The long-term goal of this work is to elucidate, in molecular detail, the in vivo signaling mechanisms of the transmembrane receptors that mediate chemotactic behavior in E. coli, with predominant focus on Tsr, the serine chemoreceptor. Tsr and other chemoreceptors form stable ternary complexes with two cytoplasmic proteins: CheA, a histidine autokinase, and CheW, which couples CheA to chemoreceptor control. Most of the prodigious signal amplification that occurs in the chemotaxis pathway takes place in these complexes, which are organized into highly cooperative arrays. The overall objectives of the next project period are to extend and test a dynamics-based model of signal transmission through a receptor dimer and to characterize the signaling and clustering properties of receptor molecules that have different dynamic behaviors and clustering abilities. Our working model proposes that the receptor's kinase-activating output emanates from molecules with intermediate structural stabilities and dynamic behaviors, rather than a discrete conformational state. In contrast, receptor molecules at either extreme of the dynamic range, i.e., ones whose structures are too """"""""molten"""""""" or too """"""""frozen"""""""", are proposed to adopt kinase-deactivating states. We expect that the proposed studies will clarify the nature of the kinase-on and kinase-off signaling states of chemoreceptors, which in turn will permit development of more incisive mechanistic models for kinase control in receptor signaling complexes. Moreover, our experiments will serve to identify the structural and functional features of receptor molecules that are most critical for assembly of receptor signaling complexes and clustered arrays. Finally, the proposed studies will determine which receptor properties are important to their highly cooperative signaling behavior and whether such signaling is accompanied by changes in the spatial organization of receptor arrays. The proposed studies have three specific aims: 1. Elucidate the mechanisms of conformational coupling between the HAMP domain and its adjoining input and output elements. 2. Assess the dynamic properties of chemoreceptor molecules and test predictions of dynamics-based signaling models.. 3. Characterize the signaling and clustering properties of mutant receptors with more quantitative and higher resolution methods.

Public Health Relevance

Chemotactic behaviors influence the environmental distributions of motile microorganisms, the composition of microbial communities such as biofilms, and host invasion during the establishment of beneficial symbioses and harmful infections. Better understanding of the molecular mechanisms of stimulus detection and sensory signaling by bacterial chemoreceptors should lead to new strategies for augmenting the beneficial behaviors of bacteria and to new therapies for harmful bacterial infections.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Prokaryotic Cell and Molecular Biology Study Section (PCMB)
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Flicker, Paula F
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University of Utah
Schools of Arts and Sciences
Salt Lake City
United States
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Flack, Caralyn E; Parkinson, John S (2018) A zipped-helix cap potentiates HAMP domain control of chemoreceptor signaling. Proc Natl Acad Sci U S A 115:E3519-E3528
Piñas, Germán E; DeSantis, Michael D; Parkinson, John S (2018) Noncritical Signaling Role of a Kinase-Receptor Interaction Surface in the Escherichia coli Chemosensory Core Complex. J Mol Biol 430:1051-1064
Lai, Run-Zhi; Han, Xue-Sheng; Dahlquist, Frederick W et al. (2017) Paradoxical enhancement of chemoreceptor detection sensitivity by a sensory adaptation enzyme. Proc Natl Acad Sci U S A 114:E7583-E7591
Lai, Run-Zhi; Gosink, Khoosheh K; Parkinson, John S (2017) Signaling Consequences of Structural Lesions that Alter the Stability of Chemoreceptor Trimers of Dimers. J Mol Biol 429:823-835
Frank, Vered; Piñas, Germán E; Cohen, Harel et al. (2016) Networked Chemoreceptors Benefit Bacterial Chemotaxis Performance. MBio 7:
Ames, Peter; Hunter, Samuel; Parkinson, John S (2016) Evidence for a Helix-Clutch Mechanism of Transmembrane Signaling in a Bacterial Chemoreceptor. J Mol Biol 428:3776-88
Piñas, Germán E; Frank, Vered; Vaknin, Ady et al. (2016) The source of high signal cooperativity in bacterial chemosensory arrays. Proc Natl Acad Sci U S A 113:3335-40
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
Mowery, Patricia; Ames, Peter; Reiser, Rebecca H et al. (2015) Chemotactic Signaling by Single-Chain Chemoreceptors. PLoS One 10:e0145267
Kitanovic, Smiljka; Ames, Peter; Parkinson, John S (2015) A Trigger Residue for Transmembrane Signaling in the Escherichia coli Serine Chemoreceptor. J Bacteriol 197:2568-79

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