Metallothionein

Metallothionein
Metallothionein superfamily, eukaryotic

Solution structure of the beta-E-domain of wheat Ec-1 metallothionein. Identifiers Symbol Pfam InterPro Metallothionein_sfam PF00131 [1] [2]

IPR003019

Available protein structures: Pfam PDB structures [3] [4] ; PDBe [5] ; PDBj [6]

RCSB PDB

PDBsum structure summary [7]

Yeast_MT

ag-substituted metallothionein from saccharomyces cerevisiae, nmr, minimized average structure Identifiers Symbol Pfam InterPro Yeast_MT PF11403 [8] [9]

IPR022710

Metallothionein

Available protein structures: Pfam PDB structures [10] [11] ; PDBe [12] ; PDBj [13]

RCSB PDB

PDBsum structure summary [14]

Metallothionein (MT) is a family of cysteine-rich, low molecular weight (MW ranging from 500 to 14000 Da) proteins. They are localized to the membrane of the Golgi apparatus. MTs have the capacity to bind both physiological (such as zinc, copper, selenium) and xenobiotic (such as cadmium, mercury, silver, arsenic) heavy metals through the thiol group of its cysteine residues, which represents nearly the 30% of its amino acidic residues. MT was discovered in 1957 by Vallee and Margoshe from purification of a Cd-binding protein from horse (equine) renal cortex. MTs function is not clear, but experimental data suggest MTs may provide protection against metal toxicity, be involved in regulation of physiological metals (Zn and Cu) and provide protection against oxidative stress. There are four main isoforms expressed in humans (family 1, see chart below): MT1 (subtypes A, B, E, F, G, H, L, M, X), MT2, MT3, MT4. In the human body, large quantities are synthesised primarily in the liver and kidneys. Their production is dependent on availability of the dietary minerals, as zinc, copper and selenium, and the amino acids histidine and cysteine.

Structure and classification

MTs are present in a vast range of taxonomic groups, ranging from prokaryotes (such as the cyanobacteria Syneccococus spp....), protozoa (p. ex. the ciliate Tetrahymena genera...), plants (such as Pisum sativum, Triticum durum, Zea mays, Quercus suber...), yeast (such as Saccharomyces cerevisiae, Candida albicans,...), invertebrates (such as the nematode Caenorhabditis elegans, the insect Drosophila melanogaster, the mollusc Mytilus edulis, or the echinoderm Strongylocentrotus purpuratus) and vertebrates (such as the chicken, Gallus gallus, or the mammalian Homo sapiens or Mus musculus). 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.

Metallothionein

Family 1

Name Vertebrate

Sequence pattern K-x(1,2)-C-C-x-C-C-P-x(2)-C M.musculus MT1

Example

MDPNCSCTTGGSCACAGSCKCKECKCTSCKKCCSCCPVGCAKCAQGCVCKGSSEKCRCCA 2 Molluscan C-x-C-x(3)-C-T-G-x(3)-C-x-C-x(3)-C-x-C-K M.edulis 10MTIV MPAPCNCIETNVCICDTGCSGEGCRCGDACKCSGADCKCSGCKVVCKCSGSCACEGGCTGPSTCKCAPGCSCK 3 Crustacean P-[GD)-P-C-C-x(3,4)-C-x-C H.americanus MTH MPGPCCKDKCECAEGGCKTGCKCTSCRCAPCEKCTSGCKCPSKDECAKTCSKPCKCCP 4 Echinoderms P-D-x-K-C-[V,F)-C-C-x(5)-C-x-C-x(4)C-C-x(4)-C-C-x(4,6)-C-C 5 Diptera C-G-x(2)-C-x-C-x(2)-Q-x(5)-C-x-C-x(2)D-C-x-C S.purpuratus SpMTA MPDVKCVCCKEGKECACFGQDCCKTGECCKDGTCCGICTNAACKCANGCKCGSGCSCTEGNCAC D.melanogaster MTNB MVCKGCGTNCQCSAQKCGDNCACNKDCQCVCKNGPKDQCCSNK 6 Nematoda K-C-C-x(3)-C-C C.elegans MT1 MACKCDCKNKQCKCGDKCECSGDKCCEKYCCEEASEKKCCPAGCKGDCKCANCHCAEQKQCGDKTHQHQGTAAAH 7 Ciliate x-C-C-C-x ? T.termophila MTT1 MDKVNSCCCGVNAKPCCTDPNSGCCCVSKTDNCCKSDTKECCTGTGEGCKCVNCKCCKPQANCCCGVNAKPCCFDPNSGCCCVSKTNNCCKSD TKECCTGTGEGCKCTSCQCCKPVQQGCCCGDKAKACCTDPNSGCCCSNKANKCCDATSKQECQTCQCCK 8 Fungal 1 C-G-C-S-x(4)-C-x-C-x(3,4)-C-x-C-S-x-C N.crassa MT MGDCGCSGASSCNCGSGCSCSNCGSK 9 Fungal 2 --C.glabrata MT2 MANDCKCPNGCSCPNCANGGCQCGDKCECKKQSCHGCGEQCKCGSHGSSCHGSCGCGDKCECK 10 Fungal 3 --C.glabrata MT2 MPEQVNCQYDCHCSNCACENTCNCCAKPACACTNSASNECSCQTCKCQTCKC 11 Fungal 4 C-X-K-C-x-C-x(2)-C-K-C Y.lipolitica MT3 MEFTTAMLGASLISTTSTQSKHNLVNNCCCSSSTSESSMPASCACTKCGCKTCKC 12 Fungal 5 --S.cerevisiae CUP1 MFSELINFQNEGHECQCQCGSCKNNEQCQKSCSCPTGCNSDDKCPCGNKSEETKKSCCSGK 13 Fungal 6 --S.cerevisiae CRS5 TVKICDCEGECCKDSCHCGSTCLPSCSGGEKCKCDHSTGSPQCKSCGEKCKCETTCTCEKSKCNCEKC 14 Procaryota K-C-A-C-x(2)-C-L-C Synechococcus sp SmtA MTTVTQMKCACPHCLCIVSLNDAIMVDGKPYCSEVCANGTCKENSGCGHAGCGCGSA 15 15.1 Plant Plant MTs Type 1 15.2 Plant MTs Type 2 15.3 Plant MTs Type 3 15.4 Plant MTs Type 4 or Ec 99 Phytochelatins and other non-proteinaceous MT-like polypeptides C-X-C-X(3)- C-X-C-X(3)- C-X-C-X(3)-spacer-C-X-C-X(3)C-X-C-X(3)- C-X-C-X(3) C-C-X(3)-C-X-C-X(3)- C-X-C-X(3)- C-X-C-X(3)-spacerC-X-C-X(3)- C-X-C-X(3)- C-X-C-X(3) --Pisum sativum MT MSGCGCGSSCNCGDSCKCNKRSSGLSYSEMETTETVILGVGPAKIQFEGAEMSAASEDGGCKCGDNCTCDPCNCK L.esculetum MT MSCCGGNCGCGSSCKCGNGCGGCKMYPDMSYTESSTTTETLVLGVGPEKTSFGAMEMGESPVAENGCKCGSDCKCNPCTCSK A.thaliana MT3 MSSNCGSCDCADKTQCVKKGTSYTFDIVETQESYKEAMIMDVGAEENNANCKCKCGSSCSCVNCTCCPN C-x(4)-C-X-C-X(3)-C-X(5)-C-X-C-X(9,11)-HTTCGCGEHC- T.aestium MT X-C-X(20)-CSCGAXCNCASC-X(3,5) --MGCNDKCGCAVPCPGGTGCRCTSARSDAAAGEHTTCGCGEHCGCNPCACGREGTPSGRANRRANCSCGAACNCASCGSTTA S.pombe EC-EC-ECG

More data on this classification are discoverable at the Expasy metallothionein page.

Metallothionein 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 procariotyc MTs show a monodominial structure (one domain with a single metallic cluster). Although no structural data is available for molluscan, nematoda and Drosophila MTs, it is commonly assumed that the former are bidominial and the latter monodominial. No conclusive data are available for Plant MTs, but two possible structures have been proposed: 1) a bidominial structure similar to that of vertebrate MTs; 2) a codominial structure, in which two Cys-rich domains interact to form a single metallic cluster. Quaternary structure has not been broadly considered for MTs. Dimerization and oligomerization processes have been observed and attributed to several molecular mechanisms, including intermolecular disulfide formation, bridging through metals bound by either Cys or His residues on different MTs, or inorganic phosphate-mediated interactions. Dimeric and polymeric MTs have been shown to acquire novel properties upon metal detoxification, but the physiological significance of these processes has been demonstrated only in the case of prokaryotic Synechococcus SmtA. The MT dimer produced by this organism forms structures similar to zinc fingers and has Zn-regulatory activity. 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),...). A novel functional classification of MTs as Zn- or Cu-thioneins is currently being developed based on these functional preferences.

Yeast
Metallothioneins are characterised by an abundance of cysteine residues and a lack of generic secondary structure motifs. Yeast Metallothionein (MT) are also alternatively named, Copper metallothionein (CUP).

Function
This protein functions in primary metal storage, transport and detoxification. More specifically, Yeast MT stores copper so therefore protects the cell against copper toxicity by tightly chelating copper ions.

Structure
For the first 40 residues in the protein the polypeptide wraps around the metal by forming two large parallel loops separated by a deep cleft containing the metal cluster.

Metallothionein

Examples
Yeast MT can be found in the following: Saccharomyces cerevisiae Neurospora crassa

Function
Metal binding
Metallothionein has been documented to bind a wide range of metals including cadmium, zinc, mercury, copper, arsenic, silver, etc. Metallation of MT was previously reported to occur cooperatively but recent reports have provided strong evidence that metal-binding occurs via a sequential, noncooperative mechanism. The observation of partially metallated 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. 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. In this way the thionein-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. 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 oxidative stress has been confirmed by MT Knockout mutants, but some experiments propose also a prooxidant role for MTs.

Expression and regulation

Metallothionein gene expression is induced by a high variety of stimuli, as metal exposure, oxidative stress, glucocorticoids, hydric stress, etc. The level of the response to these inducers depends on the MT gene. MT genes present in their promotors specific sequences for the regulation of the expression, elements as metal response elements (MRE), glucocorticoid response elements (GRE), GC-rich boxes, basal level elements (BLE), and thyroid response elements (TRE).[citation needed]

Metallothionein

Metallothionein and disease

Cancer
Because MTs play an important role in transcription factor regulation, problems with MT function or expression may lead to malignant transformation of cells and ultimately cancer. 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. There is evidence to suggest that higher levels of MT expression may also lead to resistance to chemotherapeutic drugs.[citation needed]

Autism
Heavy metal toxicity has been proposed as a hypothetical etiology of autism, and dysfunction of MT synthesis and activity may play a role in this. Many heavy metals, including mercury, lead, and arsenic have been linked to symptoms that resemble the neurological symptoms of autism. However, MT dysfunction has not specifically been linked to autistic spectrum disorders. A 2006 study, investigating children exposed to the vaccine preservative thiomersal, found that levels of MT and antibodies to MT in autistic children did not differ significantly from non-autistic children.

References
[1] http:/ / pfam. sanger. ac. uk/ family?acc=PF00131 [2] http:/ / www. ebi. ac. uk/ interpro/ entry/ IPR003019 [3] http:/ / pfam. sanger. ac. uk/ family/ PF00131?tab=pdbBlock [4] http:/ / www. rcsb. org/ pdb/ search/ smartSubquery. do?smartSearchSubtype=PfamIdQuery& pfamID=PF00131 [5] http:/ / www. ebi. ac. uk/ pdbe-srv/ PDBeXplore/ pfam/ ?pfam=PF00131 [6] http:/ / pdbj. org/ searchFor?query=PF00131 [7] http:/ / www. ebi. ac. uk/ thornton-srv/ databases/ cgi-bin/ pdbsum/ GetPfamStr. pl?pfam_id=PF00131 [8] http:/ / pfam. sanger. ac. uk/ family?acc=PF11403 [9] http:/ / www. ebi. ac. uk/ interpro/ entry/ IPR022710 [10] http:/ / pfam. sanger. ac. uk/ family/ PF11403?tab=pdbBlock [11] http:/ / www. rcsb. org/ pdb/ search/ smartSubquery. do?smartSearchSubtype=PfamIdQuery& pfamID=PF11403 [12] http:/ / www. ebi. ac. uk/ pdbe-srv/ PDBeXplore/ pfam/ ?pfam=PF11403 [13] http:/ / pdbj. org/ searchFor?query=PF11403 [14] http:/ / www. ebi. ac. uk/ thornton-srv/ databases/ cgi-bin/ pdbsum/ GetPfamStr. pl?pfam_id=PF11403

Further reading
Cherian MG, Jayasurya A, Bay BH (December 2003). "Metallothioneins in human tumors and potential roles in carcinogenesis". Mutat. Res. 533 (12): 2019. doi: 10.1016/j.mrfmmm.2003.07.013 (http://dx.doi.org/10. 1016/j.mrfmmm.2003.07.013). PMID 14643421 (http://www.ncbi.nlm.nih.gov/pubmed/14643421).

External links
Expasy metallothionein page (http://expasy.org/cgi-bin/lists?metallo.txt)

Article Sources and Contributors

Article Sources and Contributors

Metallothionein Source: http://en.wikipedia.org/w/index.php?oldid=594482063 Contributors: -OOPSIE-, Ben Thuronyi, Benbest, Biologos, Boghog, Chris the speller, Crusadeonilliteracy, DH85868993, Dcirovic, Dudewheresmywallet, Duossm49, Eubulides, Greg G, Gregogil, Hodja Nasreddin, Icairns, Idril, Ivs5982, Jcolbyk, Jinkinson, John of Reading, Jordi domenech, Juliawikijulia, Kfh123, Mushin, Narayanese, Petergans, Pietdesomere, Poco a poco, Rich Farmbrough, Rjwilmsi, Rune.welsh, Scientizzle, Silentkarter, SmartGuy Old, Talia ali, Tavilis, TenOfAllTrades, TheParanoidOne, Thsgrn, Yandman, Yggdrsil, Yobol, 62 anonymous edits

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