THIRD INTERNATIONAL FESTEM SYMPOSIUM
Metallothionein functions and structural characteristics

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Abstract

Metallothioneins (MTs) are low molecular weight proteins characterized by a high cysteine content and give rise to metal-thiolate clusters. Most MTs have two metal clusters containing three and four bivalent metal ions, respectively. The MT gene family in mammals consists of four subfamilies designated MT-1 through MT-4. MT-3 is expressed predominantly in brain and MT-4 in differentiating stratified squamous epithelial cells. Many reports have addressed MT structure and function, but despite the increasing experimental data several topics remain to be clarified, and the true function of this elusive protein has yet to be disclosed. Owing to their induction by a variety of stimuli, MTs are considered valid biomarkers in medicine and environmental studies. Here, we will discuss only a few topics taken from the latest literature. Special emphasis will be placed on MT antioxidant functions, the related oxidation of cysteines, which can give rise to intra/intermolecular bridges, and the relations between MTs and diseases which could be originated by metal dysregulation.

Introduction

Metallothioneins (MTs), first isolated in the equine kidney [1], are ubiquitous low molecular weight proteins and polypeptides of extremely high metal and cysteine content which give rise to metal-thiolate clusters. Any protein or polypeptide resembling mammalian MTs can be classified as MT [2]. MTs constitute a protein superfamily of 15 families comprising many sequences inferred from both aminoacid and polynucleotide sequences obtained from all animal phyla examined to date and also from certain fungi, plants and cyanobacteria [3]. The MT gene family in mammals consists of four subfamilies designated MT-1 through MT-4. The study of MTs includes the competences in different fields, which range from analytical chemistry and structural spectroscopy to molecular biology and medicine. There is currently no simple quantification method to detect tissue concentrations of MT whereas sophisticated 2D NMR spectroscopy shows that despite their different aminoacid sequences MTs have similar spatial structure with two metal-thiolate clusters containing three and four bivalent metal ions, respectively [4]. Increasing evidence shows that mammalian MT-1/MT-2 isoforms are involved in zinc homeostasis and protection against heavy metal toxicity and oxidative stress. MT-3 is expressed mainly in neurons but also in glia; MT-4 is mostly present in differentiating stratified squamous epithelial cells. Many reports have described MT structure, functions [5], [6], [7] and gene expression [8], but despite the increasing data several topics await clarification and the true function of this elusive protein [9] has yet to be disclosed.

Owing to their induction by a variety of stimuli, MTs are considered valid biomarkers in the medical and environmental fields. Here, we will discuss only few topics taken mostly from recent papers among the 7960 reported in Pub Med. The same site gives the following references when entering MT and the link-word in brackets: 2852 (zinc), 2781 (cadmium), 1689 (copper), 1133 (cancer), 415 (carcinoma), 55 (Alzheimer-AD), 33 (Amyotrophic Lateral Sclerosis-ALS), 15 (Parkinson), and 5 (Prion).

Section snippets

Structure

  • (1)

    Thionein: Despite the wealth of information available for the metallated mammalian MTs, the exact mechanism of the initial metal ion chelation remains unsettled as do the kinetics of removal and subsequent protein unfolding. Apo-MT has recently been reported in the cell in quantities equal to those of the metallated protein, which might indicate a potential role for MT in the absence of metals. Calculations carried out on the demetallation of CdMT1a indicate the metal free protein is

Transcription

The exact mechanisms controlling MT synthesis are not well understood but there is a general consensus that the metal responsive element-binding transcription factor-1 (MTF-1) plays an important role in MT transcription. Several lines of evidence suggest that the highly conserved six-zinc finger DNA-binding domain of MTF1 functions as a zinc-sensing domain and the linkers between the six different fingers can actively participate in modulating MTF1 translocation to the nucleus and binding to

Function

  • (1)

    MT as scavenger of free radicals: Since the classical work of Thornalley and Vasak [15] on the scavenging activity of MT toward free hydroxyl (°OH) and superoxide (O2°−) radicals produced by the xantine/xantine oxidase reaction much more evidence has accumulated on the antioxidant activity of MT by in vivo and in vitro experiments [16]. Several animal and cell models and free radical generating systems have been investigated. Using an epithelioma cell line from a piscine species (Cyprinus carpio

MT and diseases

There is a growing amount of exciting information on the genome changes from fertilization through the different stages of the individual life span and the ongoing phenotype modifications caused by diseases and environmental changes. Misregulation of gene repression and activation can be related to the etiology of animal diseases in a very large number of cases, and many transcription factors belong to the zinc-finger protein family [21]. Considering that metal metabolism is dysregulated and

MT quantification and MT as biomarker of environmental metal exposure

It is generally accepted that MT is an important defense against the detoxification of non-essential metals like cadmium and mercury. The early induction of MT by trace metals, namely cadmium, in different species makes this protein a potential and biomarker useful to assess the ecotoxicological significance of non-essential (Cd, Hg) and essential, but potentially toxic (Cu), trace metals.

The accurate measurement of MT is mandatory to assess its biomarker potential. This aspect has been revised

References (40)

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    Also, exposure of intestinal goblet-like cells (LS174T) to acetaldehyde increased expression of MUC2 which was reported to have a detrimental effect on mucus function (Elamin et al., 2014), suggesting that some cells may increase secretion of less functional mucus when exposed to chemicals. Metallothioneins (MT) can shield cells against damage caused by metals such as ROS production, DNA damage, oxidative stress, cell damage, angiogenesis, apoptosis, and increase cell proliferation (Takahashi, 2012; Carpene et al., 2007; Ruttkay-Nedecky et al., 2013). Elevated cellular Cu concentrations can trigger the transcription of MT genes and MT protein synthesis in mice (Bremner, 1987; Suzuki et al., 2002).

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