Sensor Domain of Histidine Kinase VxrA of Vibrio cholerae: Hairpin-Swapped Dimer and Its Conformational Change

Tan, Kemin; Teschler, Jennifer K.; Wu, R.; Jedrzejczak, R.; Zhou, Min; Shuvalova, L.; Endres, M.; Welk, L.; Kwon, Ki-Ryong; Anderson, W.F.; Satchell, K.J.F.; Yildiz, Fitnat H.; Joachimiak, Andrzej

doi:10.1128/jb.00643-20

Cited by 6 publications

(6 citation statements)

References 56 publications

(66 reference statements)

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“…The VxrA periplasmic domain has been crystallized, and revealed that it has a unique structural fold that forms an uncommon hairpin-swapped dimer. VxrA lacks a cytoplasmic linker region between the second transmembrane helix and the dimerization and histidine phosphotransfer (DHp) domain [51]. Structural studies revealed that the conformational change brought about by the relative rotation of the two monomers in a VxrA-SD dimer might alter the connection of transmembrane helices and, consequently, the pairing of cytoplasmic DHp domains, thereby transferring the ligand-binding signal from the periplasmic SD to the cytoplasmic kinase domain [51].…”

Section: Plos Pathogensmentioning

confidence: 99%

“…VxrA lacks a cytoplasmic linker region between the second transmembrane helix and the dimerization and histidine phosphotransfer (DHp) domain [51]. Structural studies revealed that the conformational change brought about by the relative rotation of the two monomers in a VxrA-SD dimer might alter the connection of transmembrane helices and, consequently, the pairing of cytoplasmic DHp domains, thereby transferring the ligand-binding signal from the periplasmic SD to the cytoplasmic kinase domain [51]. It is possible that VxrA and RvvA share similar activation mechanisms as many of the residues important for function in VxrA's sensing domain are conserved in RvvA.…”

Section: Plos Pathogensmentioning

confidence: 99%

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The Rvv two-component regulatory system regulates biofilm formation and colonization in Vibrio cholerae

et al. 2023

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The facultative human pathogen, Vibrio cholerae, employs two-component signal transduction systems (TCS) to sense and respond to environmental signals encountered during its infection cycle. TCSs consist of a sensor histidine kinase (HK) and a response regulator (RR); the V. cholerae genome encodes 43 HKs and 49 RRs, of which 25 are predicted to be cognate pairs. Using deletion mutants of each HK gene, we analyzed the transcription of vpsL, a biofilm gene required for Vibrio polysaccharide and biofilm formation. We found that a V. cholerae TCS that had not been studied before, now termed Rvv, controls biofilm gene transcription. The Rvv TCS is part of a three-gene operon that is present in 30% of Vibrionales species. The rvv operon encodes RvvA, the HK; RvvB, the cognate RR; and RvvC, a protein of unknown function. Deletion of rvvA increased transcription of biofilm genes and altered biofilm formation, while deletion of rvvB or rvvC lead to no changes in biofilm gene transcription. The phenotypes observed in ΔrvvA depend on RvvB. Mutating RvvB to mimic constitutively active and inactive versions of the RR only impacted phenotypes in the ΔrvvA genetic background. Mutating the conserved residue required for kinase activity in RvvA did not affect phenotypes, whereas mutation of the conserved residue required for phosphatase activity mimicked the phenotype of the rvvA mutant. Furthermore, ΔrvvA displayed a significant colonization defect which was dependent on RvvB and RvvB phosphorylation state, but not on VPS production. We found that RvvA’s phosphatase activity regulates biofilm gene transcription, biofilm formation, and colonization phenotypes. This is the first systematic analysis of the role of V. cholerae HKs in biofilm gene transcription and resulted in the identification of a new regulator of biofilm formation and virulence, advancing our understanding of the role TCSs play in regulating these critical cellular processes in V. cholerae.

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Section: Plos Pathogensmentioning

confidence: 99%

Section: Plos Pathogensmentioning

confidence: 99%

The Rvv two-component regulatory system regulates biofilm formation and colonization in Vibrio cholerae

et al. 2023

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“…Since VbrK has a TPR-like domain, they assume that a β-lactam antibiotic-sensing protein binds to this domain and activates the VbrK/VbrR system. VxrA HK of Vibrio cholerae, which is homologous to VbrK, is also involved in resistance to β-lactam antibiotics [57]. The crystal structure of the sensor domain of VxrA has been shown to adopt two different packing conformations, suggesting that this conformational change is involved in signal transduction to the cytoplasm.…”

Section: Sensing By Other Structuresmentioning

confidence: 99%

“…The crystal structure of the sensor domain of VxrA has been shown to adopt two different packing conformations, suggesting that this conformational change is involved in signal transduction to the cytoplasm. Similar to VbrK, cavities are observed at the membrane-distal site, but it is unclear whether these are the binding sites for the substrates [57].…”

Section: Sensing By Other Structuresmentioning

confidence: 99%

Diversity in Sensing and Signaling of Bacterial Sensor Histidine Kinases

Ishii

Eguchi

2021

Biomolecules

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Two-component signal transduction systems (TCSs) are widely conserved in bacteria to respond to and adapt to the changing environment. Since TCSs are also involved in controlling the expression of virulence, biofilm formation, quorum sensing, and antimicrobial resistance in pathogens, they serve as candidates for novel drug targets. TCSs consist of a sensor histidine kinase (HK) and its cognate response regulator (RR). Upon perception of a signal, HKs autophosphorylate their conserved histidine residues, followed by phosphotransfer to their partner RRs. The phosphorylated RRs mostly function as transcriptional regulators and control the expression of genes necessary for stress response. HKs sense their specific signals not only in their extracytoplasmic sensor domain but also in their cytoplasmic and transmembrane domains. The signals are sensed either directly or indirectly via cofactors and accessory proteins. Accumulating evidence shows that a single HK can sense and respond to multiple signals in different domains. The underlying molecular mechanisms of how HK activity is controlled by these signals have been extensively studied both biochemically and structurally. In this article, we introduce the wide diversity of signal perception in different domains of HKs, together with their recently clarified structures and molecular mechanisms.

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“…The downstream effectors of this system are well characterized; however, what activates VxrA remains poorly understood. A homologous system in the related bacterium V. parahaemolyticus has been proposed to bind β-lactams directly (18, 19), but strong evidence for this is lacking (20, 21). In addition, it is unlikely that β-lactams are the only activators of VxrAB; other structurally distinct antibiotics, overactive cell wall degradation enzymes, and mechanical stress also activate the system (14, 22).…”

Section: Introductionmentioning

confidence: 99%

Disrupting central carbon metabolism increases antibiotic susceptibility inVibrio cholerae

Keller

Han

Dörr

2022

Preprint

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Antibiotic tolerance, the ability of bacteria to sustain viability in the presence of typically bactericidal antibiotics for extended time periods, is an understudied contributor to treatment failure. The Gram-negative pathogen Vibrio cholerae, the causative agent of cholera disease, becomes highly tolerant to β-lactam antibiotics (penicillin and related compounds) in a process requiring the two-component system VxrAB. VxrAB is induced by exposure to cell wall damage conditions, which results in the differential regulation of >100 genes. While the effectors of VxrAB are relatively well-known, VxrAB environment-sensing and activation mechanisms remain a mystery. Here, we used transposon mutagenesis to screen for mutants that spontaneously upregulate VxrAB signaling. This screen was answered by genes known to be required for proper cell envelope homeostasis, validating the approach. Unexpectedly, we also uncovered a new connection between central carbon metabolism and antibiotic tolerance. Inactivation of pgi (vc0374, coding for Glucose-6-phosphate isomerase) resulted in an intracellular accumulation of glucose-6-phosphate and fructose-6-phosphate, concomitant with a marked cell envelope defect, resulting in VxrAB induction. Deletion of pgi also increased sensitivity to β-lactams and conferred a growth defect on salt-free LB; phenotypes that could be suppressed by deleting sugar uptake systems and by supplementing cell wall precursors in the growth medium. Our data suggest an important connection between central metabolism and cell envelope integrity and highlight a potential new target for developing novel antimicrobial agents.

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Sensor Domain of Histidine Kinase VxrA of Vibrio cholerae: Hairpin-Swapped Dimer and Its Conformational Change

Cited by 6 publications

References 56 publications

The Rvv two-component regulatory system regulates biofilm formation and colonization in Vibrio cholerae

The Rvv two-component regulatory system regulates biofilm formation and colonization in Vibrio cholerae

Diversity in Sensing and Signaling of Bacterial Sensor Histidine Kinases

Disrupting central carbon metabolism increases antibiotic susceptibility inVibrio cholerae

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