PhD Public Seminar: SAMANTHA HITT
When & Where
October 28
1:00 PM - 2:00 PM
UTH Health McGovern Medical School, MSB 2.006 and via Zoom (View in Google Map)
Contact
- Joy A. Lademora
- 7135009872
- [email protected]
Event Description
Elucidation of the Molecular Signal for the Regulator of Capsule Synthesis Stress Response
Samantha Hitt (Advisor: Anna Konovalova, PhD)
The Regulator of Capsule Synthesis (Rcs) is a highly conserved envelope stress response system in Enterobacteriaceae that responds to envelope damage, including damage caused by cell envelope targeting antibiotics. Despite its importance, how Rcs detects envelope damage remains unknown. The overall goal of my project is to identify a molecular signal and the mechanism of Rcs activation. The pathway begins with the sensor protein RcsF which forms a complex with several outer membrane proteins (OMP) which allows the surface-exposed N-terminal domain (NTD) of RcsF to co-localize with LPS at the cell surface. Due to this co-localization and the highly cationic nature of the NTD we hypothesized that RcsF monitors perturbations in LPS through direct interaction with LPS.
Utilizing a combination of biochemical, genetic and computational approaches we have determined that the NTD binds to LPS, largely through electrostatic interactions. We additionally found that loss of this interaction acts as the signal for Rcs activation, causing RcsF to undergo a conformational change and setting off a cascade of protein-protein interactions that allow the signal to be transduced through the periplasm. We also identified mutations at three different residues in the NTD that lead to heightened Rcs activity and confirmed that these mutations disrupt binding to LPS. Additionally, we confirmed that polymyxin B activates the system by competing with the NTD for binding to LPS, rather than through membrane disruption. Altogether these findings offer a mechanistic understanding of how enteric bacteria utilize this system to detect antibiotic binding to their cell surface and changes to LPS.
Advisory Committee:
- Anna Konovalova, PhD, Chair
- Mikhail Bogdanov, PhD
- Nicholas De Lay, PhD
- William Margolin, PhD
- Diana Proctor, PhD
Join via Zoom (Please contact Ms. Hitt directly for the details of her zoom meeting.)
Elucidation of the Molecular Signal for the Regulator of Capsule Synthesis Stress Response
Samantha Hitt (Advisor: Anna Konovalova, PhD)
The Regulator of Capsule Synthesis (Rcs) is a highly conserved envelope stress response system in Enterobacteriaceae that responds to envelope damage, including damage caused by cell envelope targeting antibiotics. Despite its importance, how Rcs detects envelope damage remains unknown. The overall goal of my project is to identify a molecular signal and the mechanism of Rcs activation. The pathway begins with the sensor protein RcsF which forms a complex with several outer membrane proteins (OMP) which allows the surface-exposed N-terminal domain (NTD) of RcsF to co-localize with LPS at the cell surface. Due to this co-localization and the highly cationic nature of the NTD we hypothesized that RcsF monitors perturbations in LPS through direct interaction with LPS.
Utilizing a combination of biochemical, genetic and computational approaches we have determined that the NTD binds to LPS, largely through electrostatic interactions. We additionally found that loss of this interaction acts as the signal for Rcs activation, causing RcsF to undergo a conformational change and setting off a cascade of protein-protein interactions that allow the signal to be transduced through the periplasm. We also identified mutations at three different residues in the NTD that lead to heightened Rcs activity and confirmed that these mutations disrupt binding to LPS. Additionally, we confirmed that polymyxin B activates the system by competing with the NTD for binding to LPS, rather than through membrane disruption. Altogether these findings offer a mechanistic understanding of how enteric bacteria utilize this system to detect antibiotic binding to their cell surface and changes to LPS.
Advisory Committee:
- Anna Konovalova, PhD, Chair
- Mikhail Bogdanov, PhD
- Nicholas De Lay, PhD
- William Margolin, PhD
- Diana Proctor, PhD
Join via Zoom (Please contact Ms. Hitt directly for the details of her zoom meeting.)
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