Fur-like proteins: Beyond the ferric uptake regulator (Fur) paralog

Sevilla, Emma; Bes, M. Teresa; Peleato, M. Luisa; Fillat, Marı́a F.

doi:10.1016/j.abb.2021.108770

Cited by 36 publications

(26 citation statements)

References 175 publications

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“…b The nomenclature of the DtxR family is heterogeneous with considerable species specificity. Reviewed by: c Sevilla et al. (2021) , d Merchant and Spatafora (2014) , e Varela et al.…”

Section: Metal-responsive Transcription Factorsmentioning

confidence: 99%

Battle for Metals: Regulatory RNAs at the Front Line

Charbonnier

González-Espinoza

Kehl-Fie

et al. 2022

Front. Cell. Infect. Microbiol.

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Metal such as iron, zinc, manganese, and nickel are essential elements for bacteria. These nutrients are required in crucial structural and catalytic roles in biological processes, including precursor biosynthesis, DNA replication, transcription, respiration, and oxidative stress responses. While essential, in excess these nutrients can also be toxic. The immune system leverages both of these facets, to limit bacterial proliferation and combat invaders. Metal binding immune proteins reduce the bioavailability of metals at the infection sites starving intruders, while immune cells intoxicate pathogens by providing metals in excess leading to enzyme mismetallation and/or reactive oxygen species generation. In this dynamic metal environment, maintaining metal homeostasis is a critical process that must be precisely coordinated. To achieve this, bacteria utilize diverse metal uptake and efflux systems controlled by metalloregulatory proteins. Recently, small regulatory RNAs (sRNAs) have been revealed to be critical post-transcriptional regulators, working in conjunction with transcription factors to promote rapid adaptation and to fine-tune bacterial adaptation to metal abundance. In this mini review, we discuss the expanding role for sRNAs in iron homeostasis, but also in orchestrating adaptation to the availability of other metals like manganese and nickel. Furthermore, we describe the sRNA-mediated interdependency between metal homeostasis and oxidative stress responses, and how regulatory networks controlled by sRNAs contribute to survival and virulence.

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“…b The nomenclature of the DtxR family is heterogeneous with considerable species specificity. Reviewed by: c Sevilla et al. (2021) , d Merchant and Spatafora (2014) , e Varela et al.…”

Section: Metal-responsive Transcription Factorsmentioning

confidence: 99%

Battle for Metals: Regulatory RNAs at the Front Line

Charbonnier

González-Espinoza

Kehl-Fie

et al. 2022

Front. Cell. Infect. Microbiol.

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“…which only contains one cysteine residue and is devoid of structural zinc, all PerR proteins whose structures are available to date exhibit only four cysteine residues. These four cysteines are arranged in the two canonical CXXC motifs which likely are coordinating the structural zinc [1,6,17,31]. Therefore, under mild stress conditions zinc-bound thiolates are maintained in its reduced state and are not available to perform thiol-disulfide exchanges.…”

Section: It Is Remarkable That With the Exception Of The Leptospira I...mentioning

confidence: 99%

“…FUR (Ferric Uptake Regulator) proteins form a superfamily of pivotal transcriptional regulators present in most prokaryotes. The most ubiquitous members of the family are Fur (ferric uptake regulator), Zur (zinc uptake regulator) and PerR (peroxide response regulator) [1]. In many cases they work not only as metalconcentration dependent regulators, but also respond to different signals, such as the presence of ROS and RNS, O2, the pH, the ratio C/N or the concentration of NaCl or 2oxoglutarate [2][3][4][5][6][7] working as global regulators in a wide variety of bacteria [1].…”

Section: Introductionmentioning

confidence: 99%

“…The most ubiquitous members of the family are Fur (ferric uptake regulator), Zur (zinc uptake regulator) and PerR (peroxide response regulator) [1]. In many cases they work not only as metalconcentration dependent regulators, but also respond to different signals, such as the presence of ROS and RNS, O2, the pH, the ratio C/N or the concentration of NaCl or 2oxoglutarate [2][3][4][5][6][7] working as global regulators in a wide variety of bacteria [1]. Despite their common overall structure, different working mechanisms have been proposed for the different FUR regulators, often depending on the number and properties of the metal binding sites, which can vary in the different microorganisms [8].…”

Section: Introductionmentioning

confidence: 99%

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Metal binding and oligomerization properties of FurC (PerR) from Anabaena sp. PCC7120: an additional layer of regulation?

et al. 2022

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Metal and redox homeostasis in cyanobacteria is tightly controlled to preserve the photosynthetic machinery from mismetallation and minimize cell damage. This control is mainly taken by FUR (ferric uptake regulation) proteins. FurC works as the PerR (peroxide response) paralog in Anabaena sp. PCC7120. Despite its importance, this regulator remained poorly characterized. Although FurC lacks the typical CXXC motifs present in FUR proteins, it contains a tightly bound zinc per subunit. FurC:Zn stoichiometrically binds zinc and manganese in a second site, being manganese more efficient in the binding of FurC:Zn to its DNA target PprxA. Oligomerization analyses of FurC:Zn evidence the occurrence of different aggregates ranging from dimers to octamers. Notably, intermolecular disulfide bonds are not involved in FurC:Zn dimerization, being the dimer the most reduced form of the protein. Oligomerization of dimers occurs upon oxidation of thiols by H2O2 or diamide and can be reversed by DTT. Irreversible inactivation of the regulator occurs by metal catalyzed oxidation promoted by ferrous iron. However, inactivation upon oxidation with H2O2 in the absence of iron was reverted by addition of DTT. Comparison of models for FurC:Zn dimers and tetramers obtained using AlphaFold Colab and SWISS-MODEL allowed to infer the residues forming both metal-binding sites and to propose the involvement of Cys86 in reversible tetramer formation. Our results decipher the existence of two levels of inactivation of FurC:Zn of Anabaena sp. PCC7120, a reversible one through disulfide-formed FurC:Zn tetramers and the irreversible metal catalyzed oxidation. This additional reversible regulation may be specific of cyanobacteria.

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“…Regulators of the Fur family are widespread iron-sensing repressors that control the expression of genes implicated in iron transport and storage [90] . The Fur family of metalloregulators include sensors of iron (Fur), zinc (Zur), manganese (Mur), nickel (Nur) and peroxide stress (PerR), among others [91] . Transcriptional analysis of the Mge fur mutant revealed the activation of a gene coding for a histidine-rich lipoprotein (Hrl, MG149) and a putative metal transporter annotated as a CbiMNQO uptake system (MG302-MG303-MG304), which are described earlier in this manuscript.…”

Section: Regulation Of Metal Homeostasismentioning

confidence: 99%