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1 RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan
2 Tatsuo Miyazawa Memorial Program, RIKEN Genomic Sciences Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan
3 RIKEN Harima Institute at SPring-8, 1-1-1 Kouto, Mikazuki-cho, Sayo, Hyogo 679-5148, Japan
4 Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Reprint requests to: Shigeyuki Yokoyama, Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; e-mail: yokoyama{at}biochem.s.u-tokyo.ac.jp; fax: +81-45–503-9195.
(RECEIVED July 6, 2004; FINAL REVISION October 4, 2004; ACCEPTED November 9, 2004)
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Abstract |
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-barrel with a PWWP-specific long loop connecting 2 and 3 (PR-loop), followed by a helical region including two 
-helices. Its structure was found to have a characteristic solvent-exposed hydrophobic cavity, which is composed of an abundance of aromatic residues in the 1/2 loop (- arch) and the 3/4 loop. A similar ligand binding cavity occurs at the corresponding position in the Tudor, chromo, and MBT domains, which have structural and probable evolutionary relationships with PWWP domains. These findings suggest that the PWWP domains of the HDGF family bind to some component of chromatin via the cavity.
Keywords: NMR; HDGF; HATH region; PR-loop; - arch; cavity; protein structure
Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.04975305.
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Introduction |
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Recently, the function of the PWWP domain as a chromatin targeting module has been indicated in the mammalian DNA methyltransferases, Dnmt3a and Dnmt3b, which methylate genomic DNA during gametogenesis and early embryonic development (Ge et al. 2004). Experiments using mammalian cells have shown that the PWWP domain is required for the association of Dnmt3a and Dnmt3b with chromatin, suggesting that the PWWP-mediated chromatin targeting is essential for the enzyme function during development. The functional importance of the PWWP-mediated chromatin targeting was also suggested by the fact that a missense mutation in the PWWP domain causes ICF (immunodeficiency, centromeric heterochromatin instability, and facial anomalies) syndrome, which is characterized by hypomethylation in classical satellite DNA (Shirohzu et al. 2002). Experiments revealed that the mutant protein had completely lost its chromatin targeting capacity (Ge et al. 2004). However, the ligand and its functional interaction mechanism are still unknown.
Among the PWWP-containing proteins, the largest homologous group is related to the hepatoma-derived growth factor (HDGF), which has growth-stimulating activity in several specific cells (Stec et al. 2000). The PWWP domain always occurs at the N-termini of HDGF and the HDGF-related proteins (HRPs). Its sequence is well conserved in the HDGF family (Fig. 1A
), and is also termed the HATH (homologous to amino terminus of HDGF) region (Izumoto et al. 1997). In contrast, the region outside the PWWP domain has different sequences in the HDGF family, and is termed a gene-specific region.
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Five HDGF-related proteins (HRPs) have been identified thus far: mouse HRP-1 (Izumoto et al. 1997), mouse HRP-2 (Izumoto et al. 1997), human and mouse HRP-3 (Ikegame et al. 1999; Abouzied et al. 2004), bovine HRP-4 (Dietz et al. 2002), and human LEDGF (lens epithelium-derived growth factor) (Singh et al. 2000a). In addition to the PWWP domain at the N-terminus, these proteins always have putative bipartite nuclear localization signals. The mitogenic activity was confirmed with HRP-3 in fibroblasts and renal epithelial cells, HRP-4 in fibroblasts, and LEDGF in lens epithelial cells, keratinocytes, and fibroblasts. The mRNA expression shows a broad tissue distribution of HRP-2 as well as HDGF, whereas those of HRP-1 and HRP-4 are restricted to testis and that of HRP-3 is restricted to brain. All of the HRPs, as well as HDGF, were detected in the nuclei. Presumably, the HDGF family proteins are primarily targeted to the nucleus via the nuclear localization signals. Except for their growth factor activities, the functions of HRPs 1–4 are largely unknown, while the different functions of LEDGF have recently been revealed. By virtue of its homology to HDGF, the protein was originally found to be a novel growth factor on lens epithelial cells, keratinocytes, and fibroblasts, and hence it was termed LEDGF (Singh et al. 2000b). In addition, LEDGF has been shown to be a survival factor and a transcriptional activator, which rescues cells under stress by activating the expression of stress-related genes via its binding to their promoter elements (Singh et al. 2000b; Shinohara et al. 2002).
To obtain insights into the functions of the PWWP domains of the HDGF family, we determined the solution structure of the PWWP domain of mouse HRP-3 by heteronuclear NMR methods. Detailed structural comparisons with several domains having probable evolutionary relationships revealed a characteristic cavity as a putative binding site of the PWWP domain as well as the distinguishing structural features.
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Results and Discussion |
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TOPAbstractIntroductionResults and DiscussionMaterials and methodsReferences |
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). A best-fit superposition of the ensemble of the 20 lowest-energy calculated structures is shown in Figure 2A. The root mean square deviation (RMSD) from the mean structure was 0.30 ± 0.03 Å for the backbone (N, C, C') atoms and 0.76 ± 0.03 Å for all heavy (nonproton) atoms in the well-ordered region (residues 13–29, 44–68, and 81–90). The statistics of the structures are summarized in Table 1.
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-barrel followed by a helical region, with the N- and C-termini on the same side of the molecule (Fig. 2B
). The -barrel consists of five antiparallel strands (1: 14–18, 2: 24–29, 3: 44–48, 4: 53–57; 5: 62–64). Between 4 and 5 occurs a 310-helix (1:59–61). The helical region consists of a one-turn -helix (2: 65–68), a coil region (69–72), and a 10-residue -helix (3: 81–90).
The common topology for the PWWP structures
The structures of the PWWP domains were reported from mouse DNA methyltransferase Dnmt3b (Qiu et al. 2002) and from a Schizosaccharomyces pombe protein, SPBC215.07c, of unknown function (Slater et al. 2003). Structural comparisons showed significant similarities in the -barrel region, and variations in the following helical region, revealing the structural essence of the PWWP domains (Fig. 2B). In the helical region, only the positioning of an -helix equivalent to 3 (the 3 equivalent) is virtually identical among the three PWWP structures, despite the apparent lack of sequence conservation (Fig. 1B). This common -helix is always placed in a groove between 2 and the 3/4 loop, in a fixed direction (Fig. 2B). The interactions involve highly conserved residues, including the third (Trp25) and fourth (Pro26) residues of the PWWP motif in 2 (Fig. 3A). The aromatic ring of Trp25 vertically stacks with that of Phe81 (Tyr in the Dnmt3b domain and Leu in the S. pombe domain) at the beginning of 3, and the opposite side is partially solvent accessible. The H
1 of the indole ring of Trp25 hydrogen-bonds with the O of Phe49 in the 3/4 loop. The fourth residue, Pro26, located in the middle of 2, is buried with 3. In addition, the aromatic ring of Phe49 in the 3/4 loop is snugly sandwiched between 2 and 3. This PWWP architecture involving the highly conserved residues, Trp25, Pro26, and Phe49, is essentially the same among the three PWWP structures. The positioning of 3, 2, and the 3/4 loop is probably retained in all of the PWWP domains, and is involved in forming a cavity as a putative binding site, as described later. It thus appears that the common topology for the PWWP structures is ----310--the 3 equivalent.
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). The first residue of the PWWP motif is located at the end of a loop, with the side chain accessible to the solvent, and thus its position could be occupied by several different residues. The second residue position is usually occupied by aromatic residues. The His residue at the second position is unique to the PWWP domains of the HDGF family. The PWWP structure with the PHWP residues shows that the imidazole ring of His24 in 2 is located over 1, and vertically contacts the aromatic ring of Phe63 in 5 (Fig. 3B). Instead of the His and Phe residues, the PWWP domain of the S. pombe SPBC215.07c protein with the PWWP residues has Trp138 and Thr184 at the corresponding regions, respectively, and the indole ring of Trp is located over 1 and stacks well with the methyl of Thr in 5 (Slater et al. 2003). Hence, by comparison between the two PWWP domains, it follows that the indole ring of Trp, which is larger than that of His by a phenyl ring, compensates well for the space created by the replacement of Phe by Thr in 5. One side of each of the aromatic rings of His24 and Trp138 in the HRP-3 and S. pombe domains interacts with the aliphatic portions of the invariant Lys residues in 1, Lys18 and Lys132, respectively (Fig. 3B). A similar conformation also exists in the Dnmt3b domain, with Trp and Val in the corresponding positions (Qiu et al. 2002). Hence, despite these residue differences, the structural role of the second residue of the PWWP motif is virtually identical among the three PWWP structures. As an exception to the aromatic residues, Ala, Ser, or Pro occurs at the second residue position in a small number of PWWP domains (Fig. 1B). It will be interesting to examine the PWWP structures with these aliphatic residues at the second position of the PWWP motif.
- Arch
The loop connecting 1 and 2 is composed of five residues, 19MKGYP23, in the region neighboring the conserved Lys18 through the first residue, Pro23, of the PWWP motif (Fig. 3B). According to the Ramachandran nomenclature (Efimov 1993), this region adopts a L conformation. Its conformation provides a reverse turn in the polypeptide chain and facilitates its transition from one layer to the other. Thus, this loop is called a - arch, but it is not a canonical -turn (Efimov 1993). The arch formation allows the side chains of Met19 and Tyr22 to be directed to the 3/4 loop, and to participate as components of the cavity, as described later. A similar L conformation is seen in the range of 133MSGFP137 in the S. pombe domain (Slater et al. 2003) (in the X-ray structure of the Dnmt3b domain, the electron density is not observed for Phe243, corresponding to Tyr22 in the HRP-3 domain). In all of the PWWP domains, the - arch region always contains five residues, and the predominant residue pattern is M/L/V-K-G-F/Y/H-P/S/A (Fig. 1B), suggesting the conservation of the - arch conformation among all of the domains, presumably also to allow the cavity formation.
The proline-rich loop (PR-loop) connecting 2 and 3
Within the -barrel substructure of the three PWWP domains, the only apparent differences were found in a loop connecting 2 and 3, which includes short helices in two domains (Fig. 2B). The sequence and length (8 ~ 20 residues) of this region vary among all of the PWWP domains (Fig. 1B). This loop is relatively rich in prolines, and thus we call it the proline-rich loop, PR-loop, in this paper. The characteristic feature of the PR-loop is highlighted by comparison with the corresponding loop in the Tudor domain, which has the most significant similarity to the -barrel substructure of the PWWP domain (Qiu et al. 2002; Maurer-Stroh et al. 2003; Fig. 4). In the Tudor domain, the presence of a -bulge in 2 allows the -strand to bend sufficiently to form a -barrel. Consequently, 2 and 3 form a longer -sheet than that found in the PWWP domain, and the region connecting 2 and 3 forms a short loop or a turn. In contrast, in the PWWP domain, the lack of a -bulge in 2 prevents the formation of such a long -sheet, and at the position equivalent to the -bulge, the PR-loop begins. Accordingly, 2 and 3 cross each other like the character "
," so that the connecting loop, the PR-loop, is stretched in a characteristic form.
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-stranded core element, which includes the PWWP, Tudor, chromo (chromatin-binding), and MBT (malignant brain tumor) domains (Maurer-Stroh et al. 2003). The last three domains have a ligand interaction site located at the corresponding position, where a richly aromatic site involving the - arch and the 3/4 loop plays a major role (in the chromodomain, the 2 equivalent is missing) (Sathyamurthy et al. 2003; Wang et al. 2003; Fig. 5A). The binding sites seem to be sandwiched by a clothespin made of the two sticks of 1/2 and 3/4. As for the ligand, the Tudor domain of the survival motor neuron (SMN) protein binds to methylated Arg residues in the C-terminal Arg-Gly-Gly rich tails of the Sm proteins (Selenko et al. 2001). The chromodomain binds to the methylated lysine peptide from the histone H3 tail (Jacobs and Khorasanizadeh 2002; Nielsen et al. 2002). Although the function of the MBT repeats is unknown, one ligand binding pocket per MBT repeat seems to exist at the corresponding position, which in the X-ray structure can accommodate the morpholino ring of 2-(N-morpholino) ethanesulfonic acid (MES) or the proline ring of the C-terminal peptide segment (Wang et al. 2003).
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2 of the PWWP motif, Met19 and Tyr22 in the - arch (the 1/2 loop), Thr51 in the 3/4 loop and Phe48 in 3 (Fig. 5B). Many PWWP domains possess M/L/V at position 19, Y/F/H at 22, and T/S/D/H at 51; and the more conserved residues, W (in a few, Y) at 25 and F (W) at 48 (Fig. 1B). In addition to these residues in the -barrel region, only in the PWWP domains, the 3 equivalent, which interacts with 2 (particularly, Trp25) and the 3/4 loop, appears to contribute to cavity formation. At the side of the cavity, a negatively charged residue, Glu53, exists in 4, which is an interaction site in the Tudor and chromo domains (Fig. 5A). Its probable evolutionary relationship to those domains that bind to the modified residues suggests that the PWWP domain binds to a modified residue of some chromatin component via the cavity. In the PWWP domains of the HDGF family, the cavity residues are all identical, suggesting the same ligand for a minimal element. The possibility cannot be excluded that other elements of the ligand, for example the flanking residues, differ depending on the proteins. It is notable that this cavity is followed by a hydrophobic patch composed mainly of residues in the PR-loop (Fig. 5B), which is the only region that differs in sequence and length among the PWWP domains of the HDGF family (Fig. 1A). The PR-loop may play specific roles in the interaction of other elements of the ligand, conferring ligand variations to each PWWP domain.
In the human Dnmt3b PWWP domain, a missense mutation (S282P, the corresponding position is Ala55 in 4 of the PWWP domain in this study) causes ICF syndrome (Shirohzu et al. 2002). Intriguingly, this position is quite close to the cavity, or could be one component of the cavity structure (Fig. 5B). This mutation may alter the structure or the volume of the cavity so significantly as to affect the ligand binding affinity and/or specificity.
The possible chromatin binding property of the PWWP domain is supported by its characteristic electrostatic charge distribution (Fig. 5C). The charged residues are clustered in distinctly polarized patches, which surround the putative binding cavity. A similar surface electrostatic charge distribution exists in the bromodomain, which binds selectively to multiply acetylated histone H4 peptides (Jacobson et al. 2000). Upon binding, the charged surfaces may make non-specific contacts with the nucleic acid on the basic side, and contact the core histone molecules along the acidic surface.
Concluding remarks
Recent in vivo experiments have demonstrated that the PWWP domain of DNA methyltransferases is essential for the chromatin targeting of the enzymes, suggesting a direct interaction between the PWWP domain and chromatin (Ge et al. 2004). It is quite likely that some chromatin modifications, such as modified residues, are recognized by the PWWP-containing proteins via the PWWP domain, in which the cavity shown in this study plays a key role in the interaction.
Among the HDGF family members, LEDGF preferentially associates with condensed chromatin areas (Nishizawa et al. 2001). LEDGF confers cell protection against stress-induced apoptosis by binding to the promoter elements of heat shock and stress-related genes for activation (Singh et al. 2000b; Shinohara et al. 2002), and the PWWP domain may simultaneously bind to the chromatin surrounding the genes to facilitate or regulate the DNA binding. During apoptosis, interestingly, LEDGF is reportedly cleaved at three sites, by caspases-3 and -7, into two fragments lacking the PWWP domain (65 and 58 kDa), and this cleavage abrogates its pro-survival function (Wu et al. 2002). One of the cleavage sites (-DEVPD
G-) is located in the PR-loop of LEDGF. These findings suggest the importance of the PWWP-mediated chromatin targeting for the protein function, as also seen with Dnmt3b. Similarly, the other HRPs and HDGF would be translocated to the nucleus by the nuclear localization signals, where they would associate via the PWWP domains with chromatin for their specific functions, which presumably depend on each gene-specific region in the C-terminus. Thus, the chromatin binding of these proteins seems to affect transcriptional processes, and consequently to regulate various cellular processes and development. The structural features of the PWWP domains provide insights for further experiments in the search for a ligand.
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Materials and methods |
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For NMR measurements, the purified protein was concentrated to 0.7 mM in 1H2O/2H2O (9:1) 20 mM sodium phosphate buffer (pH 6.0), containing 100 mM NaCl, 1 mM 1,4-DL-dithiothreitol-d10 (d-DTT), and 0.02% NaN3. It was stable for at least 6 mo, when stored at 4°C.
NMR spectroscopy, structure determination, and analysis
All NMR measurements were performed at 25°C on Bruker AVANCE 600 and AVANCE 800 spectrometers. Sequence-specific backbone chemical shift assignments (Wüthrich 1986) were made with the 13C/15N-labeled sample, using standard triple-resonance experiments (Bax 1994; Cavanagh et al. 1996). Assignments of side chains were obtained from HBHACONH, HCCCONNH, CCCONNH, HCCH-TOCSY, and HCCH-COSY spectra. 15N- and 13C-edited NOESY spectra with 80- and 40-msec mixing times were used to determine the distance restraints. The spectra were processed with the program NMRpipe (Delaglio et al. 1995). The program KUJIRA (N. Kobayashi, pers. comm.), created on the basis of NMRView (Johnson and Blevins 1994), was employed for optimal visualization and spectral analysis.
Automated NOE cross-peak assignments (Herrmann et al. 2002) and structure calculations with torsion angle dynamics (Güntert et al. 1997) were performed using the software package CYANA1.0.7 (Güntert 2003). Peak lists of the two NOESY spectra were generated as input with the program NMRView (Johnson and Blevins 1994). The input further contained the chemical shift list corresponding to the sequence-specific assignments. Dihedral angle restraints were derived using the program TALOS (Cornilescu et al. 1999). No hydrogen bond constraints were used.
A total of 100 structures were independently calculated. The 20 conformers of the CYANA cycle 7 with the lowest final CYANA target function values were energy-minimized in a water shell with the program OPALp (Koradi et al. 2000), using the AMBER force field (Cornell et al. 1995). The structures were validated using PROCHECK-NMR (Laskowski et al. 1996). The program MOLMOL (Koradi et al. 1996) was used to analyze the resulting 20 conformers, and to prepare drawings of the structures, unless otherwise noted in the legends.
The atomic coordinates of the 20 energy-minimized CYANA conformers of the mouse HRP-3 PWWP domain have been deposited at the RCSB Protein Data Bank (www.rcsb.org) under the PDB Accession code 1N27 [PDB] .
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Acknowledgments |
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