Mathematical Biology Seminar
Thursday, November 19 from 3:00-4:00 p.m.
Join Zoom meeting: https://ucf.zoom.us/j/91777376704
Zoom Meeting ID: 917 7737 6704
Dr. Kenneth Teter
Burnett School of Biomedical Sciences
University of Central Florida
Title: "Hsp90-Driven Delivery of Cholera Toxin into the Host Cell"
Cholera toxin (CT) is the main virulence factor produced by Vibrio cholerae, a pathogen responsible for up to 4 million annual cases of profuse and potentially fatal diarrhea. CT is released into the lumen of the small intestine, but it attacks a protein inside the intestinal cell and must therefore cross a membrane barrier in order to function. Entry into the intestinal cell involves toxin passage through a protein-conducting channel in the membrane. This "translocon" pore has a narrow diameter, so CT must unfold before it moves through the pore in a linearized state. The driving force for unidirectional toxin transport through the pore is provided by Hsp90, an intracellular chaperone that couples toxin refolding with toxin extraction from the pore: toxin refolding at the intracellular face of the pore prevents its back-sliding into the pore, thus ensuring directional movement into the cell through a Brownian ratchet. Hsp90 recognizes a specific RPPDEI amino acid sequence near the N-terminus of the toxin (residues 16-21), so the process of refolding-driven extraction can begin as soon as CT emerges at the intracellular face of the translocon pore. Toxin delivery to the cytosol is blocked when the RPPDEI sequence is located farther away from the N-terminus, which indicates a random back-and-forth motion through the translocon pore precedes the emergence of the RPPDEI sequence at the intracellular face of the pore. Potential collaborations could involve (i) calculating the probability of RPPDEI emergence at the intracellular face of the translocon pore when the sequence is located at different distances from the N-terminus and (ii) quantifying the actual efficiency of toxin delivery to the cytosol when the RPPDEI sequence is located at different distances from the N-terminus.