Chemotactic behaviors, movements toward or away from chemicals in an organism?s environment, play important roles in the lives of bacteria. Chemotaxis enables microbes to form communities such as biofilms, to find and colonize host organisms, and to successfully carry out complex, multi-host life cycles. Better understanding of how bacteria detect and respond to their chemical environment will play an important role in the development of new therapeutic strategies for preventing and treating bacterial infections. The long-term goal of this project is to elucidate, in molecular detail, the in vivo signaling mechanisms of the transmembrane receptors that mediate chemotactic behavior in E. coli, a model system for chemotaxis studies. The serine chemoreceptor Tsr forms stable ternary complexes with two cytoplasmic proteins: CheA, a histidine autokinase, and CheW, which couples CheA to chemoreceptor control. These complexes are organized into highly cooperative arrays, typically located at the cell poles, that produce most of the prodigious signal amplification known to occur in the E. coli chemotaxis pathway. The overall objectives of the next project period are to elucidate the mechanisms involved in three signaling processes: signal transmission within chemoreceptor molecules and allosteric control and kinase control in core receptor signaling complexes. Our overall working hypothesis about signal transmission within chemoreceptor molecules proposes that its structural subelements ? external ligand-binding domain, transmembrane helices, HAMP and methylation helix bundles, and cytoplasmic hairpin tip that interacts directly with CheW and CheA ? transmit and process sensory information through shifts in their dynamic behaviors and stabilities. Neighboring elements are coupled in opposition, such that destabilizing inputs to one element produce stabilizing responses in the other. The interplay of these opposing structural forces poises the receptor molecule to detect and respond to small stimulus inputs. The project will test these signaling ideas by mutationally creating structural changes in Tsr, CheA, and CheW and characterizing their signaling consequences with in vivo serine dose-response assays based on Frster Resonance Energy Transfer (FRET). Collaborations with other groups will provide molecular dynamics simulations to assess the structural and dynamics changes in the mutant proteins, single-cell FRET analyses of receptor responses, homo-FRET studies of receptor response kinetics, and cryo-electron microscopy to examine structural features of the mutant receptor arrays.
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.
|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|
|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|
|Frank, Vered; Piñas, Germán E; Cohen, Harel et al. (2016) Networked Chemoreceptors Benefit Bacterial Chemotaxis Performance. MBio 7:|
|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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