Decision letter: Tuning site-specific dynamics to drive allosteric activation in a pneumococcal zinc uptake regulator

ABSTRACT Zinc is an essential trace element for all living organisms and plays pivotal roles in various cellular processes. However, an excess of zinc is extremely deleterious to cells. Bacteria have evolved complex machineries (such as efflux/influx systems) to control the concentration at levels appropriate for the maintenance of zinc homeostasis in cells and adaptation to the environment. The Zur (zinc uptake regulator) protein is one of these functional members involved in the precise control of zinc homeostasis. Here we identified a zur homologue designated 310 from Streptococcus suis serotype 2, strain 05ZYH33, a highly invasive isolate causing streptococcal toxic shock syndrome. Biochemical analysis revealed that the protein product of gene 310 exists as a dimer form and carries zinc ions. An isogenic gene replacement mutant of gene 310, the Δ310 mutant, was obtained by homologous recombination. Physiological tests demonstrated that the Δ310 mutant is specifically sensitive to Zn2+, while functional complementation of the Δ310 mutant can restore its duration capability, suggesting that 310 is a functional member of the Zur family. Two-dimensional electrophoresis indicated that nine proteins in the Δ310 mutant are overexpressed in comparison with those in the wild type. DNA microarray analyses suggested that 121 genes in the Δ310 mutant are affected, of which 72 genes are upregulated and 49 are downregulated. The transcriptome of S. suis serotype 2 with high Zn2+ concentrations also showed 117 differentially expressed genes, with 71 upregulated and 46 downregulated. Surprisingly, more than 70% of the genes differentially expressed in the Δ310 mutant were the same as those in S. suis serotype 2 that were differentially expressed in response to high Zn2+ concentration, consistent with the notion that 310 is involved in zinc homeostasis. We thus report for the first time a novel zinc-responsive regulator, Zur, from Streptococcus suis serotype 2.

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Identification, Functional Characterization, and Regulon Prediction of the Zinc Uptake Regulator (zur) of Bacillus anthracis – An Insight Into the Zinc Homeostasis of the Pathogen

Frontiers in Microbiology ◽

10.3389/fmicb.2018.03314 ◽

2019 ◽

Vol 9 ◽

Cited By ~ 7

Author(s):

Divya Kandari ◽

Monisha Gopalani ◽

Manish Gupta ◽

Hemant Joshi ◽

Sonika Bhatnagar ◽

...

Keyword(s):

Bacillus Anthracis ◽

Functional Characterization ◽

Zinc Uptake ◽

Zinc Homeostasis ◽

Zinc Uptake Regulator ◽

Insight Into

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Control of zinc homeostasis in Agrobacterium tumefaciens via zur and the zinc uptake genes znuABC and zinT

Microbiology ◽

10.1099/mic.0.082446-0 ◽

2014 ◽

Vol 160 (11) ◽

pp. 2452-2463 ◽

Cited By ~ 16

Author(s):

Sakkarin Bhubhanil ◽

Panida Sittipo ◽

Paweena Chaoprasid ◽

Sumontha Nookabkaew ◽

Rojana Sukchawalit ◽

...

Keyword(s):

Agrobacterium Tumefaciens ◽

Dominant Role ◽

Zinc Content ◽

Zinc Uptake ◽

Zinc Homeostasis ◽

Dependent Manner ◽

Transporter Family ◽

Zinc Depletion ◽

Zinc Uptake Regulator ◽

Dose Dependent

The Agrobacterium tumefaciens zinc uptake regulator (Zur) was shown to negatively regulate the zinc uptake genes znuABC, encoding a zinc transport system belonging to the ATP-binding cassette (ABC) transporter family, and zinT, which encodes a periplasmic zinc-binding protein. The expression of znuABC and zinT was inducible when cells were grown in medium containing a metal chelator (EDTA), and this induction was shown to be specific for zinc depletion. The expression of znuABC was reduced in response to increased zinc in a dose-dependent manner, and zinT had a less pronounced but similar pattern of zinc-regulated expression. The inactivation of zur led to constitutively high expression of znuABC and zinT. In addition, a zur mutant had an increased total zinc content compared to the WT NTL4 strain, whereas the inactivation of zinT caused a reduction in the total zinc content. The zinT gene is shown to play a dominant role and to be more important than znuA and znuB for A. tumefaciens survival under zinc deprivation. ZinT can function even when ZnuABC is inactivated. However, mutations in zur, znuA, znuB or zinT did not affect the virulence of A. tumefaciens.

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Crystal Structure and Function of the Zinc Uptake Regulator FurB fromMycobacterium tuberculosis

Journal of Biological Chemistry ◽

10.1074/jbc.m609974200 ◽

2007 ◽

Vol 282 (13) ◽

pp. 9914-9922 ◽

Cited By ~ 85

Author(s):

Debora Lucarelli ◽

Santina Russo ◽

Elspeth Garman ◽

Anna Milano ◽

Wolfram Meyer-Klaucke ◽

...

Keyword(s):

Crystal Structure ◽

Structure And Function ◽

Zinc Uptake ◽

And Function ◽

Zinc Uptake Regulator

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Tuning site-specific dynamics to drive allosteric activation in a pneumococcal zinc uptake regulator

10.1101/301853 ◽

2018 ◽

Author(s):

Daiana A. Capdevila ◽

Fidel Huerta ◽

Katherine A. Edmonds ◽

My T. Le ◽

Hongwei Wu ◽

...

Keyword(s):

Conformational Dynamics ◽

Allosteric Activation ◽

Compact Structure ◽

Biological Regulation ◽

Family Function ◽

Wide Range ◽

Allosteric Mechanisms ◽

Zinc Uptake Regulator ◽

Allosteric Activator

AbstractMarR (multiple antibiotic resistance repressor) family proteins are bacterial repressors that regulate transcription in response to a wide range of chemical signals. Although specific features of MarR family function have been described, the role of atomic motions in MarRs remains unexplored thus limiting insights into the evolution of allostery in this ubiquitous family of repressors. Here, we provide the first experimental evidence that internal dynamics play a crucial functional role in MarR proteins. Streptococcus pneumoniae AdcR (adhesin-competence repressor) regulates ZnIIhomeostasis and ZnIIfunctions as an allosteric activator of DNA binding. ZnIIcoordination triggers a transition from independent domains to a more compact structure. We identify residues that impact allosteric activation on the basis of ZnII-induced perturbations of atomic motions over a wide range of timescales. These findings reconcile the distinct allosteric mechanisms proposed for other MarRs and highlight the importance of conformational dynamics in biological regulation.

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The Transcriptional Regulator Np20 Is the Zinc Uptake Regulator in Pseudomonas aeruginosa

PLoS ONE ◽

10.1371/journal.pone.0075389 ◽

2013 ◽

Vol 8 (9) ◽

pp. e75389 ◽

Cited By ~ 28

Author(s):

Matthew L. Ellison ◽

John Matthew Farrow ◽

Whitney Parrish ◽

Allison S. Danell ◽

Everett C. Pesci

Keyword(s):

Pseudomonas Aeruginosa ◽

Transcriptional Regulator ◽

Zinc Uptake ◽

Zinc Uptake Regulator

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Delineation of the Residues of Bacillus anthracis Zinc Uptake Regulator Protein Directly Involved in Its Interaction with Cognate DNA

Biological Trace Element Research ◽

10.1007/s12011-020-02427-x ◽

2020 ◽

Author(s):

Divya Kandari ◽

Hemant Joshi ◽

Neetu Tanwar ◽

Manoj Munde ◽

Rakesh Bhatnagar

Keyword(s):

Bacillus Anthracis ◽

Zinc Uptake ◽

Regulator Protein ◽

Zinc Uptake Regulator

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Regulation and Activity of a Zinc Uptake Regulator, Zur, in Corynebacterium diphtheriae

Journal of Bacteriology ◽

10.1128/jb.01392-08 ◽

2008 ◽

Vol 191 (5) ◽

pp. 1595-1603 ◽

Cited By ~ 31

Author(s):

Kelsy F. Smith ◽

Lori A. Bibb ◽

Michael P. Schmitt ◽

Diana M. Oram

Keyword(s):

Metal Ion ◽

Ion Homeostasis ◽

Transcriptional Regulator ◽

Corynebacterium Diphtheriae ◽

Zinc Uptake ◽

Mrna Levels ◽

Metal Ion Homeostasis ◽

Expression Of Genes ◽

Family Protein ◽

Zinc Uptake Regulator

ABSTRACT Regulation of metal ion homeostasis is essential to bacterial cell survival, and in most species it is controlled by metal-dependent transcriptional regulators. In this study, we describe a Corynebacterium diphtheriae ferric uptake regulator-family protein, Zur, that controls expression of genes involved in zinc uptake. By measuring promoter activities and mRNA levels, we demonstrate that Zur represses transcription of three genes (zrg, cmrA, and troA) in zinc-replete conditions. All three of these genes have similarity to genes involved in zinc uptake. Transcription of zrg and cmrA was also shown to be regulated in response to iron and manganese, respectively, by mechanisms that are independent of Zur. We demonstrate that the activity of the zur promoter is slightly decreased under low zinc conditions in a process that is dependent on Zur itself. This regulation of zur transcription is distinctive and has not yet been described for any other zur. An adjacent gene, predicted to encode a metal-dependent transcriptional regulator in the ArsR/SmtB family, is transcribed from a separate promoter whose activity is unaffected by Zur. A C. diphtheriae zur mutant was more sensitive to peroxide stress, which suggests that zur has a role in protecting the bacterium from oxidative damage. Our studies provide the first evidence of a zinc specific transcriptional regulator in C. diphtheriae and give new insights into the intricate regulatory network responsible for regulating metal ion concentrations in this toxigenic human pathogen.

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