Structural basis for the specialization of Nur, a nickel-specific Fur homolog, in metal sensing and DNA recognition

An, Young Jun; Ahn, Bo-Eun; Han, A-Reum; Kim, Hae-Mi; Chung, Kyung Min; Shin, Jung-Ho; Cho, Yoobok; Roe, Jung‐Hye; Shin, Sun

doi:10.1093/nar/gkp198

Cited by 60 publications

(93 citation statements)

References 31 publications

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“…A common feature shared by the Fur family of transcriptional regulators is that their DNA-binding activity is often regulated by a divalent metal ion whose cellular homeostasis in turn is controlled by the same regulator (11,25,34). In this study, Cu(II) has emerged as the most prominent regulator of BosR DNA-binding activity in vitro, and it is also Cu homeostasis in B. burgdorferi that is the most significantly affected by a deficiency in BosR.…”

Section: Discussionmentioning

confidence: 80%

“…Many Fur homologues have been shown to be global regulators that affect metabolism, motility, stress responses, biofilm formation, and pathogenicity (19)(20)(21)(22)(23)(24). While most Fur family members recognize palindromic DNA sequences that follow the 7-1-7 rule (i.e., a 1-bp spacer separating a pair of 7-bp palindromic sequences) (11,23), variations to this rule have been reported (6,25). Two recent genome-wide studies of Campylobacter jejuni and E. coli Fur regulons suggest that the consensus sequences targeted for activation could differ significantly from those targeted for repression and may not even be palindromic (22,24).…”

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confidence: 99%

“…To date, a total of 21 crystal structures have been reported for 12 members of the Fur family (22,(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). With the exception of the E. coli Fur structure, which is of an amino-terminal truncate, all the other structures are of full-length proteins.…”

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confidence: 99%

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BosR Is A Novel Fur Family Member Responsive to Copper and Regulating Copper Homeostasis in Borrelia burgdorferi

Wang

Santangelo

et al. 2017

J Bacteriol

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The ferric uptake regulator (Fur) family of DNA-binding proteins represses and/or activates gene transcription via divalent metal ion-dependent signal sensing. The Borrelia burgdorferi Fur homologue, also known as Borrelia oxidative stress regulator (BosR), promotes spirochetal adaptation to the mammalian host by directly repressing the lipoproteins required for tick colonization and indirectly activating those required for establishing infection in the mammal. Here, we examined whether the DNA-binding activity of BosR was regulated by any of the four most prevalent transition metal ions in B. burgdorferi, Mn, Fe, Cu, and Zn. Our data indicated that in addition to a structural site occupied by Zn(II), BosR had two regulatory sites that could be occupied by Zn(II), Fe(II), or Cu(II) but not by Mn(II). While Fe(II) had no effect, Cu(II) and Zn(II) had a dose-dependent inhibitory effect on the BosR DNA-binding activity. Competition experiments indicated that Cu(II) had a higher affinity for BosR than Zn(II) or Fe(II). A BosR deficiency in B. burgdorferi resulted in a significant increase in the Cu level but no significant change in the levels of Mn, Fe, or Zn. These data suggest that Cu regulates BosR activity, and BosR in turn regulates Cu homeostasis in B. burgdorferi. While this regulatory paradigm is characteristic of the Fur family, BosR is the first one shown to be responsive to Cu(II), which may be an adaptation to the potentially high level of Cu present in the Lyme disease spirochete. IMPORTANCE Transition metal ions serve an essential role in the metabolism of all living organisms. Members of the ferric uptake regulator (Fur) family play critical roles in regulating the cellular homeostasis of transition metals in diverse bacteria, and their DNA-binding activity is often regulated by coordination of the cognate divalent metal ions. To date, regulators with metal ion specificity to Fe(II), Mn(II), Zn(II), and Ni(II) have all been described. In this study, we demonstrate that BosR, the sole Fur homologue in Borrelia burgdorferi, is responsive to Cu(II) and regulates Cu homeostasis in this bacterium, which may be an adaption to potentially Cu-rich milieu in the Lyme disease spirochete. This study has expanded the repertoire of the Fur family's metal ion specificity.

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Section: Discussionmentioning

confidence: 80%

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BosR Is A Novel Fur Family Member Responsive to Copper and Regulating Copper Homeostasis in Borrelia burgdorferi

Wang

Santangelo

et al. 2017

J Bacteriol

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“…The amino acid sequences of many Fur homologues include two potential metal binding motifs, a conserved HHXHXXCXXC signature and another less conserved C-terminal CXXC motif. In fact, two or three metal atoms whose coordination involves amino acids of these motifs are observed in the crystal structures of several Fur homologues (1,6,9,34,39,47,48). Usually, one of the metal binding sites accommodates the regulatory metal atom, while another site has a structural character.…”

Section: Innovationmentioning

confidence: 99%

Cysteine Mutational Studies Provide Insight into a Thiol-Based Redox Switch Mechanism of Metal and DNA Binding in FurA fromAnabaenasp. PCC 7120

Botello-Morte

Pellicer

Sein‐Echaluce

et al. 2016

Antioxidants & Redox Signaling

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Aims: The ferric uptake regulator (Fur) is the main transcriptional regulator of genes involved in iron homeostasis in most prokaryotes. FurA from Anabaena sp. PCC 7120 contains five cysteine residues, four of them arranged in two redox-active CXXC motifs. The protein needs not only metal but also reducing conditions to remain fully active in vitro. Through a mutational study of the cysteine residues present in FurA, we have investigated their involvement in metal and DNA binding. , suggesting that the environments of these cysteines are mutually interdependent. Innovation: We propose that C 101 is part of a thiol/disulfide redox switch that determines FurA ability to bind the metal corepressor. Conclusion: This mechanism supports a novel feature of a Fur protein that emerges as a regulator, which connects the response to changes in the intracellular redox state and iron management in cyanobacteria. Antioxid. Redox Signal. 24, 173-185.

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“…The mechanisms of metal-specificity and metal-mediated activity modulation have been extensively investigated, revealing some common and specific principles among members of this family. Crystal structures of several metal-bound Fur regulators have been reported for iron-responsive Fur from Pseudomonas aeruginosa (PaFur) (18) and Vibrio cholerae (VcFur) (19), zincresponsive Zur from Mycobacterium tuberculosis (MtZur) (20), nickel-responsive Nur from S. coelicolor (ScNur) (21), and peroxide-sensing PerR from Bacillus subtilis (BsPerR) (22). All of the available structures demonstrate that the Fur family members are homodimeric and each monomer consists of an N-terminal DNAbinding (DB) domain, a C-terminal dimerization (D) domain, and a hinge loop between the two.…”

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Graded expression of zinc-responsive genes through two regulatory zinc-binding sites in Zur

Shin

Jung

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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189

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Zinc is one of the essential transition metals in cells. Excess or lack of zinc is detrimental, and cells exploit highly sensitive zinc-binding regulators to achieve homeostasis. In this article, we present a crystal structure of active Zur from Streptomyces coelicolor with three zinc-binding sites (C-, M-, and D-sites). Mutations of the three sites differentially affected sporulation and transcription of target genes, such that C- and M-site mutations inhibited sporulation and derepressed all target genes examined, whereas D-site mutations did not affect sporulation and derepressed only a sensitive gene. Biochemical and spectroscopic analyses of representative metal site mutants revealed that the C-site serves a structural role, whereas the M- and D-sites regulate DNA-binding activity as an on-off switch and a fine-tuner, respectively. Consistent with differential effect of mutations on target genes, zinc chelation by TPEN derepressed some genes ( znuA, rpmF2 ) more sensitively than others ( rpmG2 , SCO7682) in vivo. Similar pattern of TPEN-sensitivity was observed for Zur-DNA complexes formed on different promoters in vitro. The sensitive promoters bound Zur with lower affinity than the less sensitive ones. EDTA-treated apo-Zur gained its DNA binding activity at different concentrations of added zinc for the two promoter groups, corresponding to free zinc concentrations of 4.5 × 10 −16 M and 7.9 × 10 −16 M for the less sensitive and sensitive promoters, respectively. The graded expression of target genes is a clever outcome of subtly modulating Zur-DNA binding affinities in response to zinc availability. It enables bacteria to detect metal depletion with improved sensitivity and optimize gene-expression pattern.

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Structural basis for the specialization of Nur, a nickel-specific Fur homolog, in metal sensing and DNA recognition

Cited by 60 publications

References 31 publications

BosR Is A Novel Fur Family Member Responsive to Copper and Regulating Copper Homeostasis in Borrelia burgdorferi

BosR Is A Novel Fur Family Member Responsive to Copper and Regulating Copper Homeostasis in Borrelia burgdorferi

Cysteine Mutational Studies Provide Insight into a Thiol-Based Redox Switch Mechanism of Metal and DNA Binding in FurA fromAnabaenasp. PCC 7120

Graded expression of zinc-responsive genes through two regulatory zinc-binding sites in Zur

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