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. 2016 Jan 14;8(1):63–74. doi: 10.1007/s12551-015-0190-6

PWWP domains and their modes of sensing DNA and histone methylated lysines

Germana B Rona 1, Elis C A Eleutherio 1, Anderson S Pinheiro 1,✉
PMCID: PMC5425739  PMID: 28510146

Abstract

Chromatin plays an important role in gene transcription control, cell cycle progression, recombination, DNA replication and repair. The fundamental unit of chromatin, the nucleosome, is formed by a DNA duplex wrapped around an octamer of histones. Histones are susceptible to various post-translational modifications, covalent alterations that change the chromatin status. Lysine methylation is one of the major post-translational modifications involved in the regulation of chromatin function. The PWWP domain is a member of the Royal superfamily that functions as a chromatin methylation reader by recognizing both DNA and histone methylated lysines. The PWWP domain three-dimensional structure is based on an N-terminal hydrophobic β-barrel responsible for histone methyl-lysine binding, and a C-terminal α-helical domain. In this review, we set out to discuss the most recent literature on PWWP domains, focusing on their structural features and the mechanisms by which they specifically recognize DNA and histone methylated lysines at the level of the nucleosome.

Keywords: Epigenetics, Histone, Lysine, Methylation, PWWP Domain

Chromatin and histones

The eukaryotic genome is highly packed in a dynamic polymer called chromatin. In addition to its structural role, allowing DNA compaction within the nucleus, chromatin regulates a number of essential cellular processes, including gene transcription, cell cycle progression, DNA recombination, replication and repair (Luger et al. 2012). The basic unit of chromatin is the nucleosome, which is composed of 147 base pairs of DNA wrapped around an octamer of histones formed by a tetramer of H3-H4 and two dimers of H2A-H2B (Arents et al. 1991; Luger et al. 1997; Kornberg and Lorck 1999).

Histones undergo numerous post-translational modifications (PTMs), including lysine acetylation, lysine/arginine methylation, serine/threonine/tyrosine/histidine phosphorylation, proline isomerization, arginine deimination, lysine ubiquitination, ADP-ribosylation, sumoylation, crotonylation, propionylation, butyrylation, formylation, hydroxylation, and serine/threonine O-GlcNAcylation (Arnaudo and Garcia 2013; Andreoli and Del Rio 2014; Rothbart and Strahl 2014). Most covalent modifications are present in the intrinsically disordered N- and C-terminal tails of histones; however, some are found in their globular, folded domains (Andreoli and Del Rio 2014; Rothbart and Strahl 2014). Histone PTMs occur with high substrate specificity resulting in different outcomes in terms of chromatin structure and function (Andreoli and Del Rio 2014; Rothbart and Strahl 2014).

Since 1964, when Vincent Allfrey first described histone acetylation and methylation (Allfrey et al. 1964), much research has been focused on the correlation between histone PTMs and chromatin-dependent functions, namely transcriptional regulation. Significant advance in this field came from the discovery of proteins that incorporate, remove, and recognize PTMs in histones, acting as “writers”, “erasers”, and “readers” of the covalent marks, respectively. The first direct link between histone PTMs and transcriptional regulation was provided by the concomitant identification of a transcription-associated histone acetyl transferase, p55/GCN5 (Brownell et al. 1996), and a histone deacetylase, HDAC1/Rpd3 (Taunton et al. 1996). One major landmark was the proposal of the histone code hypothesis by Strahl and Allis (2000). Although the existence of such a code has been the subject of much debate in the literature (Henikoff 2005; Rando 2012), important concepts were introduced with it. Firstly, distinct PTMs may work individually or in combination to give rise to different biological outcomes. Therefore, two distinct PTMs may work together in a synergistic or antagonistic fashion (Strahl and Allis 2000; Cheung et al. 2000). Secondly, histone PTMs may have a direct effect on chromatin structure, altering histone–histone and histone–DNA interactions, most likely due to charge neutralization as in lysine acetylation (Shogren-Knaak et al. 2006). Finally, histone PTMs may work as specific docking sites for protein readers that selectively bind to chromatin and direct downstream events (Turner et al. 1992; Ruthenburg et al. 2011). The identification of the bromodomain as an acetyl-lysine reader module further confirmed this idea and suggested the existence of other effector proteins capable of reading histone PTMs (Dhalluin et al. 1999).

Lysine methylation

Lysine methylation is one of the major PTMs involved in the regulation of chromatin function. Depending on the specific site of methylation, the outcomes may vary significantly. Methylation of histone lysines H3K4, H3K36, and H3K79 are hallmarks of actively transcribed chromatin, while those of H3K9, H3K27, and H4K20 are silenced chromatin marks (Völkel and Angrand 2007; Wozniak and Strahl 2014). The degree of lysine methylation is also a form of transcriptional regulation and histones can be mono-, di- or trimethylated (Völkel and Angrand 2007; Wozniak and Strahl 2014). H3K4me3 is associated with active transcription, H3K9me3, H3K27me3 and H4K20me3 are involved in chromatin repression, while H3K4me1 is a known gene enhancer (Heintzman et al. 2007; Wozniak and Strahl 2014).

Methylation of specific lysines on histones is accomplished by histone lysine methyltranferases (HKMTs). These enzymes either contain a catalytic SET domain, homologous to the suppressor of variegation 3–9 from Drosophila melanogaster, or belong to the Dot1/DOT1L protein family (Völkel and Angrand 2007). Despite its stability, lysine methylation is a reversible process and can be removed by enzymes of the lysine-specific demethylase (KDM) family or enzymes carrying Jumonji (JmjC) domains (Völkel and Angrand 2007). In addition to KMTs and KDMs, a number of other protein domains are capable of binding and recognizing histone methylated lysines, acting as readers of the methylation marks. They are present in several chromatin modifying, remodeling and adaptor proteins (Taverna et al. 2007).

The royal superfamily

Among chromatin readers, we highlight the Royal superfamily, which includes Tudor, Chromo (chromatin-binding), MBT (malignant brain tumor), and PWWP domains. They are involved in several chromatin roles by identifying histone methylated lysines/arginines (Maurer-Stroh et al. 2003). This family seems to be a product of divergent evolution as they share a common ancestor structurally characterized by three conserved β-strands. These domains employ conserved aromatic residues to compose a hydrophobic cavity accountable for methyl-histone binding (Adams-Cioaba and Min 2009; Gayatri and Bedfort 2014).

The PWWP domain

The PWWP domain was first described as a structural motif in WHSC1, a HKMT involved in the Wolf–Hirschhorn syndrome (Stec et al. 1998). The Pro-Trp-Trp-Pro sequence motif is conserved in eukaryotes and the protein domains that encompass it usually contain about 90–130 amino acids. Despite conservation, some variations on the Pro-Trp-Trp-Pro sequence motif may occur. For example, the PWWP domains of the DNA methyltransferases DNMT3a/b contain SWWP motifs (Qiu et al. 2002), while that of the hepatoma-derived growth factor (HDGF) comprises a PHWP motif (Sue et al. 2004) (Fig. 1). Recently, the first position of the Pro-Trp-Trp-Pro sequence motif has been shown to regulate the PWWP domain stability and oligomerization (Hung et al. 2015). PWWP domains that contain a proline as the first amino acid residue of the Pro-Trp-Trp-Pro motif are more stable, less dynamic, and less prone to aggregation than those that display an alanine at the same position (Hung et al. 2015).

Fig. 1.

Fig. 1

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Sequence alignment of PWWP domains. Primary sequence alignment of PWWP domains with previously determined three-dimensional structures. The experimental secondary structure of mouse DNMT3b PWWP (1KHC) is depicted on top of the figure. The Pro-Trp-Trp-Pro sequence motif is highlighted by the black box. Purple boxes mark highly conserved residues, while green boxes mark similar residues. The aromatic cage residues that directly participate in histone methylated lysine binding and recognition are colored red. Sequence alignment was performed with ClustalW2

The PWWP domain is exclusively found in eukaryotes, ranging from lower eukaryotes such as protozoa and yeast to men. The human genome encodes more than 20 PWWP-containing proteins, which are located in the nucleus and play a major role in cell division, growth, and differentiation. They are implicated in various chromatin functions, including DNA modification, repair, and transcriptional regulation (Wu et al. 2011; Qin and Min 2014).

Protein-protein interactions modulate the PWWP domain function

Stec and co-workers (2000) suggested that the PWWP domain may work as a protein–protein interaction site, influencing both chromatin remodeling and transcription. In fact, the DNA methyltransferase DNMT3a directly interacts with SAL-like 3 (SALL3) through its PWWP domain. SALL3 binding decreases DNMT3a interaction with chromatin, inhibiting DNMT3a-mediated CpG island methylation (Shikauchi et al. 2009). The PWWP domain of DNMT3b interacts with the zinc-finger and homeobox protein ZHX1, leading to an increase in DNMT3b transcriptional repression (Kim et al. 2007). In addition, DNMT3b PWWP was also shown to interact with the small ubiquitin-related modifier (SUMO) E3 ligase PIAS1 (Park et al. 2008). The lens epithelium-derived growth factor LEDGF/p75, also known as PSIP1 (PC4 and SFRS1 interacting protein 1), is a transcriptional coactivator that tethers the HIV-1 integrase to active host chromatin. LEDGF/p75 interacts with the methylation-associated transcriptional modulator MeCP2 both in vitro and in human cancer cells (Leoh et al. 2012). This interaction is mediated by its N-terminal PWWP-CR1 domain and regulates MeCP2 transcriptional activity (Leoh et al. 2012). Furthermore, LEDGF/p75 PWWP was shown to interact with the transcriptional activator TOX4 and the splicing cofactor NOVA1 (Morchikh et al. 2013). These proteins seem to play a role in the regulation of LEDGF/p75 interaction with chromatin, controlling processes such as virus replication, DNA repair, and transcription (Morchikh et al. 2013). Despite the large number of binding partners, the molecular mechanisms underlying the modulation of the PWWP domain activity by protein ligands still remain to be elucidated.

Structural features of PWWP domains

To date, several three-dimensional structures of PWWP domains have been reported, including those of DNMT3a, DNMT3b, Pdp1, Pdp2, HDGF, HDGF2, HDGF-related protein 3 (HRP-3), Bromo and plant homeodomain (PHD) finger–containing protein 1 (BRPF1), BRPF2, BRPF3, LEDGF/p75, Mutated melanoma-associated antigen 1 (MUM1), MutS homolog 6 (MSH6), and Zinc finger MYND domain-containing protein 11 (ZMNYD11) (Qiu et al. 2002; Slater et al. 2003; Sue et al. 2004, 2007; Nameki et al. 2005; Lukasik et al. 2006; Laguri et al. 2008; Vezzoli et al. 2010; Wu et al. 2011; Eidahl et al. 2013; van Nuland et al. 2013; Wang et al. 2014; Wen et al. 2014). Table 1 summarizes the structural data currently available in the literature. The PWWP domain adopts a similar fold in all PWWP-containing proteins. This fold can be divided into two distinct substructural motifs: an N-terminal β−barrel substructure and a C-terminal helical substructure (Fig. 2) (Qiu et al. 2002). The N-terminal β−barrel is the most conserved feature of the PWWP domain and it consists of five antiparallel β-strands (β1−β5). The Pro-Trp-Trp-Pro motif is located at the interface of the two substructures, positioned at the end of the β−β arch that connects strands β1 and β2 (β1-β2 arch) and the beginning of β2 (Fig. 2). The first proline residue usually forms a β-bulge, while the second proline induces a bend in strand β2. In addition, the side chains of the two tryptophan residues are oppositely oriented and partially solvent exposed (Fig. 2) (Qiu et al. 2002. The β2−β3 loop is the less conserved part of the β−barrel, both in terms of amino acid composition and length, allowing for the insertion of different secondary structural elements (Qiu et al. 2002, 2012; Slater et al. 2003; Nameki et al. 2005; Vezzoli et al. 2010; Wu et al. 2011).

Table 1.

Three-dimensional structures of PWWP domains currently available in the literature

Protein PDBid Organism Structure determination DNA interaction Histone methyl-lysine interaction Reference
DNA methyltrasferase 3 beta (DNMT3b) apo 1KHC Mouse X-ray crystallography Nonspecific Qiu et al. 2002
SPBC215.07c (Pdp2) apo 1H3Z Schizosaccharomyces pombe Solution NMR Slater et al. 2003
Hepatoma derived growth factor (HDGF) apo 1RI0 Human Solution NMR Heparin Sue et al. 2004
2B8A Human Solution NMR Nonspecific Lukasik et al. 2006
Hepatoma derived growth factor (HDGF) domain-swapped dimer 2NLU Human Solution NMR Heparin Sue et al. 2007
HDGF-related protein 3 (HRP-3) apo 1N27 Human Solution NMR Nameki et al. 2005
MutS Homolog 6 (MSH6) apo 2GF1 Human Solution NMR Laguri et al. 2008
Bromo and plant homeodomain (PHD) finger–containing protein 1 (BRPF1) apo 2X35 Human X-ray crystallography H3K36me3 Vezzoli et al. 2010
3L42 Human X-ray crystallography H3K36me2, H3K36me3, H3K79me2, H3K79me3 Wu et al. 2011
BRPF1:H3K36me3 peptide complex 2X4W Human X-ray crystallography H3K36me3 Vezzoli et al. 2010
2X4X Human X-ray crystallography H3K36me3 Vezzoli et al. 2010
2X4Y Human X-ray crystallography H3K36me3 Vezzoli et al. 2010
3MO8 Human X-ray crystallography H3K36me3 Wu et al. 2011
Bromo and plant homeodomain (PHD) finger–containing protein 2 (BRPF2) apo 3LYI Human X-ray crystallography H3K36me2, H3K79me2, H3K79me3 Wu et al. 2011
Bromo and plant homeodomain (PHD) finger–containing protein 3 (BRPF3) apo 3PFS Human X-ray crystallography Wu et al. 2011
Hepatoma derived growth factor 2 (HDGF2) apo 3EAE Human X-ray crystallography H3K36me2 Wu et al. 2011
Mutated-melanoma associated antigen 1 (MUM1) apo 3PMI Human X-ray crystallography H3K36me2, H3K36me3 Wu et al. 2011
DNA methyltrasferase 3 alpha (DNMT3a):Bis-Tris complex 3LLR Human X-ray crystallography H3K36me3 Wu et al. 2011
DNMT3b:Bis-Tris complex 3QKJ Human X-ray crystallography Wu et al. 2011
HDGF2:H4K20me3 peptide complex 3QBY Human X-ray crystallography H3K36me2 Wu et al. 2011
HDGF2:H3K79me3 peptide complex 3QJ6 Human X-ray crystallography H3K36me2 Wu et al. 2011
Pdp1 apo 2L89 Schizosaccharomyces pombe Solution NMR Nonspecific H4K20me Qiu et al. 2012
Lens epithelium-derived growth factor (LEDGF/p75) apo 2M16 Human Solution NMR Nonspecific H3K36me3 Eidahl et al. 2013
3ZEH Human Solution NMR Nonspecific H3K36me3 Van Nuland et al. 2013
Zinc finger MYND domain-containing protein 11 (ZMNYD11) Bromo-ZnF-PWWP apo 4NS5 Human X-ray crystallography Nonspecific H3K36me3 Wang et al. 2014
4N4G Human X-ray crystallography H3.3K36me3 Wen et al. 2014
ZMNYD11 Bromo-ZnF-PWWP:H3.1K36me3 peptide complex 4N4H Human X-ray crystallography H3.3K36me3 Wen et al. 2014
ZMNYD11 Bromo-ZnF-PWWP:H3.3K36me3 peptide complex 4N4I Human X-ray crystallography H3.3K36me3 Wen et al. 2014
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Fig. 2.

Fig. 2

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The PWWP domain fold. Ribbon diagram of mouse DNMT3b PWWP domain three-dimensional structure (1KHC). a The PWWP domain fold can be subdivided into two distinct substructural motifs. The N-terminal β-barrel is represented in orange, while the C-terminal helical bundle is colored blue. b The Pro-Trp-Tro-Pro sequence motif is positioned in the beginning of strand β2 and displayed in sticks. Residue W245 of mouse DNMT3b PWWP is engaged in direct binding to histone methyl-lysines and is red, while other residues (S243, W244, 9246) are gray

In contrast to the β-barrel, the C-terminal helical substructure is strikingly variable and may contain two to six α-helices (Fig. 3). The PWWP domains of DNMT3a/b contain a bundle of five α-helices (Qiu et al. 2002; Wu et al. 2011). On the other hand, those of BRPF1, HDGF, HDGF2, and Pdp1 are composed of two α-helices connected by a loop (Lukasik et al. 2006; Vezzoli et al. 2010; Wu et al. 2011; Qiu et al. 2012). Recently, the structure of the PWWP domain from LEDGF/p75 revealed a C-terminal region with less helical content than its counterparts. LEDGF/p75 PWWP contains a shorter helix α3, which leads to a longer connecting loop (Eidahl et al. 2013; van Nuland et al. 2013). Despite the lack of sequence conservation, one α-helix is virtually identical in all PWWP structures determined so far (Fig. 3). This common α-helix is packed against the β-barrel. The stability of the PWWP domain arises from intramolecular hydrogen bonds and polar interactions. These interactions occur not only between residues located in the same substructure but also between residues on different substructures, such as those present in the β1−β2 arch and β3−β4 loop and the ones in the helical region (Qiu et al. 2002, 2012; Slater et al. 2003; Nameki et al. 2005; Vezzoli et al. 2010; Wu et al. 2011).

Fig. 3.

Fig. 3

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Structural diversity of the PWWP domain C-terminal helical bundle. The PWWP domain C-terminal substructure may contain two to six helices. a Ribbon diagram of mouse DNMT3b PWWP (1KHC) displaying its five α-helical bundle. b Ribbon diagram of human BRPF1 PWWP (2X35). c Ribbon diagram of human HDGF PWWP (1RI0). d Ribbon diagram of yeast Pdp1 PWWP (2L89). e Ribbon diagram of human LEDGF/p75 PWWP (2M16). The C-terminal substructures of BRPF1, HDGF, Pdp1, and LEDGF/p75 PWWP domains are composed of two α-helices connected by a loop. All C-terminal helical bundles are blue

The PWWP domain uses a basic surface to nonspecifically interact with DNA

The PWWP domain contains a significant amount of basic residues (lysines and arginines), which raises its isoelectric point to more than 9. This creates a positively charged surface that functions as a favorable interface for DNA binding. Qiu and co-workers (2002) demonstrated for the first time that the PWWP domain of DNMT3b directly binds DNA in vitro. In addition, mutations on the PWWP domains of DNMT3a and DNMT3b abolish their interaction with heterochromatin and inhibit their ability to methylate DNA (Chen et al. 2004; Ge et al. 2004). From that time until now, numerous PWWP domains have been shown to exhibit DNA-binding activity, including those of LEDGF/p75 (Singh et al. 2006; Eidahl et al. 2013; van Nuland et al. 2013), HDGF (Lukasik et al. 2006; Yang and Everett 2007), MSH6 (Laguri et al. 2008), DNMT3a (Purdy et al. 2010), Pdp1 (Qiu et al. 2012), and the Bromo-ZnF-PWWP domain of human ZMNYD11 (Wang et al. 2014). For most proteins, DNA binding occurs in a nonspecific manner, without sequence selectivity. The PWWP domain of DNMT3b binds to a 234-bp element of the pericentric chromatin as well as random genomic sequences (Chen et al. 2004). This interaction is efficiently inhibited by sheared salmon sperm DNA, indicating that DNMT3b PWWP is a nonspecific DNA-binding module (Chen et al. 2004). The PWWP domain of HDGF is unable to discriminate between A/T and C/G-rich sequences (Lukasik et al. 2006). NMR titration experiments showed that HDGF PWWP binds to a 15-bp oligonucleotide containing the CACC sequence and a mutant of this DNA, confirming the lack of sequence specificity (Lukasik et al. 2006). The PWWP domain of MSH6 binds to a double-stranded 35-bp oligonucleotide without any preference for G/T mismatches or nicked DNA (Laguri et al. 2008). Moreover, the PWWP domain of DNMT3a exhibits no clear preference for hemimethylated, double-methylated, or CpG-containing double-stranded DNA sequences (Purdy et al. 2010). Finally, consistent with previous results, the PWWP domains of Schizosaccharomyces pombe Pdp1, as well as the human proteins LEDGF/p75 and ZMNYD11 were shown to bind DNA nonspecifically (Qiu et al. 2012; van Nuland et al. 2013; Eidahl et al. 2013; Wang et al. 2014). In contrast to these data, Yang and Everett (2007) have shown that the PWWP domain of HGDF is able to specifically recognize a 37-bp DNA element common to the promoter of SMYD1, arguing about the specificity of interaction between PWWP domains and DNA. DNA binding by PWWP domains occurs with a wide range of affinities, with K d values varying from low nanomolar to high micromolar. DNA-binding affinity and stoichiometry are directly linked to DNA size, suggesting that multiple binding events may occur (Lukasik et al. 2006; Qiu et al. 2012; Eidahl et al. 2013; van Nuland et al. 2013).

NMR titration experiments revealed the DNA-binding interface of numerous PWWP-containing proteins, such as HDGF (Lukasik et al. 2006), Pdp1 (Qiu et al. 2012), and LEDGF/p75 (Eidahl et al. 2013; van Nuland et al. 2013). Several protein resonances are shifted upon addition of DNA, indicating a DNA-binding event that happens in the fast exchange regime. Most of the shifted resonances localize to a single side of the PWWP domain structure. These resonances correspond to residues located in the β1-β2 arch and Pro-Trp-Trp-Pro motif, as well as strand β2 and the helical turns in the C-terminal region. This putative DNA-binding site superimposes well with a highly positively charged surface formed by lysine and arginine residues exposed to the solvent (Fig. 4) (Lukasik et al. 2006; Qiu et al. 2012; Eidahl et al. 2013; van Nuland et al. 2013). This suggests that the PWWP–DNA interaction occurs mostly through electrostatic contacts with the phosphate backbone of the DNA, and thus agrees well with a nonspecific binding mode (Lukasik et al. 2006; Qiu et al. 2012; Eidahl et al. 2013; van Nuland et al. 2013).

Fig. 4.

Fig. 4

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The PWWP domain DNA-binding interface. a Ribbon diagram of human HDGF PWWP three-dimensional structure (2B8A). The N-terminal β-barrel is colored orange, while the C-terminal helical bundle is blue. The HDGF PWWP structure is first represented in the same orientation as Fig. 2 and then rotated 180° about the y axis. b The HDGF PWWP–DNA interface. Residues that directly engage in DNA binding are green and labeled. c Surface representation of the HDGF PWWP structure (2B8A) highlighting the residues that compose the DNA-binding interface (green). d Electrostatics distribution of the HDGF PWWP structure showing that the DNA-binding surface is positively charged

The PWWP domain acts as a histone methyl-lysine reader through a conserved aromatic cage

Structural and sequence similarities between the PWWP domain and other members of the Royal superfamily suggested a possible role in the recognition of modified histone residues. It was only in 2009 that Wang and co-workers found out that the PWWP domain of the yeast protein Pdp1 directly binds to histone 4 lysine 20 monomethylation (H4K20me1) and that this interaction is crucial for the histone methyltransferase Set9 chromatin association (Wang et al. 2009). These results first established a functional role for the PWWP domain as a methyl-lysine reader motif involved in epigenetic regulation. After the discovery that Pdp1 PWWP recognizes H4K20me1, many other PWWP domains were shown to exhibit methylated histone-binding activity, including those of BRPF1 (Vezzoli et al. 2010; Wu et al. 2011), DNMT3a (Dhayalan et al. 2010), BRPF2 (Wu et al. 2011), HDGF2 (Wu et al. 2011), WHSC1 (Wu et al. 2011), WHSC1L1 (Wu et al. 2011), LEDGF/p75 (Pradeepa et al. 2012; Eidahl et al. 2013; van Nuland et al. 2013), Ioc4 (Maltby et al. 2012; Smolle et al. 2012), ZMYND11 (Wen et al. 2014; Wang et al. 2014; Guo et al. 2014), and Pdp3 (Gilbert et al. 2014).

A high-throughput mass spectrometry screening identified the PWWP domain as a histone 3 lysine 36 trimethylation-binding module (Vermeulen et al. 2010). With the exception of Pdp1, all other PWWP domains specifically recognize H3K36me3, suggesting a functional role for this domain as a putative H3K36me3 sensor. This histone trimethylation mark is associated with the coordination of important cellular events such as transcription elongation, mRNA splicing, and expression of developmental genes (Kolasinska-Zwierz et al. 2009; Nimura et al. 2009). Interestingly, in vitro binding of purified PWWP domains to methylated histone peptides occur with very low affinities, with K d values in the low millimolar range (Vezzoli et al. 2010; Dhayalan et al. 2010; Wu et al. 2011; Qiu et al. 2012; Eidahl et al. 2013; van Nuland et al. 2013; Wen et al. 2014; Wang et al. 2014).

Structural analysis revealed that the PWWP domain binds to histone methyl-lysines through a hydrophobic cavity composed of three aromatic residues located in the β1−β2 arch, Pro-Trp-Trp-Pro motif and strand β3 (Vezzoli et al. 2010; Wu et al. 2011; Qiu et al. 2012; Eidahl et al. 2013; van Nuland et al. 2013; Wen et al. 2014; Wang et al. 2014). These amino acids side chains are perpendicularly oriented to one another, forming an aromatic cage that accommodates the trimethyl ammonium group (Fig. 5). Mutations of the residues that compose the aromatic cage abolish methylated histone peptide binding (Wang et al. 2009, 2014; Vezzoli et al. 2010; Maltby et al. 2012; Smolle et al. 2012; Wen et al. 2014; Gilbert et al. 2014; Guo et al. 2014). Moreover, this aromatic cage is a common molecular architecture found in members of the Royal superfamily. Sequence alignment shows that the aromatic cage residues are conserved among several PWWP domains, indicating a common binding mode to methylated histone tails (Vezzoli et al. 2010; Wu et al. 2011; Qiu et al. 2012; Eidahl et al. 2013; van Nuland et al. 2013; Wen et al. 2014; Wang et al. 2014) (Fig. 1). However, some PWWP domains contain a truncated version of the aromatic cage, lacking one of the three aromatic residues, and thus are unable to bind histone methyl-lysines (Gong et al. 2012).

Fig. 5.

Fig. 5

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The PWWP domain histone methyl-lysine-binding aromatic cage. Ribbon diagram of human BRPF1:H3K36me3 peptide complex three-dimensional structure (2X4W). The N-terminal β-barrel is in orange, while the C-terminal helical bundle is blue. The H3K36me3-containing histone peptide is displayed in sticks and colored magenta. The residues that compose the BRPF1 PWWP aromatic cage (Y1096, Y1099, and F1147) responsible for binding H3K36me3 are represented in sticks and colored red

In addition to the aromatic cage, the β2−β3 loop directly participates in histone interaction as it forms one of the walls of the binding pocket (Wu et al. 2011; Qiu et al. 2012). The β2−β3 loop is the region that differs mostly among PWWP domains. These structural differences suggest that the β2−β3 loop may be implicated in determining ligand binding specificity. It is worth noting that the methyl-lysine binding pocket is located in a different position than the DNA binding site. Therefore, PWWP domains employ distinct but contiguous interfaces for binding histones and DNA (Qiu et al. 2012; van Nuland et al. 2013).

The PWWP domain simultaneously binds DNA and histone methyl-lysines within the context of the nucleosome

The observation that the PWWP domain binds histones and DNA in separate regions raised the possibility that this domain may simultaneously interact with methylated histone tails and nucleosomal DNA. A GST-pull down assay demonstrated that the PWWP domain of the S. pombe protein Pdp1 directly interacts with isolated yeast nucleosomes (Wang et al. 2009). In addition, the PWWP domain of DNMT3a is able to pull down native nucleosomes purified from human cells (Dhayalan et al. 2010). Direct nucleosomal binding has been shown to a variety of PWWP-containing proteins, including Pdp1 (Wang et al. 2009; Qiu et al. 2012), DNMT3a (Dhayalan et al. 2010), Ioc4 (Maltby et al. 2012; Smolle et al. 2012), LEDGF/p75 (Eidahl et al. 2013; van Nuland et al. 2013), and ZMNYD11 (Guo et al. 2014). In all cases, nucleosomal interaction is enhanced by histone methylation. The PWWP domain of Pdp1 interacts with nucleosomes purified from wild-type yeast cells, but not with those from strains carrying the histone methyltransferase Set9 deletion or the H4K20R mutation, indicating that Pdp1 PWWP specifically recognizes H4K20me (Wang et al. 2009). Similarly, the PWWP domain of DNMT3a specifically interacts with nucleosomes harboring the H3K36me3 mark (Dhayalan et al. 2010).

The understanding of the PWWP domain binding specificity to nucleosomes has been greatly facilitated by the use of methyl-lysine analogues. In this approach, nucleosomes are reconstituted from recombinant expressed histones containing a specific K to C mutation (i.e., K36C) and further chemically modified to mimic the methylation state (i. e. H3KC36me3). The PWWP domain of Pdp1 preferentially binds to recombinant reconstituted nucleosomes carrying the H4KC20me3 analogue (Qiu et al. 2012). Furthermore, the PWWP domains of Ioc4 (Smolle et al. 2012) and LEDGF/p75 (Eidahl et al. 2013; van Nuland et al. 2013) exhibit higher affinity for H3KC36me3-containing than unmethylated nucleosomes. In vitro binding experiments using purified nucleosomes containing methyl-lysine analogues have shown that the PWWP domain affinity is higher for intact nucleosomes than for either isolated histone peptides or DNA. Qiu and co-workers (2012) demonstrated that the PWWP domain of Pdp1 interacts with H4K20me3 peptide and DNA with K d values of ~6.0 mM and ~4.2 μM, respectively. Although the interactions with the histone peptide and DNA are rather weak, Pdp1 PWWP displays enhanced binding to nucleosomes containing the H4KC20me3 methylation analogue. Moreover, Eidahl and co-workers (2013) found that GST-fused LEDGF/p75 PWWP binds to H3KC36me3-containing nucleosomes (K d ~48 nM) much more strongly than to isolated H3K36me3 peptide (K d ~2.7 mM) and DNA (K d ~1.5 μM). Similarly, van Nuland and co-workers (2013) revealed a respective four and two orders of magnitude enhancement in LEDGF/p75 PWWP binding affinity to H3KC36me3 nucleosomes (K d ~ 1.5 μM) relative to H3K36me3 peptide (K d ~17 mM) and DNA (K d ~150 μM). This affinity enhancement toward nucleosomes is probably due to concerted binding of the PWWP domain to both histone methyl-lysines and DNA.

On the basis of structural data, an atomic model for the PWWP domain-nucleosome complex has been constructed (Fig. 6) (Qiu et al. 2012; Eidahl et al. 2013; van Nuland et al. 2013). In this model, the PWWP domain contacts the two DNA duplexes wrapped around the histone core at two different binding interfaces. Each interface shows a high degree of electrostatic complementarity with the phosphate backbone of the nucleosomal DNA. In addition, the methylated histone tail emerges from between the two DNA duplexes and interacts with the PWWP domain aromatic cage located in the middle of the two DNA-binding sites (Fig. 6). The current model suggests that the hydrophobic pocket and the basic surfaces act synergistically to ensure high-affinity binding of the PWWP domain to nucleosomes (Qiu et al. 2012; Eidahl et al. 2013; van Nuland et al. 2013).

Fig. 6.

Fig. 6

Open in a new tab

Structural model of the LEDGF/p75 PWWP-nucleosome complex. (a) Ribbon diagram of the data-driven structural model of the LEDGF/p75 PWWP domain in complex with the nucleosome (3ZH1). Histones are colored gray, while nucleosomal DNA is shown in salmon. The N-terminal β-barrel of the LEDGF/p75 PWWP domain is colored orange, and the C-terminal helical bundle is colored blue. Histone H3 residues 31–42, harboring the K36 trimehthylation mark, are displayed in sticks and colored magenta (b) Same as in a rotated 180° about the x axis. (c) A zoom in on the LEDGF/p75 PWWP domain interaction with the nucleosomal particle. The aromatic cage residues Y18, W21, F44, which are directly engaged in H3K36me3 binding, are represented in sticks and colored red. In addition, residues K16, K38, K56, K73, R74, K75, which nonspecifically bind DNA, are represented in sticks and colored green

Conclusions

In conclusion, the PWWP domain, a member of the Royal superfamily, functions as a histone methyl-lysine reader, most likely H3K36me3, through a conserved aromatic cage present in its N-terminal β-barrel substructure. In addition, most PWWP domains employ basic interfaces to nonspecifically bind DNA. Nucleosomal DNA interaction results in an increase in binding affinity to histone methyl-lysines. Concerted binding to methylated histone tails and DNA leads to specific recognition of H3K36me3-containing nucleosomes. A similar mode of interaction may be used to recognize other histone PTMs located close to the nucleosomal core.

Acknowledgments

This work was supported by grants from Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and by a Brazil Initiative Collaboration grant from Brown University to A.S.P. G.B.R is recipient of a Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) graduate fellowship.

Compliance with ethical standards

Conflict of interest

Germana B. Rona declares that she has no conflict of interest.

Elis C. A. Eleutherio declares that she has no conflict of interest.

Anderson S. Pinheiro declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

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