Dr. K. Chattopadhyay
Professor, Biological Sciences

Research Area: Structure-Function Studies on Pore-Forming Protein Toxins.

Pore-forming protein toxins (PFTs) are a unique class of membrane-damaging cytolytic/cytotoxic proteins, and they are found in a wide spectrum of organisms ranging from bacteria to humans. They exert their toxic effects by punching 'holes' in the target cell membrane, thus destroying the natural permeability barrier function of the cell membrane. PFTs are, in general, synthesized as soluble monomeric molecules, and in contact with the 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 of the PFTs is elucidating the folding pathways that ensure thermodynamic compatibility of the soluble monomeric and the membrane-inserted oligomeric form of the toxin with aqueous and lipid milieu, respectively. PFTs highlight large-scale structural/conformation rearrangements in the course of their pore-formation process. Such structural alterations are mostly triggered upon interactions with the target membranes. However, it still remains unclear in most of the cases how the PFT molecular architectures sense the membrane-binding event and initiate subsequent structural/assembly readjustments toward forming membrane-embedded pores. Also, it is being appreciated in recent years that PFTs can induce a plethora of cellular responses in the target cells, exact implications and the underlying signalling mechanisms of which still remain obscure. The major research interest of my group is focused on studying the structure-function mechanisms of some of the prominent PFTs. The critical issues we address are:

Mechanistic details of oligomeric membrane pore formation by the PFTs.
Mechanism(s) associated with the cellular responses triggered by the PFTs.

• Kaur D#, Verma P#, Singh M, Sharma A, Lata K, Mukhopadhaya A*, Chattopadhyay K*. (2022) Pore formation-independent cell death induced by a b-barrel pore-forming toxin. FASEB Journal. 36(10):e22557. doi: 10.1096/fj.202200788R. [#Equal contribution][*Joint corresponding authors].
  
• Mondal AK, Sengupta N, Singh M, Biswas R, Lata K, Lahiri I, Dutta S, Chattopadhyay K. (2022) Glu289 residue in the pore-forming motif of Vibrio cholerae cytolysin is important for efficient β-barrel pore formation. J Biol Chem. 298(10):102441. doi: 10.1016/j.jbc.2022.102441.
  
• Mishra S, Kundu N, Pramanick I, Kumar A, Chattopadhyay K, Dutta S. (2022) Structural insights into thermostable direct hemolysin of Vibrio parahaemolyticus using single-particle cryo-EM. Proteins. 2022 Aug 24. doi: 10.1002/prot.26416. Online ahead of print.
  
• Mondal, A. K., Lata, K., Singh, M., Chatterjee, S., Chauhan, A., Puravankara, S., Chattopadhyay, K. (2022) Cryo-EM elucidates mechanism of action of bacterial pore-forming toxins. Biochim Biophys Acta Biomembr. 1864(11):184013.
  
• Gupta, T.#, Mondal, A. K.#, Pani, I., Chattopadhyay, K.*, Pal, S. K.* (2022) Elucidating liquid crystal-aqueous interface for the study of cholesterol-mediated action of a b-barrel pore forming toxin. Soft Matter. 18(28):5293-5301. [#Equal contribution first authors; *Joint corresponding authors]
• Lata, K., Singh, M., Chatterjee, S., and Chattopadhyay, K. (2022) Membrane dynamics and remodelling in response to the action of the membrane-damaging pore-forming toxins. J. Membr. Biol. 255(2-3):161-173 .
• Singh, M., Rupesh, N., Pandit, S. B., and Chattopadhyay K. (2022) Curcumin Inhibits Membrane-Damaging Pore-Forming Function of the β-Barrel Pore-Forming Toxin Vibrio cholerae Cytolysin. Frontiers in Microbiology. 12:809782. doi: 10.3389/fmicb.2021.809782.
• Mondal, A.K. and Chattopadhyay, K. (2022) Structures and functions of the membrane-damaging pore-forming proteins. Advances in Protein Chemistry and Structural Biology. 128:241-288.
• Sengupta, N., Mondal, A. K., Mishra, S., Chattopadhyay, K., and Dutta, S.* (2021) Single particle Cryo-EM reveals conformational variability of the oligomeric VCC β-barrel pore in a lipid bilayer. Journal of Cell Biology. 220(12):e202102035. doi: 10.1083/jcb.202102035 [*Corresponding Author].
• Verma, P. and Chattopadhyay, K. (2021) Current Perspective on the Membrane-Damaging Action of Thermostable Direct Hemolysin, an Atypical Bacterial Pore-forming Toxin. Frontiers in Molecular Biosciences. Front. Mol. Biosci., 23 July 2021 | https://doi.org/10.3389/fmolb.2021.717147.
• Verma, P., Gandhi, S., Lata, K., Chattopadhyay, K. (2021) Pore-forming toxins in infection and immunity. Biochem. Soc. Trans. 49(1):455-465.
• Mondal, A. K., Verma, P., Sengupta, N., Dutta, S., Pandit, S. B., and Chattopadhyay, K. (2021) Tyrosine in the hinge region of the pore-forming motif regulates oligomeric beta-barrel pore formation by Vibrio cholerae cytolysin. Molecular Microbiology. 115(4):508-525.
• Mondal, A. K., Verma, P., Lata, K., Singh, M., Chatterjee, S., and Chattopadhyay, K. (2020) Sequence diversity in the pore-forming motifs of the membrane-damaging protein toxins. J. Membr. Biol. 253(5): 469-478.
• Kundu, N., Verma, P., Kumar, A., Dhar, V., Dutta, S., and Chattopadhyay, K. (2020) N-terminal region of Vibrio parahaemolyticus thermostable direct hemolysin regulates the membrane-damaging action of the toxin. Biochemistry. 59(4): 605-614.
• Mondal, A. K. and Chattopadhyay, K. (2020) Taking Toll on Membranes: Curious Cases of Bacterial β-Barrel Pore-Forming Toxins. Biochemistry. 59(2): 163-170. [This article is part of the Future of Biochemistry: The Asia-Pacific Issue special issue. ]
• Mondal, A. K., Sreekumar, A., Kundu, N., Kathuria, R., Verma, P., Gandhi, S., and Chattopadhyay, K. (2018) Structural Basis and Functional Implications of the Membrane Pore-Formation Mechanisms of Bacterial Pore-Forming Toxins. Adv Exp Med Biol. 1112, 281-291 .
• Kathuria, R., Mondal, A. K., Sharma, R., Bhattacharyya, S., and Chattopadhyay, K. (2018) Revisiting the role of cholesterol in regulating the pore-formation mechanism of Vibrio cholerae cytolysin, a membrane-damaging ß-barrel pore-forming toxin. Biochemical Journal 475 (19), 3039-3055.
• Kathuria R, and Chattopadhyay K. (2018) Vibrio cholerae cytolysin:Multiple facets of the membrane interaction mechanism of a β-barrel pore-forming toxin. IUBMB Life. 70(4): 260-266. [This review article was selected for the issue highlight].
• Kundu, N., Tichkule, S., Pandit, S. B., and Chattopadhyay, K. (2017) Disulphide bond restrains C-terminal Region of thermostable direct hemolysin during folding to promote oligomerization. Biochemical Journal 474 (2), 317-331.
• Rai, A. K., and Chattopadhyay, K. (2016) Revisiting the oligomerization mechanism of Vibrio cholerae cytolysin, a beta-barrel pore-forming toxin. Biochem. Biophys. Res. Com., 474 (3), 421-427.
• Khilwani, B., and Chattopadhyay, K. (2015) Signaling beyond punching holes: modulation of cellular responses by Vibrio cholerae cytolysin. Toxins, 7(8), 3344-3358.
• Rai. A. K., Kundu, N., and Chattopadhyay, K. (2015) Physicochemical constraints of elevated pH affect efficient membrane interaction and arrest an abortive membrane-bound oligomeric intermediate of the beta-barrel pore-forming toxin Vibrio cholerae cytolysin. Archives of Biochemistry and Biophysics. 583, 9-17.
• Rai, A. K., and Chattopadhyay, K. (2015) Revisiting the membrane interaction mechanism of a membrane-damaging β-barrel pore-forming toxin Vibrio cholerae cytolysin. Molecular Microbiology, 97(6), 1051-1062.
• Lata, K., and Chattopadhyay, K. (2015) Helicobacter pylori TlyA Forms Amyloid-like Aggregates with Potent Cytotoxic Activity. Biochemistry, 54 (23), 3649-3659.
• Khilwani, B., Mukhopadhaya, A.*, and Chattopadhyay, K.* (2015) Transmembrane Oligomeric form of Vibrio cholerae Cytolysin Triggers TLR2/TLR6-dependent Pro-inflammatory Responses in Monocytes and Macrophages. Biochemical Journal, 466 (1), 147-161. [*Joint Corresponding Authors]
• Rai, A. K., and Chattopadhyay, K. (2015) Vibrio cholerae cytolysin: structure-function mechanism of an atypical β-barrel pore-forming toxin. Adv. Exp. Med. Biol, 842, 109-125.
• 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.
• Lata, K, Paul, K., and Chattopadhyay, K. (2014) Functional characterization of Helicobacter pylori TlyA: Pore-forming hemolytic activity and cytotoxic property of the protein. Biochem. Biophys. Res. Com., 444 (2), 153-157.
• Paul, K. and Chattopadhyay, K. (2014) Pre-pore oligomer formation by Vibrio cholerae cytolysin: Insights from a truncated variant lacking the pore-forming pre-stem loop. Biochem. Biophys. Res. Com., 443 (1), 189-193.
• 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. (*These authors contributed equally to this work)
• 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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