Protein - Nucleic Acids Interactions

Research Interests

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 catalyzing 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), while it also plays a role in a newly discovered and as yet uncharacterized interferon response antiviral pathway.

We are currently looking for group members at all levels. You can express your interest by sending your CV to Alekos Athanasiadis.

Group Members

Matteo De Rosa	Postdoc
	Tel: 21 440 7947
Sónia Zacarias	External Masters Student
	Tel: 21 440 7947
Diogo Ribeiro	External Masters Student
	Tel: 21 440 7947
Krzysztof Kus	2010 PIBS
	Tel: 21 446 4648

Research Project

Molecular basis of the recognition of foreign nucleic acids in innate immunity

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.

Research Project

Computational modeling of the A to I RNA editing process

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.

Funding

European Commission Marie Curie International Reintegration Grant (231000)

Fundação para a Ciência e Tecnologia (PTDC/BIA-PRO/112962/2009)
Recognition of pathogen nucleic acids by innate immunity: Structure-function studies of the cytoplasmic DNA receptor DAI pathway.

Collaborators

Massachusetts Institute of Technology/Cambridge
Rich Alex

ITQB/Oeiras
Maria Armenia Carrondo

Lehigh University/Bethlehem
Maas Stefan

Publications

(Selected) November (2011).

Athanasiadis A. (2011). Zalpha-domains: At the intersection between RNA editing and innate immunity Semin Cell Dev Biol doi:10.1016/j.semcdb.2011.11.001

Santos ME, Athanasiadis A, Leitao AB, Dupasquier L, Sucena E. (2011). Alternative splicing and gene duplication in the evolution of the FoxP gene sub-family Mol Biol Evol 28 :237-47

de Rosa M, de Sanctis D, Rosario AL, Archer M, Rich A, Athanasiadis A (coresponding author) and Carrondo MA. : (2010). Crystal structure of a junction between two Z-DNA helices PNAS 107 (20) :9088-9092

Placido D, Brown BA II, Lowenhaupt K, Rich A, and Athanasiadis, A. (2007). A Left Handed RNA Double Helix Bound by the Zα Domain of the RNA Editing Enzyme ADAR1 Structure 15(4) :395-404

Athanasiadis, A, Maas S, Placido D, Brown BA. 2nd, Lowenhaupt, K and Rich A. (2005). The crystal structure of the Zb domain from the RNA editing enzyme ADAR1. J Mol Biol 19;351(3) :496-507

Athanasiadis A, Rich A and Maas S. (2004). Widespread A-I RNA editing in Alu-containing mRNAs in the human transcriptome. PLoS Biology 2(12)

Rashkova S, Athanasiadis, A and Pardue M.L. (2003). Intracellular targeting of Gag proteins of the Drosophila telomeric retrotransposons J Virol 77(11) :6376-84

Athanasiadis, A, Anderluh G, Macek P and Turk D. (2001). Crystal structure of the soluble form of Equinatoxin II, a pore forming toxin from the Sea Anemone Actinia Equina. Structure (Cell Press) 9 :341-346

Magyar Z, Meszaros T, Miskolczi P, Deak M, Feher A, Brown S, Kondorosi E, Athanasiadis, A, Pongor S, Bilgin M, Bako L, Koncz C and Dudits D. (1997). Cell cycle phase specificity of putative cyclin-dependent kinase variants in synchronized alfalfa cells Plant Cell 9 :223-235

Athanasiadis, A, Papanikolau Y, Rina M, Papadovasilaki M, Petratos K, Bouriotis V, Daugter S and Kokkinidis M. (1997). Purification, Crystallization and Preliminary X-ray Analysis of the M.BseCI DNA Methyltransferase from Bacillus stearothermophilus. Acta Crystallographica D53 :477-479

Athanasiadis, A, Vlassi M, Kotsifaki D, Tucker PA, Wilson KS and Kokkinidis M. (1994). Crystal structure of the PvuII endonuclease reveals extensive structural homologies to EcoRV. Nature Structural Biology. 1. 469-475. See comment in "No limits on restriction" Nature 370(6484) :78

Athanasiadis, A and Kokkinidis M. (1991). Purification, Crystallization and Preliminary X-ray Diffraction Studies of the Pvu II Endonuclease. J. Mol. Biol. 222

Athanasiadis, A, Gregoriu M, Thanos D, Kokkinidis M and Papamatheakis J. (1990). Complete nucleotide sequence of the Pvu II restriction enzyme gene from Proteus vulgaris. Nucl. Acids Res. 18 :6434-6435