Metallothioneins

Metallothioneins (MT) are a family of small cytoplasmic proteins that have the ability to bind heavy metals . They occur in almost all animals and plants , as well as in some prokaryotes , and are characterized by the lack of aromatic amino acids and an exceptionally high cysteine content of approx. 30%. The first MT were isolated from horse kidney in 1957.

The task of MT in the organism is not fully understood, but there are indications that they are involved in the elimination of toxic metals (especially cadmium , but also mercury , silver ). Some authors also consider it possible that they have regulatory functions for physiological metals such as copper and zinc , and their role as part of a protective mechanism against oxidative stress is also discussed.

Four isoforms are expressed in humans , in large quantities mainly in the liver and kidneys .

Structure and classification

The proteins are relatively small at 3.5 to 14 kDa . The amino acid sequence contains characteristic Cys-Cys or Cys-X-Cys motifs.

Primary structure

Metallothioneins are divided into classes in different ways based on their primary structure . The division into three classes according to Fowler et al. (1987) includes class I MT, which are homologous to the horse kidney protein, class II MT without these homologies and class III MT, which correspond to the plant phytochelatins . Phytochelatins are enzymatically synthesized cysteine-rich peptides that are no longer counted among the MT.

In 2001, Binz and Kagi established a new system that takes into account both taxonomic aspects and characteristics of the cysteine distribution within the polypeptide. The 15 classes are shown in the table below. The vegetable metallothioneins (class 15) were further divided into four subclasses by Cobbet and Goldsborough in 2002 on the basis of the intramolecular cysteine distribution.

family	Sequence pattern	example
1. Vertebrates	Kx (1,2) -CCxCCPx (2) -C	M. musculus MT1
2. Mollusks	CxCx (3) -CTGx (3) -CxCx (3) -CxCK	M. edulis 10MTIV
3. Crustaceans	P- [GD) -PCCx (3,4) -CxC	H. americanus MTH
4. Echinoderms	PDxKC- [V, F) -CCx (5) -CxCx (4) - CCx (4) -CCx (4,6) -CC	S. purpuratus SpMTA
5. Diptera	CGx (2) -CxCx (2) -Qx (5) -CxCx (2) DCxC	D. melanogaster MTNB
6. Nematodes	KCCx (3) -CC	C. elegans MT1
7. Ciliates	xCCCx?	T.termophila MTT1
8. Mushrooms 1	CGCSx (4) -CxCx (3,4) -CxCSxC	N. crassa MT
9. Mushrooms 2	---	C. glabrata MT2
10. Mushrooms 3	---	C. glabrata MT2
11. Mushrooms 4	CXKCxCx (2) -CKC	Y. lipolitica MT3
12. Mushrooms 5	---	S. cerevisiae CUP1
13. Mushrooms 6	---	S. cerevisiae CRS5
14. Prokaryotes	KCACx (2) -CLC	Synechococcus sp. SmtA
15.1. Plant MTs Type 1	CXCX (3) - CXCX (3) - CXCX (3) -Spacer- CXCX (3) - CXCX (3) - CXCX (3)	Pisum sativum MT
15.2. Plant MTs type 2	CCX (3) -CXCX (3) - CXCX (3) - CXCX (3) -Spacer- CXCX (3) - CXCX (3) - CXCX (3)	L. esculentum MT
15.3. Plant MTs type 3	---	A. thaliana MT3
15.4. Plants MTs Type 4 or EC	Cx (4) -CXCX (3) -CX (5) -CXCX (9,11) -HTTCGCGEHC- XCX (20) -CSCGAXCNCASC-X (3.5)	T. aestium MT

Secondary structures

Secondary structures were observed in the metallothioneins SmtA from Syneccochoccus , MT3 from vertebrates, SpMTA from echinoderms, MT from the fish Notothenia Coriiceps and MTH from crustaceans. The occurrence of secondary structures is assumed to be rare and the function is not known.

Tertiary structures

The occurrence of tertiary structures is also very heterogeneous. In vertebrates, echinoderms and crustaceans, the protein with divalent metal ions shows a structure with 2 domains , but in yeast and prokaryotes only one domain.

Quaternary structures

Quaternary structures have received little attention so far. Dimerization and oligomerization processes can be explained by various molecular mechanisms: formation of disulfide bridges between the molecules, formation of bonds between already bound metals of different MT, binding of a bound metal ion to a histidine residue or through the interaction of inorganic phosphate ions.

An alternative functional classification of MT based on their binding specificity is currently being developed.

function

Bonding of metals

Metallothioneins have the ability to bind toxic heavy metals such as mercury so that they can no longer develop their harmful effects. In high concentrations, MT-crystals or form inclusion bodies ( inclusion bodies ) which could accumulate in tissues.

MTs may also be involved in the uptake, transport and regulation of the physiological metal ion zinc . The binding sites are usually rich in cysteine, and often bind three or four zinc ions. In some MTs, histidine residues are also involved in binding. The concentration of the ion in the organism is regulated by binding and releasing the zinc ions. Zinc acts as an activator of transcription factors ( zinc fingers ). The transport of zinc ions into different compartments can also be understood as a signaling pathway - in neurons in the brain , zinc signaling takes place within and between cells.

Oxidative stress

Cysteine residues can bind reactive oxygen species such as the hydroxyl radical and the superoxide anion and thus render them harmless. Cysteine is oxidized to cystine and the bound metals are released.

literature

P.-A. Binz, JHR Kägi: Metallothionein. Molecular Evolution and Classification. In: Metallothionein. Vol. 4, 1999, ZDB -ID 340351-8 , pp. 7-13.
Klaassen et al .: Metallothionein: An Intracellular Protein to Protect Against Cadmium Toxicity. In: Annual Review of Pharmacology and Toxicology . Vol. 39, No. 1, 1999, pp. 267-294.

Individual evidence

↑ BA Fowler, CE Hildebrand, Y. Kojima, M. Webb: Nomenclature of Metallothionein. In: Experientia Supplementum. Vol. 52, 1987, ISSN 0071-335X , pp. 19-22.
^ Wolfgang Maret .: The function of zinc metallothionein: a link between cellular zinc and redox state. In: The journal of nutrition. Vol. 130, No. 5, 2000, ISSN 0022-3166 , pp. 1455S-1458S.
↑ MV Kumari, M. Hiramatsu, M. Ebadi: Free radical scavenging actions of metallothionein isoforms I and II . In: Free Radical Research . 29, No. 2, 1998, pp. 93-101. PMID 9790511 .

Web links

Uniprot: Metallothioneins: classification and list of entries Further information on the classification

[1] BA Fowler, CE Hildebrand, Y. Kojima, M. Webb: Nomenclature of Metallothionein. In: Experientia Supplementum. Vol. 52, 1987, ISSN 0071-335X , pp. 19-22.

[2] Wolfgang Maret .: The function of zinc metallothionein: a link between cellular zinc and redox state. In: The journal of nutrition. Vol. 130, No. 5, 2000, ISSN 0022-3166 , pp. 1455S-1458S.

[3] MV Kumari, M. Hiramatsu, M. Ebadi: Free radical scavenging actions of metallothionein isoforms I and II . In: Free Radical Research . 29, No. 2, 1998, pp. 93-101. PMID 9790511 .