Hammering out details: regulating metal levels in eukaryotes

Ehrensberger, Kate M.; Bird, Amanda J.

doi:10.1016/j.tibs.2011.07.002

Cited by 55 publications

(49 citation statements)

References 70 publications

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“…These include C 2 H 2 -type zinc fingers in Zap1, MTF-1, and now Loz1 and a cysteine/histidinerich domain in AD1 from Zap1 (4,22). Deletion of a cysteinerich metallothionein-like domain from the copper-responsive regulator Crr1 in Chlamydomonas also leads to increased expression of genes required for zinc uptake and the hyperaccumulation of zinc, suggesting that this may be another type of zinc-sensing domain (25,26).…”

Section: Discussionmentioning

confidence: 99%

“…As a consequence, all organisms rely on mechanisms to maintain optimal intracellular levels of zinc. In eukaryotes, zinc-responsive transcription factors play a primary role in maintaining zinc homeostasis by controlling the expression of genes necessary for zinc transport and/or zinc storage (4). Transcription factors that regulate gene expression in response to zinc levels include Zap1 from Saccharomyces cerevisiae, MTF-1 in mammals and fish, Loz1 in Schizosaccharomyces pombe, and bZip19 and bZip23 in Arabidopsis thaliana (5)(6)(7)(8).…”

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confidence: 99%

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The Double Zinc Finger Domain and Adjacent Accessory Domain from the Transcription Factor Loss of Zinc Sensing 1 (Loz1) Are Necessary for DNA Binding and Zinc Sensing

Ehrensberger

Corkins

Choi³

et al. 2014

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

The Double Zinc Finger Domain and Adjacent Accessory Domain from the Transcription Factor Loss of Zinc Sensing 1 (Loz1) Are Necessary for DNA Binding and Zinc Sensing

Ehrensberger

Corkins

Choi³

et al. 2014

Journal of Biological Chemistry

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“…Dried cells were solubilized in 400 l 30% HNO 3 and lysed by incubation at 95°C for 10 min with shaking at 500 rpm. Samples were prepared for inductively coupled plasma mass spectrometry (ICP-MS) by diluting 300 l of lysed cells into 2.7 ml 2.5% HNO 3 . Metal concentrations were calculated from the standard curve using 1-to 30-ppb metal stock solutions and normalized to the total protein concentration, determined using a DC protein assay (Bio-Rad).…”

Section: Methodsmentioning

confidence: 99%

“…T ransition metals from manganese (Mn) to zinc (Zn) in the first row of the periodic table serve as essential cofactors in metalloenzymes that are required for many important cellular processes, including replication, regulation, and central metabolism, among all domains of life (1)(2)(3). Despite their importance, excess transition metals can impair bacterial growth.…”

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confidence: 99%

Functional Determinants of Metal Ion Transport and Selectivity in Paralogous Cation Diffusion Facilitator Transporters CzcD and MntE in Streptococcus pneumoniae

Martin

Giedroc

2016

J Bacteriol

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Cation diffusion facilitators (CDFs) are a large family of divalent metal transporters that collectively possess broad metal specificity and contribute to intracellular metal homeostasis and virulence in bacterial pathogens. Streptococcus pneumoniae expresses two homologous CDF efflux transporters, MntE and CzcD. Cells lacking mntE or czcD are sensitive to manganese (Mn) or zinc (Zn) toxicity, respectively, and specifically accumulate Mn or Zn, respectively, thus suggesting that MntE selectively transports Mn, while CzcD transports Zn. Here, we probe the origin of this metal specificity using a phenotypic growth analysis of pneumococcal variants. Structural homology to Escherichia coli YiiP predicts that both MntE and CzcD are dimeric and each protomer harbors four pairs of conserved metal-binding sites, termed the A site, the B site, and the C1/C2 binuclear site. We find that single amino acid mutations within both the transmembrane domain A site and the B site in both CDFs result in a cellular metal sensitivity similar to that of the corresponding null mutants. However, multiple mutations in the predicted cytoplasmic C1/C2 cluster of MntE have no impact on cellular Mn resistance, in contrast to the analogous substitutions in CzcD, which do have on impact on cellular Zn resistance. Deletion of the MntE-specific C-terminal tail, present only in Mn-specific bacterial CDFs, resulted in only a modest growth phenotype. Further analysis of MntE-CzcD functional chimeric transporters showed that Asn and Asp in the ND-DD A-site motif of MntE and the most N-terminal His in the HD-HD site A of CzcD (the specified amino acids are underlined) play key roles in transporter metal selectivity. IMPORTANCECation diffusion facilitator (CDF) proteins are divalent metal ion transporters that are conserved in organisms ranging from bacteria to humans and that play important roles in cellular physiology, from metal homeostasis and resistance to type I diabetes in vertebrates. The respiratory pathogen Streptococcus pneumoniae expresses two metal CDF transporters, CzcD and MntE. How CDFs achieve metal selectivity is unclear. We show here that CzcD and MntE are true paralogs, as CzcD transports zinc, while MntE selectively transports manganese. Through the use of an extensive collection of pneumococcal variants, we show that a primary determinant for metal selectivity is the A site within the transmembrane domain. This extends our understanding of how CDFs discriminate among transition metals. T ransition metals from manganese (Mn) to zinc (Zn) in the first row of the periodic table serve as essential cofactors in metalloenzymes that are required for many important cellular processes, including replication, regulation, and central metabolism, among all domains of life (1-3). Despite their importance, excess transition metals can impair bacterial growth. Excess iron (Fe) is harmful due to its participation in Fenton chemistry, which produces a highly reactive hydroxyl radical that can damage biomolecules (4-7). Other transition m...

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“…Cells therefore rely on mechanisms to maintain a relatively constant intracellular level of zinc despite fluctuations in the extracellular environment. In eukaryotes, zincresponsive transcription factors play a central role in zinc homeostasis by regulating the expression of genes required for zinc transport or zinc storage (6). In Saccharomyces cerevisiae, the transcription factor Zap1 binds to zinc-responsive elements located in target gene promoters and activates gene expression when cytoplasmic zinc levels are low (7).…”

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confidence: 99%

Zinc finger protein Loz1 is required for zinc-responsive regulation of gene expression in fission yeast

Corkins¹,

May²,

Ehrensberger

et al. 2013

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

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In Schizosaccharomyces pombe, alcohol dehydrogenase 1 (Adh1) is an abundant zinc-requiring enzyme that catalyses the conversion of acetaldehyde to ethanol during fermentation. In a zinc-replete cell, adh1 is highly expressed. However, in zinc-limited cells, adh1 gene expression is repressed, and cells induce the expression of an alternative alcohol dehydrogenase encoded by the adh4 gene. In our studies examining this zinc-dependent switch in alcohol dehydrogenase gene expression, we isolated an adh1Δ strain containing a partial loss of function mutation that resulted in higher levels of adh4 transcripts in zinc-replete cells. This mutation also led to the aberrant expression of other genes that are typically regulated by zinc. Using linkage analysis, we have mapped the position of this mutation to a single gene called Loss Of Zinc sensing 1 (loz1). Loz1 is a 55-kDa protein that contains a double C 2 H 2 -type zinc finger domain. The mapped mutation that disrupts Loz1 function leads to an arginine to glycine substitution in the second zinc finger domain, suggesting that the double zinc finger domain is important for Loz1 function. We show that loz1Δ cells hyperaccumulate zinc and that Loz1 is required for gene repression in zinc-replete cells. We also have found that Loz1 negatively autoregulates its own expression. We propose that Loz1 is a unique metalloregulatory factor that plays a central role in zinc homeostasis in S. pombe. metallosensor | metallothionein | ncRNA | noncoding RNA

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Hammering out details: regulating metal levels in eukaryotes

Cited by 55 publications

References 70 publications

The Double Zinc Finger Domain and Adjacent Accessory Domain from the Transcription Factor Loss of Zinc Sensing 1 (Loz1) Are Necessary for DNA Binding and Zinc Sensing

The Double Zinc Finger Domain and Adjacent Accessory Domain from the Transcription Factor Loss of Zinc Sensing 1 (Loz1) Are Necessary for DNA Binding and Zinc Sensing

Functional Determinants of Metal Ion Transport and Selectivity in Paralogous Cation Diffusion Facilitator Transporters CzcD and MntE in Streptococcus pneumoniae

Zinc finger protein Loz1 is required for zinc-responsive regulation of gene expression in fission yeast

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