Sandbox Z-DNA: Difference between revisions
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=== Double Stranded RNA adenosine deaminase 1, ADAR1 === | === Double Stranded RNA adenosine deaminase 1, ADAR1 === | ||
ADAR1 belongs to the family of deaminases that modify double stranded mRNA by catalyzing the conversion of adenine to inosine which is translated to guanosine. This may result in the expression of an amino acid different from the one encoded by the gene at that site. ADAR1 is a complex protein with two Z-DNA binding motifs called <scene name='Sandbox_Z-DNA/ | ADAR1 belongs to the family of deaminases that modify double stranded mRNA by catalyzing the conversion of adenine to inosine which is translated to guanosine. This may result in the expression of an amino acid different from the one encoded by the gene at that site. ADAR1 is a complex protein with two Z-DNA binding motifs called <scene name='Sandbox_Z-DNA/Adar1zalpha/3'>Z-alpha</scene> and Z-beta. It also has three copies of double-stranded RNA binding motif (DRBM) and a catalytic domain related to ''E.coli'' cytidine deaminase. Z-alpha alone can not only bind to Z-DNA with high affinity but also interact with Z-beta to form a slightly different binding domain. Z-alpha belongs to winged-helix-turn-helix family. It consists of a helix-turn-helix motif containing alpha-2 and alpha-3 and a C- terminal beta-sheet which constrains the the fold by contacting the residues on between alpha-2 and alpha-3. Alpha-3 and C-terminal beta sheet are involved in binding to Z-DNA. 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 blocking 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. Thus the result suggests that Z-DNA formation in the promoter region is itself involved in the regulation of transcription. | ||
=== Vaccinia virus E3L protein === | === Vaccinia virus E3L protein === | ||
Revision as of 22:59, 14 July 2009
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Z-DNA is relatively a new structural form of a DNA which has a different structure from the more common 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 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.[1] Z-DNA is thought play a role in regulation of gene expression, DNA processing events and/or genetic instability.[2]
StructureStructure
Z-DNA can form invitro from B-DNA by raising negative super helical stress or under physiological salt conditions when deoxycytosine is 5-methylated. The formation of Z-DNA which requires energy is an active process invivo. A mechanism for initiation of Z-DNA involves formation of negative supercoils behind a moving RNA polymerase when it moves through DNA double helix. [1][2] `
Z-DNA binding proteinsZ-DNA binding proteins
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Double Stranded RNA adenosine deaminase 1, ADAR1Double Stranded RNA adenosine deaminase 1, ADAR1
ADAR1 belongs to the family of deaminases that modify double stranded mRNA by catalyzing the conversion of adenine to inosine which is translated to guanosine. This may result in the expression of an amino acid different from the one encoded by the gene at that site. ADAR1 is a complex protein with two Z-DNA binding motifs called and Z-beta. It also has three copies of double-stranded RNA binding motif (DRBM) and a catalytic domain related to E.coli cytidine deaminase. Z-alpha alone can not only bind to Z-DNA with high affinity but also interact with Z-beta to form a slightly different binding domain. Z-alpha belongs to winged-helix-turn-helix family. It consists of a helix-turn-helix motif containing alpha-2 and alpha-3 and a C- terminal beta-sheet which constrains the the fold by contacting the residues on between alpha-2 and alpha-3. Alpha-3 and C-terminal beta sheet are involved in binding to Z-DNA. 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 blocking 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. Thus the result suggests that Z-DNA formation in the promoter region is itself involved in the regulation of transcription.
Vaccinia virus E3L proteinVaccinia virus E3L protein
E3L protein of vaccinia virus acts as an immune modulator and is required for replication of the virus. The region of E3L is similar to the Z-alpha domain of ADAR1 but has a lower binding affinity to Z-DNA than ADAR1 or DLM-1. Though the C-terminal of E3L is sufficient for viral replication it is the N-terminal which is responsible for pathogenicity. Mutations or deletions in the N-terminal region reduces the pathogenicity of the virus. Replacement of this domain with its corresponding analogues from ADAR1 or DLM-1 generates a chimeric virus which is as lethal as the wild type virus. Thus a drug which can block the binding of E3L to Z-DNA may be an effective therapy in preventing pathogenicity. Similarity of E3L to variola also suggests that such drugs might be effective against small pox. [2][3] `
DLM-1DLM-1
DLM-1 is also known as Z-DNA binding protein 1 (ZBP1). DLM-1 is a tumor associated gene expressed in lymphatic tissues and is upregulated in the peritoneal lining of mice with mouse ovarian ascites tumor. DLM-1 has two Z-DNA binding domains analogous to the Z-alpha and Z- beta domains in ADAR1. Comparison of Z-DNA binding of DLM-1 and ADAR1 revealed a common structure recognition core within the binding domain. However the role of DLM-1 binding to Z-DNA in tumor development is not known.
Z-DNA binding proteins have common structural characteristics. Z-DNA 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.[2]
Movie Depicting ADAR1 binding to Z-DNAMovie Depicting ADAR1 binding to Z-DNA
Comparison of helix parameters of the three forms of DNAComparison of helix parameters of the three forms of DNA
| Parameter | A-DNA | B-DNA | Z-DNA |
|---|---|---|---|
| Helix sense | Right | Right | Left |
| Residues per turn | 11 | 10 | 12 |
| Axial rise (A°) | 2.55 | 3.4 | 3.7 |
| Helix pitch | 28 | 34 | 45 |
| Base pair tilt (°) | 20 | -6 | 7 |
| Rotation per residue | 33 | 36 | -30 |
| Diameter of helix (A°) | 23 | 20 | 18 |
ReferencesReferences
- ↑ 1.0 1.1 Rich A, Zhang S. Timeline: Z-DNA: the long road to biological function. Nat Rev Genet. 2003 Jul;4(7):566-72. PMID:12838348 doi:10.1038/nrg1115
- ↑ 2.0 2.1 2.2 2.3 Wang G, Vasquez KM. Z-DNA, an active element in the genome. Front Biosci. 2007 May 1;12:4424-38. PMID:17485386
- ↑ Kim YG, Lowenhaupt K, Oh DB, Kim KK, Rich A. Evidence that vaccinia virulence factor E3L binds to Z-DNA in vivo: Implications for development of a therapy for poxvirus infection. Proc Natl Acad Sci U S A. 2004 Feb 10;101(6):1514-8. Epub 2004 Feb 2. PMID:14757814 doi:10.1073/pnas.0308260100