Research Area I: Structure-Function Studies on Pore-Forming Protein Toxins.
Pore-forming protein toxins (PFTs) represent a special class of membrane damaging cytolytic proteins, and they are found in wide spectrum of organisms ranging from bacteria to humans. They exert their toxic effects by punching 'holes' into target cell membrane, thus destroying the natural permeability barrier function of the cell membrane. PFTs are, in general, synthesized as water-soluble monomeric molecules, and in contact with target cell membranes they form membrane-inserted oligomeric pores. However, in spite of sharing this overall general scheme, PFTs differ significantly from each other in the intricate details of their pore formation mechanisms. A major mechanistic challenge associated with the membrane pore formation process by PFTs is elucidating the folding pathways that ensure thermodynamic compatibility of the water-soluble monomeric and the membrane-inserted oligomeric form of the toxin with aqueous and lipid milieu, respectively. One of the major research interests of my group is focused on studying structure-function relationship of some of the prominent bacterial PFTs. The critical issues we address are:
Mechanistic details of oligomeric membrane channel formation by PFTs.
Mechanism(s) associated with cellular responses triggered by PFTs.
Research Area II: Structure-Function Studies on Immunologically Important T cell Costimulatory Molecules.
An optimal T cell immune response depends critically on costimulatory signals triggered by a wide array of receptor-ligand interactions at the interface of T cells and antigen presenting cells. A balance between positive and negative T cell costimulatory signals is extremely crucial in terms of generating an optimal protective immune response, while at the same time maintaining a state of immunological tolerance. Activation of T cell costimulatory pathway, in general, follows a common paradigm in which interaction between the extracellular domains of the costimulatory receptors and their cognate ligands triggers the intracellular signaling cascades. Understanding the structural basis of costimulatory interactions is central toward developing therapeutic strategies to manipulate T cell-mediated immune responses in various disease conditions. We explore the critical structural features involved in the costimulatory interactions, and plan to utilize our structure-based knowledge to develop therapeutic strategies targeting T cell immunity.
- Lata, K. and Chattopadhyay, K. (2014) Helicobacter pylori TlyA agglutinates liposomes, and induces fusion and permeabilization of the liposome membranes. Biochemistry, 53 (22), 3553-3563.
- Rai, A. K., and Chattopadhyay, K. (2014) Trapping of Vibrio cholerae Cytolysin in the Membrane-bound Monomeric State Blocks Membrane Insertion and Functional Pore Formation by the Toxin. J. Biol. Chem, 289 (24), 16978-16987.
- Rai, A. K., Paul, K., and Chattopadhyay, K. (2013) Functional mapping of the lectin activity site on the β-Prism domain of Vibrio cholerae cytolysin: implications for the membrane pore-formation mechanism of the toxin. J. Biol. Chem, 288 (3), 1665-1673.
- Paul, K. and Chattopadhyay, K. (2012) Single point mutation in Vibrio cholerae cytolysin compromises membrane pore-formation mechanism of the toxin. FEBS Journal, 279 (21), 4039-4051.
- Paul, K. and Chattopadhyay, K. (2011) Unfolding distinguishes the Vibrio cholerae cytolysin precursor from the mature form of the toxin. Biochemistry, 50 (19), 3936-3945.
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