Metallothionein

Metallothionein superfamily (plant)
Beta-E-domain of wheat Ec-1 metallothionein bound to zinc ions. Cysteines in yellow, zinc in purple. (PDB: 2KAK​)[1]
Identifiers
Symbol	Metallothionein_sfam
Pfam	PF00131
InterPro	IPR003019
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary PDB PDB: 1dfs​ PDB: 1dft​ PDB: 1dmc​ PDB: 1dmd​ PDB: 1dme​ PDB: 1dmf​ PDB: 1j5l​ PDB: 1j5m​ PDB: 1ji9​ PDB: 1m0g​

Yeast MT
Saccharomyces cerevisiae MT metallothionein bound to copper ions. Cysteines in yellow, copper in brown. (PDB: 1AQS​)
Identifiers
Symbol	Yeast metallothionein
Pfam	PF11403
Pfam clan	CL0461
InterPro	IPR022710
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Metallothionein (MT) is a family of

Metallothioneins are rich in thiols, causing them to bind a number of trace metals. Metallothionein is one of the few eukaryotic proteins playing a substantial role in metal detoxification. Zinc and Cadmium are tetrahedrally coordinated to cysteine residues, and each metallothionein protein molecule may bind up to 7 atoms of Zn or Cd.[5] The biosynthesis of metallothionein appears to increase several-fold during periods of oxidative stress to shield the cells against cytotoxicity and DNA damage. Metallothionein biosynthesis can also be induced by certain hormones, pharmaceuticals, alcohols, and other compounds.^[6] Metallothionein expression is upregulated during fetal development, particularly in liver tissue.^[7]

Structure and classification

MTs are present in a vast range of taxonomic groups, ranging from prokaryotes (such as the cyanobacteria

The MTs from this diverse taxonomic range represent a high-heterogeneity sequence (regarding molecular weight and number and distribution of Cys residues) and do not show general homology; in spite of this, homology is found inside some taxonomic groups (such as vertebrate MTs).

From their primary structure, MTs have been classified by different methods. The first one dates from 1987, when Fowler et al., established three classes of MTs: Class I, including the MTs which show homology with horse MT, Class II, including the rest of the MTs with no homology with horse MT, and Class III, which includes phytochelatins, Cys-rich enzymatically synthesised peptides. The second classification was performed by Binz and Kagi in 2001, and takes into account taxonomic parameters and the patterns of distribution of Cys residues along the MT sequence. It results in a classification of 15 families for proteinaceous MTs. Family 15 contains the plant MTs, which in 2002 have been further classified by Cobbet and Goldsbrough into 4 Types (1, 2, 3 and 4) depending on the distribution of their Cys residues and a Cys-devoid regions (called spacers) characteristic of plant MTs.

A table including the principal aspects of the two latter classifications is included.

More data on this classification are discoverable at the Expasy metallothionein page.^[8]

Secondary structure elements have been observed in several MTs SmtA from Syneccochoccus, mammalian MT3, Echinoderma SpMTA, fish Notothenia coriiceps MT, Crustacean MTH, but until this moment, the content of such structures is considered to be poor in MTs, and its functional influence is not considered.

Tertiary structure of MTs is also highly heterogeneous. While vertebrate, echinoderm and crustacean MTs show a bidominial structure with divalent metals as Zn(II) or Cd(II) (the protein is folded so as to bind metals in two functionally independent domains, with a metallic cluster each), yeast and prokaryotic MTs show a monodominial structure (one domain with a single metallic cluster). In yeast, the first 40

Metallothioneins have diverse metal-binding preferences, which have been associated with functional specificity. As an example, the mammalian Mus musculus MT1 preferentially binds divalent metal ions (Zn(II), Cd(II),...), while yeast CUP1 is selective for monovalent metal ions (Cu(I), Ag(I),...). Strictly metal-selective MTs with metal-specific physiological functions were discovered by Dallinger et al. (1997) in pulmonate snails (Gastropoda, Mollusca).^[10] The Roman snail (Helix pomatia), for example, possesses a Cd-selective (CdMT) and a Cu-selective isoform (CuMT) involved in Cd detoxification and Cu regulation, respectively.^[10] While both isoforms contain unvaried numbers and positions of Cys residues responsible for metal ligation, metal selectivity is apparently achieved by sequence modulation of amino acid residues not directly involved in metal binding (Palacios et al. 2011).^[10][11]

A novel functional classification of MTs as Zn- or Cu-thioneins is currently being developed based on these functional preferences.

Function

The main biological function of metallothioneins is to maintain homeostasis of the essential metals zinc and copper, but metallothioneins also protect against metal toxicity and oxidative stress.^[12]

Metal binding

Metallothionein has been documented to bind a wide range of metals including cadmium,^[13] lead,^[14] zinc, mercury, copper, arsenic, silver, etc. Metalation of MT was previously reported to occur cooperatively ^{[citation needed]} but recent reports have provided strong evidence that metal-binding occurs via a sequential, noncooperative mechanism.^[15] The observation of partially metalated MT (that is, having some free metal binding capacity) suggest that these species are biologically important.

Metallothioneins likely participate in the uptake, transport, and regulation of zinc in biological systems. Mammalian MT binds three Zn(II) ions in its beta domain and four in the alpha domain. Cysteine is a sulfur-containing amino acid, hence the name "-thionein". However, the participation of inorganic sulfide and chloride ions has been proposed for some MT forms. In some MTs, mostly bacterial, histidine participates in zinc binding. By binding and releasing zinc, metallothioneins (MTs) may regulate zinc levels within the body. Zinc, in turn, is a key element for the activation and binding of certain transcription factors through its participation in the zinc finger region of the protein.^[16][17] Metallothionein also carries zinc ions (signals) from one part of the cell to another. When zinc enters a cell, it can be picked up by thionein (which thus becomes "metallothionein") and carried to another part of the cell where it is released to another organelle or protein.^[18] In this way thionein and metallothionein becomes a key component of the zinc signaling system in cells. This system is particularly important in the brain, where zinc signaling is prominent both between and within nerve cells. It also seems to be important for the regulation of the tumor suppressor protein p53.

Control of oxidative stress

Cysteine residues from MTs can capture harmful oxidant radicals like the superoxide and hydroxyl radicals.^[19] In this reaction, cysteine is oxidized to cystine, and the metal ions which were bound to cysteine are liberated to the media. As explained in the Expression and regulation section, this Zn can activate the synthesis of more MTs. This mechanism has been proposed to be an important mechanism in the control of the oxidative stress by MTs. The role of MTs in reducing oxidative stress has been confirmed by MT Knockout mutants, but some experiments propose also a prooxidant role for MTs.^{[citation needed]}

In mammalian cells, spontaneous mutagenesis is caused to a large extent by oxidative DNA damage, and the occurrence of such damage can be blocked by metallothionein.^[20]

Metallothionein also plays a role in hematopoietic cell differentiation and proliferation, as well as prevention of apoptosis of early differentiated cells. Induced MT levels were adversely associated with sensitivity to etoposide-induced apoptosis, signifying that MT is a potential negative controller of apoptosis.^[21]

Expression and regulation

Metallothionein gene expression is induced by a high variety of stimuli, as metal exposure, oxidative stress, glucocorticoids,

Because MTs play an important role in transcription factor regulation, defects in MT function or expression may lead to malignant transformation of cells and ultimately cancer.^[25] Studies have found increased expression of MTs in some cancers of the breast, colon, kidney, liver, skin (melanoma), lung, nasopharynx, ovary, prostate, mouth, salivary gland, testes, thyroid and urinary bladder; they have also found lower levels of MT expression in hepatocellular carcinoma and liver adenocarcinoma.^[26]

Evidence suggests that greater MT expression may cause resistance to chemotherapy.^[27]

Autism

Heavy metal toxicity has been

A low zinc to copper ratio has been seen as a biomarker for autism and suggested as an indication that the metallothionein system has been affected.[30]

Further, there is indication that the mother's zinc levels may affect the developing baby's immunological state that may lead to autism and could be again an indication that the metallothionein system has been affected.^[31]

Role of Metallothionein in Cardiovascular disease

Metallothionein (MT) is an indirect redox balance regulator which regulates nuclear factor red blood cell 2-related factor 2 (Nrf2) in the body. However, MT plays an important role in the anti-injury protection of the cardiovascular system, mainly in its inhibitory effect on ischemia-reperfusion injury. Also, the MT activation of the Nrf2 mediates intermittent hypoxia (IH) cardiomyopathy protection.^[32]

Transgenic mice with a deletion of any Nrf2 gene (Nrf2-KO) are highly susceptible to the cardiovascular effects of intermittent hypoxia (IH) via cardiac oxidative damage, inflammation, fibrosis, and dysfunction.^[32]

Moreover, the specific overexpression in cardiomyocytes of Nrf2 (Nrf2-TG) in transgenic mice[KC1]  is impervious to cardiac oxidative damage, inflammation, fibrosis, and dysfunction caused by intermittent hypoxia (IH)[KC2] . In response to IH, Nrf2 and its downstream antioxidants are strongly MT-dependent Nrf2 and may [KC3] act as a compensatory response to IH exposure by up-regulating MT (downstream antioxidant target genes) to protect the heart.^[32]

Prolonged exposure to IH reduces the binding of Nrf2 factor to the MT promoter gene, thereby inhibiting MT translation and expression. Moreover, a complex PI3K/Akt/GSK3B/Fyn signaling network provides cardio protection against IH when Nrf2 or MT is overexpressed in the heart. By activating the PI3K/Akt/GSK3B/Fyn signaling pathway, MT increaseNrf2 expression and transcriptional function in response to IH exposure. Although not yet proven, these effects suggest that it is possible to activate PI3K/Akt/GSK3B/Fyn dependent signaling pathways through cardiac MT overexpression to prevent chronic IH-induced cardiomyopathy and downregulation of Nrf2.^[32]

Therefore, Nrf2 or MT may be a potential treatment to avoid chronic IH-induced cardiomyopathy.

Identifiers
Symbol	Human metallothionein
PDB Code	2FJ4
Classification	Metal Binding Protein

See also

• Phytochelatin

References