La identificación en la construcción identitaria

Andrey Zavialov, Ph.D., Academy of Finland Research Fellow, Group leader, Turku Centre for Biotechnology, University of Turku, Tykistökatu 6, FI-20520,Turku, Finland,

Tel. +358403776216, Fax. +358-2-3338000 Email: [email protected]

Biography:

Andrey Zavialov (b. 1975) has obtained his M.S. in Biotechnology from Russian Chemical Technology University (Moscow) and a Ph.D. in Molecular Biology from Uppsala University (Sweden). Between 2005-2010 Dr Zavialov received his postdoctoral training in Immunology at Institute of Cellular and Molecular Pharmacology (France) and worked as a research scientist and an assistant research professor at A*-STAR’s Singapore Immunology Network (SIgN) and University of Hawaii at Manoa (U.S.A.). Dr. Zavialov is a recipient of the Harold M. Weintraub graduate student Award, EMBO and HFSP long-term fellowships. In 2011 he was selected as a Research Fellow of the Academy of Finland.

Personnel:

Graduate students: Maksym Skaldin (M.S.), Salim Reza (M.S.) Description of the project:

Two distinct enzymes of adenosine deaminase, ADA1 and ADA2, have been found in humans. Inherited mutations in ADA1 result in severe combined immunodeficiency (SCID). This observation led to extensive studies of the structure and function of this enzyme that have revealed its important role in lymphocyte activation. In contrast, the physiological role of ADA2 is unknown. ADA2 activity in serum is increased in various diseases in which monocytes/ macrophages are activated. We have found that ADA2 is a heparin- binding protein. This allowed us to obtain highly purified enzyme and to study its biochemistry. ADA2 was identified as a member of a new class of adenosine deaminase related growth factors (ADGF), which are present in almost all organisms from flies to humans. Biochemical data suggest that ADA2 may be active at sites of inflammation during hypoxia and in areas of tumor growth where the adenosine concentration is significantly elevated and the extracellular pH is low. We showed that ADA2 is secreted by monocytes undergoing differentiation into macrophages or dendritic cells, and that activated T cells are likely the main target for ADA2. T cells bound the enzyme via A2A and A2B adenosine receptors expressed on their cell surface. It has been further demonstrated that ADA2 induces T cell proliferation independently of their activation with antigen, and that the resulting proliferating cells are CD4+ _{T-helper cells. Moreover, our recent results show}

that ADA2 binds to CD39+_CD25+ _{T regulatory cells and induces}

proliferation of Th17- polarized T helper cells in the presence of Tregs, monocytes and ADA2. While this function is shared with ADA1, the unique role of ADA2 is to promote CD4+ _{T cell dependent}

differentiation of monocytes into macrophages. The recently solved structure of ADA2 allows us to establish the role of unique ADA2 domains in the enzyme’s interaction with its specific receptor. The comparison of catalytic centres in the structure of ADA1 and ADA2 reveals differences in the binding pockets for the ADA inhibitor, deoxycoformycin. This opens the possibility of using structure- based drug design to find a specific inhibitor for ADA2, which

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could be chemically synthesize and tested in vitro. Our studies will explore the possibility that ADA2 is an immunomodulatory protein, which may directly or indirectly affect immune responses against intracellular pathogens or tumor cell proliferation. Our goal is to establish the physiological role of ADA2 in inflammation and tumor immunity and to explore its therapeutic potential.

Funding:

The Academy of Finland Collaborators:

Dr. Anton Zavialov (University of Turku), Dr. Yuanan Lu (University of hawaii, U.S.A.), Dr. Rafael Franco (University of Barcelona, Spain), Dr. Sergey Lavrenov ( Gauze Institute of new antibiotics, Moscow, Russia).

Selected Publications:

Zavialov, A. V., Yu X., Spillmann D., and Lauvau G. (2010) Structural basis for the growth factor activity of human adenosine deaminase ADA2. J. Biol. Chem. 285: 12367-12377.

Zavialov, A. V., Gracia E., Glaichenhaus N., Franco R., and Lauvau G. (2010) Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages. J. Leukoc. Biol 88: 279-290. Gao, N., Zavialov A.V., Ehrenberg M., and Frank J. (2007). Specific interaction between EF-G and RRF and its implication for GTP- dependent ribosome splitting into subunits. J. Mol. Biol. 374: 1345-1358.

Gao, H., Zhou Z., Rawat U., Huang C., Bouakaz L., Wang C., Cheng Z., Liu Y., Zavialov A., Gursky R., Sanyal S., Ehrenberg M., Frank J. and Song H. (2007) RF3 induces ribosomal conformational changes responsible for dissociation of class I release factors. Cell 129: 929-941.

Rawat, U., Gao H., Zavialov A., Gursky R., Ehrenberg M. and Frank J. (2006) Interactions of the Release Factor RF1 with the Ribosome as Revealed by Cryo-EM. J. Mol. Biol. 357: 1144-1153.

Hauryliuk, V., Zavialov A., Kisselev L., and Ehrenberg M. (2006) Class-1 release factor eRF1 promotes GTP binding by class-2 release factor eRF3. Biochimie 88: 747-757.

Zavialov, A. V., Hauryliuk V.V. and Ehrenberg M. (2005) Splitting of the posttermination ribosome into subunits by the concerted action of RRF and EF-G. Mol. Cell 18: 675-686.

Zavialov, A. V., Hauryliuk V.V and Ehrenberg M. (2005) Guanine- nucleotide exchange on ribosome-bound elongation factor G initiates the translocation of tRNAs. J. Biol. 4: 9.

Zavialov, A. V., and Engstrom A. (2005) Human ADA2 belongs to a new family of growth factors with adenosine deaminase activity.

Biochem J. 391: 51-57.

Gao, N., Zavialov A.V., Li W., Sengupta J., Valle M., Gursky R.P., Ehrenberg M. and Frank J. (2005) Mechanism for the disassembly of the posttermination complex inferred from cryo-EM studies. Mol.

Cell 18: 663-674.

Frank, J., Sengupta J., Gao H., Li W., Valle M., Zavialov A. and Ehrenberg M. (2005) The role of tRNA as a molecular spring in decoding, accommodation, and peptidyl transfer. FEBS Lett. 579: 959-962.

Allen, G. S., Zavialov A., Gursky R., Ehrenberg M. and Frank J. (2005) The cryo-EM structure of a translation initiation complex from Escherichia coli. Cell 121: 703-712.

Zavialov, A. V., and Ehrenberg M. (2003) Peptidyl-tRNA regulates the GTPase activity of translation factors. Cell 114: 113-122. Valle, M., Zavialov A., Sengupta J., Rawat U., Ehrenberg M. and Frank J. (2003) Locking and unlocking of ribosomal motions. Cell 114: 123-134.

Valle, M., Zavialov A., Li W., Stagg S.M., Sengupta J., Nielsen R.C., Nissen P., Harvey S.C., Ehrenberg M. and Frank J. (2003) Incorporation of aminoacyl-tRNA into the ribosome as seen by cryo-electron microscopy. Nat. Struct. Biol. 10: 899-906.

Rawat, U. B., Zavialov A.V., Sengupta J., Valle M., Grassucci R.A., Linde J., Vestergaard B., Ehrenberg M., and Frank J. (2003) A cryo-electron microscopic study of ribosome-bound termination factor RF2. Nature 421: 87-90.

Pedersen, K., Zavialov A.V., Pavlov M.Y., Elf J., Gerdes K. and Ehrenberg M. (2003) The bacterial toxin RelE displays codon-specific cleavage of mRNAs in the ribosomal A site. Cell 112: 131-140. Mora, L., Zavialov A., Ehrenberg M and Buckingham R.H. (2003) Stop codon recognition and interactions with peptide release factor RF3 of truncated and chimeric RF1 and RF2 from Escherichia coli.

Mol. Microbiol. 50: 1467-1476.

Klaholz B. P., Pape T., Zavialov A.V., Myasnikov A.G., Orlova E.V., Vestergaard B., Ehrenberg M., and van Heel M. (2003) Structure of the Escherichia coli ribosomal termination complex with release factor 2. Nature 421: 90-94.

Zavialov, A. V., Mora L., Buckingham R.H. and Ehrenberg M. (2002) Release of peptide promoted by the GGQ motif of class 1 release factors regulates the GTPase activity of RF3. Mol. Cell 10: 789- 798.

Zavialov, A. V., Buckingham R.H. and Ehrenberg M. (2001) A posttermination ribosomal complex is the guanine nucleotide exchange factor for peptide release factor RF3. Cell 107: 115-124.

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