Reversible zinc exchange between metallothionein and the estrogen receptor zinc finger

Cano‐Gauci, Danielle F.; Sarkar, Bibudhendra

doi:10.1016/0014-5793(96)00356-0

Cited by 116 publications

(63 citation statements)

References 24 publications

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“…K S ϭ 9 ϫ 10 11 M Ϫ1 for a model CCCC zinc finger peptide (15) and 2 ϫ 10 12 M Ϫ1 for Zn-MT (17). This is consistent with a report describing Zn-MT/thionein-mediated activationdeactivation of the estrogen receptor (14). For CCHH zinc finger peptides and proteins, the apparent stability constants for in TTK is not known, although our results suggested that the value for TTK should be greater than that for Sp1 and similar or possibly higher than that for the synthetic Cp-1 zinc finger (15).…”

Section: Discussionsupporting

confidence: 92%

“…Incubation of metal-free thionein with CCHH zinc finger transcription factors Sp1 (12) and TFIIIA (13) inhibits DNA binding, suggesting zinc abstraction by thionein as a mechanism for regulating gene expression. Reciprocal zinc exchange is suggested as a mechanism for regulating gene expression in a study in which Zn-MT and thionein could activate or inhibit DNA binding by the estrogen receptor (14), a CCCC zinc finger protein.…”

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confidence: 99%

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Modulation of DNA Binding of a Tramtrack Zinc Finger Peptide by the Metallothionein-Thionein Conjugate Pair

Roesijadi¹,

Bogumil²,

Vašák³

et al. 1998

Journal of Biological Chemistry

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The ability of metallothionein (MT) to modulate DNA binding by a two-finger peptide of Tramtrack (TTK), a CCHH zinc transcription factor, was investigated using metal-bound and metal-deficient forms of rabbit MT-2 and the TTK peptide. Thionein inhibited DNA binding by zinc-bound TTK, and Zn-MT restored DNA-binding by zinc-deficient apo-TTK. "Free" zinc at low concentrations was as effective as Zn-MT in restoring DNA binding by apopeptide but was inhibitory at concentrations equal to zinc bound to 2 mol eq and higher of Zn-MT. Substitution of cadmium for zinc reduced the affinity of the peptide for its DNA binding site. This effect was reversed by incubation with Zn-MT. The circular dichroic spectra of the TTK peptide indicated that zinc removal resulted in loss of ␣-helical structures, which are sites of DNA contact points. Reconstitution with cadmium resulted in stoichiometric substitution of 2 mol of Cd/mol of peptide but not recovery of ␣-helical structures. Incubation of Cd-TTK with Zn-MT restored the secondary structure expected for zinc-bound TTK. The ability of Zn-MT and thionein to restore or inhibit DNAbinding by TTK was associated with effects on the metallation status of the peptide and related alterations in its secondary structure.The low molecular weight metal-binding protein metallothionein (MT) 1 is proposed to have functions in metal ion regulation and detoxification (1) and as a scavenger of free radicals (2). Roles for MT in dynamic intermolecular metal exchange reactions are consistent with the high thermodynamic stability (3) and high kinetic lability of its metal binding sites (4, 5). Metal exchange can also be facilitated by cellular redox couples such as ). An early focus on enzyme activation by Zn-MT implicated MT as a zinc donor to apometallic forms of metalloenzymes such as aldolase, thermolysin, and carbonic anhydrase (10) and pyridoxal kinase (11). Recent studies on the effect of MTs on interactions between zinc transcription factors and their cognate DNAs implicate MTs in gene regulation. Incubation of metal-free thionein with CCHH zinc finger transcription factors Sp1 (12) and TFIIIA (13) inhibits DNA binding, suggesting zinc abstraction by thionein as a mechanism for regulating gene expression. Reciprocal zinc exchange is suggested as a mechanism for regulating gene expression in a study in which Zn-MT and thionein could activate or inhibit DNA binding by the estrogen receptor (14), a CCCC zinc finger protein.Zinc transcription factors appear uniquely qualified as potential partner molecules in metal exchange reactions with MT. Reported stability constants for zinc binding by zinc finger peptides and proteins are in a similar range, i.e. within 1 or 2 orders of magnitude, as that of . Additionally, it appears that the kinetics for zinc exchange in these structures are also relatively rapid (18). Direct examination of the metal transfer process has shown that zinc can be transferred from an ␣-domain peptide of human MT-2 (␣-hMT-2) to a peptide derived from the third finger of Sp1...

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Modulation of DNA Binding of a Tramtrack Zinc Finger Peptide by the Metallothionein-Thionein Conjugate Pair

Roesijadi¹,

Bogumil²,

Vašák³

et al. 1998

Journal of Biological Chemistry

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“…However, cutaneous MT might have such a role, being a recognized antioxidant and a photoimmune protectant in both mice and humans, as well as a readily inducible factor by topical equol treatment in SSUVirradiated normal-haired mouse skin (9,10). There is now evidence from cultured human tumor cell lines that the MT gene is regulated by the ER (17) and that the zinc-finger domain of the ER is supplied with zinc by MT (18), demonstrating an intimate intracellular relationship between MT and estrogenic activity. In addition, two other phytoestrogens, genistein and apigenin, have, like equol and NV-07␣, also been shown to stimulate MT expression, and this was preferentially mediated by the ER-␤ in cultured human cells (19,20).…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor signaling protects against immune suppression by UV radiation exposure

Widyarini

Domanski

Painter

et al. 2006

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

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The phytoestrogenic isoflavonoid equol is known to protect against solar-simulated UV radiation-induced inflammation, immunosuppression, and skin carcinogenesis. The mechanism may involve antioxidant actions, because equol not only is a radical scavenger but also enhances the induction of a relevant cutaneous antioxidant, metallothionein. However, this study in female hairless mice examined whether the estrogenicity of the isoflavonoid might be responsible. Protection by topically applied equol against photoimmune suppression was found to be strongly and dosedependently inhibited by the estrogen receptor (ER) antagonist ICI 182,780. Furthermore, ICI 182,780 alone was found to significantly exacerbate immunosuppression resulting from solar-simulated UV radiation irradiation, suggesting a natural role for the ER in photoimmune protection. In support of this role, topical application of the physiological ligand 17-␤-estradiol also provided dosedependent photoimmune protection, inhibitable by ICI 182,780, that was attributed largely to the inactivation of the downstream actions of cis-urocanic acid, an important endogenous immunosuppressive photoproduct. Thus, a hitherto unrecognized function of the ER as a normal photoprotective immune regulator in the skin was revealed. The relationship between equol and cutaneous metallothionein suggests an association of the ER with this inducible antioxidant in constraining the photoimmune-suppressed state and therefore in the prevention of the facilitation of photocarcinogenesis by this immunological defect. This role for the ER may underlie important gender-specific differences in UV-responsiveness that would reflect different needs for environmental photoprotection in males and females.cis-urocanic acid ͉ equol ͉ hairless mouse ͉ ICI 182,780 ͉ steroid hormone R ecent studies in mice with topically applied isoflavonoids derived from the red clover, Trifolium pratense, have shown that these phytochemicals may protect effectively against UV radiation-induced skin damage. Particular interest has centered on equol ([S]-4Ј7-dihydroxyisoflavane), an isoflavonoid metabolite produced from the dietary isoflavone daidzein by the gut microflora in mammals. Equol has been found to protect mice not only against UV radiation-induced cutaneous inflammation, observed as the sunburn reaction, but also against photoimmune suppression, which is evident as a defective contact hypersensitivity (CHS) reaction (1). Consistent with this observation, it was found that topical application to humans of an equol-related synthetic isoflavonoid, NV-07␣, also protected against the UV radiation-induced suppression of the elicited Mantoux reaction (2). In mice it was shown that the immunoprotective mechanism of topically applied equol involved inactivation of the downstream actions of cis-urocanic acid, a major UV-induced immunosuppressive photoproduct produced in the skin (1). Because chronic photoimmune suppression is a prerequisite for the promotion of UV radiation-initiated tumors (3), and because topica...

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“…Mammalian isoforms MT-1 and -2 are commonly isolated with seven Zn 2ϩ ions bound exclusively to the thiolate groups of cysteine residues in two clusters (8). In view of the cellular importance of zinc, there is considerable interest in establishing the conditions in which, and locations where, MT acquires or releases zinc (5,(9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

A metallothionein containing a zinc finger within a four-metal cluster protects a bacterium from zinc toxicity

Blindauer

Harrison

Parkinson

et al. 2001

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

172

183

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Zinc is essential for many cellular processes, including DNA synthesis, transcription, and translation, but excess can be toxic. A zinc-induced gene, smtA, is required for normal zinc-tolerance in the cyanobacterium Synechococcus PCC 7942. Here we report that the protein SmtA contains a cleft lined with Cys-sulfur and His-imidazole ligands that binds four zinc ions in a Zn4Cys9His2 cluster. The thiolate sulfurs of five Cys ligands provide bridges between the two ZnCys 4 and two ZnCys3His sites, giving two fused six-membered rings with distorted boat conformations. The inorganic core strongly resembles the Zn4Cys11 cluster of mammalian metallothionein, despite different amino acid sequences, a different linear order of the ligands, and presence of histidine ligands. Also, SmtA contains elements of secondary structure not found in metallothioneins. One of the two Cys4-coordinated zinc ions in SmtA readily exchanges with exogenous metal ( 111 Cd), whereas the other is inert. The thiolate sulfur ligands bound to zinc in this site are buried within the protein.Regions of ␤-strand and ␣-helix surround the inert site to form a zinc finger resembling the zinc fingers in GATA and LIM-domain proteins. Eukaryotic zinc fingers interact specifically with other proteins or DNA and an analogous interaction can therefore be anticipated for prokaryotic zinc fingers. SmtA now provides structural proof for the existence of zinc fingers in prokaryotes, and sequences related to the zinc finger motif can be identified in several bacterial genomes.

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Reversible zinc exchange between metallothionein and the estrogen receptor zinc finger

Cited by 116 publications

References 24 publications

Modulation of DNA Binding of a Tramtrack Zinc Finger Peptide by the Metallothionein-Thionein Conjugate Pair

Modulation of DNA Binding of a Tramtrack Zinc Finger Peptide by the Metallothionein-Thionein Conjugate Pair

Estrogen receptor signaling protects against immune suppression by UV radiation exposure

A metallothionein containing a zinc finger within a four-metal cluster protects a bacterium from zinc toxicity

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