Structural zinc binding sites shaped for greater works: Structure-function relations in classical zinc finger, hook and clasp domains

Padjasek, Michał; Kocyła, Anna; Kluska, Katarzyna; Kerber, Olga; Tran, Józef Ba; Krężel, Artur

doi:10.1016/j.jinorgbio.2019.110955

Cited by 46 publications

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References 144 publications

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“…Zinc finger (ZF) domains are one of the most abundant structural motifs found in proteins, with a wide range of physiological roles including transcriptional regulation, signal transduction, DNA repair, cell migration, etc. [1][2][3][4][5] Although ZFs contain Zn(II) in their native structures, they provide an impressive range of binding properties for monovalent (Cu(I) and Au(I)), divalent (Cd(II), Pb(II), Hg(II), Pt(II), Fe(II), Co(II), and Ni(II)) and trivalent (Sb(III) and As(III)) metal ions. These cations can compete with Zn(II), impacting the native domain structure (Fig.…”

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“…S1a, ESI †) and as a consequence influencing the biological functions of ZFs due to their various coordination geometries, ionic radii and ligand specificities. [4][5][6][7][8] Moreover, they can promote multinuclear species formation, cysteinyl sulfur oxidation or incomplete coordination. [9][10][11] All of these outcomes are important in the case of toxic metal ions, which can be absorbed into the body from diet, drinking water, by inhalation, dermal exposure or medical intervention, eventually finding their way to cells to exert toxicity by abolishing the ZF functions.…”

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Formation of highly stable multinuclear Ag_nS_nclusters in zinc fingers disrupts their structure and function

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Formation of highly stable multinuclear Ag_nS_nclusters in zinc fingers disrupts their structure and function

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“…Zinc is known to play a key role in stabilizing the protein structure and to exert the stabilization effect at all levels of protein structure organization, i.e., secondary, tertiary, and quaternary. In most proteins (~90%) zinc ions are coordinated to cysteine, histidine, aspartate, and glutamate residues [ 29 , 30 ]. Depending on their functional role, zinc binding sites in protein can be divided into the following five main classes: catalytic, structural, cluster, transport, and intermolecular [ 30 , 31 , 32 ].…”

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confidence: 99%

“…In most proteins (~90%) zinc ions are coordinated to cysteine, histidine, aspartate, and glutamate residues [ 29 , 30 ]. Depending on their functional role, zinc binding sites in protein can be divided into the following five main classes: catalytic, structural, cluster, transport, and intermolecular [ 30 , 31 , 32 ]. The most common are structural sites consisting of Cys and His residues in a tetrahedral geometry [ 29 , 30 ].…”

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confidence: 99%

“…Depending on their functional role, zinc binding sites in protein can be divided into the following five main classes: catalytic, structural, cluster, transport, and intermolecular [ 30 , 31 , 32 ]. The most common are structural sites consisting of Cys and His residues in a tetrahedral geometry [ 29 , 30 ]. Cysteine is the preferential amino acid in such sites.…”

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XANES Measurements for Studies of Adsorbed Protein Layers at Liquid Interfaces

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X-ray absorption near edge structure (XANES) spectra for protein layers adsorbed at liquid interfaces in a Langmuir trough have been recorded for the first time. We studied the parkin protein (so-called E3 ubiquitin ligase), which plays an important role in pathogenesis of Parkinson disease. Parkin contains eight Zn binding sites, consisting of cysteine and histidine residues in a tetracoordinated geometry. Zn K-edge XANES spectra were collected in the following two series: under mild radiation condition of measurements (short exposition time) and with high X-ray radiation load. XANES fingerprint analysis was applied to obtain information on ligand environments around zinc ions. Two types of zinc coordination geometry were identified depending on X-ray radiation load. We found that, under mild conditions, local zinc environment in our parkin preparations was very similar to that identified in hemoglobin, treated with a solution of ZnCl2 salt. Under high X-ray radiation load, considerable changes in the zinc site structure were observed; local zinc environment appeared to be almost identical to that defined in Zn-containing enzyme alkaline phosphatase. The formation of a similar metal site in unrelated protein molecules, observed in our experiments, highlights the significance of metal binding templates as essential structural modules in protein macromolecules.

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An Extremely Stable Interprotein Tetrahedral Hg(Cys)₄ Core Forms in the Zinc Hook Domain of Rad50 Protein at Physiological pH

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Padjasek

Tran

et al. 2022

Chemistry A European J

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In nature, thiolate-based systems are the primary targets of divalent mercury (Hg II ) toxicity. The formation of Hg (Cys) x cores in catalytic and structural protein centers mediates mercury's toxic effects and ultimately leads to cellular damage. Multiple studies have revealed distinct Hg IIthiolate coordination preferences, among which linear Hg II complexes are the most commonly observed in solution at physiological pH. Trigonal or tetrahedral geometries are formed at basic pH or in tight intraprotein Cys-rich metal sites. So far, no interprotein tetrahedral Hg II complex formed at neutral pH has been reported. Rad50 protein is a part of the multiprotein MRN complex, a major player in DNA damage-repair processes. Its central region consists of a conserved CXXC motif that enables dimerization of two Rad50 molecules by coordinating Zn II . Dimerized motifs form a unique interprotein zinc hook domain (Hk) that is critical for the biological activity of the MRN. Using a series of lengthdifferentiated peptide models of the Pyrococcus furiosus zinc hook domain, we investigated its interaction with Hg II . Using UV-Vis, CD, PAC, and 199 Hg NMR spectroscopies as well as anisotropy decay, we discovered that all Rad50 fragments preferentially form homodimeric Hg(Hk) 2 species with a distorted tetrahedral HgS 4 coordination environment at physiological pH; this is the first example of an interprotein mercury site displaying tetrahedral geometry in solution. At higher Hg II content, monomeric HgHk complexes with linear geometry are formed. The Hg(Cys) 4 core of Rad50 is extremely stable and does not compete with cyanides, NAC, or DTT. Applying ITC, we found that the stability constant of the Rad50 Hg(Hk) 2 complex is approximately three orders of magnitude higher than those of the strongest Hg II complexes known to date.

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Structural zinc binding sites shaped for greater works: Structure-function relations in classical zinc finger, hook and clasp domains

Cited by 46 publications

References 144 publications

Formation of highly stable multinuclear Ag_nS_nclusters in zinc fingers disrupts their structure and function

Formation of highly stable multinuclear Ag_nS_nclusters in zinc fingers disrupts their structure and function

XANES Measurements for Studies of Adsorbed Protein Layers at Liquid Interfaces

An Extremely Stable Interprotein Tetrahedral Hg(Cys)₄ Core Forms in the Zinc Hook Domain of Rad50 Protein at Physiological pH

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Structural zinc binding sites shaped for greater works: Structure-function relations in classical zinc finger, hook and clasp domains

Cited by 46 publications

References 144 publications

Formation of highly stable multinuclear AgnSnclusters in zinc fingers disrupts their structure and function

Formation of highly stable multinuclear AgnSnclusters in zinc fingers disrupts their structure and function

XANES Measurements for Studies of Adsorbed Protein Layers at Liquid Interfaces

An Extremely Stable Interprotein Tetrahedral Hg(Cys)4 Core Forms in the Zinc Hook Domain of Rad50 Protein at Physiological pH

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Product

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Formation of highly stable multinuclear Ag_nS_nclusters in zinc fingers disrupts their structure and function

Formation of highly stable multinuclear Ag_nS_nclusters in zinc fingers disrupts their structure and function

An Extremely Stable Interprotein Tetrahedral Hg(Cys)₄ Core Forms in the Zinc Hook Domain of Rad50 Protein at Physiological pH