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

Deadline for manuscript submissions: closed (31 January 2014) | Viewed by 122445

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Dr. Eugene A. Permyakov

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Institute for Biological Instrumentation, Russian Academy of Sciences, 142290 Pushchino, Russia
Interests: protein physics; luminescence (fluorescence, phosphorescence) spectroscopy of proteins; scanning and titration calorimetry of proteins; metal binding proteins; calcium binding proteins
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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

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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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379 KiB

Open AccessArticle

Enhanced Adsorption and Recovery of Uranyl Ions by NikR Mutant-Displaying Yeast

by Kouichi Kuroda, Kazuki Ebisutani, Katsuya Iida, Takashi Nishitani and Mitsuyoshi Ueda

Biomolecules 2014, 4(2), 390-401; https://doi.org/10.3390/biom4020390 - 11 Apr 2014

Cited by 13 | Viewed by 6671

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 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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18550 KiB

Open AccessReview

Interactions between Calcium and Alpha-Synuclein in Neurodegeneration

by Alex Rcom-H'cheo-Gauthier, Jacob Goodwin and Dean L. Pountney

Biomolecules 2014, 4(3), 795-811; https://doi.org/10.3390/biom4030795 - 14 Aug 2014

Cited by 61 | Viewed by 10147

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, 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

by Joy Mitra, Erika N. Guerrero, Pavana M. Hegde, Haibo Wang, Istvan Boldogh, Kosagi Sharaf Rao, Sankar Mitra and Muralidhar L. Hegde

Biomolecules 2014, 4(3), 678-703; https://doi.org/10.3390/biom4030678 - 17 Jul 2014

Cited by 28 | Viewed by 10193

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, 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

by Pietro Vidossich and Alessandra Magistrato

Biomolecules 2014, 4(3), 616-645; https://doi.org/10.3390/biom4030616 - 08 Jul 2014

Cited by 79 | Viewed by 11874

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 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

by Hideshi Yokoyama and Satoshi Fujii

Biomolecules 2014, 4(3), 600-615; https://doi.org/10.3390/biom4030600 - 26 Jun 2014

Cited by 9 | Viewed by 7216

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 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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436 KiB

Open AccessReview

Evolutionary Implications of Metal Binding Features in Different Species’ Prion Protein: An Inorganic Point of View

by Diego La Mendola and Enrico Rizzarelli

Biomolecules 2014, 4(2), 546-565; https://doi.org/10.3390/biom4020546 - 23 May 2014

Cited by 11 | Viewed by 6639

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, PrP^C, into a misfolded form rich in β-sheet structure, PrP^Sc, but the detailed mechanistic aspects of prion protein conversion remain enigmatic. There is uncertainty on the precise physiological function of PrP^C in healthy individuals. Several evidences support the notion of its role in copper homeostasis. PrP^C 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

by Shane Viars, Jason Valentine and Marcy Hernick

Biomolecules 2014, 4(2), 527-545; https://doi.org/10.3390/biom4020527 - 16 May 2014

Cited by 10 | Viewed by 7503

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 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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1057 KiB

Open AccessReview

The Role of Histidine-Proline-Rich Glycoprotein as Zinc Chaperone for Skeletal Muscle AMP Deaminase

by Maria Ranieri-Raggi, Arthur J. G. Moir and Antonio Raggi

Biomolecules 2014, 4(2), 474-497; https://doi.org/10.3390/biom4020474 - 05 May 2014

Cited by 16 | Viewed by 9457

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 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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Metallothioneins, Unconventional Proteins from Unconventional Animals: A Long Journey from Nematodes to Mammals

by Gloria Isani and Emilio Carpenè

Biomolecules 2014, 4(2), 435-457; https://doi.org/10.3390/biom4020435 - 22 Apr 2014

Cited by 90 | Viewed by 10376

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 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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2804 KiB

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Zinc-Binding Cysteines: Diverse Functions and Structural Motifs

by Nicholas J. Pace and Eranthie Weerapana

Biomolecules 2014, 4(2), 419-434; https://doi.org/10.3390/biom4020419 - 17 Apr 2014

Cited by 164 | Viewed by 18461

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, 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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Design of Catalytically Amplified Sensors for Small Molecules

by Olga V. Makhlynets and Ivan V. Korendovych

Biomolecules 2014, 4(2), 402-418; https://doi.org/10.3390/biom4020402 - 17 Apr 2014

Cited by 17 | Viewed by 9470

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 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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Effect of Metals on Kinetic Pathways of Amyloid-β Aggregation

by Francis Hane and Zoya Leonenko

Biomolecules 2014, 4(1), 101-116; https://doi.org/10.3390/biom4010101 - 10 Jan 2014

Cited by 94 | Viewed by 12327

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 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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