The receptors that mediate chemotaxis by Escherichia coli are the best characterized members of a large family of bacterial chemoreceptors and a larger family of prokaryotic and eukaryotic sensory receptors. This proposal focuses on sensory transduction by these chemoreceptors, with emphasis on transmembrane and intermolecular signaling. The proposed work is a combination of biochemical, biophysical, genetic and structural approaches, concentrating in many projects on the chemoreceptor Trg. In the current funding period the PI created, characterized and utilized a collection of Trg variants with one or two cysteines per polypeptide chain, placed primarily in one or both transmembrane segments. Extensive use will be made of this collection of mutant receptors in experiments designed to address central issues of transmembrane organization and signaling. The principal aims of the proposal are to: (1) determine helical interactions in the transmembrane domain; (2) measure distances between pairs of positions in the transmembrane segments, or between a specific position and the membrane surface; and (3) define the molecular details of the conformational change involved in transmembrane signaling. Several of these studies will include the use of electron paramagnetic resonance spectroscopy and will be done in collaboration with Dr. Wayne Hubbell. In other studies the interaction of chemoreceptor and ligand-occupied binding proteins will be investigated using surface plasmon resonance. The """"""""minority"""""""" chemoreceptor Trg is effective in ligand-induced signaling but defective in steady-state activation of the CheA signaling kinase. The basis of this signaling behavior will be investigated by physiological, genetic and biochemical studies with the hope of learning about the little-understood phenomenon of signal amplification in the bacterial chemosensory system. In addition, genetic and biochemical approaches will be used to characterize interactions between the three chemoreceptor domains, and efforts will be directed toward obtaining particles and two-dimensional crystal of receptor-CheW-CheA complexes suitable for structural analysis by electron microscopy.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Microbial Physiology and Genetics Subcommittee 2 (MBC)
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Washington State University
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Mello, Bernardo A; Pan, Wenlin; Hazelbauer, Gerald L et al. (2018) A dual regulation mechanism of histidine kinase CheA identified by combining network-dynamics modeling and system-level input-output data. PLoS Comput Biol 14:e1006305
Akkaladevi, Narahari; Bunyak, Filiz; Stalla, David et al. (2018) Flexible Hinges in Bacterial Chemoreceptors. J Bacteriol 200:
Bartelli, Nicholas L; Hazelbauer, Gerald L (2016) Bacterial Chemoreceptor Dynamics: Helical Stability in the Cytoplasmic Domain Varies with Functional Segment and Adaptational Modification. J Mol Biol 428:3789-804
Parkinson, John S; Hazelbauer, Gerald L; Falke, Joseph J (2015) Signaling and sensory adaptation in Escherichia coli chemoreceptors: 2015 update. Trends Microbiol 23:257-66
Bartelli, Nicholas L; Hazelbauer, Gerald L (2015) Differential backbone dynamics of companion helices in the extended helical coiled-coil domain of a bacterial chemoreceptor. Protein Sci 24:1764-76
Li, Mingshan; Hazelbauer, Gerald L (2014) Selective allosteric coupling in core chemotaxis signaling complexes. Proc Natl Acad Sci U S A 111:15940-5
Amin, Divya N; Hazelbauer, Gerald L (2012) Influence of membrane lipid composition on a transmembrane bacterial chemoreceptor. J Biol Chem 287:41697-705
Hazelbauer, Gerald L (2012) Bacterial chemotaxis: the early years of molecular studies. Annu Rev Microbiol 66:285-303
Li, Mingshan; Hazelbauer, Gerald L (2011) Core unit of chemotaxis signaling complexes. Proc Natl Acad Sci U S A 108:9390-5
Li, Mingshan; Khursigara, Cezar M; Subramaniam, Sriram et al. (2011) Chemotaxis kinase CheA is activated by three neighbouring chemoreceptor dimers as effectively as by receptor clusters. Mol Microbiol 79:677-85

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