Structural insights into Vibrio cholerae ompU transcription activation
[eng] Cholera is an acute life-threatening infection caused by the bacterium Vibrio cholerae, a devastating pathogen in least developed countries, which caused six world pandemics, apart from the ongoing one. Despite current efforts to eradicate the disease by vaccination and sanitation improvements...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/210200 |
| Acceso en línea: | https://hdl.handle.net/2445/210200 http://hdl.handle.net/10803/690649 |
| Access Level: | acceso abierto |
| Palabra clave: | Vibriosi Còlera Virulència (Microbiologia) Transcripció genètica Microscòpia electrònica Vibrio infections Cholera Virulence (Microbiology) Genetic transcription Electron microscopy |
| Sumario: | [eng] Cholera is an acute life-threatening infection caused by the bacterium Vibrio cholerae, a devastating pathogen in least developed countries, which caused six world pandemics, apart from the ongoing one. Despite current efforts to eradicate the disease by vaccination and sanitation improvements, the World Health Organization estimates 1.3 to 4 million infections per year and more than 100,000 deaths worldwide. A global source of cholera outbreak has been observed since 2021. The rise of V. cholerae antibiotic resistant strains evidences the need of new or repurposed drugs. Understanding the virulence activation mechanism of V. cholerae might open new ways to fight the infection. ToxR is the master regulator of virulence-related gene activation in V. cholerae epidemic strains. This transcription factor is a transmembrane protein with a sensor domain at the periplasmic space and a DNA binding domain at the cytoplasm, linked by a single-pass transmembrane region. When V. cholerae reaches the small intestine, ToxR recruits TcpP, which activates the expression cascades for the Cholera Toxin (CT) and Toxin Co-regulated Pilus (TCP). Moreover, ToxR directly activates the expression of OmpU, a bile salt resistance porin, which allows V. cholerae surviving during host colonization. Using single-particle cryo-EM, we have solved the atomic structures of the ompU promoter transcription activation complex comprising V. cholerae’s RNA polymerase, a 69bp ompU promoter fragment, and the ToxR DNA binding domain. Based on the structures we propose a model for the ompU transcription activation where the RNA polymerase is recruited and transcription is activated through the ToxR DNA binding domain interaction with the α-CTD of the RNA polymerase. |
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