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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Inorganic Chemistry".

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 19273

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Dr. Eugene A. Permyakov

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Guest Editor

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
Special Issues, Collections and Topics in MDPI journals

Dr. Sergey Permyakov

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Guest Editor

Director of the Institute for Biological Instrumentation of the Russian Academy of Sciences, 7 Institutskaya str., Pushchino, 142290 Moscow Region, Russia
Interests: protein purification; bioinformatics and computational biology; protein–protein interaction; structural biology; protein folding; microcalorimetry

Special Issue Information

Dear Colleagues,

Metal ions play a very important role in functioning of all biological systems, without any exceptions,. All biological processes occur, even when only in the background of high concentrations of metal ions and some directly depend on metal ions. Specific interactions of metal ions with biopolymers and, firstly, with proteins, play a critical role. Ten to thirteen metals are vitally important for living organisms: Na, K, Mg, Ca, Mn, Fe, Co, Zn, Cu, Ni, V, W, Mo. Metal ions are also essential in proteins: structural, regulatory, and enzymatic. The binding of some metal ions increases stability of proteins or protein domains. Some metal ions can regulate various cell processes as first, second or third messengers. Some others, especially transition metal ions, take part in the catalysis process in many enzymes. They are further an integral part of many enzymes and are indispensable in several catalytic reactions, e.g., hydrolytic, redox and isomerization reactions. In particular, transition metals, such as Fe, Cu, and Mn, are involved in many redox processes requiring electron transfer. Alkali and alkaline earth ions, especially Na(I), K(I), and Ca(II), play a vital role in triggering cellular responses. Metal ions are increasingly studied by researchers due to their involvement in many pathological processes. In spite of the fact that many metal binding proteins are well studied, a detailed study of structural, physico-chemical and functional properties of metal binding proteins and their interactions is still an important and ongoing task in modern biology. The Special Issue of Molecules aims to identify and review the latest achievements in the area of studies of metal binding proteins: their structure, properties and functions.

Prof. Dr. Eugene Permyakov
Dr. Sergey Permyakov
Guest Editors

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Keywords

Metalloproteins
Metal binding proteins
Structure
Properties
Functions

Published Papers (5 papers)

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Research

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21 pages, 3524 KiB

Open AccessArticle

Atroxlysin-III, A Metalloproteinase from the Venom of the Peruvian Pit Viper Snake Bothrops atrox (Jergón) Induces Glycoprotein VI Shedding and Impairs Platelet Function

by Luciana S. Oliveira, Maria Inácia Estevão-Costa, Valéria G. Alvarenga, Dan E. Vivas-Ruiz, Armando Yarleque, Augusto Martins Lima, Ana Cavaco, Johannes A. Eble and Eladio F. Sanchez

Molecules 2019, 24(19), 3489; https://doi.org/10.3390/molecules24193489 - 26 Sep 2019

Cited by 11 | Viewed by 3425

Abstract

Atroxlysin-III (Atr-III) was purified from the venom of Bothrops atrox. This 56-kDa protein bears N-linked glycoconjugates and is a P-III hemorrhagic metalloproteinase. Its cDNA-deduced amino acid sequence reveals a multidomain structure including a proprotein, a metalloproteinase, a disintegrin-like and a cysteine-rich domain. Its identity with bothropasin and jararhagin from Bothrops jararaca is 97% and 95%, respectively. Its enzymatic activity is metal ion-dependent. The divalent cations, Mg²⁺ and Ca²⁺, enhance its activity, whereas excess Zn²⁺ inhibits it. Chemical modification of the Zn²⁺-complexing histidine residues within the active site by using diethylpyrocarbonate (DEPC) inactivates it. Atr-III degrades plasma fibronectin, type I-collagen, and mainly the α-chains of fibrinogen and fibrin. The von Willebrand factor (vWF) A1-domain, which harbors the binding site for GPIb, is not hydrolyzed. Platelets interact with collagen via receptors for collagen, glycoprotein VI (GPVI), and α2β1 integrin. Neither the α2β1 integrin nor its collagen-binding A-domain is fragmented by Atr-III. In contrast, Atr-III cleaves glycoprotein VI (GPVI) into a soluble ~55-kDa fragment (sGPVI). Thereby, it inhibits aggregation of platelets which had been stimulated by convulxin, a GPVI agonist. Selectively, Atr-III targets GPVI antagonistically and thus contributes to the antithrombotic effect of envenomation by Bothrops atrox. Full article

(This article belongs to the Special Issue Metalloproteins)

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10 pages, 1344 KiB

Open AccessArticle

Finding High-Quality Metal Ion-Centric Regions Across the Worldwide Protein Data Bank

by Sen Yao and Hunter N.B. Moseley

Molecules 2019, 24(17), 3179; https://doi.org/10.3390/molecules24173179 - 01 Sep 2019

Cited by 4 | Viewed by 2628

Abstract

As the number of macromolecular structures in the worldwide Protein Data Bank (wwPDB) continues to grow rapidly, more attention is being paid to the quality of its data, especially for use in aggregated structural and dynamics analyses. In this study, we systematically analyzed 3.5 Å regions around all metal ions across all PDB entries with supporting electron density maps available from the PDB in Europe. All resulting metal ion-centric regions were evaluated with respect to four quality-control criteria involving electron density resolution, atom occupancy, symmetry atom exclusion, and regional electron density discrepancy. The resulting list of metal binding sites passing all four criteria possess high regional structural quality and should be beneficial to a wide variety of downstream analyses. This study demonstrates an approach for the pan-PDB evaluation of metal binding site structural quality with respect to underlying X-ray crystallographic experimental data represented in the available electron density maps of proteins. For non-crystallographers in particular, we hope to change the focus and discussion of structural quality from a global evaluation to a regional evaluation, since all structural entries in the wwPDB appear to have both regions of high and low structural quality. Full article

(This article belongs to the Special Issue Metalloproteins)

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25 pages, 3904 KiB

Open AccessFeature PaperArticle

Experimental Insight into the Structural and Functional Roles of the ‘Black’ and ‘Gray’ Clusters in Recoverin, a Calcium Binding Protein with Four EF-Hand Motifs

by Sergey E. Permyakov, Alisa S. Vologzhannikova, Ekaterina L. Nemashkalova, Alexei S. Kazakov, Alexander I. Denesyuk, Konstantin Denessiouk, Viktoriia E. Baksheeva, Andrey A. Zamyatnin, Jr., Evgeni Yu. Zernii, Vladimir N. Uversky and Eugene A. Permyakov

Molecules 2019, 24(13), 2494; https://doi.org/10.3390/molecules24132494 - 08 Jul 2019

Cited by 2 | Viewed by 2942

Abstract

Recently, we have found that calcium binding proteins of the EF-hand superfamily (i.e., a large family of proteins containing helix-loop-helix calcium binding motif or EF-hand) contain two types of conserved clusters called cluster I (‘black’ cluster) and cluster II (‘grey’ cluster), which provide a supporting scaffold for the Ca²⁺ binding loops and contribute to the hydrophobic core of the EF-hand domains. Cluster I is more conservative and mostly incorporates aromatic amino acids, whereas cluster II includes a mix of aromatic, hydrophobic, and polar amino acids of different sizes. Recoverin is EF-hand Ca²⁺-binding protein containing two ‘black’ clusters comprised of F35, F83, Y86 (N-terminal domain) and F106, E169, F172 (C-terminal domain) as well as two ‘gray’ clusters comprised of F70, Q46, F49 (N-terminal domain) and W156, K119, V122 (C-terminal domain). To understand a role of these residues in structure and function of human recoverin, we sequentially substituted them for alanine and studied the resulting mutants by a set of biophysical methods. Under metal-free conditions, the ‘black’ clusters mutants (except for F35A and E169A) were characterized by an increase in the α-helical content, whereas the ‘gray’ cluster mutants (except for K119A) exhibited the opposite behavior. By contrast, in Ca²⁺-loaded mutants the α-helical content was always elevated. In the absence of calcium, the substitutions only slightly affected multimerization of recoverin regardless of their localization (except for K119A). Meanwhile, in the presence of calcium mutations in N-terminal domain of the protein significantly suppressed this process, indicating that surface properties of Ca²⁺-bound recoverin are highly affected by N-terminal cluster residues. The substitutions in C-terminal clusters generally reduced thermal stability of recoverin with F172A (‘black’ cluster) as well as W156A and K119A (‘gray’ cluster) being the most efficacious in this respect. In contrast, the mutations in the N-terminal clusters caused less pronounced differently directed changes in thermal stability of the protein. The substitutions of F172, W156, and K119 in C-terminal domain of recoverin together with substitution of Q46 in its N-terminal domain provoked significant but diverse changes in free energy associated with Ca²⁺ binding to the protein: the mutant K119A demonstrated significantly improved calcium binding, whereas F172A and W156A showed decrease in the calcium affinity and Q46A exhibited no ion coordination in one of the Ca²⁺-binding sites. The most of the N-terminal clusters mutations suppressed membrane binding of recoverin and its inhibitory activity towards rhodopsin kinase (GRK1). Surprisingly, the mutant W156A aberrantly activated rhodopsin phosphorylation regardless of the presence of calcium. Taken together, these data confirm the scaffolding function of several cluster-forming residues and point to their critical role in supporting physiological activity of recoverin. Full article

(This article belongs to the Special Issue Metalloproteins)

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Review

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16 pages, 601 KiB

Open AccessReview

The Versatile Role of Matrix Metalloproteinase for the Diverse Results of Fibrosis Treatment

by Hong-Meng Chuang, Yu-Shuan Chen and Horng-Jyh Harn

Molecules 2019, 24(22), 4188; https://doi.org/10.3390/molecules24224188 - 19 Nov 2019

Cited by 24 | Viewed by 3902

Abstract

Fibrosis is a type of chronic organ failure, resulting in the excessive secretion of extracellular matrix (ECM). ECM protects wound tissue from infection and additional injury, and is gradually degraded during wound healing. For some unknown reasons, myofibroblasts (the cells that secrete ECM) do not undergo apoptosis; this is associated with the continuous secretion of ECM and reduced ECM degradation even during de novo tissue formation. Thus, matrix metalloproteinases (MMPs) are considered to be a potential target of fibrosis treatment because they are the main groups of ECM-degrading enzymes. However, MMPs participate not only in ECM degradation but also in the development of various biological processes that show the potential to treat diseases such as stroke, cardiovascular diseases, and arthritis. Therefore, treatment involving the targeting of MMPs might impede typical functions. Here, we evaluated the links between these MMP functions and possible detrimental effects of fibrosis treatment, and also considered possible approaches for further applications. Full article

(This article belongs to the Special Issue Metalloproteins)

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30 pages, 14493 KiB

Open AccessReview

Formation of Unstable and very Reactive Chemical Species Catalyzed by Metalloenzymes: A Mechanistic Overview

by Henrique S. Fernandes, Carla S. Silva Teixeira, Sérgio F. Sousa and Nuno M. F. S. A. Cerqueira

Molecules 2019, 24(13), 2462; https://doi.org/10.3390/molecules24132462 - 04 Jul 2019

Cited by 15 | Viewed by 5634

Abstract

Nature has tailored a wide range of metalloenzymes that play a vast array of functions in all living organisms and from which their survival and evolution depends on. These enzymes catalyze some of the most important biological processes in nature, such as photosynthesis, respiration, water oxidation, molecular oxygen reduction, and nitrogen fixation. They are also among the most proficient catalysts in terms of their activity, selectivity, and ability to operate at mild conditions of temperature, pH, and pressure. In the absence of these enzymes, these reactions would proceed very slowly, if at all, suggesting that these enzymes made the way for the emergence of life as we know today. In this review, the structure and catalytic mechanism of a selection of diverse metalloenzymes that are involved in the production of highly reactive and unstable species, such as hydroxide anions, hydrides, radical species, and superoxide molecules are analyzed. The formation of such reaction intermediates is very difficult to occur under biological conditions and only a rationalized selection of a particular metal ion, coordinated to a very specific group of ligands, and immersed in specific proteins allows these reactions to proceed. Interestingly, different metal coordination spheres can be used to produce the same reactive and unstable species, although through a different chemistry. A selection of hand-picked examples of different metalloenzymes illustrating this diversity is provided and the participation of different metal ions in similar reactions (but involving different mechanism) is discussed. Full article

(This article belongs to the Special Issue Metalloproteins)

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