Metallothionein 1

Metallothionein

Metallothionein superfamily, eukaryotic

Solution structure of the beta-E-domain of wheat Ec-1 metallothionein.

Identifiers

Symbol Metallothionein_sfam

Pfam PF00131 [1]

InterPro IPR003019 [2]

Available protein structures:

Pfam structures [3]

PDB RCSB PDB [4]; PDBe [5]; PDBj [6]

PDBsum structure summary [7]

Yeast_MT

ag-substituted metallothionein from saccharomyces cerevisiae, nmr, minimized average structure

Identifiers

Symbol Yeast_MT

Pfam PF11403 [8]

InterPro IPR022710 [9]

Metallothionein 2

Available protein structures:

Pfam structures [10]

PDB RCSB PDB [11]; PDBe [12]; PDBj [13]

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 bothphysiological (such as zinc, copper, selenium) and xenobiotic (such as cadmium, mercury, silver, arsenic) heavymetals 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 metaltoxicity, be involved in regulation of physiological metals (Zn and Cu) and provide protection against oxidativestress. 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 andkidneys. Their production is dependent on availability of the dietary minerals, as zinc, copper and selenium, and theamino acids histidine and cysteine.

Structure and classificationMTs are present in a vast range of taxonomic groups, ranging from prokaryotes (such as the cyanobacteriaSyneccococus spp....), protozoa (p. ex. the ciliate Tetrahymena genera...), plants (such as Pisum sativum, Triticumdurum, 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, orthe echinoderm Strongylocentrotus purpuratus) and vertebrates (such as the chicken, Gallus gallus, or themammalian Homo sapiens or Mus musculus).The MTs from this diverse taxonomic range represent a high-heterogeneity sequence (regarding molecular weightand number and distribution of Cys residues) and do not show general homology; in spite of this, homology is foundinside some taxonomic groups (such as vertebrate MTs).From their primary structure, MTs have been classified by different methods. The first one dates from 1987, whenFowler 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 includesphytochelatins, Cys-rich enzymatically synthesised peptides. The second classification was performed by Binz andKagi in 2001, and takes into account taxonomic parameters and the patterns of distribution of Cys residues along theMT 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 thedistribution 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 3

Family Name Sequence pattern Example

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

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

S.purpuratus SpMTA

MPDVKCVCCKEGKECACFGQDCCKTGECCKDGTCCGICTNAACKCANGCKCGSGCSCTEGNCAC

5 Diptera C-G-x(2)-C-x-C-x(2)-Q-x(5)-C-x-C-x(2)D-C-x-C 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 MT3MEFTTAMLGASLISTTSTQSKHNLVNNCCCSSSTSESSMPASCACTKCGCKTCKC

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 Plant

15.1 Plant MTs Type

1

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)

Pisum sativum MT

MSGCGCGSSCNCGDSCKCNKRSSGLSYSEMETTETVILGVGPAKIQFEGAEMSAASEDGGCKCGDNCTCDPCNCK

15.2 Plant MTs Type

2

C-C-X(3)-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)

L.esculetum MT

MSCCGGNCGCGSSCKCGNGCGGCKMYPDMSYTESSTTTETLVLGVGPEKTSFGAMEMGESPVAENGCKCGSDCKCNPCTCSK

15.3 Plant MTs Type

3

--- A.thaliana MT3

MSSNCGSCDCADKTQCVKKGTSYTFDIVETQESYKEAMIMDVGAEENNANCKCKCGSSCSCVNCTCCPN

15.4 Plant MTs Type

4 or Ec

C-x(4)-C-X-C-X(3)-C-X(5)-C-X-C-X(9,11)-HTTCGCGEHC-

X-C-X(20)-CSCGAXCNCASC-X(3,5)

T.aestium MT

MGCNDKCGCAVPCPGGTGCRCTSARSDAAAGEHTTCGCGEHCGCNPCACGREGTPSGRANRRANCSCGAACNCASCGSTTA

99 Phytochelatins

and other

non-proteinaceous

MT-like

polypeptides

--- S.pombe

EC-EC-ECG

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

Metallothionein 4

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 suchstructures 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 abidominial structure with divalent metals as Zn(II) or Cd(II) (the protein is folded so as to bind metals in twofunctionally independent domains, with a metallic cluster each), yeast and procariotyc MTs show a monodominialstructure (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 bidominialstructure similar to that of vertebrate MTs; 2) a codominial structure, in which two Cys-rich domains interact to forma single metallic cluster.Quaternary structure has not been broadly considered for MTs. Dimerization and oligomerization processes havebeen 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-mediatedinteractions. Dimeric and polymeric MTs have been shown to acquire novel properties upon metal detoxification, butthe physiological significance of these processes has been demonstrated only in the case of prokaryoticSynechococcus SmtA. The MT dimer produced by this organism forms structures similar to zinc fingers and hasZn-regulatory activity.Metallothioneins have diverse metal-binding preferences, which have been associated with functional specificity. Asan example, the mammalian Mus musculus MT1 preferentially binds divalent metal ions (Zn(II), Cd(II),...), whileyeast CUP1 is selective for monovalent metal ions (Cu(I), Ag(I),...). A novel functional classification of MTs asZn- or Cu-thioneins is currently being developed based on these functional preferences.

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

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

StructureFor the first 40 residues in the protein the polypeptide wraps around the metal by forming two large parallel loopsseparated by a deep cleft containing the metal cluster.

Metallothionein 5

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

Function

Metal bindingMetallothionein 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 haveprovided strong evidence that metal-binding occurs via a sequential, noncooperative mechanism. The observation ofpartially metallated MT (that is, having some free metal binding capacity) suggest that these species are biologicallyimportant.Metallothioneins likely participate in the uptake, transport, and regulation of zinc in biological systems. MammalianMT binds three Zn(II) ions in its beta domain and four in the alpha domain. Cysteine is a sulfur-containing aminoacid, hence the name "-thionein". However, the participation of inorganic sulfide and chloride ions has beenproposed for some MT forms. In some MTs, mostly bacterial, histidine participates in zinc binding. By binding andreleasing zinc, metallothioneins (MTs) may regulate zinc levels within the body. Zinc, in turn, is a key element forthe activation and binding of certain transcription factors through its participation in the zinc finger region of theprotein. 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 whereit is released to another organelle or protein. In this way the thionein-metallothionein becomes a key component ofthe zinc signaling system in cells. This system is particularly important in the brain, where zinc signaling isprominent both between and within nerve cells. It also seems to be important for the regulation of the tumorsuppressor protein p53.

Control of oxidative stressCysteine residues from MTs can capture harmful oxidant radicals like the superoxide and hydroxyl radicals. In thisreaction, 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. Thismechanism has been proposed to be an important mechanism in the control of the oxidative stress by MTs. The roleof MTs in oxidative stress has been confirmed by MT Knockout mutants, but some experiments propose also aprooxidant role for MTs.

Expression and regulationMetallothionein 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 genespresent in their promotors specific sequences for the regulation of the expression, elements as metal responseelements (MRE), glucocorticoid response elements (GRE), GC-rich boxes, basal level elements (BLE), and thyroidresponse elements (TRE).[citation needed]

Metallothionein 6

Metallothionein and disease

CancerBecause MTs play an important role in transcription factor regulation, problems with MT function or expression maylead to malignant transformation of cells and ultimately cancer. Studies have found increased expression of MTs insome 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 inhepatocellular carcinoma and liver adenocarcinoma.There is evidence to suggest that higher levels of MT expression may also lead to resistance to chemotherapeuticdrugs.[citation needed]

AutismHeavy metal toxicity has been proposed as a hypothetical etiology of autism, and dysfunction of MT synthesis andactivity may play a role in this. Many heavy metals, including mercury, lead, and arsenic have been linked tosymptoms that resemble the neurological symptoms of autism. However, MT dysfunction has not specifically beenlinked to autistic spectrum disorders. A 2006 study, investigating children exposed to the vaccine preservativethiomersal, found that levels of MT and antibodies to MT in autistic children did not differ significantly fromnon-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 7

Article Sources and ContributorsMetallothionein 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

Image Sources, Licenses and ContributorsFile:Metallothionein.png Source: http://en.wikipedia.org/w/index.php?title=File:Metallothionein.png License: GNU General Public License Contributors: Jmol software developing teamFile:PDB 1aoo EBI.jpg Source: http://en.wikipedia.org/w/index.php?title=File:PDB_1aoo_EBI.jpg License: unknown Contributors: -

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MetallothioneinStructure and classification YeastFunction Structure Examples

FunctionMetal bindingControl of oxidative stress

Expression and regulation Metallothionein and diseaseCancer Autism

ReferencesFurther reading External links

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