Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Metallothioneins in Bioinorganic Chemistry: Recent Developments

Special Issue Editors
Special Issue Information
Keywords
Benefits of Publishing in a Special Issue
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioinorganic Chemistry".

Deadline for manuscript submissions: closed (16 April 2017) | Viewed by 68703

Share This Special Issue

Special Issue Editor

PD. Dr. Eva Freisinger

E-Mail Website
Guest Editor

Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
Interests: structures and properties of plant metallothioneins; gene cloning, protein over-expression, and purification; spectroscopic and biochemical characterization of MTs; determination of metal ion binding affinities and redox states; structure determination of MTs by X-ray and NMR
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

“Metallothioneins”—this is the name of a superfamily combining proteins with two rather basic characteristics, a high percentage of thiolate groups in form of cysteine residues and the ability to coordinate certain metal ions via these thiolate ligands. There is, however, no requirement for a specific function or structure. While the name was initially invented 60 years ago for a class of proteins found in mammalians, all having very similar sequences and a common three-dimensional structure involving metal-thiolate clusters, nowadays, proteins from nearly all kingdoms of life, among them vertebrates, molluscs, nematodes, prokaryotes, fungi, and plants are included. Often the classification as metallothionein is solely based on the respective gene sequence without further knowledge about the metal ion binding ability of the encoded protein. The elucidation of the metal ion binding modes including cluster formation, the spectroscopic properties and last not least the three-dimensional structures of the members of this very variable superfamily belongs to the classical research fields of Bioinorganic Chemistry. Beyond this basic characterisation, unravelling the diversity of functions including, but not being restricted to, metal ion homeostasis and detoxification as well as redox activities, investigating the role of MTs in certain diseases, and inventing biotechnological applications are hot topics in MT research.

It is the aim of this Special Issue to highlight the recent developments in the field in form of Topical Reviews, Articles, and Short Communications. I invite you all to make this Special Issue a valuable source of new and exciting information about this very unique protein superfamily.

PD. Dr. Eva Freisinger
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

metallothioneins (MTs)
metal clusters
zinc
cadmium
copper
metal ion homeostasis
heavy metal detoxification
reactive oxygen species (ROS) scavenging
spectroscopy

Benefits of Publishing in a Special Issue

Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Published Papers (10 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

2363 KiB

Open AccessArticle

Metallothionein from Wild Populations of the African Catfish Clarias gariepinus: From Sequence, Protein Expression and Metal Binding Properties to Transcriptional Biomarker of Metal Pollution

by Ethel M’kandawire, Agnieszka Mierek-Adamska, Stephen R. Stürzenbaum, Kennedy Choongo, John Yabe, Maxwell Mwase, Ngonda Saasa and Claudia A. Blindauer

Int. J. Mol. Sci. 2017, 18(7), 1548; https://doi.org/10.3390/ijms18071548 - 18 Jul 2017

Cited by 30 | Viewed by 7016

Abstract

Anthropogenic pollution with heavy metals is an on-going concern throughout the world, and methods to monitor release and impact of heavy metals are of high importance. With a view to probe its suitability as molecular biomarker of metal pollution, this study has determined a coding sequence for metallothionein of the African sharptooth catfish Clarias gariepinus. The gene product was recombinantly expressed in Escherichia coli in presence of Zn(II), Cd(II), or Cu, and characterised by Electrospray Ionisation Mass Spectrometry and elemental analysis. C. gariepinus MT displays typical features of fish MTs, including 20 conserved cysteines, and seven bound divalent cations (Zn(II) or Cd(II)) when saturated. Livers from wild C. gariepinus fish collected in all three seasons from four different sites on the Kafue River of Zambia were analysed for their metal contents and for MT expression levels by quantitative PCR. Significant correlations were found between Zn and Cu levels and MT expression in livers, with MT expression clearly highest at the most polluted site, Chililabombwe, which is situated in the Copperbelt region. Based on our findings, hepatic expression of MT from C. gariepinus may be further developed as a major molecular biomarker of heavy metal pollution resulting from mining activities in this region. Full article

(This article belongs to the Special Issue Metallothioneins in Bioinorganic Chemistry: Recent Developments)

► Show Figures

Graphical abstract

2338 KiB

Open AccessArticle

Biomphalaria glabrata Metallothionein: Lacking Metal Specificity of the Protein and Missing Gene Upregulation Suggest Metal Sequestration by Exchange Instead of through Selective Binding

by Michael Niederwanger, Sara Calatayud, Oliver Zerbe, Sílvia Atrian, Ricard Albalat, Mercè Capdevila, Òscar Palacios and Reinhard Dallinger

Int. J. Mol. Sci. 2017, 18(7), 1457; https://doi.org/10.3390/ijms18071457 - 6 Jul 2017

Cited by 16 | Viewed by 5841

Abstract

The wild-type metallothionein (MT) of the freshwater snail Biomphalaria glabrata and a natural allelic mutant of it in which a lysine residue was replaced by an asparagine residue, were recombinantly expressed and analyzed for their metal-binding features with respect to Cd²⁺, Zn²⁺ and Cu⁺, applying spectroscopic and mass-spectrometric methods. In addition, the upregulation of the Biomphalaria glabrata MT gene was assessed by quantitative real-time detection PCR. The two recombinant proteins revealed to be very similar in most of their metal binding features. They lacked a clear metal-binding preference for any of the three metal ions assayed—which, to this degree, is clearly unprecedented in the world of Gastropoda MTs. There were, however, slight differences in copper-binding abilities between the two allelic variants. Overall, the missing metal specificity of the two recombinant MTs goes hand in hand with lacking upregulation of the respective MT gene. This suggests that in vivo, the Biomphalaria glabrata MT may be more important for metal replacement reactions through a constitutively abundant form, rather than for metal sequestration by high binding specificity. There are indications that the MT of Biomphalaria glabrata may share its unspecific features with MTs from other freshwater snails of the Hygrophila family. Full article

(This article belongs to the Special Issue Metallothioneins in Bioinorganic Chemistry: Recent Developments)

► Show Figures

Graphical abstract

2394 KiB

Open AccessArticle

Analysis of Metal-Binding Features of the Wild Type and Two Domain-Truncated Mutant Variants of Littorina littorea Metallothionein Reveals Its Cd-Specific Character

by Òscar Palacios, Elena Jiménez-Martí, Michael Niederwanger, Selene Gil-Moreno, Oliver Zerbe, Sílvia Atrian, Reinhard Dallinger and Mercè Capdevila

Int. J. Mol. Sci. 2017, 18(7), 1452; https://doi.org/10.3390/ijms18071452 - 6 Jul 2017

Cited by 20 | Viewed by 4965

Abstract

After the resolution of the 3D structure of the Cd₉-aggregate of the Littorina littorea metallothionein (MT), we report here a detailed analysis of the metal binding capabilities of the wild type MT, LlwtMT, and of two truncated mutants lacking either the N-terminal domain, Lltr2MT, or both the N-terminal domain, plus four extra flanking residues (SSVF), Lltr1MT. The recombinant synthesis and in vitro studies of these three proteins revealed that LlwtMT forms unique M₉-LlwtMT complexes with Zn(II) and Cd(II), while yielding a complex mixture of heteronuclear Zn,Cu-LlwtMT species with Cu(I). As expected, the truncated mutants gave rise to unique M₆-LltrMT complexes and Zn,Cu-LltrMT mixtures of lower stoichiometry with respect to LlwtMT, with the SSVF fragment having an influence on their metal binding performance. Our results also revealed a major specificity, and therefore a better metal-coordinating performance of the three proteins for Cd(II) than for Zn(II), although the analysis of the Zn(II)/Cd(II) displacement reaction clearly demonstrates a lack of any type of cooperativity in Cd(II) binding. Contrarily, the analysis of their Cu(I) binding abilities revealed that every LlMT domain is prone to build Cu₄-aggregates, the whole MT working by modules analogously to, as previously described, certain fungal MTs, like those of C. neoformans and T. mesenterica. It is concluded that the Littorina littorea MT is a Cd-specific protein that (beyond its extended binding capacity through an additional Cd-binding domain) confers to Littorina littorea a particular adaptive advantage in its changeable marine habitat. Full article

(This article belongs to the Special Issue Metallothioneins in Bioinorganic Chemistry: Recent Developments)

► Show Figures

Graphical abstract

1448 KiB

Open AccessArticle

Function of Metallothionein-3 in Neuronal Cells: Do Metal Ions Alter Expression Levels of MT3?

by Jamie Bousleiman, Alexa Pinsky, Sohee Ki, Angela Su, Irina Morozova, Sergey Kalachikov, Amen Wiqas, Rae Silver, Mary Sever and Rachel Narehood Austin

Int. J. Mol. Sci. 2017, 18(6), 1133; https://doi.org/10.3390/ijms18061133 - 25 May 2017

Cited by 21 | Viewed by 6552

Abstract

A study of factors proposed to affect metallothionein-3 (MT3) function was carried out to elucidate the opaque role MT3 plays in human metalloneurochemistry. Gene expression of Mt2 and Mt3 was examined in tissues extracted from the dentate gyrus of mouse brains and in human neuronal cell cultures. The whole-genome gene expression analysis identified significant variations in the mRNA levels of genes associated with zinc homeostasis, including Mt2 and Mt3. Mt3 was found to be the most differentially expressed gene in the identified groups, pointing to the existence of a factor, not yet identified, that differentially controls Mt3 expression. To examine the expression of the human metallothioneins in neurons, mRNA levels of MT3 and MT2 were compared in BE(2)C and SH-SY5Y cell cultures treated with lead, zinc, cobalt, and lithium. MT2 was highly upregulated by Zn²⁺ in both cell cultures, while MT3 was not affected, and no other metal had an effect on either MT2 or MT3. Full article

(This article belongs to the Special Issue Metallothioneins in Bioinorganic Chemistry: Recent Developments)

► Show Figures

Graphical abstract

2158 KiB

Open AccessArticle

Regulatory Plasticity of Earthworm wMT-2 Gene Expression

by Victoria Drechsel, Karl Schauer, Maja Šrut and Martina Höckner

Int. J. Mol. Sci. 2017, 18(6), 1113; https://doi.org/10.3390/ijms18061113 - 24 May 2017

Cited by 15 | Viewed by 5610

Abstract

Metallothioneins (MTs) are multifunctional proteins occurring throughout the animal kingdom. While the expression and transcriptional regulation of MTs is well-studied in vertebrates, the mechanism of MT activation is still unknown for most invertebrates. Therefore, we examined wMT-2 gene regulation and expression patterns in Lumbricus rubellus and L. terrestris. Transcription levels, the occupation of DNA binding sites, the expression of putative transcriptional regulators, and promotor DNA methylation were determined. We found that wMT-2 expression does not follow a circadian pattern. However, Cd-induced wMT-2 induction was observed, and was, interestingly, suppressed by physical injury. Moreover, the promotor region that is responsible for the wMT-2 gene regulation was elucidated. ATF, a putative transcriptional regulator, showed increased phosphorylation upon Cd exposure, suggesting that it plays a major role in wMT-2 gene activation. The promotor methylation of wMT-2, on the other hand, is probably not involved in transcriptional regulation. Elucidating the regulatory mechanism of the earthworm MT gene activation might provide insights into the molecular coordination of the environmental stress response in invertebrates, and might also reveal a link to wound repair and, in a broader sense, to immunity. Full article

(This article belongs to the Special Issue Metallothioneins in Bioinorganic Chemistry: Recent Developments)

► Show Figures

Graphical abstract

1380 KiB

Open AccessArticle

The Application of Curve Fitting on the Voltammograms of Various Isoforms of Metallothioneins–Metal Complexes

by Miguel Angel Merlos Rodrigo, Jorge Molina-López, Ana Maria Jimenez Jimenez, Elena Planells Del Pozo, Pavlina Adam, Tomas Eckschlager, Ondrej Zitka, Lukas Richtera and Vojtech Adam

Int. J. Mol. Sci. 2017, 18(3), 610; https://doi.org/10.3390/ijms18030610 - 11 Mar 2017

Cited by 10 | Viewed by 5493

Abstract

The translation of metallothioneins (MTs) is one of the defense strategies by which organisms protect themselves from metal-induced toxicity. MTs belong to a family of proteins comprising MT-1, MT-2, MT-3, and MT-4 classes, with multiple isoforms within each class. The main aim of this study was to determine the behavior of MT in dependence on various externally modelled environments, using electrochemistry. In our study, the mass distribution of MTs was characterized using MALDI-TOF. After that, adsorptive transfer stripping technique with differential pulse voltammetry was selected for optimization of electrochemical detection of MTs with regard to accumulation time and pH effects. Our results show that utilization of 0.5 M NaCl, pH 6.4, as the supporting electrolyte provides a highly complicated fingerprint, showing a number of non-resolved voltammograms. Hence, we further resolved the voltammograms exhibiting the broad and overlapping signals using curve fitting. The separated signals were assigned to the electrochemical responses of several MT complexes with zinc(II), cadmium(II), and copper(II), respectively. Our results show that electrochemistry could serve as a great tool for metalloproteomic applications to determine the ratio of metal ion bonds within the target protein structure, however, it provides highly complicated signals, which require further resolution using a proper statistical method, such as curve fitting. Full article

(This article belongs to the Special Issue Metallothioneins in Bioinorganic Chemistry: Recent Developments)

► Show Figures

Graphical abstract

Review

Jump to: Research

1299 KiB

Open AccessReview

Proteomic High Affinity Zn²⁺ Trafficking: Where Does Metallothionein Fit in?

by David H. Petering and Afsana Mahim

Int. J. Mol. Sci. 2017, 18(6), 1289; https://doi.org/10.3390/ijms18061289 - 17 Jun 2017

Cited by 28 | Viewed by 6978

Abstract

The cellular constitution of Zn-proteins and Zn-dependent signaling depend on the capacity of Zn²⁺ to find specific binding sites in the face of a plethora of other high affinity ligands. The most prominent of these is metallothionein (MT). It serves as a storage site for Zn²⁺ under various conditions, and has chemical properties that support a dynamic role for MT in zinc trafficking. Consistent with these characteristics, changing the availability of zinc for cells and tissues causes rapid alteration of zinc bound to MT. Nevertheless, zinc trafficking occurs in metallothionein-null animals and cells, hypothetically making use of proteomic binding sites to mediate the intracellular movements of zinc. Like metallothionein, the proteome contains a large concentration of proteins that strongly coordinate zinc. In this environment, free Zn²⁺ may be of little significance. Instead, this review sets forth the basis for the hypothesis that components of the proteome and MT jointly provide the platform for zinc trafficking. Full article

(This article belongs to the Special Issue Metallothioneins in Bioinorganic Chemistry: Recent Developments)

► Show Figures

Graphical abstract

604 KiB

Open AccessReview

The Functions of Metamorphic Metallothioneins in Zinc and Copper Metabolism

by Artur Krężel and Wolfgang Maret

Int. J. Mol. Sci. 2017, 18(6), 1237; https://doi.org/10.3390/ijms18061237 - 9 Jun 2017

Cited by 219 | Viewed by 11213

Abstract

Recent discoveries in zinc biology provide a new platform for discussing the primary physiological functions of mammalian metallothioneins (MTs) and their exquisite zinc-dependent regulation. It is now understood that the control of cellular zinc homeostasis includes buffering of Zn²⁺ ions at picomolar concentrations, extensive subcellular re-distribution of Zn²⁺, the loading of exocytotic vesicles with zinc species, and the control of Zn²⁺ ion signalling. In parallel, characteristic features of human MTs became known: their graded affinities for Zn²⁺ and the redox activity of their thiolate coordination environments. Unlike the single species that structural models of mammalian MTs describe with a set of seven divalent or eight to twelve monovalent metal ions, MTs are metamorphic. In vivo, they exist as many species differing in redox state and load with different metal ions. The functions of mammalian MTs should no longer be considered elusive or enigmatic because it is now evident that the reactivity and coordination dynamics of MTs with Zn²⁺ and Cu⁺ match the biological requirements for controlling—binding and delivering—these cellular metal ions, thus completing a 60-year search for their functions. MT represents a unique biological principle for buffering the most competitive essential metal ions Zn²⁺ and Cu⁺. How this knowledge translates to the function of other families of MTs awaits further insights into the specifics of how their properties relate to zinc and copper metabolism in other organisms. Full article

(This article belongs to the Special Issue Metallothioneins in Bioinorganic Chemistry: Recent Developments)

► Show Figures

Graphical abstract

869 KiB

Open AccessReview

Mammalian Metallothionein-3: New Functional and Structural Insights

by Milan Vašák and Gabriele Meloni

Int. J. Mol. Sci. 2017, 18(6), 1117; https://doi.org/10.3390/ijms18061117 - 24 May 2017

Cited by 79 | Viewed by 7953

Abstract

Metallothionein-3 (MT-3), a member of the mammalian metallothionein (MT) family, is mainly expressed in the central nervous system (CNS). MT-3 possesses a unique neuronal growth inhibitory activity, and the levels of this intra- and extracellularly occurring metalloprotein are markedly diminished in the brain of patients affected by a number of metal-linked neurodegenerative disorders, including Alzheimer’s disease (AD). In these pathologies, the redox cycling of copper, accompanied by the production of reactive oxygen species (ROS), plays a key role in the neuronal toxicity. Although MT-3 shares the metal-thiolate clusters with the well-characterized MT-1 and MT-2, it shows distinct biological, structural and chemical properties. Owing to its anti-oxidant properties and modulator function not only for Zn, but also for Cu in the extra- and intracellular space, MT-3, but not MT-1/MT-2, protects neuronal cells from the toxicity of various Cu(II)-bound amyloids. In recent years, the roles of zinc dynamics and MT-3 function in neurodegeneration are slowly emerging. This short review focuses on the recent developments regarding the chemistry and biology of MT-3. Full article

(This article belongs to the Special Issue Metallothioneins in Bioinorganic Chemistry: Recent Developments)

► Show Figures

Graphical abstract

4227 KiB

Open AccessReview

Residue Modification and Mass Spectrometry for the Investigation of Structural and Metalation Properties of Metallothionein and Cysteine-Rich Proteins

by Gordon W. Irvine and Martin J. Stillman

Int. J. Mol. Sci. 2017, 18(5), 913; https://doi.org/10.3390/ijms18050913 - 26 Apr 2017

Cited by 11 | Viewed by 5599

Abstract

Structural information regarding metallothioneins (MTs) has been hard to come by due to its highly dynamic nature in the absence of metal-thiolate cluster formation and crystallization difficulties. Thus, typical spectroscopic methods for structural determination are limited in their usefulness when applied to MTs. Mass spectrometric methods have revolutionized our understanding of protein dynamics, structure, and folding. Recently, advances have been made in residue modification mass spectrometry in order to probe the hard-to-characterize structure of apo- and partially metalated MTs. By using different cysteine specific alkylation reagents, time dependent electrospray ionization mass spectrometry (ESI-MS), and step-wise “snapshot” ESI-MS, we are beginning to understand the dynamics of the conformers of apo-MT and related species. In this review we highlight recent papers that use these and similar techniques for structure elucidation and attempt to explain in a concise manner the data interpretations of these complex methods. We expect increasing resolution in our picture of the structural conformations of metal-free MTs as these techniques are more widely adopted and combined with other promising tools for structural elucidation. Full article

(This article belongs to the Special Issue Metallothioneins in Bioinorganic Chemistry: Recent Developments)

► Show Figures

Journal Menu

Journal Browser

Metallothioneins in Bioinorganic Chemistry: Recent Developments

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (10 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI