The long-term goal of this proposal is to define how bacteria modulate their physiology, growth, and development in response to chemical and physical changes in their environment. The project described here utilizes an interdisciplinary and innovative set of genetic, biochemical, biophysical, and computational approaches that will address this question on multiple scales, from the cellular/systems level to the level of molecular structure. The proposed experiments are of biological import, not only to the study of bacterial signal transduction, but cell signaling in general. Results obtained from this project will provide the scientific community with an integrative understanding of bacterial sensory transduction, from signal detection to cellular response. Importantly, as a number of environmental regulatory proteins have been defined as virulence determinants in bacterial pathogens, this work has the potential to inform new therapeutic routes to control certain bacterial infections. Studies will be specifically focused on a multi-protein regulatory system that can function to sense and integrate information about the light environment, chemical and physical stressors, and cellular redox state. This regulatory system will be investigated in the model bacterium, Caulobacter crescentus. However, the genes encoding this system are conserved in a number of bacterial species relevant to human health including the pathogen, Brucella abortus.
The specific aims of this project are: 1) Define the mechanism by which LovK-LovR independently controls transcription through two distinct regulatory pathways 2) Characterize the molecular basis of HfiA function as a cell surface adhesin inhibitor. 3) Define the structural basis of PhyR activation by phosphorylation.

Public Health Relevance

Bacterial cells must detect and adapt to a broad range of chemical and physical signals in their environment to survive. This project is centered on developing a molecular-level understanding of a regulatory system that modulates bacterial cell physiology in response to environmental perturbation. Understanding regulatory mechanisms that govern bacterial physiology can greatly impact our ability to manipulate and control bacterial growth and infection in clinical settings.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM087353-08
Application #
9247228
Study Section
Prokaryotic Cell and Molecular Biology Study Section (PCMB)
Program Officer
Reddy, Michael K
Project Start
2009-08-01
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Herrou, Julien; Crosson, Sean; Fiebig, Aretha (2017) Structure and function of HWE/HisKA2-family sensor histidine kinases. Curr Opin Microbiol 36:47-54
Willett, Jonathan W; Crosson, Sean (2017) Atypical modes of bacterial histidine kinase signaling. Mol Microbiol 103:197-202
Eaton, Daniel S; Crosson, Sean; Fiebig, Aretha (2016) Proper Control of Caulobacter crescentus Cell Surface Adhesion Requires the General Protein Chaperone DnaK. J Bacteriol 198:2631-42
Meyer, Peter A; Socias, Stephanie; Key, Jason et al. (2016) Data publication with the structural biology data grid supports live analysis. Nat Commun 7:10882
Fiebig, Aretha; Herrou, Julien; Willett, Jonathan et al. (2015) General Stress Signaling in the Alphaproteobacteria. Annu Rev Genet 49:603-25
Herrou, Julien; Willett, Jonathan W; Crosson, Sean (2015) Structured and Dynamic Disordered Domains Regulate the Activity of a Multifunctional Anti-? Factor. MBio 6:e00910
Fiebig, Aretha; Herrou, Julien; Fumeaux, Coralie et al. (2014) A cell cycle and nutritional checkpoint controlling bacterial surface adhesion. PLoS Genet 10:e1004101
Boutte, Cara C; Crosson, Sean (2013) Bacterial lifestyle shapes stringent response activation. Trends Microbiol 21:174-80
Henry, Jonathan T; Crosson, Sean (2013) Chromosome replication and segregation govern the biogenesis and inheritance of inorganic polyphosphate granules. Mol Biol Cell 24:3177-86
Herrou, Julien; Rotskoff, Grant; Luo, Yun et al. (2012) Structural basis of a protein partner switch that regulates the general stress response of ýý-proteobacteria. Proc Natl Acad Sci U S A 109:E1415-23

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