New insight into transmembrane topology of Staphylococcus aureus histidine kinase AgrC

Wang, Lina; Quan, Chunshan; Xiong, Wen; Xiaojing, Qu; Sheng-di, Fan; Hu, Wenzhong

doi:10.1016/j.bbamem.2013.12.006

Cited by 15 publications

(11 citation statements)

References 37 publications

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“…Only short segments of the protein are predicted to be located outside the cell. This predicted topology is remarkably similar to the recently refined topology map of AgrC that was verified using substituted cysteine accessibility and green fluorescent protein fusions (27). A survey of the region from blpH through blpA in 229 strains for which the whole-genome sequence (WGS) was available (WGS strains) confirmed that there are four major allelic variants of blpH (blpH P164 , blpH R6 , blpH 6A , and blpH T4 ).…”

Section: Resultsmentioning

confidence: 51%

An Electrostatic Interaction between BlpC and BlpH Dictates Pheromone Specificity in the Control of Bacteriocin Production and Immunity in Streptococcus pneumoniae

2015

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The blp locus of Streptococcus pneumoniae secretes and regulates bacteriocins, which mediate both intra-and interspecific competition in the human nasopharynx. There are four major alleles of the gene blpH, which encodes the receptor responsible for activating the blp locus when bound to one of four distinct peptide pheromones (BlpC). The allelic variation of blpH is presumably explained by a need to restrict cross talk between competing strains. The BlpH protein sequences have polymorphisms distributed throughout the sequence, making identification of the peptide binding site difficult to predict. To identify the pheromone binding sites that dictate pheromone specificity, we have characterized the four major variants and two naturally occurring chimeric versions of blpH in which recombination events appear to have joined two distinct blpH alleles together. Using these allelic variants, a series of laboratory-generated chimeric blpH alleles, and site-directed mutants of both the receptor and peptide, we have demonstrated that BlpC binding to some BlpH types involves an electrostatic interaction between the oppositely charged residues of BlpC and the first transmembrane domain of BlpH. An additional recognition site was identified in the second extracellular loop. We identified naturally occurring BlpH types that have the capacity to respond to more than one BlpC type; however, this change in specificity results in a commensurate drop in overall sensitivity. These natural recombination events were presumably selected for to balance the need to sense bacteriocin-secreting neighbors with the need to turn on bacteriocin production at a low density. IMPORTANCEBacteria use quorum sensing to optimize gene expression to accommodate for local bacterial density and diffusion rates. To prevent interception of quorum-sensing signals by neighboring strains, the genomes of single species often encode strain-specific signal/receptor pairs. The blp locus in Streptococcus pneumoniae that drives bacteriocin secretion is controlled by quorum sensing that involves the interaction of the signal/receptor pair BlpC/BlpH. We show that the pneumococcal population can be divided into several distinct BlpC/BlpH pairs; however, there are examples of naturally occurring chimeric receptors that can bind to more than one BlpC type. The trade-off for this broadened specificity is a loss of overall receptor sensitivity. This suggests that under certain conditions, the advantage of signal interception can trump the requirements for self-induction. Streptococcus pneumoniae (pneumococcus) is a common pediatric pathogen that colonizes the nasopharynx of a majority of children by 1 year of age (1, 2). During this first year of life, children may be colonized at any point with as many as four different pneumococcal serotypes (3) and even multiple strains of the same pneumococcal serotype (4). The introduction of the multivalent conjugate pneumococcal vaccine has resulted in decreased colonization with the seven targeted serotypes. These strai...

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Section: Resultsmentioning

confidence: 51%

An Electrostatic Interaction between BlpC and BlpH Dictates Pheromone Specificity in the Control of Bacteriocin Production and Immunity in Streptococcus pneumoniae

2015

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“…The basis of AIP-AgrC specificity has recently been elucidated; AgrC possesses an extracellular N-terminal domain and seven transmembrane domains. Binding of AIP induces a conformational change within the cytoplasmic helix that links the sensor and kinase domains of AgrC, enabling autophosphorylation [14,23]. However, binding of heterologous AIP (from S. aureus expressing one of the three other allelic variants of Agr) causes the helical linker to twist in the opposite direction, preventing autokinase activity [14,23,24].…”

mentioning

confidence: 98%

“…Binding of AIP induces a conformational change within the cytoplasmic helix that links the sensor and kinase domains of AgrC, enabling autophosphorylation [14,23]. However, binding of heterologous AIP (from S. aureus expressing one of the three other allelic variants of Agr) causes the helical linker to twist in the opposite direction, preventing autokinase activity [14,23,24]. The binding of AIP to AgrC is the target for the anti-quorumsensing molecule Solonamide B, which prevents AgrC activation in all allelic variants of Agr, inhibiting quorum-sensing and subsequent virulence gene expression via Agr activation [19] (Figure 1).…”

mentioning

confidence: 99%

What role does the quorum-sensing accessory gene regulator system play during Staphylococcus aureus bacteremia?

Painter¹,

Krishna²,

Wigneshweraraj³

et al. 2014

Trends in Microbiology

147

139

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“…We determined the most suitable detergent for membrane solubilization and kinase activity of AgrC (Wang, Quan, Xiong, Qu, & Fan, ). In addition, by the GFP fusion method and substituted cysteine accessibility method (SCAM) we confirmed that there are seven transmembrane segments in AgrC; the N terminus is located outside the cell, and the C terminus is located inside the cell (Wang, Quan, Xiong, Qu, & Fan, ). In a previous study, an artificial cell membrane system with truncated AgrC (AgrC TM5‐6C ) was successfully constructed.…”

Section: Introductionmentioning

confidence: 76%

Proteoliposome‐based model for screening inhibitors targeting histidine kinase AgrC

et al. 2019

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AgrC, as an integral membrane receptor protein with histidine kinase activity, is an important component of the agr quorum‐sensing system of Staphylococcus aureus. AgrC acts as a sensor for the recognition of environmental signals and transduction of the signals into the cytoplasm. Therefore, AgrC is considered to be a compelling target for the development of novel quorum‐sensing inhibitors. Here, we constructed a proteoliposome‐based model for screening inhibitors targeting AgrC by incorporating AgrC into liposomes. We demonstrated that the dissolution state of the liposome was a critical factor in the reconstruction of the AgrC proteoliposome, in which AgrC maintained similar orientation and function as those in natural biological membranes. Two monomers, namely, rhein and aloeemodin, were successfully screened out as inhibitors targeting AgrC by the proteoliposome‐based model from 14 traditional Chinese medicine monomers. The inhibitory effects of these compounds on the growth of suspended bacteria was dose dependent, and subinhibitory concentrations of these compounds significantly reduced the expression of three virulence factors (hla, clfA, and clpP), that are regulated by the agr system. The results preliminarily indicated that rhein and aloeemodin can inhibit the agr signaling pathway and also indirectly confirmed the feasibility and effectiveness of the AgrC proteoliposome as a drug screening model.

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New insight into transmembrane topology of Staphylococcus aureus histidine kinase AgrC

Cited by 15 publications

References 37 publications

An Electrostatic Interaction between BlpC and BlpH Dictates Pheromone Specificity in the Control of Bacteriocin Production and Immunity in Streptococcus pneumoniae

An Electrostatic Interaction between BlpC and BlpH Dictates Pheromone Specificity in the Control of Bacteriocin Production and Immunity in Streptococcus pneumoniae

What role does the quorum-sensing accessory gene regulator system play during Staphylococcus aureus bacteremia?

Proteoliposome‐based model for screening inhibitors targeting histidine kinase AgrC

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