Mechanism of agonism and antagonism of the <i>Pseudomonas aeruginosa</i> quorum sensing regulator QscR with non‐native ligands

Wysoczynski-Horita, Christina Leigh; Boursier, Michelle E.; Hill, Ryan C.; Hansen, Kirk C.; Blackwell, Helen E.; Churchill, Mair E. A.

doi:10.1111/mmi.13930

Cited by 36 publications

(30 citation statements)

References 66 publications

(142 reference statements)

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“…3). The more interesting result is that the PAS domain of VqmA was quite different from that of other characterized LuxR proteins (17)(18)(19)(20), but similar to that of some signal proteins of other non-LuxR family proteins ( Fig. 4 and Fig.…”

Section: Overall Structure Of the Vqma-dpo-dna Complexmentioning

confidence: 80%

“…The DBD region was relatively conserved. We compared the DBD region of VqmA with several proteins with known structures of the LuxR family in sequence and three-dimensional conformation (17)(18)(19)(20)(21). The results showed that although VqmA and other LuxR family proteins were not very conservative in sequence, but they were consistent in three-dimensional conformation (Fig.…”

Section: Overall Structure Of the Vqma-dpo-dna Complexmentioning

confidence: 98%

“…As with most HLH-superfamily proteins, VqmA shows high structural conservation with many transcription factors in its DNA-binding domain (17)(18)(19)(20), but there are a lot of differences between the key residues associated with DNA binding (Fig. 3).…”

Section: Dpo-binding Pocket Serves As An Allosteric Sitementioning

confidence: 99%

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Crystal structure of the Vibrio cholerae VqmA–ligand–DNA complex provides insight into ligand-binding mechanisms relevant for drug design

Guo

et al. 2019

Journal of Biological Chemistry

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VqmA is a highly conserved transcriptional regulator of the quorum-sensing system of Vibrio cholerae, a major human pathogen that continues to imperil human health. VqmA represses biofilm formation and plays an important role in V. cholerae pathogenicity in the human host. Although VqmA's biological function is well understood, the molecular mechanisms by which its specific ligand (and effector), 3,5-dimethylpyrazine-2-ol (DPO), controls transcription of the target gene, vqmR, remain obscure. To elucidate the molecular mechanism of DPO binding, we used structural analyses and biochemical assays to study the V. cholerae VqmA-DPO-DNA complex. These analyses revealed that VqmA contains an N-terminal homodimer domain (PAS) and a C-terminal DNA-binding domain (DBD). We observed that VqmA directly binds to a DPO molecule via a compact hydrophobic pocket, consisting of a sixstranded antiparallel ␤-sheet and several ␣-helices. We also found that the VqmA dimer interacts with the quasi-palindromic sequence of the vqmR promoter through its DBD. The results of the biochemical studies indicated that a water atom and VqmA residues Phe-67 and Lys-101 play a key role in effector recognition, which is also assisted by Tyr-36 and Phe-99. This is the first molecular level view of the VqmA dimer bound to DPO and DNA. The structure-function analyses presented here improve our understanding of the complex mechanisms in the transcriptional regulation of VqmA in Vibrio spp. and may inform the design of drugs to manage V. cholerae infections.

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Section: Overall Structure Of the Vqma-dpo-dna Complexmentioning

confidence: 80%

Section: Overall Structure Of the Vqma-dpo-dna Complexmentioning

confidence: 98%

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Crystal structure of the Vibrio cholerae VqmA–ligand–DNA complex provides insight into ligand-binding mechanisms relevant for drug design

Guo

et al. 2019

Journal of Biological Chemistry

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“…Although our study is focused on the activation of AHL receptors, noncognate AHLs can also inhibit receptor activity through a variety of mechanisms (7, 15, 16, 18, 41–44). To explore inhibitory effects of noncognate AHLs, we tested our AHL panel for inhibition of LasR, QscR, CviR, or LuxR activity.…”

Section: Resultsmentioning

confidence: 99%

Quorum Sensing Signal Selectivity and the Potential for Interspecies Cross Talk

Wellington

Greenberg

2019

mBio

104

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Many species of proteobacteria communicate with kin and coordinate group behaviors through a form of cell-cell signaling called acyl-homoserine lactone (AHL) quorum sensing (QS). Most AHL receptors are thought to be specific for their cognate signal, ensuring that bacteria cooperate and share resources only with closely related kin cells. Although specificity is considered fundamental to QS, there are reports of “promiscuous” receptors that respond broadly to nonself signals. These promiscuous responses expand the function of QS systems to include interspecies interactions and have been implicated in both interspecies competition and cooperation. Because bacteria are frequently members of polymicrobial communities, AHL cross talk between species could have profound impacts. To better understand the prevalence of QS promiscuity, we measured the activity of seven QS receptors in their native host organisms. To facilitate comparison of our results to previous studies, we also measured receptor activity using heterologous expression inEscherichia coli. We found that the standardE. colimethods consistently overestimate receptor promiscuity and sensitivity and that overexpression of the receptors is sufficient to account for the discrepancy between native andE. colireporters. Additionally, receptor overexpression resulted in AHL-independent activity inPseudomonas aeruginosa. Using our activation data, we developed a quantitative score of receptor selectivity. We find that the receptors display a wide range of selectivity and that most receptors respond sensitively and strongly to at least one nonself signal, suggesting a broad potential for cross talk between QS systems.IMPORTANCESpecific recognition of cognate signals is considered fundamental to cell signaling circuits as it creates fidelity in the communication system. In bacterial quorum sensing (QS), receptor specificity ensures that bacteria cooperate only with kin. There are examples, however, of QS receptors that respond promiscuously to multiple signals. “Eavesdropping” by these promiscuous receptors can be beneficial in both interspecies competition and cooperation. Despite their potential significance, we know little about the prevalence of promiscuous QS receptors. Further, many studies rely on methods requiring receptor overexpression, which is known to increase apparent promiscuity. By systematically studying QS receptors in their natural parent strains, we find that the receptors display a wide range of selectivity and that there is potential for significant cross talk between QS systems. Our results provide a basis for hypotheses about the evolution and function of promiscuous signal receptors and for predictions about interspecies interactions in complex microbial communities.

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“…Similarly, the orphan P. aeruginosa LuxR-type receptor QscR contains such a loop (SI Appendix, Fig. S6), and QscR displays ligand promiscuity (37,38). Conversely, CviR and TraR display strict specificity for their cognate autoinducers (11,18,39,40).…”

Section: Homoserine Lactonementioning

confidence: 99%

Structural determinants driving homoserine lactone ligand selection in the Pseudomonas aeruginosa LasR quorum-sensing receptor

McCready

Paczkowski

Henke³

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Quorum sensing is a cell-cell communication process that bacteria use to orchestrate group behaviors. Quorum sensing is mediated by signal molecules called autoinducers. Autoinducers are often structurally similar, raising questions concerning how bacteria distinguish among them. Here, we use the Pseudomonas aeruginosa LasR quorum-sensing receptor to explore signal discrimination. The cognate autoinducer, 3OC 12 homoserine lactone (3OC 12 HSL), is a more potent activator of LasR than other homoserine lactones. However, other homoserine lactones can elicit LasR-dependent quorum-sensing responses, showing that LasR displays ligand promiscuity. We identify mutants that alter which homoserine lactones LasR detects. Substitution at residue S129 decreases the LasR response to 3OC 12 HSL, while enhancing discrimination against noncognate autoinducers. Conversely, the LasR L130F mutation increases the potency of 3OC 12 HSL and other homoserine lactones. We solve crystal structures of LasR ligand-binding domains complexed with noncognate autoinducers. Comparison with existing structures reveals that ligand selectivity/ sensitivity is mediated by a flexible loop near the ligand-binding site. We show that LasR variants with modified ligand preferences exhibit altered quorum-sensing responses to autoinducers in vivo. We suggest that possessing some ligand promiscuity endows LasR with the ability to optimally regulate quorum-sensing traits.crystal structure | LasR | Pseudomonas aeruginosa | quorum sensing | homoserine lactone

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Mechanism of agonism and antagonism of the Pseudomonas aeruginosa quorum sensing regulator QscR with non‐native ligands

Cited by 36 publications

References 66 publications

Crystal structure of the Vibrio cholerae VqmA–ligand–DNA complex provides insight into ligand-binding mechanisms relevant for drug design

Crystal structure of the Vibrio cholerae VqmA–ligand–DNA complex provides insight into ligand-binding mechanisms relevant for drug design

Quorum Sensing Signal Selectivity and the Potential for Interspecies Cross Talk

Structural determinants driving homoserine lactone ligand selection in the Pseudomonas aeruginosa LasR quorum-sensing receptor

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