Tatiana G. Kutateladze, Ph.D.

Assistant Professor of Pharmacology

Department of Pharmacology
University of Colorado at Denver and Health Sciences Center
P.O. Box 6508 MS 8303
Aurora, Colorado 80045

Office: (303) 724-3593 Room: L18-6112
Lab: (303) 724-3589, (303) 724-3586
Fax: 303.724-3663
Email: Tatiana.Kutateladze@uchsc.edu

EDUCATION/EXPERIENCE

HONORS, AWARDS & PATENTS

Research Interests

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 other biochemical and biophysical approaches to study three-dimensional structures and dynamics of chromatin- and phosphoinositide (PI)-recognizing proteins implicated in cancer, Muscular Dystrophy, Parkinson’s and other human diseases. The high-resolution structures of the macromolecular complexes facilitate our knowledge on how these molecules contribute to the diseases and whether their signaling pathways can be regulated.

One of our major research directions involves understanding the role of covalent histone tail modifications and their recognition by specific effector-proteins in chromatin structure and gene expression. Despite a variety of known histone marks, only a few protein domains have been identified that recognize or ‘read’ precise histone modifications. We are interested in the identification and structural characterization of novel chromatin-interacting modules. In collaboration with Or Gozani at Stanford University, we found that the PHD finger of inhibitor of growth 2 (ING2) tumor suppressor binds trimethylated at lysine 4 histone H3 (H3K4me3) representing a new family of modules that target this epigenetic mark (Shi et al., 2006, Nature). The crystal structure of the H3K4me3-PHD complex, solved at 2Å resolution, reveals a conserved mode of methyl-lysine recognition by PHD fingers and displays key elements that define the binding specificity (Pena et al., 2006, Nature).

ING2 is a member of the ING family of tumor suppressors that are implicated in oncogenesis, growth regulation, DNA damage repair, apoptosis and chromatin remodeling. The expression level of ING proteins is substantially reduced in many tumors, particularly in those that have metastasized to lymph nodes. We seek to gain insights into the ING-mediated tumor suppressive mechanisms through the structural characterization of ING proteins in complex with their binding partners.

Another research project in the laboratory is aimed at determining the mechanistic principles of membrane docking and insertion by PI-binding domains. Vital processes including growth, differentiation, vesicular trafficking, cytoskeletal rearrangement and survival of cells require anchoring of ANTH/ENTH, FYVE, PH and PX domain-containing proteins to PI-enriched cell membranes. Many of these proteins are directly implicated in tumorigenesis and/or involved in down-regulation of proliferative pathways by internalizing oncogenic growth factor receptors. We explore the molecular basis and functional significance of the activation and recruitment of the PI-recognizing proteins to endocytic membranes. We are particularly interested in understanding how PI-containing membranes are selectively recognized and whether such recognition is regulated by other factors (Lee et al., 2005, PNAS; Brunecky et al., 2005, Biochemistry).

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

Selected Recent Publications:

1. Pena, 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.
2. 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.
3. 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.
4. Kutateladze, T.G. 2006. Phosphatidylinositol 3-phosphate recognition and membrane docking by the FYVE domain, Biochim. Biophys. Acta-Molecular and Cell Biology of Lipids, online April 7.
5. 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.
6. 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.
7. Brunecky, R., Lee, S., Rzepecki, P.W., Overduin, M., Prestwich, G.D., Kutateladze, A.G., Kutateladze T.G. 2005. Investigation of the binding geometry of a peripheral membrane protein, Biochemistry, 44, 16064-71.
8. Lee, S.A., Eyeson, R., Cheever, M.L., Geng, J., Verkhusha, V.V., Burd, C., Overduin, M., Kutateladze, T.G. 2005. Targeting of the FYVE domain to endosomal membranes is regulated by a histidine switch, Proc. Natl. Acad. Sci. USA, 102, 13052-7.