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Matteo de Rosa, Sonia Zacarias, Alekos Athanasiadis
The RNA-dependent protein kinase PKR plays a central role in the antiviral defense of vertebrates by shutting down protein translation upon detection of viral dsRNA in the cytoplasm. In some teleost fish, PKZ, a homolog of PKR, performs the same function, but surprisingly, instead of dsRNA binding domains, it harbors two Z-DNA/Z-RNA-binding domains belonging to the Zalpha domain family. Zalpha domains have also been found in other proteins, which have key roles in the regulation of interferon responses such as ADAR1 and DNA-dependent activator of IFN-regulatory factors (DAI) and in viral proteins involved in immune response evasion such as the poxviral E3L and the Cyprinid Herpesvirus 3 ORF112...
November 1, 2013: Nucleic Acids Research
Ana Rita Tomé, Krzysztof Kuś, Silvia Correia, Lara Martins Paulo, Sónia Zacarias, Matteo de Rosa, Delio Figueiredo, R Michael E Parkhouse, Alekos Athanasiadis
Zalpha domains are a subfamily of the winged helix-turn-helix domains sharing the unique ability to recognize CpG repeats in the left-handed Z-DNA conformation. In vertebrates, domains of this family are found exclusively in proteins that detect foreign nucleic acids and activate components of the antiviral interferon response. Moreover, poxviruses encode the Zalpha domain-containing protein E3L, a well-studied and potent inhibitor of interferon response. Here we describe a herpesvirus Zalpha-domain-containing protein (ORF112) from cyprinid herpesvirus 3...
April 2013: Journal of Virology
Chunrong Yang, Jianguo Su, Qingmei Li, Rongfang Zhang, Youliang Rao
ADAR (adenosine deaminase acting on RNA) is an RNA editing enzyme that targets both coding and noncoding dsRNAs (double stranded RNAs) and converts adenosine to inosine, which is read by translation machinery and by polymerases during RNA-dependent RNA replication as if it is guanosine. This editing is a widespread post-transcriptional modification event in animals. In this study, we identified the full-length cDNA sequence of Ctenopharyngodon idella ADAR1 (designated as CiADAR1) and detected the mRNA expression patterns in response to dsRNA (polyinosinic-polycytidylic acid sodium salt, poly(I:C)) and grass carp reovirus (GCRV)...
October 2012: Fish & Shellfish Immunology
Alekos Athanasiadis
The involvement of A to I RNA editing in antiviral responses was first indicated by the observation of genomic hyper-mutation for several RNA viruses in the course of persistent infections. However, in only a few cases an antiviral role was ever demonstrated and surprisingly, it turns out that ADARs - the RNA editing enzymes - may have a prominent pro-viral role through the modulation/down-regulation of the interferon response. A key role in this regulatory function of RNA editing is played by ADAR1, an interferon inducible RNA editing enzyme...
May 2012: Seminars in Cell & Developmental Biology
Matteo de Rosa, Daniele de Sanctis, Ana Lucia Rosario, Margarida Archer, Alexander Rich, Alekos Athanasiadis, Maria Armenia Carrondo
The double helix of DNA, when composed of dinucleotide purine-pyrimidine repeats, can adopt a left-handed helical structure called Z-DNA. For reasons not entirely understood, such dinucleotide repeats in genomic sequences have been associated with genomic instability leading to cancer. Adoption of the left-handed conformation results in the formation of conformational junctions: A B-to-Z junction is formed at the boundaries of the helix, whereas a Z-to-Z junction is commonly formed in sequences where the dinucleotide repeat is interrupted by single base insertions or deletions that bring neighboring helices out of phase...
May 18, 2010: Proceedings of the National Academy of Sciences of the United States of America
Chu-Xin Wu, Shu-Jun Wang, Gang Lin, Cheng-Yu Hu
PKZ was the most recently discovered member of eIF2alpha kinase family in fish. CaPKZ, the first identified fish PKZ, possessed a conserved eIF2alpha kinase catalytic domain in C-terminal and two Z-DNA binding domains (Zalpha) in N-terminal. The Zalpha of CaPKZ closely resembled that of other Z-DNA binding proteins: ADAR1, DLM-1, and E3L. In order to understand more about the function of CaPKZ, we expressed and purified three constructed peptides of CaPKZ (P(Zalpha)): P(Zalpha1Zalpha2), P(Zalpha1Zalpha1) and P(Zalpha2)(Zalpha2)...
May 2010: Fish & Shellfish Immunology
Young-Min Kang, Jongchul Bang, Eun-Hae Lee, Hee-Chul Ahn, Yeo-Jin Seo, Kyeong Kyu Kim, Yang-Gyun Kim, Byong-Seok Choi, Joon-Hwa Lee
The human RNA editing enzyme ADAR1 (double-stranded RNA deaminase I) deaminates adenine in pre-mRNA to yield inosine, which codes as guanine. ADAR1 has two left-handed Z-DNA binding domains, Z alpha and Z beta, at its NH(2)-terminus and preferentially binds Z-DNA, rather than B-DNA, with high binding affinity. The cocrystal structure of Z alpha(ADAR1) complexed to Z-DNA showed that one monomeric Z alpha(ADAR1) domain binds to one strand of double-stranded DNA and a second Z alpha(ADAR1) monomer binds to the opposite strand with 2-fold symmetry with respect to DNA helical axis...
August 19, 2009: Journal of the American Chemical Society
Doyoun Kim, Hye Yeon Hwang, Yang Gyun Kim, Kyeong Kyu Kim
PKZ, a PKR-like eIF2alpha kinase, consists of a Z-DNA-specific binding domain (Zalpha) and an eIF2alpha kinase domain. The kinase activity of PKZ is modulated by the binding of Zalpha to Z-DNA. The mechanisms underlying Z-DNA binding and the subsequent stimulation of PKZ raise intriguing questions. Interestingly, the Z-DNA-binding domain of PKZ from goldfish (Carassius auratus; caZalpha(PKZ)) shows limited sequence homology to other canonical Zalpha domains, suggesting that it may have a distinct Z-DNA-recognition mode...
March 1, 2009: Acta Crystallographica. Section F, Structural Biology and Crystallization Communications
Akinori Takaoka, Shigeki Shinohara
Microbial sensing mediated by pattern recognition receptors (PRRs) is the first key step to trigger innate immune responses, represented by the induction of type I interferons (IFNs), proinflammatory cytokines and chemokines. This innate signaling elicits an efficient activation of more specific responses in adaptive immunity. Such coordinated responses in the two systems are essential for the optimal elimination of invading microbes. Despite a major advance in our understanding of RNA sensors, TLR9 remained the only known sensor of DNA...
June 2008: Uirusu
Juliane Lippmann, Stefan Rothenburg, Nikolaus Deigendesch, Julia Eitel, Karolin Meixenberger, Vincent van Laak, Hortense Slevogt, Philippe Dje N'guessan, Stefan Hippenstiel, Trinad Chakraborty, Antje Flieger, Norbert Suttorp, Bastian Opitz
Intracellular bacteria and cytosolic stimulation with DNA activate type I IFN responses independently of Toll-like receptors, most Nod-like receptors and RIG-like receptors. A recent study suggested that ZBP1 (DLM-1/DAI) represents the long anticipated pattern recognition receptor which mediates IFNalpha/beta responses to cytosolic DNA in mice. Here we show that Legionella pneumophila infection, and intracellular challenge with poly(dA-dT), but not with poly(dG-dC), induced expression of IFNbeta, full-length hZBP1 and a prominent splice variant lacking the first Zalpha domain (hZBP1DeltaZalpha) in human cells...
December 2008: Cellular Microbiology
Vladimir A Yerokhin, Ulrich D Jentschura
A high-precision numerical calculation is reported for the self-energy correction to the hyperfine splitting and to the bound-electron g factor in hydrogenlike ions with low nuclear charge numbers. The binding nuclear Coulomb field is treated to all orders, and the nonperturbative remainder beyond the known Zalpha-expansion coefficients is determined. For the 3He+ ion, the nonperturbative remainder yields a contribution of -450 Hz to the normalized difference of the 1S and 2S hyperfine-structure intervals, to be compared with the experimental uncertainty of 71 Hz and with the theoretical error of 50 Hz due to other contributions...
April 25, 2008: Physical Review Letters
Jianguo Su, Zuoyan Zhu, Yaping Wang
Double-stranded RNA-activated protein kinase (PKR) plays an important role in interferon-induced antiviral responses, and is also involved in intracellular signaling pathways, including the apoptosis, proliferation, and transcription pathways. In the present study, a PKR-like gene was cloned and characterized from rare minnow Gobiocypris rarus. The full length of the rare minnow PKR-like (GrPKZ) cDNA is 1946 bp in length and encodes a polypeptide of 503 amino acids with an estimated molecular mass of 57,355 Da and a predicted isoelectric point of 5...
July 2008: Fish & Shellfish Immunology
Ivan S Terekhov, Alexander I Milstein, Valeri N Kotov, Oleg P Sushkov
We calculate exactly the vacuum polarization charge density in the field of a subcritical Coulomb impurity, Z|e|/r, in graphene. Our analysis is based on the exact electron Green's function, obtained by using the operator method, and leads to results that are exact in the parameter Zalpha, where alpha is the "fine-structure constant" of graphene. Taking into account also electron-electron interactions in the Hartree approximation, we solve the problem self-consistently in the subcritical regime, where the impurity has an effective charge Z(eff), determined by the localized induced charge...
February 22, 2008: Physical Review Letters
Dong Van Quyen, Sung Chul Ha, Ky Lowenhaupt, Alexander Rich, Kyeong Kyu Kim, Yang-Gyun Kim
The E3L gene is essential for pathogenesis in vaccinia virus. The E3L gene product consists of an N-terminal Z alpha domain and a C-terminal double-stranded RNA (dsRNA) binding domain; the left-handed Z-DNA-binding activity of the Z alpha domain of E3L is required for viral pathogenicity in mice. E3L is highly conserved among poxviruses, including the smallpox virus, and it is likely that the orthologous Z alpha domains play similar roles. To better understand the biological function of E3L proteins, we have investigated the Z-DNA-binding behavior of five representative Z alpha domains from poxviruses...
2007: Nucleic Acids Research
Diana Placido, Bernard A Brown, Ky Lowenhaupt, Alexander Rich, Alekos Athanasiadis
The A form RNA double helix can be transformed to a left-handed helix, called Z-RNA. Currently, little is known about the detailed structural features of Z-RNA or its involvement in cellular processes. The discovery that certain interferon-response proteins have domains that can stabilize Z-RNA as well as Z-DNA opens the way for the study of Z-RNA. Here, we present the 2.25 A crystal structure of the Zalpha domain of the RNA-editing enzyme ADAR1 (double-stranded RNA adenosine deaminase) complexed to a dUr(CG)(3) duplex RNA...
April 2007: Structure
Nikolaus Deigendesch, Friedrich Koch-Nolte, Stefan Rothenburg
Z-DNA binding protein 1 (ZBP1) belongs to a family of proteins that contain the Zalpha domain, which binds specifically to left-handed Z-DNA and Z-RNA. Like all vertebrate proteins in the Zalpha family, it contains two Zalpha-like domains and is highly inducible by immunostimulation. Using circular dichroism spectroscopy and electrophoretic mobility shift assays we show that both Zalpha domains can bind Z-DNA independently and that substrate binding is greatly enhanced when both domains are linked. Full length ZBP1 and a prominent splice variant lacking the first Zalpha domain (DeltaZalpha) showed strikingly different subcellular localizations...
2006: Nucleic Acids Research
Hong Thanh Pham, Mi-Young Park, Kyeong Kyu Kim, Yang-Gyun Kim, Jin-Hyun Ahn
We investigated the subcellular distribution of human ZBP1, which harbors the N-terminal Z-DNA binding domains, Zalpha and Zbeta. ZBP1 was distributed primarily in the cytoplasm and occasionally as nuclear foci in interferon (IFN)-treated primary hepatocellular carcinoma cells, and in several other transfected cell types. In leptomycin B (LMB)-treated cells, endogenous ZBP1 efficiently accumulated in nuclear foci, which overlapped PML oncogenic domains (PODs) or nuclear bodies (NBs). In transfection assays, the unique C-terminal region of ZBP1 was necessary for its typical cytoplasmic localization...
September 15, 2006: Biochemical and Biophysical Research Communications
Sung Chul Ha, Dong Van Quyen, Hye-Yeon Hwang, Doo-Byoung Oh, Bernard A Brown, Seon Min Lee, Hyun-Ju Park, Jin-Hyun Ahn, Kyeong Kyu Kim, Yang-Gyun Kim
ZBP1 is involved in host responses against cellular stresses, including tumorigenesis and viral infection. Structurally, it harbors two copies of the Zalpha domain containing the Zalpha motif, at its N terminus. Here, we attempted to characterize the Z-DNA binding activities of two Zalpha domains in the human ZBP1, hZalpha(ZBP1) and hZbeta(ZBP1), using circular dichroism (CD). Our results indicated that both hZalpha(ZBP1) and hZbeta(ZBP1) are viable Z-DNA binders, and their binding activities are comparable to those of previously-established Zalpha domains...
February 2006: Biochimica et Biophysica Acta
Andrzej Czarnecki, Ulrich D Jentschura, Krzysztof Pachucki
General expressions for quantum electrodynamic corrections to the one-loop self-energy [of order alpha(Zalpha)6] and for the two-loop Lamb shift [of order alpha2(Zalpha)6] are derived. The latter includes all diagrams with closed fermion loops. The general results are valid for arbitrary excited non-S hydrogenic states and for the normalized Lamb shift difference of states, defined as Delta N = n3deltaE(nS) - delta E(1S). We present numerical results for one-loop and two-loop corrections for excited S, P, and D states...
October 28, 2005: Physical Review Letters
Alekos Athanasiadis, Diana Placido, Stefan Maas, Bernard A Brown, Ky Lowenhaupt, Alexander Rich
The Zalpha domains represent a growing subfamily of the winged helix-turn-helix (HTH) domain family whose members share a remarkable ability to bind specifically to Z-DNA and/or Z-RNA. They have been found exclusively in proteins involved in interferon response and, while their importance in determining pox viral pathogenicity has been demonstrated, their actual target and biological role remain obscure. Cellular proteins containing Zalpha domains bear a second homologous domain termed Zbeta, which appears to lack the ability to bind left-handed nucleic acids...
August 19, 2005: Journal of Molecular Biology
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