Protein - Nucleic Acids Interactions
Sequence is not fate. Proteins demonstrate an impressive ability not only to recognize and bind to particular pieces of nucleic acids code but also to alter its information content by catalysing reactions that rearrange its sequence or specifically change one nucleotide for another. Organisms have found in such mechanisms the means for creating sequence diversity as it is gloriously exemplified in the diversification of immunoglobulin genes. The recent realization that multi-cellular organisms achieve phenotypic complexity without a parallel increase in number of genes has highlighted the importance of posttranscriptional RNA modifications in creating and fine-tuning a much larger repertoire of proteins originating from a small number of genes. I am interested in the study of the molecular mechanisms involved in such diversification of RNA and DNA sequence as well as understanding the consequences of such processes for molecular evolution dynamics. In this direction I am employing the tools of computational, molecular and structural biology in the study of RNA and DNA editing. My work presently focuses on the A to I RNA editing process which alters the sequence of thousands of human pre-mRNAs (Athanasiadis et al., 2004), having this way a prominent role in regulating Innate Immune responses to dsRNA.
The A to I RNA editing process targets imperfect stem loop structures in pre-mRNAs. Such structures are ubiquitous in the transcriptome of all higher eukaryotes. We are interested in developing computational models of the enzymatic specificity for this mRNA modification and use these models to study the dynamics and evolution of novel targets of RNA editing.
The innate immunity system for vertebrates represents the front-end of their defense against invading viruses and bacteria. Its activation is based on the recognition of pathogen associated molecular patterns (PAMPs) by specialized receptors. Central in the pathogen recognition process is the detection of nucleic acids. However, how exactly foreign nucleic acids are distinguished from host DNA and RNA is poorly understood and of great importance since false recognition leads to severe auto-immune disorders. DAI is a protein which recently was identified as a receptor for dsDNA in the cytoplasm. This receptor for nucleic acids shares DNA/RNA binding domains with the interferon inducible RNA editing enzyme ADAR1. We are aiming to characterize the protein/nucleic acids interactions of this interferon response pathway by means of biochemistry and structural biology.
- Rakus, K., Ronsmans, M., Forlenza, M., Boutier, M., Piazzon, M.C., Jazowiecka-Rakus, J., Gatherer, D., Athanasiadis, A., Farnir, F., Davison, A.J., P. Boudinot, P., Michiels, T., Wiegertjes, G.F., Vanderplasschen, A. (2017) Conserved fever pathways across vertebrates: A Herpesvirus expressed decoy TNF-alpha receptor delays behavioral fever in fish.. Cell Host Microbe 21(2):244-253
- Kus, K., Rakus, K., Boutier, M., Tsigkri, T., Gabriel, L., Vanderplasschen, A., Athanasiadis, A. (2015) The Structure of the Cyprinid herpesvirus 3 ORF112-Zalpha.Z-DNA Complex Reveals a Mechanism of Nucleic Acids Recognition Conserved with E3L, a Poxvirus Inhibitor of Interferon Response.. J Biol Chem 290:30713-30725
- Remy, E., Cabrito, T.R., Batista, R.A., Hussein, M.A., Teixeira, M.C., Athanasiadis, A., Sa-Correia, I., Duque, P. (2014) Intron retention in the 5’UTR of the novel ZIF2 transporter enhances translation to promote zinc tolerance in Arabidopsis. PLoS Genet 10:e1004375
- Koyama, T., Rodrigues, M. A., Athanasiadis, A., Shingleton, A. W., Mirth, C. K. (2014) Nutritional control of body size through FoxO-Ultraspiracle mediated ecdysone biosynthesis.. eLife 3:e03091
- de Rosa, M., Zacarias, S., Athanasiadis, A. (2013) Structural basis for Z-DNA binding and stabilization by the zebrafish Z-DNA dependent protein kinase PKZ. Nucleic Acids Res 41:9924-9933
- Athanasiadis, A. (2012) Zalpha-domains: at the intersection between RNA editing and innate immunity. Seminars in Cell & Developmental Biology 23:275-280
- Santos, M.E., Athanasiadis, A., Leitao, A.B., Dupasquier, L., Sucena, E. (2011) Alternative splicing and gene duplication in the evolution of the FoxP gene sub-family. Mol Biol Evol 28:237-247
- de Rosa, M., de Sanctis, D., Rosario, A.L., Archer, M., Rich, A., Athanasiadis, A.*, Carrondo, M.A. * Corresponding Author (2010) Crystal structure of a junction between two Z-DNA helices. Proc Natl Acad Sci U S A 107:9088-9092
- Placido, D., Brown, B.A., 2nd, Lowenhaupt, K., Rich, A., Athanasiadis, A. (2007) A left-handed RNA double helix bound by the Z alpha domain of the RNA-editing enzyme ADAR1. Structure 15:395-404
- Athanasiadis, A., Rich, A., Maas, S. (2004) Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome. PLoS Biol 2:e391