2010) Critical determinants for chromatin binding by Saccharomyces cerevisiae Yng1 exist outside of the plant homeodomain finger. Genetics 185: 469–477.
    Coscoy L and Ganem D (2003) PHD domains and E3 ubiquitin ligases: viruses make the connection. Trends in Cell Biology 13: 7–12.
    Coscoy L, Sanchez DJ and Ganem D (2001) A novel class of herpesvirus-encoded membrane-bound E3 ubiquitin ligases regulates endocytosis of proteins involved in immune recognition. Journal of Cell Biology 155: 1265–1273.
    Eberharter A, Vetter I, Ferreira R and Becker PB (2004) ACF1 improves the effectiveness of nucleosome mobilization by ISWI through PHD-histone contacts. EMBO Journal 23: 4029–4039.
    Fiedler M, Sanchez-Barrena MJ, Nekrasov M et al. (2008) Decoding of methylated histone H3 tail by the Pygo-BCL9 Wnt signaling complex. Molecular Cell 30: 507–518.
    Garcia-Dominguez M, March-Diaz R and Reyes JC (2008) The PHD domain of plant PIAS proteins mediates sumoylation of bromodomain GTE proteins. Journal of Biological Chemistry 283: 21469–21477.
    Gozani O, Karuman P, Jones DR et al. (2003) The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor. Cell 114: 99–111.
    Guccione E, Bassi C, Casadio F et al. (2007) Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive. Nature 449: 933–937.
    Hom RA, Chang PY, Roy S et al. (2010) Molecular mechanism of MLL PHD3 and RNA recognition by the Cyp33 RRM domain. Journal of Molecular Biology 400: 145–154.
    Iberg AN, Espejo A and Cheng D (2008) Arginine methylation of the histone H3 tail impedes effector binding. Journal of Biological Chemistry 283: 3006–3010.
    van Ingen H, van Schaik FM, Wienk H et al. (2008) Structural insight into the recognition of the H3K4me3 mark by the TFIID subunit TAF3. Structure 16: 1245–1256.
    Ivanov AV, Peng H, Yurchenko V et al. (2007) PHD domain-mediated E3 ligase activity directs intramolecular sumoylation of an adjacent bromodomain required for gene silencing. Molecular Cell 28: 823–837.
    Iwase S, Lan F, Bayliss P et al. (2007) The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 128: 1077–1088.
    Jenuwein T and Allis CD (2001) Translating the histone code. Science 293: 1074–1080.
    Kaadige MR and Ayer DE (2006) The polybasic region that follows the plant homeodomain zinc finger 1 of Pf1 is necessary and sufficient for specific phosphoinositide binding. Journal of Biological Chemistry 281: 28831–28836.
    Karagianni P, Amazit L, Qin J and Wong J (2008) ICBP90, a novel methyl K9 H3 binding protein linking protein ubiquitination with heterochromatin formation. Molecular Cell Biology 28: 705–717.
    Kirmizis A, Santos-Rosa H, Penkett CJ et al. (2007) Arginine methylation at histone H3R2 controls deposition of H3K4 trimethylation. Nature 449: 928–932.
    Kirmizis A, Santos-Rosa H, Penkett CJ et al. (2009) Distinct transcriptional outputs associated with mono- and dimethylated histone H3 arginine 2. Nature Structural Molecular Biology 16: 449–451.
    Kouzarides T (2007a) Chromatin modifications and their function. Cell 128: 693–705.
    Kouzarides T (2007b) SnapShot: histone-modifying enzymes. Cell 131: 822.
    Lan F, Collins RE, De Cegli R et al. (2007) Recognition of unmethylated histone H3 lysine 4 links BHC80 to LSD1-mediated gene repression. Nature 448: 718–722.
    Li B, Gogol M, Carey M et al. (2007a) Combined action of PHD and chromo domains directs the Rpd3S HDAC to transcribed chromatin. Science 316: 1050–1054.
    Li F, Huarte M, Zaratiegui M et al. (2008) Lid2 is required for coordinating H3K4 and H3K9 methylation of heterochromatin and euchromatin. Cell 135: 272–283.
    Li H, Fischle W, Wang W et al. (2007b) Structural basis for lower lysine methylation state-specific readout by MBT repeats of L3MBTL1 and an engineered PHD finger. Molecular Cell 28: 677–691.
    Li H, Ilin S, Wang W et al. (2006) Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature 442: 91–95.
    Matthews AG, Kuo AJ, Ramón-Maiques S et al. (2007) RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination. Nature 450: 1106–1110.
    Matthews JM, Bhati M, Lehtomaki E et al. (2009) It takes two to tango: the structure and function of LIM, RING, PHD and MYND domains. Current Pharmaceutical Design 15: 3681–3696.
    Miller TC, Rutherford TJ, Johnson CM, Fiedler M and Bienz M (2010) Allosteric remodelling of the histone H3 binding pocket in the Pygo2 PHD finger triggered by its binding to the B9L/BCL9 co-factor. Journal of Molecular Biology 401: 969–984.
    Palacios A, Garcia P, Padro D et al. (2006) Solution structure and NMR characterization of the binding to methylated histone tails of the plant homeodomain finger of the tumour suppressor ING4. FEBS Letters 580: 6903–6908.
    Pena PV, Davrazou F, Shi X et al. (2006) Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2. Nature 442: 100–103.
    Ragvin A, Valvatne H, Erdal S et al. (2004) Nucleosome binding by the bromodomain and PHD finger of the transcriptional cofactor p300. Journal of Molecular Biology 337: 773–788.
    Ramón-Maiques S, Kuo AJ, Carney D et al. (2007) The plant homeodomain finger of RAG2 recognizes histone H3 methylated at both lysine-4 and arginine-2. Proceedings of the National Academy of Sciences of the USA 104: 18993–18998.
    Ruthenburg AJ, Allis CD and Wysocka J (2007) Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Molecular Cell 25: 15–30.
    Saksouk N, Avvakumov N, Champagne KS et al. (2009) HBO1 HAT complexes target chromatin throughout gene coding regions via multiple PHD finger interactions with histone H3 tail. Molecular Cell 33: 257–265.
    Scheel H and Hofmann K (2003) No evidence for PHD fingers as ubiquitin ligases. Trends in Cell Biology 13: 285–287 author reply 287–288.
    Schindler U, Beckmann H and Cashmore AR (1993) HAT3.1, a novel Arabidopsis homeodomain protein containing a conserved cysteine-rich region. Plant Journal 4: 137–150.
    Shi X, Hong T, Walter KL et al. (2006) ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442: 96–99.
    Taverna SD, Ilin S, Rogers RS et al. (2006) Yng1 PHD finger binding to H3 trimethylated at K4 promotes NuA3 HAT activity at K14 of H3 and transcription at a subset of targeted ORFs. Molecular Cell 24: 785–796.
    Taverna SD, Li H, Ruthenburg AJ, Allis CD and Patel DJ (2007) How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nature Structural and Molecular Biology 14: 1025–1040.
    Vermeulen M, Mulder KW, Denissov S et al. (2007) Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell 131: 58–69.
    Wang GG, Song J, Wang Z et al. (2009) Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger. Nature 459: 847–851.
    Wang Z, Song J, Milne TA et al. (2010) Pro isomerization in MLL1 PHD3-bromo cassette connects H3K4me readout to CyP33 and HDAC-mediated repression. Cell 141: 1183–1194.
    Wen H, Li J, Song T et al. (2010) Recognition of histone H3K4 trimethylation by the plant homeodomain of PHF2 modulates histone demethylation. Journal of Biological Chemistry 285: 9322–9326.
    Wysocka J, Swigut T, Xiao H et al. (2006) A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 442: 86–90.
    Zeng L, Yap KL, Ivanov AV et al. (2008) Structural insights into human KAP1 PHD finger-bromodomain and its role in gene silencing. Nature Structural and Molecular Biology 15: 626–633.
    Zeng L, Zhang Q, Li S et al. (2010) Mechanism and regulation of acetylated histone binding by the tandem PHD finger of DPF3b. Nature 466: 258–262.
 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.
    Bienz M (2006) The PHD finger, a nuclear protein-interaction domain. Trends in Biochemical Sciences 31: 35–40.
    Chi P, Allis CD and Wang GG (2010) Covalent histone modifications – miswritten, misinterpreted and mis-erased in human cancers. Nature Reviews. Cancer 10: 457–469.
    other Focus on chromatin (2007) Nature Structural and Molecular Biology. 14: 985–1115.
    Musselman CA and Kutateladze TG (2009) PHD fingers: epigenetic effectors and potential drug targets. Molecular Interventions 9: 314–323.
    Ruthenburg AJ, Li H, Patel DJ and Allis CD (2007) Multivalent engagement of chromatin modifications by linked binding modules. Nature Reviews. Molecular Cell Biology 8: 983–994.
    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.

Related Sub-Topics:

Protein Structure | Nucleic Acid Structure | Posttranslational Modification | Chromosomes and Chromatin Modifications | Biomolecular Interactions | Proteins: Structure, Function, Metabolism
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Chromatin Recognition Protein Modules: The PHD Finger
 
How to Cite close
Lallous, Nada, and Ramón‐Maiques, Santiago(Feb 2011) Chromatin Recognition Protein Modules: The PHD Finger. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023176]