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Tatiana Kutateladze, Associate Professor

Ph.D. (1988), Moscow State University
 

 

 

Contact Info:

Molecular Biology
University of Colorado

Tatiana Kutateladze, Ph.D.  Research One South
(RC1-South), Room 6112 Tatiana.Kutateladze@ucdenver.edu Phone: 303-724-3593

Research in my laboratory focuses on the molecular mechanisms underlying protein-protein and protein-phospholipid interactions. We apply high field Nuclear Magnetic Resonance (NMR) spectroscopy, X-ray crystallography, and biochemical and molecular biology approaches to determine the three-dimensional structures and functions of chromatin- and phosphoinositide (PI)-binding proteins implicated in cancer and other human diseases.

The study of epigenetics and deciphering the 'histone code' are the major directions in the lab. Histone proteins, around which DNA is wrapped, undergo a variety of posttranslational modifications (PTM) including methylation, acetylation, phosphorylation and ubiquitination. The single covalent modifications or a combination of these epigenetic marks recruit specific protein effectors to nucleosomes propagating the signals essential for chromatin remodeling and regulation of gene expression. Although various modifying enzymes that 'write' or 'erase' the histone marks have recently been identified, only a few protein domains that recognize or 'read' the precise histone modifications are known. Depending on the modification, the reading effector can either facilitate gene expression or condense the chromatin. Our goal is to identify and structurally and biochemically characterize novel 'readers' of PTMs and establish the functional significance of the histone code recognition. In collaboration with Or Gozani at Stanford University, we found that the PHD fingers of ING tumor suppressors bind histone H3 trimethylated at lysine 4 (H3K4me3) and represent a new family of protein modules able to 'read' this epigenetic mark. The crystal structure of the H3K4me3-PHD complex reveals key elements that define the binding specificity.  

 

Tumor suppressors ING1-5 are implicated in growth regulation, DNA damage repair, apoptosis and chromatin remodeling. The expression level of ING proteins is altered in many human malignancies. We seek to gain insights into the ING-mediated tumor suppression mechanisms through the structural characterization of ING proteins in complex with their binding partners.

The second major research project in our group is aimed at determining the mechanistic principles of membrane docking by PI-binding domains. PIs are produced by mono-, bis- and tris-phosphorylation of the inositol headgroup of PtdIns. Each PI exhibits a unique stereochemistry and elicits distinct biological responses. Collectively, seven known PI isomers create a remarkably complex signaling network, which could be viewed as a 'PI code' model. The levels and activity of PIs are tightly regulated by PI kinases, phosphatases and phospholipases that either initiate or terminate the signaling cascades by phosphorylating, dephosphorylating and hydrolyzing PIs. Individual PIs are highly concentrated in separate pools of intracellular membranes. They serve as markers of the cell compartments such as the plasma membrane, early endosomes, multivesicular bodies and Golgi apparatus, and form specific docking sites for lipid-binding effectors. Anchoring of the ANTH, ENTH, FYVE, PH and PX domain-containing proteins to PI-enriched cell membranes is required for many vital processes including growth, differentiation, vesicular trafficking, cytoskeletal rearrangement and survival of cells. The majority of these proteins is involved in down-regulation of proliferative pathways by internalizing oncogenic growth factor receptors. We are interested in elucidating the molecular basis of activation and recruitment of the PI-binding proteins to the distinct endocytic membranes.

 

The latter project leads to a broader goal with the focus on drug discovery and design. Recent remarkable developments in NMR spectroscopy offer radically new approaches in this area. We use structural information as a basis to produce ligands, including small organic molecules and synthetic peptides that precisely fit defined binding pockets. We hope that our structural studies on the dopamine transporter will lead to new approaches in rational design of therapeutic agents for treatment of depression, schizophrenia and other neurological and psychiatric disorders. ​​​​​​​

 

Peña, P. V., Davrazou, F., Shi, X., Walter, K., Verkhusha, V. V., Gozani, O., Zhao, R. and Kutateladze, T. G. 2006. "Molecular mechanism of histone H3K4Me3 recognition by Plant Homeodomain of ING2 tumor suppressor, Nature, 442, 100-3.

Shi, X., Hong, T., Walter, K. L., Ewalt, M., Michishita, E., Hung, T., Carney, D., Peña, P.V., Lan, F., Kaadige, M. R., Lacoste, N., Cayrou, C., Davrazou, F., Saha, A., Cairns, B. R., Ayer, D. E., Kutateladze, T. G., Shi, Y., Côté, J., Chua, K. F. and Gozani, O. 2006. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression, Nature, 442, 96-9.

Chen, Z., Zang, J., Whetstine, J., Hong, X., Davrazou, F., Kutateladze, T. G., Mao, Q., Pan, C., Dai, S., Shi, Y., and Zhang, G. 2006. Crystal structure of the catalytic core domain of a novel histone demethylase, Cell, 125, 691-702.

Lee, S.A., Kovacs, J., Stahelin, R., Cheever, M.L., Overduin, M., Setty, T.G., Burd, C., Cho, W. and Kutateladze, T.G. 2006. Molecular mechanism of membrane docking by the Vam7p PX domain. J. Biol. Chem., 281, 37091-101.

Kutateladze, T.G. 2006. Phosphatidylinositol 3-phosphate recognition and membrane docking by the FYVE domain, Biochim. Biophys. Acta-Molecular and Cell Biology of Lipids, 1761, 868-77.

Gajewiak, J., Xu, Y., Lee, S. A., Kutateladze, T. G., and Prestwich, G. D. 2006. Synthesis and Molecular Recognition of Phosphatidylinositol-3-methylenephosphate, Org. Letters, 8, 2811-3.

Xu, Y., Lee, S.A., Kutateladze, T.G., Sbrissa, D., Shisheva, A., Prestwich, G.D. 2006. Chemical synthesis and molecular recognition of phosphatase-resistant analogues of phosphatidylinositol-3-phosphate, J. Am. Chem. Soc., 128, 885-97.

Matthews, A.G.W., Kuo, A., Ramon-Maiques S., Han, S., Champagne, K.S., Gallardo, M., Carney, D., Cheung, P., Ciccone, D.N., Walter, K.L., Utz, P.J., Shi, Y., Kutateladze, T.G., Yang, W., Gozani, O. and Oettinger, M.A. 2007. RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination. Nature, 450, 1106-10.

Hom, R.A., Vora, M., Regner, M., Subach, O.M., Cho, W., Verkhusha, V.V., Stahelin, R. and Kutateladze, T. G. 2007. pH-Dependent Binding of the Epsin ENTH Domain and the AP180 ANTH Domain to PI(4,5)P2-containing Bilayers. J. Mol. Biol., 373, 412-23.

Kutateladze, T.G. 2007. Mechanistic similarities in docking of the FYVE and PX domains to phosphatidylinositol 3-phosphate containing membranes. Prog. Lipid Res., 46, 315-27.

Huang, W., Zhang, H., Davrazou, F., Kutateladze, T.G., Shi, X., Gozani, O. and Prestwich, G.D. 2007. Stabilized Phosphatidylinositol-5-Phosphate Analogues as Ligands for the Nuclear Protein ING2: Chemistry, Biology and Molecular Modeling. J. Am. Chem. Soc., 129, 6498-6506.

Shi X., Kachirskaia I., Walter K.L., Kuo J.H., Lake A., Davrazou F., Chan S.M., Martin D.G., Fingerman I.M., Briggs S.D., Howe L., Utz P.J., Kutateladze T.G., Lugovskoy A.A., Bedford M.T. and Gozani O. 2007. Proteome-wide analysis in S. cerevisiae identifies several PHD fingers as novel direct and selective binding modules of histone H3 methylated at either lysine 4 or lysine 36. J. Biol. Chem., 282, 2450-5.

Champagne, K.S., Saksouk, N., Peña, P.V., Johnson, K., Ullah, M., Yang, X.J., Côte, J., and Kutateladze, T.G. 2008. The crystal structure of the ING5 PHD finger in complex with an H3K4me3 histone peptide. Proteins, 72, 1371-6.

He, J., Haney, R.M., Vora, M., Verkhusha, V.V., Stahelin, R.V. and Kutateladze, T.G. 2008. Molecular mechanism of membrane targeting by GRP1 PH domain. J. Lipid Res. (cover), 49, 303-12.

He, J. and Kutateladze, T.G. 2008. Sequence-specific 1H, 13C and 15N resonance assignments of GRP1 PH domain. Biomol. NMR Assign., 2, 97-9.

Peña, P. V., Hom, R.A., Hung, T., Lin, H., Kuo, A.J., Wong, R.PC., Subach, O.M., Champagne, K.S., Zhao, R., Verkhusha, V.V., Li, G., Gozani, O. and Kutateladze, T. G. 2008. Histone H3K4me3 binding is required for the DNA repair and apoptotic activities of ING1 tumor suppressor. J. Mol. Biol., 380, 303-12.

Hung, T., Binda, O., Champagne, K.S., Kuo, A.J., Johnson, K., Chang, H.Y., Simon, M.D., Kutateladze, T.G. and Gozani, O. 2009. ING4 mediates crosstalk between histone H3 K4 trimethylation and H3 acetylation to attenuate cellular transformation. Mol. Cell, 33, 248-56.

Saksouk, N., Avvakumov, N., Champagne, K.S., Hung, T., Doyon, Y., Cayrou, C., Ulla, M., Landry, A.J., Cote, V., Yang, X.J., Gozani, O., Kutateladze, T.G. and Cote, J. 2009. HBO1 HAT complexes target chromatin throughout gene coding regions via multiple PHD finger interactions with histone H3 tail. Mol. Cell, 33, 257-65.

Peña, P. V., Musselman, C.A., Kuo, A.J., Gozani, O., and Kutateladze, T. G. 2009. NMR assignments and histone specificity of the ING2 PHD finger. Mag. Res. Chem., 47, 352-8.

He, J., Vora, M., Haney, R.M., Filonov, G.S., Musselman, C.A., Burd, C.G., Kutateladze, A.G., Verkhusha, V.V., Stahelin, R.V. and Kutateladze, T.G. 2009. Membrane insertion of the FYVE domain is modulated by pH. Proteins, 76, 852-60.

Champagne, K.S. and Kutateladze, T.G. 2009. Structural insight into histone recognition by the ING PHD fingers, Curr. Drug Targets, 5, 432-41.

Musselman, C.A., Mansfield, R.E., Garske, A.L., Davrazou, F., Kwan, A., Oliver, S.S., OLeary, H., Denu, J.M., Mackay, J.P. and Kutateladze, T.G. 2009. Binding of the CHD4 PHD2 finger to histone H3 is modulated by covalent modifications, Biochem. J., in press.