Crystal structure of the periplasmic sensor domain of histidine kinase VbrK suggests indirect sensing of β-lactam antibiotics

Goh, Boon Chong; Chua, Yong Kang; Qian, Xinlei; Lin, Jianqing; Savko, Martin; Dedon, Peter C.; Lescar, Julien

doi:10.1016/j.jsb.2020.107610

Cited by 7 publications

(6 citation statements)

References 34 publications

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“…While this paper was in final preparation and review, two groups reported the structure of V. parahaemolyticus VbrK-SD, which is 63% identical to VxrA (34,35). They found VbrK-SD in monomeric form in both structures and solution.…”

Section: Discussionmentioning

confidence: 99%

“…It is not clear how monomeric VbrK-SD can form a dimer for signal transduction through the membrane, as is typical of the HK of TCS, or if it maintains its monomeric state and utilizes a completely unknown signing mechanism. One of the studies also demonstrated that that VbrK-SD does not directly bind antibiotics (35). This could suggest that the VxrA-SD also utilizes an indirect mechanism to sense antibiotic stress, but further study is needed.…”

Section: Discussionmentioning

confidence: 99%

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

Tan

Teschler

et al. 2021

J Bacteriol

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VxrA and VxrB are cognate histidine kinase (HK) - response regulator (RR) pairs of a two-component signaling system (TCS) found in Vibrio cholerae, a bacterial pathogen that causes cholera. The VxrAB TCS positively regulates virulence, the Type VI Secretion System, biofilm formation, and cell wall homeostasis in V. cholerae, providing protection from environmental stresses and contributing to the transmission and virulence of the pathogen. The VxrA HK has a unique periplasmic sensor domain (SD) and, remarkably, lacks a cytoplasmic linker domain between the second transmembrane helix and the dimerization and histidine phosphotransfer (DHp) domain, indicating that this system may utilize a potentially unique signal sensing and transmission TCS mechanism. In this study, we have determined several crystal structures of VxrA-SD and its mutants. These structures reveal a novel structural fold forming an unusual β hairpin-swapped dimer. A conformational change caused by relative rotation of the two monomers in a VxrA-SD dimer could potentially change the association of transmembrane helices and, subsequently, the pairing of cytoplasmic DHp domains. Based on the structural observation, we propose a putative scissor-like closing regulation mechanism for the VxrA HK. IMPORTANCE V. cholerae has a dynamic life cycle, which requires rapid adaptation to changing external conditions. Two-component signal transduction (TCS) systems allow V. cholerae to sense and respond to these environmental changes. The VxrAB TCS positively regulates a number of important V. cholerae phenotypes, including virulence, the Type Six Secretion System, biofilm formation, and cell wall homeostasis. Here, we provide the crystal structure of the VxrA sensor histidine kinase sensing domain and propose a mechanism for signal transduction. The cognate signal for VxrAB remains unknown, however, in this work we couple our structural analysis with functional assessments of key residues to further our understanding of this important TCS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Tan

Teschler

et al. 2021

J Bacteriol

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“…Production of this β-lactamase is regulated by the VbrK/VbrR TCS [77]. The periplasmic region of VbrK consists of two heterogeneous domains: the domain distal to the membrane is identified as tetratricopeptide (TPR)-like and the proximal domain as PAS-like based on their structural homology (Figure 2d) [55,56]. The PAS-like domain has no conserved cleft.…”

Section: Sensing By Other Structuresmentioning

confidence: 99%

“…However, this has not yet been experimentally clarified. In contrast, Goh et al performed an interaction analysis between β-lactams and VbrK using isothermal titration calorimetry and reported that there was no interaction between the two [56]. 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.…”

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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Crystal structure of the periplasmic sensor domain of histidine kinase VbrK suggests indirect sensing of β-lactam antibiotics

Cited by 7 publications

References 34 publications

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

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

Diversity in Sensing and Signaling of Bacterial Sensor Histidine Kinases

Disrupting central carbon metabolism increases antibiotic susceptibility inVibrio cholerae

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