Please note: this site relies heavily on the use of javascript. Without a javascript-enabled browser, this site will not function correctly. Please enable javascript and reload the page, or switch to a different browser.
21  structures 201  species 0  interactions 581  sequences 4  architectures

Family: Metallothio (PF00131)

Summary: Metallothionein

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Metallothionein". More...

Metallothionein Edit Wikipedia article

Metallothionein superfamily, eukaryotic
Metallothionein.png
Solution structure of the beta-E-domain of wheat Ec-1 metallothionein.[1]
Identifiers
Symbol Metallothionein_sfam
Pfam PF00131
InterPro IPR003019
Yeast_MT
PDB 1aoo EBI.jpg
ag-substituted metallothionein from saccharomyces cerevisiae, nmr, minimized average structure
Identifiers
Symbol Yeast_MT
Pfam PF11403
InterPro IPR022710

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.[2]

MT was discovered in 1957 by Vallee and Margoshe from purification of a Cd-binding protein from horse (equine) renal cortex.[3] 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.

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 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 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
γEC-γEC-γECG

More data on this classification are discoverable at the Expasy metallothionein page.[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 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.[5] 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.[5]

Examples

Yeast MT can be found in the following:[6]

  • Saccharomyces cerevisiae
  • Neurospora crassa

Function

Metal binding

Metallothionein has been documented to bind a wide range of metals including cadmium,[7] 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.[8] 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.[9] 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 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.[10] 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.[11]

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.[12] 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.[13]

See also

References

  1. ^ PDB 2KAK; Peroza EA, Schmucki R, Güntert P, Freisinger E, Zerbe O (March 2009). "The beta(E)-domain of wheat E(c)-1 metallothionein: a metal-binding domain with a distinctive structure". J. Mol. Biol. 387 (1): 207–18. doi:10.1016/j.jmb.2009.01.035. PMID 19361445. 
  2. ^ Sigel H, Sigel A, ed. (2009). Metallothioneins and Related Chelators (Metal Ions in Life Sciences). Metal Ions in Life Sciences 5. Cambridge, England: Royal Society of Chemistry. ISBN 1-84755-899-2. 
  3. ^ Margoshes M, Vallee BL (1957). "A cadmium protein from equine kidney cortex". Journal of American Chemical Society 79 (17): 4813. doi:10.1021/ja01574a064. 
  4. ^ "Metallothioneins: classification and list of entries". www.uniprot.org. 
  5. ^ a b Peterson CW, Narula SS, Armitage IM (January 1996). "3D solution structure of copper and silver-substituted yeast metallothioneins". FEBS Lett. 379 (1): 85–93. doi:10.1016/0014-5793(95)01492-6. PMID 8566237. 
  6. ^ Butt TR, Ecker DJ (September 1987). "Yeast metallothionein and applications in biotechnology". Microbiol. Rev. 51 (3): 351–64. PMC 373116. PMID 3312986. 
  7. ^ Freisinger E, Vašák M (2013). "Cadmium in metallothioneins". Met Ions Life Sci 11: 339–71. doi:10.1007/978-94-007-5179-8_11. PMID 23430778. 
  8. ^ Krezel A, Maret W (September 2007). "Dual nanomolar and picomolar Zn(II) binding properties of metallothionein". J. Am. Chem. Soc. 129 (35): 10911–21. doi:10.1021/ja071979s. PMID 17696343. 
  9. ^ Kumari MV, Hiramatsu M, Ebadi M (August 1998). "Free radical scavenging actions of metallothionein isoforms I and II". Free Radic. Res. 29 (2): 93–101. doi:10.1080/10715769800300111. PMID 9790511. 
  10. ^ Krizkova S, Fabrik I, Adam V, Hrabeta J, Eckschlager T, Kizek R (2009). "Metallothionein--a promising tool for cancer diagnostics". Bratisl Lek Listy 110 (2): 93–7. PMID 19408840. 
  11. ^ Cherian, M. (2003). "Metallothioneins in human tumors and potential roles in carcinogenesis". Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 533: 201–209. doi:10.1016/j.mrfmmm.2003.07.013.  edit
  12. ^ Drum DA (October 2009). "Are toxic biometals destroying your children's future?". Biometals 22 (5): 697–700. doi:10.1007/s10534-009-9212-9. PMID 19205900. 
  13. ^ Singh VK, Hanson J (June 2006). "Assessment of metallothionein and antibodies to metallothionein in normal and autistic children having exposure to vaccine-derived thimerosal". Pediatr Allergy Immunol 17 (4): 291–6. doi:10.1111/j.1399-3038.2005.00348.x. PMID 16771783. 

Further reading

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Metallothionein Provide feedback

No Pfam abstract.

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR003019

Metallothioneins (MT) are small proteins that bind heavy metals, such as zinc, copper, cadmium, nickel, etc. They have a high content of cysteine residues that bind the metal ions through clusters of thiolate bonds [PUBMED:1779825, PUBMED:2959513]. An empirical classification into three classes has been proposed by Fowler and coworkers [PUBMED:2959504] and Kojima [PUBMED:1779826]. Members of class I are defined to include polypeptides related in the positions of their cysteines to equine MT-1B, and include mammalian MTs as well as from crustaceans and molluscs. Class II groups MTs from a variety of species, including sea urchins, fungi, insects and cyanobacteria. Class III MTs are atypical polypeptides composed of gamma-glutamylcysteinyl units [PUBMED:2959504].

This original classification system has been found to be limited, in the sense that it does not allow clear differentiation of patterns of structural similarities, either between or within classes. Consequently, all class I and class II MTs (the proteinaceous sequences) have now been grouped into families of phylogenetically-related and thus alignable sequences. This system subdivides the MT superfamily into families, subfamilies, subgroups, and isolated isoforms and alleles.

The metallothionein superfamily comprises all polypeptides that resemble equine renal metallothionein in several respects [PUBMED:2959504]: e.g., low molecular weight; high metal content; amino acid composition with high Cys and low aromatic residue content; unique sequence with characteristic distribution of cysteines, and spectroscopic manifestations indicative of metal thiolate clusters. A MT family subsumes MTs that share particular sequence-specific features and are thought to be evolutionarily related. The inclusion of a MT within a family presupposes that its amino acid sequence is alignable with that of all members. Fifteen MT families have been characterised, each family being identified by its number and its taxonomic range: e.g., Family 1: vertebrate MTs [see http://www.bioc.unizh.ch/mtpage/protali.html].

This entry is a superfamily of metallothioneins, containing 3 families. All members are from eukaryotes.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

Loading domain graphics...

Pfam Clan

This family is a member of clan Metallothionein (CL0461), which has the following description:

This superfamily contains related families of metallothioneins, prokaryotes and eukaryotes.

The clan contains the following 5 members:

Metallothi_Euk2 Metallothio Metallothio_6 Metallothio_Euk Metallothio_Pro

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(21)
Full
(581)
Representative proteomes NCBI
(522)
Meta
(0)
RP15
(14)
RP35
(17)
RP55
(30)
RP75
(109)
Jalview View  View  View  View  View  View  View   
HTML View  View  View  View  View  View     
PP/heatmap 1 View  View  View  View  View     
Pfam viewer View  View             

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(21)
Full
(581)
Representative proteomes NCBI
(522)
Meta
(0)
RP15
(14)
RP35
(17)
RP55
(30)
RP75
(109)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(21)
Full
(581)
Representative proteomes NCBI
(522)
Meta
(0)
RP15
(14)
RP35
(17)
RP55
(30)
RP75
(109)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download    
Gzipped Download   Download   Download   Download   Download   Download   Download    

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: metalthio;
Type: Domain
Author: Sonnhammer ELL
Number in seed: 21
Number in full: 581
Average length of the domain: 58.90 aa
Average identity of full alignment: 56 %
Average coverage of the sequence by the domain: 96.13 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.6 20.6
Trusted cut-off 20.6 20.6
Noise cut-off 20.5 20.4
Model length: 63
Family (HMM) version: 15
Download: download the raw HMM for this family

Species distribution

Sunburst controls

Show

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

Loading sunburst data...

Tree controls

Hide

The tree shows the occurrence of this domain across different species. More...

Loading...

Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Metallothio domain has been found. There are 21 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

Loading structure mapping...