Heme-Based Oxygen Sensors of Commensal, Symbiotic, and Pathogenic Bacteria
dc.contributor.advisor | Gilles-Gonzalez, Marie-Alda | en |
dc.creator | Tuckerman, Jason Robert | en |
dc.date.accessioned | 2012-08-15T14:41:25Z | |
dc.date.available | 2012-08-15T14:41:25Z | |
dc.date.issued | 2012-08-15 | |
dc.description.abstract | Direct oxygen sensors are proteins that serve as "on-off switches" to cause reversible and adaptive changes in the activities of other proteins or genes, with great specificity in response to fluctuations in oxygen concentration. The heme-based oxygen sensors are a large class of direct oxygen sensors that feature direct binding of oxygen to a sensory heme-containing domain. This heme-binding region couples to a regulatory domain within the same polypeptide. The types of functionalities controlled by these oxygen-specific switches are diverse, and include the regulation of protein activities, gene expression, and second messenger elaboration. A primary focus of this work was the biochemical characterization of a pair of heme-based oxygen sensors involved in the control of the bacterial second messenger cyclic diguanylic acid (c-di-GMP) in Escherichia coli. We discovered that these enzymes, designated DosC and DosP, serve as a diguanylate cyclase and c-di-GMP phosphodiesterase pair that associate with components of the E. coli RNA degradosome in vivo. Importantly, one member of these degradosomes, PNPase, is a direct, high-affinity target of c-di-GMP. These findings imply that specialized oxygen-sensing degradosomes exist in E. coli. In these oxygen-sensing degradosomes cellular oxygen levels regulate PNPase processing of specific RNA transcripts via c-di-GMP. A secondary focus of this work was the characterization of a novel two-component system in M. tuberculosis involved in the non-replicating persistent phase of this bacterium in a typical TB infection. Here, the activities of two heme-containing histidine kinases, DosT and DevS, were discovered to be inhibited specifically by oxygen. As DosT and DevS are the primary regulators of the dormancy survival regulator (DosR/DevR) transcription factor, these results contributed a molecular explanation for the numerous observations linking oxygen and DevR to the dormancy phenotype of M. tuberculosis seen both in vitro and in vivo. | en |
dc.identifier.oclc | 812530082 | |
dc.identifier.uri | https://hdl.handle.net/2152.5/1115 | |
dc.language.iso | en | en |
dc.subject | Cyclic GMP | en |
dc.subject | RNA | en |
dc.subject | Second Messenger Systems | en |
dc.title | Heme-Based Oxygen Sensors of Commensal, Symbiotic, and Pathogenic Bacteria | en |
dc.type | Thesis | en |
dc.type.material | Text | en |
thesis.date.available | 2014-07-10 | |
thesis.degree.department | Graduate School of Biomedical Sciences | en |
thesis.degree.discipline | Biological Chemistry | en |
thesis.degree.grantor | UT Southwestern Medical Center | en |
thesis.degree.level | Doctoral | en |
thesis.degree.name | Doctor of Philosophy | en |