Special Issue "Metal Binding Proteins"

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (31 January 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Eugene Permyakov

Director of the Institute for Biological Instrumentation of the Russian Academy of Sciences, 7 Institutskaya str., Pushchino, Moscow region 142290, Russia
Website | E-Mail
Phone: 7 495 624 57 49
Fax: +7 4967 33 05 22
Interests: metal binding proteins; calcium binding proteins; intrinsically disordered proteins; intrinsic protein fluorescence; parvalbumin; α-lactalbumin; S100 proteins; recoverin

Special Issue Information

Dear Colleagues,

Metal ions play very important role in functioning of all, without any exceptions, biological systems. From ten to twelve metals are very important for vital activity of living organisms: sodium, potassium, magnesium, calcium, manganese, iron, cobalt, zinc, nickel, vanadium, molybdenum and tungsten. Sometimes these metals are called “life metals”. Specific interactions of metal ions with proteins play very important role. Metal ions play several major roles in proteins: structural, regulatory, and enzymatic. The binding of some metal ions increase stability of proteins or protein domains. Some metal ions can regulate various cell processes being first, second or third messengers. Calcium is the most universal carrier of signals to cells. Calcium regulates all important aspects of cell activity, beginning with fertilization and ending with the apoptotic suicide at the end of the life cycle. Metal ions are an integral part of many enzymes and are indispensable in many catalytic reactions. In spite of the fact that many metal binding proteins are well studied, detailed study of structural, physico-chemical and functional properties of metal binding proteins and their interactions is still an important and actual task of modern metalloproteomics.
We cordially welcome you to join us in this endeavor. Comprehensive reviews or original research articles is most welcome. We look forward to reading your contributions.

Prof. Dr. Eugene Permyakov
Guest Editor

Manuscript Submission Information

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Keywords

  • metals
  • metal binding proteins
  • regulation
  • enzymes
  • structure
  • function

Published Papers (12 papers)

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Research

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Open AccessArticle Enhanced Adsorption and Recovery of Uranyl Ions by NikR Mutant-Displaying Yeast
Biomolecules 2014, 4(2), 390-401; https://doi.org/10.3390/biom4020390
Received: 4 February 2014 / Revised: 12 March 2014 / Accepted: 14 March 2014 / Published: 11 April 2014
Cited by 3 | PDF Full-text (379 KB) | HTML Full-text | XML Full-text
Abstract
Uranium is one of the most important metal resources, and the technology for the recovery of uranyl ions (UO22+) from aqueous solutions is required to ensure a semi-permanent supply of uranium. The NikR protein is a Ni2+-dependent transcriptional
[...] Read more.
Uranium is one of the most important metal resources, and the technology for the recovery of uranyl ions (UO22+) from aqueous solutions is required to ensure a semi-permanent supply of uranium. The NikR protein is a Ni2+-dependent transcriptional repressor of the nickel-ion uptake system in Escherichia coli, but its mutant protein (NikRm) is able to selectively bind uranyl ions in the interface of the two monomers. In this study, NikRm protein with ability to adsorb uranyl ions was displayed on the cell surface of Saccharomyces cerevisiae. To perform the binding of metal ions in the interface of the two monomers, two metal-binding domains (MBDs) of NikRm were tandemly fused via linker peptides and displayed on the yeast cell surface by fusion with the cell wall-anchoring domain of yeast α-agglutinin. The NikRm-MBD-displaying yeast cells with particular linker lengths showed the enhanced adsorption of uranyl ions in comparison to the control strain. By treating cells with citrate buffer (pH 4.3), the uranyl ions adsorbed on the cell surface were recovered. Our results indicate that the adsorption system by yeast cells displaying tandemly fused MBDs of NikRm is effective for simple and concentrated recovery of uranyl ions, as well as adsorption of uranyl ions. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
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Review

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Open AccessReview Interactions between Calcium and Alpha-Synuclein in Neurodegeneration
Biomolecules 2014, 4(3), 795-811; https://doi.org/10.3390/biom4030795
Received: 26 March 2014 / Revised: 25 June 2014 / Accepted: 14 July 2014 / Published: 14 August 2014
Cited by 18 | PDF Full-text (18550 KB) | HTML Full-text | XML Full-text
Abstract
In Parkinson’s disease and some atypical Parkinson’s syndromes, aggregation of the α-synuclein protein (α-syn) has been linked to neurodegeneration. Many triggers for pathological α-syn aggregation have been identified, including port-translational modifications, oxidative stress and raised metal ions, such as Ca2+. Recently,
[...] Read more.
In Parkinson’s disease and some atypical Parkinson’s syndromes, aggregation of the α-synuclein protein (α-syn) has been linked to neurodegeneration. Many triggers for pathological α-syn aggregation have been identified, including port-translational modifications, oxidative stress and raised metal ions, such as Ca2+. Recently, it has been found using cell culture models that transient increases of intracellular Ca2+ induce cytoplasmic α-syn aggregates. Ca2+-dependent α-syn aggregation could be blocked by the Ca2+ buffering agent, BAPTA-AM, or by the Ca2+ channel blocker, Trimethadione. Furthermore, a greater proportion of cells positive for aggregates occurred when both raised Ca2+ and oxidative stress were combined, indicating that Ca2+ and oxidative stress cooperatively promote α-syn aggregation. Current on-going work using a unilateral mouse lesion model of Parkinson’s disease shows a greater proportion of calbindin-positive neurons survive the lesion, with intracellular α-syn aggregates almost exclusively occurring in calbindin-negative neurons. These and other recent findings are reviewed in the context of neurodegenerative pathologies and suggest an association between raised Ca2+, α-syn aggregation and neurotoxicity. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
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Open AccessReview New Perspectives on Oxidized Genome Damage and Repair Inhibition by Pro-Oxidant Metals in Neurological Diseases
Biomolecules 2014, 4(3), 678-703; https://doi.org/10.3390/biom4030678
Received: 29 April 2014 / Revised: 24 June 2014 / Accepted: 25 June 2014 / Published: 17 July 2014
Cited by 11 | PDF Full-text (691 KB) | HTML Full-text | XML Full-text
Abstract
The primary cause(s) of neuronal death in most cases of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, are still unknown. However, the association of certain etiological factors, e.g., oxidative stress, protein misfolding/aggregation, redox metal accumulation and various types of damage to the genome,
[...] Read more.
The primary cause(s) of neuronal death in most cases of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, are still unknown. However, the association of certain etiological factors, e.g., oxidative stress, protein misfolding/aggregation, redox metal accumulation and various types of damage to the genome, to pathological changes in the affected brain region(s) have been consistently observed. While redox metal toxicity received major attention in the last decade, its potential as a therapeutic target is still at a cross-roads, mostly because of the lack of mechanistic understanding of metal dyshomeostasis in affected neurons. Furthermore, previous studies have established the role of metals in causing genome damage, both directly and via the generation of reactive oxygen species (ROS), but little was known about their impact on genome repair. Our recent studies demonstrated that excess levels of iron and copper observed in neurodegenerative disease-affected brain neurons could not only induce genome damage in neurons, but also affect their repair by oxidatively inhibiting NEIL DNA glycosylases, which initiate the repair of oxidized DNA bases. The inhibitory effect was reversed by a combination of metal chelators and reducing agents, which underscore the need for elucidating the molecular basis for the neuronal toxicity of metals in order to develop effective therapeutic approaches. In this review, we have focused on the oxidative genome damage repair pathway as a potential target for reducing pro-oxidant metal toxicity in neurological diseases. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
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Open AccessReview QM/MM Molecular Dynamics Studies of Metal Binding Proteins
Biomolecules 2014, 4(3), 616-645; https://doi.org/10.3390/biom4030616
Received: 18 March 2014 / Revised: 5 June 2014 / Accepted: 6 June 2014 / Published: 8 July 2014
Cited by 27 | PDF Full-text (1502 KB) | HTML Full-text | XML Full-text
Abstract
Mixed quantum-classical (quantum mechanical/molecular mechanical (QM/MM)) simulations have strongly contributed to providing insights into the understanding of several structural and mechanistic aspects of biological molecules. They played a particularly important role in metal binding proteins, where the electronic effects of transition metals have
[...] Read more.
Mixed quantum-classical (quantum mechanical/molecular mechanical (QM/MM)) simulations have strongly contributed to providing insights into the understanding of several structural and mechanistic aspects of biological molecules. They played a particularly important role in metal binding proteins, where the electronic effects of transition metals have to be explicitly taken into account for the correct representation of the underlying biochemical process. In this review, after a brief description of the basic concepts of the QM/MM method, we provide an overview of its capabilities using selected examples taken from our work. Specifically, we will focus on heme peroxidases, metallo-β-lactamases, α-synuclein and ligase ribozymes to show how this approach is capable of describing the catalytic and/or structural role played by transition (Fe, Zn or Cu) and main group (Mg) metals. Applications will reveal how metal ions influence the formation and reduction of high redox intermediates in catalytic cycles and enhance drug metabolism, amyloidogenic aggregate formation and nucleic acid synthesis. In turn, it will become manifest that the protein frame directs and modulates the properties and reactivity of the metal ions. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
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Open AccessReview Structures and Metal-Binding Properties of Helicobacter pylori Neutrophil-Activating Protein with a Di-Nuclear Ferroxidase Center
Biomolecules 2014, 4(3), 600-615; https://doi.org/10.3390/biom4030600
Received: 11 January 2014 / Revised: 3 June 2014 / Accepted: 4 June 2014 / Published: 26 June 2014
Cited by 5 | PDF Full-text (2503 KB) | HTML Full-text | XML Full-text
Abstract
Helicobacter pylori causes severe diseases, such as chronic gastritis, peptic ulcers, and stomach cancers. H. pylori neutrophil-activating protein (HP-NAP) is an iron storage protein that forms a dodecameric shell, promotes the adhesion of neutrophils to endothelial cells, and induces the production of reactive
[...] Read more.
Helicobacter pylori causes severe diseases, such as chronic gastritis, peptic ulcers, and stomach cancers. H. pylori neutrophil-activating protein (HP-NAP) is an iron storage protein that forms a dodecameric shell, promotes the adhesion of neutrophils to endothelial cells, and induces the production of reactive oxygen radicals. HP-NAP belongs to the DNA-protecting proteins under starved conditions (Dps) family, which has significant structural similarities to the dodecameric ferritin family. The crystal structures of the apo form and metal-ion bound forms, such as iron, zinc, and cadmium, of HP-NAP have been determined. This review focused on the structures and metal-binding properties of HP-NAP. These metal ions bind at the di-nuclear ferroxidase center (FOC) by different coordinating patterns. In comparison with the apo structure, metal loading causes a series of conformational changes in conserved residues among HP-NAP and Dps proteins (Trp26, Asp52, and Glu56) at the FOC. HP-NAP forms a spherical dodecamer with 23 symmetry including two kinds of pores. Metal ions have been identified around one of the pores; therefore, the negatively-charged pore is suitable for the passage of metal ions. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
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Open AccessReview Evolutionary Implications of Metal Binding Features in Different Species’ Prion Protein: An Inorganic Point of View
Biomolecules 2014, 4(2), 546-565; https://doi.org/10.3390/biom4020546
Received: 20 February 2014 / Revised: 29 April 2014 / Accepted: 6 May 2014 / Published: 23 May 2014
Cited by 3 | PDF Full-text (436 KB) | HTML Full-text | XML Full-text
Abstract
Prion disorders are a group of fatal neurodegenerative conditions of mammals. The key molecular event in the pathogenesis of such diseases is the conformational conversion of prion protein, PrPC, into a misfolded form rich in β-sheet structure, PrPSc, but
[...] Read more.
Prion disorders are a group of fatal neurodegenerative conditions of mammals. The key molecular event in the pathogenesis of such diseases is the conformational conversion of prion protein, PrPC, into a misfolded form rich in β-sheet structure, PrPSc, but the detailed mechanistic aspects of prion protein conversion remain enigmatic. There is uncertainty on the precise physiological function of PrPC in healthy individuals. Several evidences support the notion of its role in copper homeostasis. PrPC binds Cu2+ mainly through a domain composed by four to five repeats of eight amino acids. In addition to mammals, PrP homologues have also been identified in birds, reptiles, amphibians and fish. The globular domain of protein is retained in the different species, suggesting that the protein carries out an essential common function. However, the comparison of amino acid sequences indicates that prion protein has evolved differently in each vertebrate class. The primary sequences are strongly conserved in each group, but these exhibit a low similarity with those of mammals. The N-terminal domain of different prions shows tandem amino acid repeats with an increasing amount of histidine residues going from amphibians to mammals. The difference in the sequence affects the number of copper binding sites, the affinity and the coordination environment of metal ions, suggesting that the involvement of prion in metal homeostasis may be a specific characteristic of mammalian prion protein. In this review, we describe the similarities and the differences in the metal binding of different species’ prion protein, as revealed by studies carried out on the entire protein and related peptide fragments. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
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Open AccessReview Structure and Function of the LmbE-like Superfamily
Biomolecules 2014, 4(2), 527-545; https://doi.org/10.3390/biom4020527
Received: 6 February 2014 / Revised: 18 April 2014 / Accepted: 18 April 2014 / Published: 16 May 2014
Cited by 2 | PDF Full-text (2377 KB) | HTML Full-text | XML Full-text
Abstract
The LmbE-like superfamily is comprised of a series of enzymes that use a single catalytic metal ion to catalyze the hydrolysis of various substrates. These substrates are often key metabolites for eukaryotes and prokaryotes, which makes the LmbE-like enzymes important targets for drug
[...] Read more.
The LmbE-like superfamily is comprised of a series of enzymes that use a single catalytic metal ion to catalyze the hydrolysis of various substrates. These substrates are often key metabolites for eukaryotes and prokaryotes, which makes the LmbE-like enzymes important targets for drug development. Herein we review the structure and function of the LmbE-like proteins identified to date. While this is the newest superfamily of metallohydrolases, a growing number of functionally interesting proteins from this superfamily have been characterized. Available crystal structures of LmbE-like proteins reveal a Rossmann fold similar to lactate dehydrogenase, which represented a novel fold for (zinc) metallohydrolases at the time the initial structure was solved. The structural diversity of the N-acetylglucosamine containing substrates affords functional diversity for the LmbE-like enzyme superfamily. The majority of enzymes identified to date are metal-dependent deacetylases that catalyze the hydrolysis of a N-acetylglucosamine moiety on substrate using a combination of amino acid side chains and a single bound metal ion, predominantly zinc. The catalytic zinc is coordinated to proteins via His2-Asp-solvent binding site. Additionally, studies indicate that protein dynamics play important roles in regulating access to the active site and facilitating catalysis for at least two members of this protein superfamily. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
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Open AccessReview The Role of Histidine-Proline-Rich Glycoprotein as Zinc Chaperone for Skeletal Muscle AMP Deaminase
Biomolecules 2014, 4(2), 474-497; https://doi.org/10.3390/biom4020474
Received: 6 February 2014 / Revised: 8 April 2014 / Accepted: 10 April 2014 / Published: 5 May 2014
Cited by 6 | PDF Full-text (1057 KB) | HTML Full-text | XML Full-text
Abstract
Metallochaperones function as intracellular shuttles for metal ions. At present, no evidence for the existence of any eukaryotic zinc-chaperone has been provided although metallochaperones could be critical for the physiological functions of Zn2+ metalloenzymes. We propose that the complex formed in skeletal
[...] Read more.
Metallochaperones function as intracellular shuttles for metal ions. At present, no evidence for the existence of any eukaryotic zinc-chaperone has been provided although metallochaperones could be critical for the physiological functions of Zn2+ metalloenzymes. We propose that the complex formed in skeletal muscle by the Zn2+ metalloenzyme AMP deaminase (AMPD) and the metal binding protein histidine-proline-rich glycoprotein (HPRG) acts in this manner. HPRG is a major plasma protein. Recent investigations have reported that skeletal muscle cells do not synthesize HPRG but instead actively internalize plasma HPRG. X-ray absorption spectroscopy (XAS) performed on fresh preparations of rabbit skeletal muscle AMPD provided evidence for a dinuclear zinc site in the enzyme compatible with a (μ-aqua)(μ-carboxylato)dizinc(II) core with two histidine residues at each metal site. XAS on HPRG isolated from the AMPD complex showed that zinc is bound to the protein in a dinuclear cluster where each Zn2+ ion is coordinated by three histidine and one heavier ligand, likely sulfur from cysteine. We describe the existence in mammalian HPRG of a specific zinc binding site distinct from the His-Pro-rich region. The participation of HPRG in the assembly and maintenance of skeletal muscle AMPD by acting as a zinc chaperone is also demonstrated. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
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Open AccessReview Metallothioneins, Unconventional Proteins from Unconventional Animals: A Long Journey from Nematodes to Mammals
Biomolecules 2014, 4(2), 435-457; https://doi.org/10.3390/biom4020435
Received: 30 January 2014 / Revised: 19 March 2014 / Accepted: 21 March 2014 / Published: 22 April 2014
Cited by 27 | PDF Full-text (1243 KB) | HTML Full-text | XML Full-text
Abstract
Metallothioneins (MTs) are ubiquitous low molecular weight cysteine-rich proteins characterized by high affinity for d10 electron configuration metals, including essential (Zn and Cu) and non-essential (Cd and Hg) trace elements. The biological role of these ancient and well-conserved multifunctional proteins has been debated
[...] Read more.
Metallothioneins (MTs) are ubiquitous low molecular weight cysteine-rich proteins characterized by high affinity for d10 electron configuration metals, including essential (Zn and Cu) and non-essential (Cd and Hg) trace elements. The biological role of these ancient and well-conserved multifunctional proteins has been debated since MTs were first discovered in 1957. Their main hypothesized functions are: (1) homeostasis of Zn and Cu; (2) detoxification of Cd, and Hg; and (3) free radical scavenging. This review will focus on MTs in unconventional animals, those not traditionally studied in veterinary medicine but of increasing interest in this field of research. Living in different environments, these animals represent an incredible source of physiological and biochemical adaptations still partly unexplored. The study of metal-MT interactions is of great interest for clinicians and researchers working in veterinary medicine, food quality and endangered species conservation. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
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Open AccessReview Zinc-Binding Cysteines: Diverse Functions and Structural Motifs
Biomolecules 2014, 4(2), 419-434; https://doi.org/10.3390/biom4020419
Received: 6 February 2014 / Revised: 19 March 2014 / Accepted: 20 March 2014 / Published: 17 April 2014
Cited by 40 | PDF Full-text (2804 KB) | HTML Full-text | XML Full-text
Abstract
Cysteine residues are known to perform essential functions within proteins, including binding to various metal ions. In particular, cysteine residues can display high affinity toward zinc ions (Zn2+), and these resulting Zn2+-cysteine complexes are critical mediators of protein structure,
[...] Read more.
Cysteine residues are known to perform essential functions within proteins, including binding to various metal ions. In particular, cysteine residues can display high affinity toward zinc ions (Zn2+), and these resulting Zn2+-cysteine complexes are critical mediators of protein structure, catalysis and regulation. Recent advances in both experimental and theoretical platforms have accelerated the identification and functional characterization of Zn2+-bound cysteines. Zn2+-cysteine complexes have been observed across diverse protein classes and are known to facilitate a variety of cellular processes. Here, we highlight the structural characteristics and diverse functional roles of Zn2+-cysteine complexes in proteins and describe structural, computational and chemical proteomic technologies that have enabled the global discovery of novel Zn2+-binding cysteines. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
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Open AccessReview Design of Catalytically Amplified Sensors for Small Molecules
Biomolecules 2014, 4(2), 402-418; https://doi.org/10.3390/biom4020402
Received: 6 February 2014 / Revised: 21 March 2014 / Accepted: 26 March 2014 / Published: 17 April 2014
Cited by 10 | PDF Full-text (236 KB) | HTML Full-text | XML Full-text
Abstract
Catalytically amplified sensors link an allosteric analyte binding site with a reactive site to catalytically convert substrate into colored or fluorescent product that can be easily measured. Such an arrangement greatly improves a sensor’s detection limit as illustrated by successful application of ELISA-based
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Catalytically amplified sensors link an allosteric analyte binding site with a reactive site to catalytically convert substrate into colored or fluorescent product that can be easily measured. Such an arrangement greatly improves a sensor’s detection limit as illustrated by successful application of ELISA-based approaches. The ability to engineer synthetic catalytic sites into non-enzymatic proteins expands the repertoire of analytes as well as readout reactions. Here we review recent examples of small molecule sensors based on allosterically controlled enzymes and organometallic catalysts. The focus of this paper is on biocompatible, switchable enzymes regulated by small molecules to track analytes both in vivo and in the environment. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
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Open AccessReview Effect of Metals on Kinetic Pathways of Amyloid-β Aggregation
Biomolecules 2014, 4(1), 101-116; https://doi.org/10.3390/biom4010101
Received: 7 December 2013 / Revised: 4 January 2014 / Accepted: 7 January 2014 / Published: 10 January 2014
Cited by 29 | PDF Full-text (523 KB) | HTML Full-text | XML Full-text
Abstract
Metal ions, including copper and zinc, have been implicated in the pathogenesis of Alzheimer’s disease through a variety of mechanisms including increased amyloid-β affinity and redox effects. Recent reports have demonstrated that the amyloid-β monomer does not necessarily travel through a definitive intermediary
[...] Read more.
Metal ions, including copper and zinc, have been implicated in the pathogenesis of Alzheimer’s disease through a variety of mechanisms including increased amyloid-β affinity and redox effects. Recent reports have demonstrated that the amyloid-β monomer does not necessarily travel through a definitive intermediary en-route to a stable amyloid fibril structure. Rather, amyloid-β misfolding may follow a variety of pathways resulting in a fibrillar end-product or a variety of oligomeric end-products with a diversity of structures and sizes. The presence of metal ions has been demonstrated to alter the kinetic pathway of the amyloid-β peptide which may lead to more toxic oligomeric end-products. In this work, we review the contemporary literature supporting the hypothesis that metal ions alter the reaction pathway of amyloid-β misfolding leading to more neurotoxic species. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
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