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The Z[alpha] domain from human ADAR1 binds to the Z-DNA conformer of many different sequences
Introduction
Materials And Methods
DNA
Protein expression constructs
Bandshift assays
Plasmid shift assay
Circular dichroism (CD)
Atomic force microscopy (AFM)
Results
Requirements for high affinity binding by Z[alpha]
Sequence specificity of Z[alpha]
AFM results
Discussion
Acknowledgements
References
The Z[alpha] domain from human ADAR1 binds to the Z-DNA conformer of many different sequences
ABSTRACT
INTRODUCTION
Double-stranded RNA adenosine deaminase (ADAR1) belongs to a family of enzymes that act on double-stranded RNA (dsRNA) to deaminate adenosine and produce inosine (1). Since inosine is translated as guanosine, the informational content of the RNA is changed. This process can lead to the site-specific substitution of one amino acid for another, altering the functional properties of a protein. Examples of this type of RNA editing have been shown to affect the ion conductance of kainate- and AMPA-type glutamate receptors, the cGMP response of the serotonin HT2C receptor, and the catalytic properties, as well as the intracellular localization, of [alpha]2,6-sialyltransferase (2-6).
Adenosine to inosine (A to I) editing is found to be ubiquitous in metazoa and is present in most, if not all, tissues (7). The minimal requirement for the reaction is a dsRNA substrate. Currently no consensus sequence is apparent in the RNAs edited by this reaction, suggesting either that each ADAR enzyme edits only a subset of substrates, or that the editing reaction is not solely regulated by RNA binding preference (8). The former possibility is supported by the site-specific nature of modifications found in physiological substrates (2-6). The later alternative is supported by the rather promiscuous nature of ADAR1 and ADAR2 editing in vitro, where any dsRNA substrate longer than 30 bp is readily modified (9). A similar promiscuity also occurs in vivo, resulting in hypermutation of viruses (10).
The ADAR family of enzymes often use dsRNA editing substrates that incorporate introns. Sequences within introns, called exon complementary sites (ECS), basepair to exons and guide editing (11). ECS have been defined for glutamate and serotonin HT2C receptors (4,5,11-13). The involvement of introns requires that editing occurs before splicing, or that splicing be delayed until editing has occurred. Since many regions capable of forming dsRNA exist in pre-mRNA, the action of ADAR enzymes must be tightly regulated.
The recent demonstration that ADAR1 has two Z-DNA binding motifs suggests one way in which the activity of this enzyme may be targeted (14). Z-DNA is a higher energy conformer of DNA that is left-handed, but can be formed by isomerization from B-DNA under conditions of negative superhelicity (15,16). The ease with which a particular DNA segment forms Z-DNA depends on its sequence, and can be accurately quantitated using in vitro techniques (17). Sequences of alternating d(CG) flip easily, while runs of d(TA) and sequences without purine-pyrimidine repeats form Z-DNA more poorly. In vivo, negative supercoiling can be generated by the passage of a transcribing RNA polymerase through a gene (18). Although the level of negative supercoiling is constrained by topoisomerases and by other proteins that unwind DNA, it has been demonstrated that the formation of Z-DNA occurs inside cells during transcription (19). Experiments using agarose-embedded permeabilized nuclei also demonstrate the transcription-dependent formation of Z-DNA (20,21). Sequences that switch between B- and Z-DNA conformations can thus act as an indicator of the transcriptional state of a gene. It is thus possible that ADAR1 is selectively targeted to nascent RNAs through its Z-DNA binding motifs (22). A role for Z-DNA in the direct regulation of the deaminase domain is unlikely as in vitro assays are not affected by the inclusion of Z-DNA in incubation buffers (14). Also, mutants that lack the Z[alpha] and Z[beta] are active in these assays (10).
In order to further understand the sequence specificity of Z[alpha], studies were performed using bandshift assays to examine the binding of this motif to different B-form and Z-form sequences. Our conclusion is that a peptide containing the Z[alpha] motif is specific for the Z-DNA conformation rather than for a particular sequence. This assertion is verified by using atomic force microscopy to demonstrate multiple binding sites in supercoiled plasmids which lack canonical Z-DNA forming sequences. These results suggest that the targeting of ADAR1 to a gene is most likely to occur when levels of negative supercoiling are sufficient to initiate Z-DNA formation, and is less likely to be dependent on the affinity of ADAR1 for a particular sequence.
MATERIALS AND METHODS
DNA
Synthetic deoxynucleotides were obtained from Life Technologies. Plasmids pDPL6 (2.2 kb) and its derivative pDHg16 containing a d(CG)13 insert have been previously described (23,24).
Protein expression constructs
Two series of constructs were used. The first was based on the pGEX-5x1 GST fusion system, and required cleavage with factor Xa to release Z[alpha] peptides (14). This system was used to prepare (Z[alpha])2 and Z[alpha]Z[beta] constructs, using a G4TG4SG4S flexible linker to join the two motifs. The other system used pET-28a vectors with a His-tag that was removed using thrombin, and was used to express residues 122-200 of Z[alpha], as well as the C125S mutant, which was made using the QuiKChange kit from Stratagene. Proteins were made in Escherichia coli strain Novablue and purified using either glutathione agarose (Pharmacia) or TALON metal affinity resin (Clontech) following the manufacturer's instructions. Z[alpha] peptides made from His-tag constructs were additionally purified using MonoS (Pharmacia) ion-exchange chromatography run in 50 mM HEPES, (pH 7.4) and eluted with NaCl.
Bandshift assays
These were performed using a partially brominated probe as previously described (14) or using 32P-labeled deoxyoligonucleotides that had been gel purified on a 20% non-denaturing polyacrylamide gel. When these latter probes were used, magnesium was omitted from the buffer used during incubation with Z[alpha]-related peptides, and 0.5 mM EDTA used instead. Electrophoresis was performed at 7.5 V/cm rather than 12 V/cm as with the longer probe.
Plasmid shift assay
DNA and protein were mixed together in a final volume of 12 µl, using 70 ng of plasmid and the indicated concentration of Z[alpha]. Complexes were resolved in a 1% agarose gel buffered with 0.5× TBE and run at 6 V/cm for 3 h. Gels were then stained with ethidium bromide and photographed.
Circular dichroism (CD)
Spectra were collected on a Aviv 60DS CD spectrometer as described previously (14) using the conditions given in the figure legends.
Atomic force microscopy (AFM)
AFM was performed using functionalized aminopropyl mica (AP-mica) as a substrate for the sample preparation (25 and references therein). Aliquots of 10 µl of the DNA (0.5 µg/ml) in TE buffer plus 100 mM of NaCl were placed onto pieces of AP-mica for 2 min, rinsed with deionized water and argon-dried. Images were taken in air with NanoScope III instrument (Digital Instruments, Inc., Santa Barbara, CA) operating in tapping mode. NanoProbe TESP probes (Digital Instruments, Inc., Santa Barbara, CA) and conical sharp silicon tips (K-tek International, Portland, OR) were used for imaging in air. The typical tapping frequency was 240-280 kHz; scanning rate was 2-3 Hz.
RESULTS
We have previously described a bandshift assay that uses a partially brominated DNA oligonucleotide of alternating d(CG) that flips into the Z-DNA conformation under physiological conditions when 10 mM Mg2+ is present (24). This assay allows biological tissues to be tested for the presence of Z-DNA binding activities (26), and led directly to the discovery that ADAR1 is a Z-DNA binding protein (27). The assay was used to map the two Z-DNA binding motifs of ADAR1, Z[alpha] and Z[beta] (14). Here we further characterize the Z[alpha] motif and examine its sequence specificity.
Requirements for high affinity binding by Z[alpha]
A number of DNA binding proteins are known to bind with high affinity to DNA only as multimers (e.g. 28). In order to assess whether this was also true for peptides containing Z[alpha], a construct was made that used a 15 amino acid flexible linker to join Z[alpha] to a second Z[alpha]. Z[alpha] was also linked to Z[beta] to test for interaction between these two sub-domains of ADAR1. The constructs are referred to as (Z[alpha])2 and Z[alpha]Z[beta] respectively. They were tested in a bandshift assay as shown in Figure
Figure 1. Z-DNA bandshifts using Z[alpha], (Z[alpha])2 and Z[alpha]Z[beta] constructs showing binding to a partially brominated d(CG)33-35 oligonucleotide (24). Protein-DNA complexes were preformed by mixing the indicated amount of protein with 100 pg of 32P-labeled probe in a reaction mix containing 1 µg of sheared salmon sperm DNA, 50 mM NaCl, 10 mM MgCl2 and 10 mM Tris-HCl (pH 7.4). Complexes were resolved on a 6% PAGE gel. Free probe migrates at the bottom of the gel, and a number of discrete bandshifts are observed, indicating that the probe has multiple binding sites. All constructs were prepared by factor Xa digests of GST fusion proteins (14). (A) Titrations were performed using 5-fold dilutions of Z[alpha] (lanes 1-4) and 10-fold dilutions of (Z[alpha])2 (lanes 5-8), starting with 10 ng of protein in lanes 4 and 8. (B) Competition experiments performed with (Z[alpha])2 using 5-fold dilutions of unlabeled B-form poly d(CG) (lanes 1-3) or the same polymer stabilized in the Z-DNA conformation by chemical bromination (24) (lanes 4-6). Lanes 3 and 6 contain 35 ng of competitor. In lane 0, there is no additional competitor added. (C) Competition experiments performed using Z[alpha]Z[beta] as detailed in (B). The competition experiments shown in (B) and (C) were performed on the same gel and have equivalent exposure time. They confirm that these constructs are Z-DNA specific, and the binding sites formed by (Z[alpha])2 and (Z[alpha]Z[beta]) differ in character. Further evidence for the requirement that Z[alpha] binds DNA as a dimer was developed using a more defined probe consisting of a d[(CG)3 T3(CG)3] hairpin [referred to as d(CG)3 hairpin to indicate the composition of the hairpin stem]. In solution, this probe adopts the B-DNA conformation. It was reasoned that if the energy of binding of Z[alpha] was sufficiently high, the interaction of Z[alpha] could stabilize this sequence in the Z-DNA conformation. As shown in Figure Figure 2. Bandshift assay of Z[alpha], Z[alpha](C125S) and Z[alpha] plus 100 mM 2-mercaptoethanol using a d[(CG)3T3(CG)3] hairpin probe. Protein was diluted in 5-fold dilution steps, starting at 5 µM, and was incubated in the absence of any added competitor in 10 mM Tris-HCl, 20 mM NaCl, 0.5 mM Na2EDTA (pH 7.4) with 32P-labeled probe in a final volume of 12 µl. Complexes were resolved on a 6% non-denaturing PAGE gel. Free probe migrates at the bottom of the gel. The probe has only a single protein binding site, and the Z[alpha] dimer only binds one probe molecule. Collectively the results presented in Figures 
Sequence specificity of Z[alpha]
In addition to the d(CG)3 hairpin probe described above, other hairpin sequences were also tested for bandshift activity, including those with d(CA)3 and d(TA)3 stems (only the upper strand sequence is given). These probes did not result in measurable bandshifts. Although such results could indicate that Z[alpha] lacked specificity for these sequences, another possibility was that there was not enough of these sequences in the Z-DNA conformation (due to the high energetic cost of initiating Z-DNA formation) to produce a bandshift. In order to examine this explanation, a series of probes 12 bp in length, which have two Z[alpha] binding sites, were made and tested in a band shift assay. One binding site was always d(CG)3 while the sequence of the other was varied. It was reasoned that binding of Z[alpha] to the first site would help force the second site into the Z-DNA conformation, as the energetic cost of forming Z-DNA with short sequences is similar to that of maintaining a B-Z junction (4 kcal/mol) if the oligomer were half B- and half Z-DNA. Therefore this approach allows the affinity of Z[alpha] for the second site to be measured. The results obtained with this assay are shown in Figure
Figure 3. Bandshift assays of Z[alpha] using probes with two binding sites. Protein was incubated in the absence of any added competitor in 10 mM Tris-HCl, 25 mM NaCl, 0.5 mM Na2EDTA (pH 7.4) with 5 nM 32P-labeled probe in a final volume of 12 µl. Complexes were resolved on a 6% non-denaturing PAGE gel. Free probe migrates at the bottom of the gel. Bandshifts were performed using the following hairpins with a dT3 loop (A) d[(TA)3(CG)3T3(CG)3(TA)3], (B) d[(CG)3-(CG)3T3(CG)3(CG)3], (C) d[(CA)3(CG)3T3(CG)3(TG)3], (D) d[(TG)3(CG)3-T3(CG)3(CA)3]. Titrations are performed in 2-fold dilution steps starting with the highest concentration of Z[alpha] (1.2 µM) in lane 10. It is of interest that the d(TA)3 can be flipped to Z-DNA by Z[alpha] under physiological conditions. This transition has been seen previously using 5 M NaCl and transition metals (30). The transition from B- to Z- DNA can be followed by CD (31). An example of the changes that occur is shown in Figure Figure 4. CD titration of Z[alpha] complexed to DNA hairpins with two binding sites. The DNA hairpins d[(CG)6T3(CG)6] (A) and d[(TA)3(CG)3T3(CG)3(TA)3] (B) were titrated with Z[alpha] peptide in 50 mM Tris-HCl, 50 mM NaCl, 0.1 mM Na2EDTA (pH 7.4) at 30°C in an Aviv 60DS spectrometer. Spectra obtained using a ratio of 1 mol of Z[alpha] to 2 mol of basepairs are shown (solid lines). Reference spectra obtained in the absence of protein (dotted line) and in 4 M NaCl (dashed line) are also shown. In 4 M salt hairpins d[(CG)6T3d(CG)6] forms Z-DNA, while d[(TA)3(CG)3T3(CG)3(TA)3] undergoes only a partial transition (32) However, Z[alpha] can stabilize d(TA)3 in the Z-DNA conformation as shown by the solid line in (B). The CD signal produced Z[alpha] alone is equivalent to baseline in the region of 250-300 nm, but becomes strongly negative below 240 nm. The effect of Z[alpha] on DNA was examined by AFM using supercoiled plasmids. AFM allows the visualization of structures at nanometer-range resolution (33-35), and has been greatly improved by the use of functionalized mica surfaces (AP-mica; 25,36-39). AP-mica has aminopropyl groups on the surface allowing the attachment of DNA to this surface via electrostatic interaction between anionic DNA polymer and cationic AP-mica surface. Previous work has shown the elegance of this method for studying plasmid topology (25). It has been recently demonstrated that structure and dynamics of supercoil-stabilized cruciforms can be studied by AFM (40). As shown in Figure Figure 5. AFM of supercoiled pDLP6 (A) and its derivative pDHg16 (23) (B), at bacterial superhelical density. The presence of the d(CG)13 insert in pDHg16 causes a loss of writhe. Plasmids were prepared in TE buffer plus 100 mM NaCl and deposited onto AP-mica. Inserts in each panel are enlarged images of the same samples (rescans over the smaller area). The bar size in the inserts is 100 nm. The AFM method is also well suited for examining conformational changes caused by binding of proteins (34,35,39). It was therefore of interest to examine the effects of Z[alpha] on supercoiled DNA. First, concentrations of Z[alpha] and plasmid were titrated for use in AFM studies. The binding of Z[alpha] to plasmid was evaluated using non-denaturing agarose electrophoresis in the absence of ethidium bromide (Fig. Figure 6. Plasmid shift assays of pDPL6 (A) and pDHg16 (B) in the presence of Z[alpha]. Plasmid (70 ng, 0.11 µM bp) at bacterial superhelical density was incubated with Z[alpha] in 12 µl of 10 mM Tris-HCl, 20 mM NaCl, 0.5 mM Na2EDTA (pH 7.4). Complexes were resolved on a 1% agarose gel run in TBE buffer, and then visualized with ethidium bromide. Lane 4 contains 2.3 µM Z[alpha]; lane 3, 0.46 µM; lane 2, 0.09 µM; and lane 1, 0.02 µM. Lane 0 contains no added protein. The positions of nicked circular (N) and supercoiled plasmids (S) are indicated. The experiments shown in (A) and (B) were performed at the same time using the same agarose gel. The AFM data for pDHg16 complexed with Z[alpha] at different concentrations are shown in Figure Figure 7. AFM of Z[alpha] bound to pDHg16, showing relaxation of supercoils and kinking of DNA induced by Z[alpha]. The concentrations of Z[alpha] and pDHg16 used in (A) are equivalent to those of lane 3 in Figure 6 while in (B) the same amounts as in lane 4 of Figure 6 were used. Inserts in each panel are enlarged images of the same samples (rescans over the small area). The bar size in the inserts is 100 nm. Abrupt changes in DNA path, referred to as kinks in the text, are apparent when these insets are compared to those of Figure 5B. Bright blobs that are associated with the kinks are highlighted by arrows. These blobs are referred to as nodules in the text and are likely to represent regions containing Z[alpha] bound to DNA. The biological role of Z-DNA is unknown. The presence of Z-DNA binding motifs in ADAR1, an enzyme that acts on nascent RNAs to change their informational content, suggests that these motifs may play a role in regulating the editing process. One possibility is that the Z-DNA formed during transcription allows the enzyme to be targeted to particular sites within genes. In order to test this hypothesis, it is necessary to know the binding specificity of the ADAR1 Z-DNA binding motifs. If these motifs show strong sequence-specificity, then the search for genes that are edited by ADAR1 would be simplified, as only a limited subset of genes with those sequences would be candidates for editing. However, the results reported here suggest that the Z[alpha] motif is not sequence-specific, but rather conformation-specific. We have demonstrated that dimers of Z[alpha] flips not only d(CG) into the Z-conformer, but also d(TA), implying that Z[alpha] has only limited base specificity. The question of which sequences are bound by Z[alpha] in vivo thus becomes: what genes contain regions of localized negative superhelicity sufficient to flip a particular sequence into the Z-DNA conformation? We thus need to consider the possibility that non-canonical Z-DNA forming sequences may be of importance in the regulation of editing. In the appropriate context, these sequences may form Z-DNA and then bind ADAR1. There are situations where inducibility of Z-DNA formation may be valuable in the regulation of ADAR1. For example, during development, the onset of editing of RNAs for glutamate receptors occurs much later than the onset of transcription (2), indicating that neither the presence of RNA nor the passage of the polymerase is sufficient for initiation of editing. In addition, messages, such as that of GluR-B, contain sites that are fully edited (Q/R site) and others (e.g. R/G site) that are only partially edited (4). This difference in editing efficiency suggests the importance of local factors in determining whether editing occurs within a gene. Z-DNA may be one of these factors. Two general types of model for the control Z-DNA formation can be proposed. Both rely on the movement of an RNA polymerase through a gene to generate negative supercoiling (18). One relies on the inhibition of factors that actively remove supercoils (the minus model) and the other on the presence of factors that actively increase negative supercoiling (the plus model). In the minus model, release of torsional strain by topoisomerases is prevented, for example through phosphorylation, or restricted nuclear localization, allowing formation of Z-DNA. In the plus model, additional torsional strain is generated by the action of a second factor, for example, another polymerase. One candidate could be RNA polymerase III. RNA polymerase III transcriptional units are widespread throughout introns. They are ten times more frequent than RNA Pol II dependent genes and often produce RNAs with no known function. However, the act of transcription by RNA polymerase III would increase negative supercoiling of adjacent DNA regions and possibly flip surrounding DNA segments into the Z-DNA conformation. In the case of ADAR1, this mechanism would allow the timing and amount of editing to be regulated through changes in RNA polymerase III activity without altering transcription by RNA polymerase II. The question remains of how Z[alpha] stabilizes Z-DNA. The results reported here suggest that the interaction does not require sequence-specific recognition, raising the possibility that Z[alpha] binds to the minor groove of Z-DNA. As with B-DNA, the minor groove of Z-DNA is information poor and does not allow good base discrimination (41). In addition, it is thought that differences in hydration of the minor groove may partially explain why d(CG)n forms Z-DNA better than poly d(TA)n (42). Interaction of Z[alpha] with the minor groove of Z-DNA may replace the need for water in stabilizing this conformation. The other possibility that Z[alpha] binds to a B-Z junction is not supported by the CD data, which show a complete inversion of the CD spectra. Formation of a B-Z junction would cause only a half transition. The AFM studies are consistent with these general conclusions. This technique allows visualization of changes to plasmid topology caused by Z[alpha]. Relaxation of plasmid supercoils is observed, as would be expected by reversing the twist of DNA from right-handed to left-handed. In addition, a number of kinks are observed in the DNA (as indicated by arrows in the Fig. The nature of the kinks produced by binding of Z[alpha] in the plasmids is of interest. It has been proposed on both experimental and theoretical grounds that junctions between B- and Z-DNA are intrinsically bent (32,43), an interpretation favored by the evidence reported here. The binding properties of Z[alpha] to Z-DNA closely resembles the binding of chicken lung ADAR1 to Z-DNA (27). When the original, partially brominated probe is used in the bandshift assay, both ADAR1 and Z[alpha] show slow kinetic off-rates. In this particular assay, the gel lacks the Mg2+ necessary to stabilize the probe in the Z-DNA conformation (24). The lack of Mg2+ requires that the protein remains bound to the probe during electrophoresis. Any probe released from the protein will return to the B-DNA conformation and thus be unavailable for rebinding, resulting in a loss of the bandshift. Both ADAR1 and Z[alpha] produce very stable bandshifts with no significant breakdown of the protein-probe complex, suggesting that both have slow off-rates from Z-DNA. Structurally related proteins that bind to Z-DNA, but have a fast off-rate are unlikely to be detected by the bandshift assays described here. They can of course be characterized using preformed Z-DNA substrates in BIAcore assays (14). It is unlikely that the Z[alpha] exists in vivo as a disulfide linked dimer. The z[alpha]z[alpha] binding site could instead be formed by an association of two ADAR1 promoted by other sequences in the protein. Alternatively, Z[alpha] may combine with other partners to form a functional Z-DNA binding site. In ADAR1, Z[beta] may be used to form a z[alpha]z[beta] binding site, a possibility suggested by the results shown in Figure Studies on B-DNA binding proteins have focused on sequence-specific recognition. In contrast, the strategy used by Z[alpha] seems to depend more upon the conformational properties of a particular sequence rather than on its precise base composition. Thus recognition of a sequence by Z[alpha] is context-specific, occurring only under energetic conditions that favor Z-DNA formation. Likewise, regulation of biological processes by Z[alpha], when it occurs, is also likely to be context-specific rather than sequence-specific. This work was supported by grants from the National Science Foundation, the Office for Naval Research and the National Institutes of Health.
AFM results
DISCUSSION
ACKNOWLEDGEMENTS
REFERENCES
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