Redox Sensing by Fe<sup>2+</sup>in Bacterial Fur Family Metalloregulators

Pinochet-Barros, Azul; Helmann, John D.

doi:10.1089/ars.2017.7359

Cited by 66 publications

(63 citation statements)

References 121 publications

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“…The bacterial intracellular "free" iron concentration is primarily regulated by a global transcription factor Ferric uptake regulator (Fur) (1)(2)(3)(4). It has been generally assumed that when the intracellular "free" iron concentration is elevated, Fur binds "free" ferrous iron and the iron-bound Fur represses the genes encoding for iron uptake systems and stimulates the genes encoding for iron storage proteins (5)(6)(7)(8)(9). The crystallographic studies of the Fur proteins from Escherichia coli (10), Mycobacterium tuberculosis (11), Vibrio cholerae (12), Helicobacter pylori (13), Campylobacter jejuni (14), and Francisella tularensis (15) have revealed that Fur protein exists as a homodimer or tetramer (8) with each monomer containing three putative metal binding sites.…”

Section: Introductionmentioning

confidence: 99%

Ferric uptake regulator (Fur) reversibly binds a [2Fe-2S] cluster to sense intracellular iron homeostasis in Escherichia coli

Fontenot

Tasnim

Valdes

et al. 2020

Journal of Biological Chemistry

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The ferric uptake regulator (Fur) is a global transcription factor that regulates intracellular iron homeostasis in bacteria. The current hypothesis states that when the intracellular “free” iron concentration is elevated, Fur binds ferrous iron and the iron-bound Fur represses the genes encoding for iron uptake systems and stimulates the genes encoding for iron storage proteins. However, the “iron-bound” Fur has never been isolated from any bacteria. Here we report that the Escherichia coli Fur has a bright red color when expressed in E. coli mutant cells containing an elevated intracellular “free” iron content due to deletion of the iron-sulfur cluster assembly proteins IscA and SufA. The acid-labile iron and sulfide content analyses in conjunction with the electron paramagnetic resonance and Mössbauer spectroscopy measurements and the site-directed mutagenesis studies show that the red Fur protein binds a [2Fe-2S] cluster via conserved cysteine residues. The occupancy of the [2Fe-2S] cluster in Fur protein is about 31% in the E. coli iscA/sufA mutant cells and is decreased to about 4% in wild-type E. coli cells. Depletion of the intracellular “free” iron content using the membrane-permeable iron chelator 2,2’-dipyridyl effectively removes the [2Fe-2S] cluster from Fur in E. coli cells, suggesting that Fur senses the intracellular “free” iron content via reversible binding of a [2Fe-2S] cluster. The binding of the [2Fe-2S] cluster in Fur appears to be highly conserved, as the Fur homolog from Haemophilus influenzae expressed in E. coli cells also reversibly binds a [2Fe-2S] cluster to sense intracellular iron homeostasis.

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Section: Introductionmentioning

confidence: 99%

Ferric uptake regulator (Fur) reversibly binds a [2Fe-2S] cluster to sense intracellular iron homeostasis in Escherichia coli

Fontenot

Tasnim

Valdes

et al. 2020

Journal of Biological Chemistry

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“…Different redox state sensing mechanisms would be of great importance for bacteria for a fast response to changes in redox state of the external environment of the oral cavity or periodontal pockets, as well as inside the host cells. For example, PerR proteins sense hydrogen peroxide by metal-catalyzed His oxidation, which leads to conformational changes and dissociation from DNA and activation of expression of oxidative stress response genes [74,75]. On the other hand, in the classic OxyR paradigm, H 2 O 2 oxidizes Cys residues, influencing the DNA-OxyR interaction, which leads to the activation of genes encoding proteins with antioxidant function.…”

Section: Discussionmentioning

confidence: 99%

PgRsp Is a Novel Redox-Sensing Transcription Regulator Essential for Porphyromonas gingivalis Virulence

Śmiga

Olczak

2019

Microorganisms

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Porphyromonas gingivalis is one of the etiological agents of chronic periodontitis. Both heme and oxidative stress impact expression of genes responsible for its survival and virulence. Previously we showed that P. gingivalis ferric uptake regulator homolog affects expression of a gene encoding a putative Crp/Fnr superfamily member, termed P. gingivalis redox-sensing protein (PgRsp). Although PgRsp binds heme and shows the highest similarity to proteins assigned to the CooA family, it could be a member of a novel, separate family of proteins with unknown function. Expression of the pgrsp gene is autoregulated and iron/heme dependent. Genes encoding proteins engaged in the oxidative stress response were upregulated in the pgrsp mutant (TO11) strain compared with the wild-type strain. The TO11 strain showed higher biomass production, biofilm formation, and coaggregation ability with Tannerella forsythia and Prevotella intermedia. We suggest that PgRsp may regulate production of virulence factors, proteases, Hmu heme acquisition system, and FimA protein. Moreover, we observed growth retardation of the TO11 strain under oxidative conditions and decreased survival ability of the mutant cells inside macrophages. We conclude that PgRsp protein may play a role in the oxidative stress response using heme as a ligand for sensing changes in redox status, thus regulating the alternative pathway of the oxidative stress response alongside OxyR.

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“…Oxidation of PerR leads to loss of the iron cofactor and its dissociation from DNA to derepress transcription of genes involved in the antioxidant response. The mechanistic differences between Fur and PerR from heterotrophic bacteria have recently been reviewed (291). PerR may function as both activator and repressor of gene expression.…”

Section: Regulation By Metal-catalyzed Oxidation: Perrmentioning

confidence: 99%

“…Transduction of these redox signals is frequently carried out by transcriptional regulatory proteins through a variety of mechanisms (237,334,364). Owing to the tight relationship between iron metabolism and redox homeostasis, the activity of many major regulators relies on iron, either as an ion cofactor assembled in iron-sulfur clusters or as heme-based sensors (80,121,134,274,288,291).…”

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confidence: 99%

Redox-Based Transcriptional Regulation in Prokaryotes: Revisiting Model Mechanisms

Sevilla

Bes

González

et al. 2019

Antioxidants & Redox Signaling

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Redox-responsive transcriptional regulation is an intricate process as identical signals may be sensed and transduced by different transcription factors, which often interplay with other DNA-binding proteins with or without regulatory activity. Although there is much information about some key regulators, many others remain to be fully characterized due to the instability of their clusters under oxygen. Understanding the mechanisms and the regulatory networks operated by these regulators is essential for the development of future applications in biotechnology and medicine. Antioxid. Redox Signal. 00, 000-000.

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Redox Sensing by Fe²⁺in Bacterial Fur Family Metalloregulators

Cited by 66 publications

References 121 publications

Ferric uptake regulator (Fur) reversibly binds a [2Fe-2S] cluster to sense intracellular iron homeostasis in Escherichia coli

Ferric uptake regulator (Fur) reversibly binds a [2Fe-2S] cluster to sense intracellular iron homeostasis in Escherichia coli

PgRsp Is a Novel Redox-Sensing Transcription Regulator Essential for Porphyromonas gingivalis Virulence

Redox-Based Transcriptional Regulation in Prokaryotes: Revisiting Model Mechanisms

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Redox Sensing by Fe2+in Bacterial Fur Family Metalloregulators

Cited by 66 publications

References 121 publications

Ferric uptake regulator (Fur) reversibly binds a [2Fe-2S] cluster to sense intracellular iron homeostasis in Escherichia coli

Ferric uptake regulator (Fur) reversibly binds a [2Fe-2S] cluster to sense intracellular iron homeostasis in Escherichia coli

PgRsp Is a Novel Redox-Sensing Transcription Regulator Essential for Porphyromonas gingivalis Virulence

Redox-Based Transcriptional Regulation in Prokaryotes: Revisiting Model Mechanisms

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Redox Sensing by Fe²⁺in Bacterial Fur Family Metalloregulators