Metal binding properties, stability and reactivity of zinc fingers

Kluska, Katarzyna; Adamczyk, Justyna; Krężel, Artur

doi:10.1016/j.ccr.2018.04.009

Cited by 183 publications

(216 citation statements)

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“…This enables calculation of the formation constant K 12 based on the fixed constant of Zn(Hk14) 2 and total Cd II concentration (Figure b) . The K 12 values calculated based on the exchange mode are slightly higher than the values obtained potentiometrically or in competition with complexones (Table ), probably due to intrinsically low resolution of the method in terms of stability determination and were not included in further discussion. Nonetheless, the results prove that Zn II ‐to‐Cd II swap is a fast and efficient process that can occur inside a cell, causing Cd II ‐induced toxic effects.…”

Section: Resultsmentioning

confidence: 91%

“…Our previous results have shown that the zinc hook domain is among the most stable Zn II complexes found in proteins and their natural domains. For example, the Zn(Hk45) 2 complex is more stable than the most stable natural zinc fingers described so far, such as Sp1‐3, MTF‐1, or Zif268‐2, when competing in the micromolar range with Hk45 . When concentrations of both protein fragments decrease, zinc fingers demonstrate a higher tendency to bind Zn II .…”

Section: Resultsmentioning

confidence: 96%

“…Fivefold molar excesso fZ n II over Hk14 slows down the exchange in such aw ay that ah igher concentration of Cd II is necessary to swap the hook-bound Zn II .T his enablesc alculation of the formationc onstant K 12 based on the fixed constant of Zn(Hk14) 2 and total Cd II concentration (Figure 8b). [54] The K 12 values calcu-lated based on the exchange mode are slightly highert han the values obtained potentiometricallyo ri nc ompetition with complexones (Table2), probablyd ue to intrinsically low resolution of the methodi nt erms of stabilityd etermination [47,53] and Table 3. Affinities of selected low-molecular-weight ligands, peptides, and proteins for Cd II collecteda cross the literature that form highly stable complexes.S tability constants wered eterminedu nder various conditions, which are listed.…”

Section: Stabilityc Omparison Of CD Ii -Substitutedh Ook Domain Withmentioning

confidence: 99%

“…For example, the Zn(Hk45) 2 complex is more stable than the most stable naturalz inc fingers described so far,s uch as Sp1-3, MTF-1, or Zif268-2, when competing in the micromolar range with Hk45. [33,47,53] When concentrations of both protein fragments decrease, zinc fingersd emonstrate a higher tendency to bind Zn II .S uch behaviorc omes from the fact that the hook domain forms an ML 2 -type complex,w hereas zinc fingersa nd most other proteins form an ML-type complex. Our recent resultso btained on various zinc domains with differentZ n II -to-protein stoichiometry,y et similar affinity, showedc oncentration dependence for metal-mediated complexes.…”

Section: Stabilityc Omparison Of CD Ii -Substitutedh Ook Domain Withmentioning

confidence: 99%

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Metal Exchange in the Interprotein Zn^II‐Binding Site of the Rad50 Hook Domain: Structural Insights into Cd^II‐Induced DNA‐Repair Inhibition

Padjasek

Maciejczyk

Nowakowski

et al. 2020

Chemistry A European J

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CdII is a major genotoxic agent that readily displaces ZnII in a multitude of zinc proteins, abrogates redox homeostasis, and deregulates cellular metalloproteome. To date, this displacement has been described mostly for cysteine(Cys)‐rich intraprotein binding sites in certain zinc finger domains and metallothioneins. To visualize how a ZnII‐to‐CdII swap can affect the target protein's status and thus understand the molecular basis of CdII‐induced genotoxicity an intermolecular ZnII‐binding site from the crucial DNA repair protein Rad50 and its zinc hook domain were examined. By using a length‐varied peptide base, ZnII‐to‐CdII displacement in Rad50’s hook domain is demonstrated to alter it in a bimodal fashion: 1) CdII induces around a two‐orders‐of‐magnitude stabilization effect (log K12ZnII =20.8 vs. log K12CdII =22.7), which defines an extremely high affinity of a peptide towards a metal ion, and 2) the displacement disrupts the overall assembly of the domain, as shown by NMR spectroscopic and anisotropy decay data. Based on the results, a new model explaining the molecular mechanism of CdII genotoxicity that underlines CdII’s impact on Rad50’s dimer stability and quaternary structure that could potentially result in abrogation of the major DNA damage response pathway is proposed.

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Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 96%

Section: Stabilityc Omparison Of CD Ii -Substitutedh Ook Domain Withmentioning

confidence: 99%

Section: Stabilityc Omparison Of CD Ii -Substitutedh Ook Domain Withmentioning

confidence: 99%

See 2 more Smart Citations

Metal Exchange in the Interprotein Zn^II‐Binding Site of the Rad50 Hook Domain: Structural Insights into Cd^II‐Induced DNA‐Repair Inhibition

Padjasek

Maciejczyk

Nowakowski

et al. 2020

Chemistry A European J

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“…Accordingly, the majority of redox-active zinc centers are of the tetrathiolate type [48]. Further discussion of the reactivity of various zinc thiolate sites can be found in a recent review [49].…”

Section: The Redox Activity Of Zinc-sulfur (Thiolate) Coordination Enmentioning

confidence: 99%

The redox biology of redox-inert zinc ions

Maret

2019

Free Radical Biology and Medicine

180

124

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Zinc(II) ions are redox-inert in biology. Yet, their interaction with sulfur of cysteine in cellular proteins can confer ligandcentered redox activity on zinc coordination sites, control protein functions, and generate signalling zinc ions as potent effectors of many cellular processes. The specificity and relative high affinity of binding sites for zinc allow regulation in redox biology, free radical biology, and the biology of reactive species. Understanding the role of zinc in these areas of biology requires an understanding of how cellular Zn2+ is homeostatically controlled and can serve as a regulatory ion in addition to Ca2+, albeit at much lower concentrations. A rather complex system of dozens of transporters and metallothioneins buffer the relatively high (hundreds of micromolar) total cellular zinc concentrations in such a way that the available zinc ion concentrations are only picomolar but can fluctuate in signalling. The proteins targeted by Zn2+ transients include enzymes controlling phosphorylation and redox signalling pathways. Networks of regulatory functions of zinc integrate gene expression and metabolic and signalling pathways at several hierarchical levels. They affect enzymatic catalysis, protein structure and protein-protein/biomolecular interactions and add to the already impressive number of catalytic and structural functions of zinc in an estimated three thousand human zinc proteins. The effects of zinc on redox biology have adduced evidence that zinc is an antioxidant. Without further qualifications, this notion is misleading and prevents a true understanding of the roles of zinc in biology. Its antioxidant-like effects are indirect and expressed only in certain conditions because a lack of zinc and too much zinc have pro-oxidant effects. Teasing apart these functions based on quantitative considerations of homeostatic control of cellular zinc is critical because opposite consequences are observed depending on the concentrations of zinc: pro-or anti-apoptotic, pro-or anti-inflammatory and cytoprotective or cytotoxic. The article provides a biochemical basis for the links between redox and zinc biology and discusses why zinc has pleiotropic functions. Perturbation of zinc metabolism is a consequence of conditions of redox stress. Zinc deficiency, either nutritional or conditioned, and cellular zinc overload cause oxidative stress. Thus, there is causation in the relationship between zinc metabolism and the many diseases associated with oxidative stress. Highlights• Redox-inert zinc ions regulate some aspects of redox biology and the biology or reactive species.• Control of cellular zinc homeostasis determines antioxidant-like or pro-oxidant effects.• Zinc deficiency and overload cause oxidative stress.• Disorders of zinc metabolism are a cause or consequence of diseases associated with oxidative stress.Abbreviations ER, endoplasmic reticulum; GCL, glutamate cysteine ligase; MT, metallothionein; MTF-1, metal regulatory element (MRE)-binding transcription factor-1; NOS, nitric oxide syntha...

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Structures of Silver Fingers and a Pathway to Their Genotoxicity

et al. 2022

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Recently, we demonstrated that Ag I can directly replace Zn II in zinc fingers (ZFs). The cooperative binding of Ag I to ZFs leads to a thermodynamically irreversible formation of silver clusters destroying the native ZF structure. Thus, a reported loss of biological function of ZF proteins is a likely consequence of such replacement. Here, we report an X-ray absorption spectroscopy (XAS) study of Ag n S n clusters formed in ZFs to probe their structural features. Selective probing of the local environment around Ag I by XAS showed the predominance of digonal Ag I coordination to two sulfur donors, coordinated with an average AgÀ S distance at 2.41 Å. No AgÀ N bonds were present. A mixed AgS 2 /AgS 3 geometry was found solely in the CCCH Ag I À ZF. We also show that cooperative replacement of Zn II ions with the studied Ag 2 S 2 clusters occurred in a three-ZF transcription factor protein 1MEY#, leading to a dissociation of 1MEY# from the complex with its cognate DNA.

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Metal binding properties, stability and reactivity of zinc fingers

Cited by 183 publications

References 381 publications

Metal Exchange in the Interprotein Zn^II‐Binding Site of the Rad50 Hook Domain: Structural Insights into Cd^II‐Induced DNA‐Repair Inhibition

Metal Exchange in the Interprotein Zn^II‐Binding Site of the Rad50 Hook Domain: Structural Insights into Cd^II‐Induced DNA‐Repair Inhibition

The redox biology of redox-inert zinc ions

Structures of Silver Fingers and a Pathway to Their Genotoxicity

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Metal binding properties, stability and reactivity of zinc fingers

Cited by 183 publications

References 381 publications

Metal Exchange in the Interprotein ZnII‐Binding Site of the Rad50 Hook Domain: Structural Insights into CdII‐Induced DNA‐Repair Inhibition

Metal Exchange in the Interprotein ZnII‐Binding Site of the Rad50 Hook Domain: Structural Insights into CdII‐Induced DNA‐Repair Inhibition

The redox biology of redox-inert zinc ions

Structures of Silver Fingers and a Pathway to Their Genotoxicity

Contact Info

Product

Resources

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Metal Exchange in the Interprotein Zn^II‐Binding Site of the Rad50 Hook Domain: Structural Insights into Cd^II‐Induced DNA‐Repair Inhibition

Metal Exchange in the Interprotein Zn^II‐Binding Site of the Rad50 Hook Domain: Structural Insights into Cd^II‐Induced DNA‐Repair Inhibition