Z-DNA: Difference between revisions
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< | <StructureSection load='Z-DNA.pdb' size='350' side='right' scene='Z-DNA/Z-dna_new/1' caption=''> | ||
Z-DNA <scene name='Z-DNA/Z-dna_new/1'>(default scene)</scene> is a form of DNA that has a different structure from the more common <scene name='Sandbox_Z-DNA/Bdna/3'>B-DNA</scene> form.It is a left-handed double helix wherein the sugar-phosphate backbone has a zigzag pattern due to the alternate stacking of bases in [http://proteopedia.org/wiki/index.php/Syn_and_anti_nucleosides anti-conformation and syn conformation]. In Z-DNA only a minor groove is present and the major groove is absent. The residues that allow sequence-specific recognition of Z-DNA are present on the convex outer surface.<ref name = 'Rich'> PMID:12838348</ref> This DNA form is thought to play a role in the regulation of gene expression, DNA processing events and/or genetic instability.<ref name = 'Wang'>PMID:17485386</ref> | '''Z-DNA''' <scene name='Z-DNA/Z-dna_new/1'>(default scene)</scene> is a form of DNA that has a different structure from the more common <scene name='Sandbox_Z-DNA/Bdna/3'>B-DNA</scene> form.It is a left-handed double helix wherein the sugar-phosphate backbone has a zigzag pattern due to the alternate stacking of bases in [http://proteopedia.org/wiki/index.php/Syn_and_anti_nucleosides anti-conformation and syn conformation]. In Z-DNA only a minor groove is present and the major groove is absent. The residues that allow sequence-specific recognition of Z-DNA are present on the convex outer surface.<ref name = 'Rich'> PMID:12838348</ref> This DNA form is thought to play a role in the regulation of gene expression, DNA processing events and/or genetic instability.<ref name = 'Wang'>PMID:17485386</ref> | ||
See also [[Z-DNA model tour]] and [[B-DNA tour]]. | |||
== Structure == | == Structure == | ||
Whenever B-DNA transforms into Z-DNA two<scene name='Sandbox_Z-DNA/B-zjunction/7'> B-Z junctions </scene> form. The crystal structure of these junctions revealed<scene name='Sandbox_Z-DNA/Extruded/12'> two extruded bases</scene>, <scene name='Z-DNA/Extruded/2'>adenine</scene> and <scene name='Z-DNA/Extruded/3'>thymine</scene> at the junction. A crucial finding from this structure is that a right handed DNA can transform to a left handed DNA or vice versa by the disruption and extrusion of a base pair. It has also been suggested that the extruded base pairs at B-Z DNA junction may be sites for DNA modification.<ref>PMID:16237447</ref> | Z-DNA (<scene name='Sandbox_Z-DNA/B-z/7'>B-Z DNA junction</scene>, PDB entry [[2acj]]) can form ''in vitro'' from B-DNA by raising negative super helical stress or under low salt conditions when deoxycytosine is 5-methylated. The formation of Z-DNA ''in vivo'' is an energy requiring process. It forms behind a RNA polymerase moving through a DNA double helix during transcription and is subsequently stabilized due to the generation of negative supercoils. Z-DNA is the first single crystal X-ray structure of a DNA fragment. It was crystallized as a self complementary DNA hexamer d(CG)<sub>3</sub> by Andrew Wang, Alexander Rich and their co-workers at MIT in 1979. <ref name = 'Rich'>PMID:12838348</ref><ref name ='Wang'>PMID:17485386</ref> | ||
Whenever B-DNA transforms into Z-DNA two <scene name='Sandbox_Z-DNA/B-zjunction/7'>B-Z junctions</scene> form. The crystal structure of these junctions revealed<scene name='Sandbox_Z-DNA/Extruded/12'> two extruded bases</scene>, <scene name='Z-DNA/Extruded/2'>adenine</scene> and <scene name='Z-DNA/Extruded/3'>thymine</scene> at the junction. A crucial finding from this structure is that a right handed DNA can transform to a left handed DNA or vice versa by the disruption and extrusion of a base pair. It has also been suggested that the extruded base pairs at B-Z DNA junction may be sites for DNA modification.<ref>PMID:16237447</ref> | |||
== Z-DNA binding proteins == | == Z-DNA binding proteins == | ||
=== Double Stranded RNA adenosine deaminase 1, ADAR1 === | === Double Stranded RNA adenosine deaminase 1, ADAR1 === | ||
ADAR1 <scene name='Sandbox_Z-DNA/Adar1/3'> | ADAR1 (<scene name='Sandbox_Z-DNA/Adar1/3'>Z-ALPHA and Z-DNA complex</scene>, [[1qbj]]) belongs to the family of deaminases that modify double stranded mRNA by catalyzing the conversion of adenine to inosine which is then translated to guanosine. It is a complex protein with two Z-DNA binding motifs called <scene name='Sandbox_Z-DNA/Adar1zalpha/10'>Z-alpha</scene> and Z-beta.<ref name = 'Wang'>PMID:17485386</ref> ADAR1 also has three copies of double-stranded RNA binding motif (DRBM) and a catalytic domain related to ''E.coli'' cytidine deaminase. The binding motif Z-alpha belongs to winged-helix-turn-helix family of proteins. It consists of a <scene name='Z-DNA/Adar1zalpha/1'>helix-turn-helix motif</scene> which has two alpha helices (<scene name='Z-DNA/Adar1zalpha/2'>alpha-2</scene> and <scene name='Z-DNA/Adar1zalpha/3'>alpha-3 also called the recognition</scene>) connected by a short strand of amino acids and a <scene name='Sandbox_Z-DNA/Adar1zalpha/15'>C- terminal beta-sheet</scene>. The beta sheet constrains the fold by contacting the residues between alpha-2 and alpha-3. | ||
The contact surface between <scene name='Sandbox_Z-DNA/Adar1/4'>Z-alpha and DNA</scene> consists of residues from the helix alpha-3 and COOH-terminal beta hairpin. Hydrogen bonding is present between <scene name='Z-DNA/Aminoacid/1'>amino acids</scene> Lys<sup>169</sup>, Lys <sup>170</sup>, Asn<sup>173</sup>, Arg<sup>174</sup> and Tyr<sup>177</sup> in the helix alpha-3 and <scene name='Z-DNA/Dnanucleotides/2'>five consecutive phosphates on Z-DNA</scene>. Lys<sup>169</sup>, Asn<sup>173</sup>, Arg<sup>174</sup>, Trp<sup>195</sup> make water mediated phosphate contacts with Z-DNA. In addition Thr<sup>191</sup> and Arg<sup>174</sup> <scene name='Z-DNA/Thrarg/1'>bind to the furanose oxygens</scene> of G2 and G6 on Z-DNA. An important interaction is the <scene name='Z-DNA/Tyrosine_and_g4/1'>Vanderwaal's bond</scene> between aromatic ring of Tyr<sup>177</sup> and the carbon 8 of G4. This is unique to Z-DNA as the interaction requires the base to be in syn conformation. Pro<sup>192</sup>, Pro <sup>193</sup> form another set of <scene name='Z-DNA/Pro/1'>important Vanderwaal's interactions</scene> with Z-DNA where the pyrrolidine rings bond with the sugar-phosphate backbone from phosphate 2 to phosphate 3. Pro<sup>192</sup> is conserved in Z-alpha and its homologues and forms a cis peptide bond which positions beta loop against the Z-DNA surface.<ref name = SchwartzRich>PMID: 10364558</ref> | The contact surface between <scene name='Sandbox_Z-DNA/Adar1/4'>Z-alpha and DNA</scene> consists of residues from the helix alpha-3 and COOH-terminal beta hairpin. Hydrogen bonding is present between <scene name='Z-DNA/Aminoacid/1'>amino acids</scene> Lys<sup>169</sup>, Lys <sup>170</sup>, Asn<sup>173</sup>, Arg<sup>174</sup> and Tyr<sup>177</sup> in the helix alpha-3 and <scene name='Z-DNA/Dnanucleotides/2'>five consecutive phosphates on Z-DNA</scene>. Lys<sup>169</sup>, Asn<sup>173</sup>, Arg<sup>174</sup>, Trp<sup>195</sup> make water mediated phosphate contacts with Z-DNA. In addition Thr<sup>191</sup> and Arg<sup>174</sup> <scene name='Z-DNA/Thrarg/1'>bind to the furanose oxygens</scene> of G2 and G6 on Z-DNA. An important interaction is the <scene name='Z-DNA/Tyrosine_and_g4/1'>Vanderwaal's bond</scene> between aromatic ring of Tyr<sup>177</sup> and the carbon 8 of G4. This is unique to Z-DNA as the interaction requires the base to be in syn conformation. Pro<sup>192</sup>, Pro <sup>193</sup> form another set of <scene name='Z-DNA/Pro/1'>important Vanderwaal's interactions</scene> with Z-DNA where the pyrrolidine rings bond with the sugar-phosphate backbone from phosphate 2 to phosphate 3. Pro<sup>192</sup> is conserved in Z-alpha and its homologues and forms a cis peptide bond which positions beta loop against the Z-DNA surface.<ref name = SchwartzRich>PMID: 10364558</ref> | ||
[[Image:Hbonding_Z-DNA.png|left|thumb|400px|Polar Interactions between ADAR1 and Z-DNA]] | [[Image:Hbonding_Z-DNA.png|left|thumb|400px|Polar Interactions between ADAR1 and Z-DNA]] | ||
{{Clear}} | |||
The double stranded RNA substrate for ADAR1 is formed by folding of 3' intron back onto the exon containing the site to be edited. This shows that the editing of RNA occurs before the splicing of RNA providing an explanation for the binding of Z-DNA by ADAR1. Z-DNA may localize the editing activity of ADAR1 to a particular region within a gene, thus preventing indiscriminate modification. This allows for editing of the nascent transcript and blocks further transcription of gene. It has also been suggested that the extent of adenosine to inosine is proportional to amount of Z-DNA and also the ease with which the surrounding sequences adopt Z-DNA conformation. According to a study binding of ADAR1 to Z-DNA resulted in the increase in promoter activity of the gene which suggests that Z-DNA formation in the promoter region is itself involved in the regulation of transcription.<ref name = 'Rich'>PMID:12838348</ref> | The double stranded RNA substrate for ADAR1 is formed by folding of 3' intron back onto the exon containing the site to be edited. This shows that the editing of RNA occurs before the splicing of RNA providing an explanation for the binding of Z-DNA by ADAR1. Z-DNA may localize the editing activity of ADAR1 to a particular region within a gene, thus preventing indiscriminate modification. This allows for editing of the nascent transcript and blocks further transcription of gene. It has also been suggested that the extent of adenosine to inosine is proportional to amount of Z-DNA and also the ease with which the surrounding sequences adopt Z-DNA conformation. According to a study binding of ADAR1 to Z-DNA resulted in the increase in promoter activity of the gene which suggests that Z-DNA formation in the promoter region is itself involved in the regulation of transcription.<ref name = 'Rich'>PMID:12838348</ref> | ||
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Z-DNA binding proteins have common structural characteristics. The binding domains of these proteins can substitute one another and thus can act as competitive inhibitors against one another. As explained above, disruption in the Z-DNA binding region of E3L reduces its pathogenicity. All these observations are important pointers towards the biological importance of Z-DNA.<ref name ='Wang'>PMID:17485386</ref> | Z-DNA binding proteins have common structural characteristics. The binding domains of these proteins can substitute one another and thus can act as competitive inhibitors against one another. As explained above, disruption in the Z-DNA binding region of E3L reduces its pathogenicity. All these observations are important pointers towards the biological importance of Z-DNA.<ref name ='Wang'>PMID:17485386</ref> | ||
=== High-resolution crystal structure of Z-DNA in complex with Cr3+ cations <ref>DOI 10.1007/s00775-015-1247-5</ref>=== | |||
Trivalent chromium, a d<sup>3</sup> cation, is poorly taken up by living cells. The Cr<sup>3+</sup> ions are the final product of in vivo Cr<sup>6+</sup> metabolism. However, Cr<sup>3+</sup> in contrast to Cr<sup>6+</sup> can form coordination complexes with macromolecules in the cells. In vitro biochemical experiments have shown that exposure of cells to Cr6+ yields binary (DNA–Cr<sup>3+</sup>) and ternary (DNA–Cr<sup>3+</sup>–ligand) adducts, DNA crosslinks, as well as oxidative DNA lesions. Despite the interest in DNA–Cr<sup>3+</sup> interactions in biological systems, the existing literature provides detailed crystallographic structural data for only two, low-resolution DNA–Cr<sup>3+</sup>:DNA polymerase-β complexes, PDB [[1zqe]] (3.7 Å) ֵand [[1huz]] (2.6 ֵÅ). | |||
Our work is part of our project aimed at characterizing metal-binding properties of left-handed Z-DNA helices. The three Cr3+ cations found in the asymmetric unit of the d(CGCGCG)<sub>2</sub>–Cr<sup>3+</sup> crystal structure do not form direct coordination bonds with either the guanine N/O atoms or the phosphate groups of the Z-DNA. <scene name='69/693575/Cv/6'>Note the alternate conformations</scene> (<span style="color:lime;background-color:black;font-weight:bold;">I, green</span>; <span style="color:orange;background-color:black;font-weight:bold;">II, orange</span>) along the DNA chains. <scene name='69/693575/Cv/7'>Click here to see the animation of this scene</scene>. <font color='darkmagenta'><b>Cr<sup>3+</sup> cations shown as purple spheres</b></font>. Instead, only water-mediated contacts between the nucleic acid and the Cr<sup>3+</sup> cations are observed. The coordination spheres of Cr<sup>3+</sup>(1) and Cr<sup>3+</sup>(2) contain six water molecules each. The Cr<sup>3+</sup>(1) and Cr<sup>3+</sup>(2) ions are bridged by three water molecules from their coordination spheres, one of which (Wat1) is split into two sites. The hydration patterns of Cr<sup>3+</sup>(1) and Cr<sup>3+</sup>(2) are <scene name='69/693575/Cv/8'>irregular and difficult to define</scene> (<font color='red'><b>water molecules are represented by red spheres</b></font>). The Cr<sup>3+</sup>(3) cation has <scene name='69/693575/Cv/9'>distorted square pyramidal geometry</scene>. | |||
We have used Z-DNA crystals to obtain accurate information about the geometrical parameters characterizing the coordination of Cr3+ ions by left-handed Z-DNA. The d(CGCGCG)2–Cr<sup>3+</sup> structure is an excellent illustration of the flexibility of the Z-DNA molecule, visible in the adoption of multiple conformations (by the phosphate groups and the G2 nucleotide), in response to changes in its electrostatic and hydration environment, caused by the introduction of hydrated metal complexes. | |||
</StructureSection> | |||
__NOTOC__ | |||
== Movie Depicting ADAR1 binding to Z-DNA == | == Movie Depicting ADAR1 binding to Z-DNA == | ||
< | <html5media height="315" width="560">http://www.youtube.com/embed/tvrWkld8TBY</html5media> | ||
== Comparison of the three helices and helical parameters of DNA == | == Comparison of the three helices and helical parameters of DNA == | ||
''Sources''<ref>http://203.129.231.23/indira/nacc/</ref> | ''Sources''<ref>http://203.129.231.23/indira/nacc/</ref> | ||
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|colspan="4"|''Sources:<ref name="Rich1984">PMID:6383204</ref><ref name="Rich1979">PMID: 514347</ref><ref> Sinden, Richard R (1994-01-15). ''DNA structure and function'' (1st ed.). Academic Press. pp. 398. ISBN 0-12-645750-6.</ref> | |colspan="4"|''Sources:<ref name="Rich1984">PMID:6383204</ref><ref name="Rich1979">PMID: 514347</ref><ref> Sinden, Richard R (1994-01-15). ''DNA structure and function'' (1st ed.). Academic Press. pp. 398. ISBN 0-12-645750-6.</ref> | ||
|} | |} | ||
==3D structures of Z-DNA== | |||
Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}} | |||
[[1woe]], [[3qba]], [[1i0t]], [[6aqt]], [[6aqv]], [[6aqw]], [[6aqx]], [[2ie1]], [[1da1]], [[1ick]], [[313d]], [[314d]], [[390d]], [[391d]], [[392d]], [[3p4j]], [[3qba]], [[3wbo]], [[400d]], [[4fs5]], [[4fs6]], [[4hif]], [[4hig]], [[2hto]], [[2htt]], [[4r15]], [[4xsn]], [[6bst]] – ZDNA hexamer CGCGCG<br /> | |||
[[1v9g]] – ZDNA hexamer CGCGCG - Neutron<br /> | |||
[[1tne]] – ZDNA hexamer CGCGCG - NMR<br /> | |||
[[2obz]] – ZDNA hexamer CGCGUG<br /> | |||
[[362d]] – ZDNA hexamer TGCGCA<br /> | |||
[[1qbj]] – ZDNA hexamer CGCGCG + hADAR1 Zα domain - human<br /> | |||
[[2heo]] - ZDNA hexamer CGCGCG + Z-DNA-binding protein Zα domain – mouse<br /> | |||
[[1sfu]] - ZDNA hexamer CGCGCG + Pox virus Z-DNA-binding protein Zα domain <br /> | |||
[[4wcg]] - ZDNA hexamer CGCGCG + Herpes virus 3 Z-DNA-binding protein Zα domain <br /> | |||
[[1j75]] - ZDNA hexamer CGCGCG + DLM-1 Z-DNA-binding protein Zα domain <br /> | |||
[[3f21]] - ZDNA hexamer CACGTG + double-stranded RNA-specific adenosine deaminase Z-DNA-binding protein Zα domain <br /> | |||
[[3f21]] - ZDNA hexamer CGTACG + double-stranded RNA-specific adenosine deaminase Z-DNA-binding protein Zα domain <br /> | |||
[[3eyi]] - ZDNA hexamer CGCGCG + Z-DNA-binding protein Zβ domain<br /> | |||
[[1j75]] - ZDNA hexamer CGCGCG + DLM-1 Zα domain<br /> | |||
[[3fqb]] - ZDNA hexamer CGCGTG + Ba<br /> | |||
==Additional Resources== | |||
For additional information, see: [[Nucleic Acids]] | |||
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== References == | == References == | ||
<references/> | <references/> | ||
[[Category: Topic Page]] | |||