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Molecular Biology Program
 

Tatiana Kutateladze, 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. ​​​​​​​

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