Metalloregulators: Arbiters of Metal Sufficiency

Helmann, John D.; Soonsanga, Sumarin; Gabriel, Scott E.

doi:10.1007/7171_2006_073

Cited by 25 publications

(19 citation statements)

References 151 publications

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“…Once the metallic gold nanoparticles were formed, however, reactive oxygen species may no longer be produced (46). The determinants involved in metal or metalloid resistance that are upregulated after treatment with gold complexes are controlled by MerR-or ArsR-type regulators, which usually bind "soft" metals or metalloids (30,47,48). Gold complexes may cause here a gratuitous induction of determinants that may not deal with the noble metal (Table 5).…”

Section: Discussionmentioning

confidence: 99%

“…After incubation for 72 h at 30°C on a shaking incubator at 100 rpm, the cells were fixed directly with 3% glutaraldehyde (Sigma, Taufkirchen, Germany) in 0.1 M sodium cacodylate buffer (SCB) for 3 h, centrifuged at 5,000 rpm for 5 min, and taken up in 4% agar-SCB, followed by one wash step with SCB overnight at 4°C and three wash steps with the same buffer for 5 min. After fixation with osmium tetroxide for 1 h, the samples were dehydrated in a series of ethanol (10,30, and 50%). The cells were then treated with 1% uranylacetate-70% ethanol for 1 h and further dehydrated with a series of 70, 90, and 100% ethanol.…”

Section: Methodsmentioning

confidence: 99%

“…CupR from C. metallidurans is a MerR-type regulatory protein able to bind gold complexes (29). MerR-type regulators usually stay at their operator on the DNA and repress the respective downstream operon in the absence of their target metal but shift to an activator conformation when the target metal is bound (30). Upregulation of the cup determinant might therefore indicate the presence of gold in the cytoplasm of C. metallidurans.…”

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confidence: 99%

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Influence of Copper Resistance Determinants on Gold Transformation by Cupriavidus metallidurans Strain CH34

et al. 2013

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confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Influence of Copper Resistance Determinants on Gold Transformation by Cupriavidus metallidurans Strain CH34

et al. 2013

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“…Detection of free metal ions in the cytoplasm by these sensors rapidly induces the transcription of sets of genes mostly coding for efflux or detoxification systems (2)(3)(4)(5). Two functional regions composed of residues from both monomers can easily be distinguished in the structures of these dimeric regulators, namely, the DNA-binding and metal-binding regions.…”

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confidence: 99%

A Single Serine Residue Determines Selectivity to Monovalent Metal Ions in Metalloregulators of the MerR Family

2015

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MerR metalloregulators alleviate toxicity caused by an excess of metal ions, such as copper, zinc, mercury, lead, cadmium, silver, or gold, by triggering the expression of specific efflux or detoxification systems upon metal detection. The sensor protein binds the inducer metal ion by using two conserved cysteine residues at the C-terminal metal-binding loop (MBL). Divalent metal ion sensors, such as MerR and ZntR, require a third cysteine residue, located at the beginning of the dimerization (␣5) helix, for metal coordination, while monovalent metal ion sensors, such as CueR and GolS, have a serine residue at this position. This serine residue was proposed to provide hydrophobic and steric restrictions to privilege the binding of monovalent metal ions. Here we show that the presence of alanine at this position does not modify the activation pattern of monovalent metal sensors. In contrast, GolS or CueR mutant sensors with a substitution of cysteine for the serine residue respond to monovalent metal ions or Hg(II) with high sensitivities. Furthermore, in a mutant deleted of the Zn(II) exporter ZntA, they also trigger the expression of their target genes in response to either Zn(II), Cd(II), Pb(II), or Co(II). IMPORTANCESpecificity in a stressor's recognition is essential for mounting an appropriate response. MerR metalloregulators trigger the expression of specific resistance systems upon detection of heavy metal ions. Two groups of these metalloregulators can be distinguished, recognizing either ؉1 or ؉2 metal ions, depending on the presence of a conserved serine in the former or a cysteine in the latter. Here we demonstrate that the serine residue in monovalent metal ion sensors excludes divalent metal ion detection, as its replacement by cysteine renders a pan-metal ion sensor. Our results indicate that the spectrum of signals detected by these sensors is determined not only by the metal-binding ligand availability but also by the metal-binding cavity flexibility.A set of bacterial metal ion sensors of the MerR family of transcriptional regulators are essential for controlling toxicity caused by an excess of essential heavy metal ions, such as copper (Cu) or zinc (Zn), or the presence of toxic-only heavy metal ions, such as mercury (Hg), lead (Pb), cadmium (Cd), silver (Ag), or gold (Au) ions (1). Detection of free metal ions in the cytoplasm by these sensors rapidly induces the transcription of sets of genes mostly coding for efflux or detoxification systems (2-5). Two functional regions composed of residues from both monomers can easily be distinguished in the structures of these dimeric regulators, namely, the DNA-binding and metal-binding regions. These regions are connected by two 34-residue antiparallel coiledcoil helices, one from each monomer, which cross over at the dimer interface. According to the current model, the signal detected at the metal-binding site is transmitted through allosteric changes to the DNA-binding domain, resulting in transcriptional activation of the target genes via a ...

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“…The intracellular concentration of essential metals or the presence of harmful elements is monitored by a set of transcriptional regulators that modulate the expression of factors that rapidly restore metal homeostasis (4,5). A large class of these metalloregulators belongs to the MerR family, a group of proteins that share similarity at the N-terminal DNA-binding domain (6)(7)(8)(9). According to the current model, dimeric metal-sensing MerR regulators control gene transcription via a DNA distortion mechanism.…”

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confidence: 99%

Dissecting the Metal Selectivity of MerR Monovalent Metal Ion Sensors in Salmonella

et al. 2013

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Two homologous transcription factors, CueR and GolS, that belong to the MerR metalloregulatory family are responsible for Salmonella Cu and Au sensing and resistance, respectively. They share similarities not only in their sequences, but also in their target transcription binding sites. While CueR responds similarly to Au, Ag, or Cu to induce the expression of its target genes, GolS shows higher activation by Au than by Ag or Cu. We showed that the ability of GolS to distinguish Au from Cu resides in the metal-binding loop motif. Here, we identify the amino acids within the motif that determine in vivo metal selectivity. We show that residues at positions 113 and 118 within the metal-binding loop are the main contributors to metal selectivity. The presence of a Pro residue at position 113 favors the detection of Cu, while the presence of Pro at position 118 disfavors it. Our results highlight the molecular bases that allow these regulators to coordinate the correct metal ion directing the response to a particular metal injury.T ransition metal homeostasis influences many fundamental aspects of bacterial cell physiology and pathogenesis (1-3). The intracellular concentration of essential metals or the presence of harmful elements is monitored by a set of transcriptional regulators that modulate the expression of factors that rapidly restore metal homeostasis (4, 5). A large class of these metalloregulators belongs to the MerR family, a group of proteins that share similarity at the N-terminal DNA-binding domain (6-9). According to the current model, dimeric metal-sensing MerR regulators control gene transcription via a DNA distortion mechanism. Both the apo-and the metal-bound regulator recognize and interact with their target operators (a dyad-symmetric DNA sequence at the promoter region of their target genes). Binding of the metal ion at the C-terminal inductor-binding site would provoke an allosteric change at the N-terminal DNA binding region of the protein, which in turn transduces changes in the promoter structure resulting in transcription activation of the expression of genes coding mostly for efflux or detoxification systems (10-12).Most of the metal ion sensors of the MerR family are poorly selective because they cannot distinguish between cognate metals with similar physicochemical properties, including charge and coordination chemistry. For example, the Cu sensor CueR can discriminate between metal ions with ϩ1 and ϩ2 charges, but it cannot distinguish between monovalent metal ions of group 1B-i.e., Cu(I), Ag(I), and Au(I) (13). Structural studies indicate that CueR has only two coordinating ligands, the S-atoms of the conserved C112 and C120 residues which are appropriate for the interaction with the ϩ1 metal ion in a linear array but not to coordinate metal ions with a ϩ2 charge, which requires higher number of ligands (14). The recent identification of two Au-selective MerR sensors, first in the bacterial pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) and then in Cupriavidus met...

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Metalloregulators: Arbiters of Metal Sufficiency

Cited by 25 publications

References 151 publications

Influence of Copper Resistance Determinants on Gold Transformation by Cupriavidus metallidurans Strain CH34

Influence of Copper Resistance Determinants on Gold Transformation by Cupriavidus metallidurans Strain CH34

A Single Serine Residue Determines Selectivity to Monovalent Metal Ions in Metalloregulators of the MerR Family

Dissecting the Metal Selectivity of MerR Monovalent Metal Ion Sensors in Salmonella

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