Thymosin beta-4

Last updated
TMSB4X
Available structures
PDB Human UniProt search: PDBe RCSB
Identifiers
Aliases TMSB4X , FX, PTMB4, TB4X, TMSB4, thymosin beta 4, X-linked, thymosin beta 4 X-linked
External IDs OMIM: 300159 GeneCards: TMSB4X
Gene location (Human)
Ideogram human chromosome X.svg
Chr. X chromosome (human) [1]
Human chromosome X ideogram.svg
HSR 1996 II 3.5e.svg
Red rectangle 2x18.png
Band Xp22.2Start12,975,110 bp [1]
End12,977,227 bp [1]
RNA expression pattern
PBB GE TMSB4X 216438 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_021109

n/a

RefSeq (protein)

NP_066932

n/a

Location (UCSC) Chr X: 12.98 – 12.98 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

Thymosin beta-4 is a protein that in humans is encoded by the TMSB4X gene. [3] [4] [5] Recommended INN (International Nonproprietary Name) for thymosin beta-4 is 'timbetasin', as published by the World Health Organization (WHO). [6]

Contents

The protein consists (in humans) of 43 amino acids (sequence: SDKPDMAEI EKFDKSKLKK TETQEKNPLP SKETIEQEKQ AGES) and has a molecular weight of 4921 g/mol. [7]

Thymosin-β4 is a major cellular constituent in many tissues. Its intracellular concentration may reach as high as 0.5 mM. [8] Following Thymosin α1, β4 was the second of the biologically active peptides from Thymosin Fraction 5 to be completely sequenced and synthesized. [9]

Function

This gene encodes an actin sequestering protein which plays a role in regulation of actin polymerization. The protein is also involved in cell proliferation, migration, and differentiation. This gene escapes X inactivation and has a homolog on chromosome Y (TMSB4Y). [5]

Biological activities of thymosin β4

Any concepts of the biological role of thymosin β4 must inevitably be coloured by the demonstration that total ablation of the thymosin β4 gene in the mouse allows apparently normal embryonic development of mice which are fertile as adults. [10]

Actin binding

Thymosin β4 was initially perceived as a thymic hormone. However this changed when it was discovered that it forms a 1:1 complex with G (globular) actin, and is present at high concentration in a wide range of mammalian cell types. [11] When appropriate, G-actin monomers polymerize to form F (filamentous) actin, which, together with other proteins that bind to actin, comprise cellular microfilaments. Formation by G-actin of the complex with β-thymosin (= "sequestration") opposes this.

Due to its profusion in the cytosol and its ability to bind G-actin but not F-actin, thymosin β4 is regarded as the principal actin-sequestering protein in many cell types. Thymosin β4 functions like a buffer for monomeric actin as represented in the following reaction: [12]

F-actin ↔ G-actin + Thymosin β4 ↔ G-actin/Thymosin β4

Release of G-actin monomers from thymosin β4 occurs as part of the mechanism that drives actin polymerization in the normal function of the cytoskeleton in cell morphology and cell motility.

The sequence LKKTET, which starts at residue 17 of the 43-aminoacid sequence of thymosin beta-4, and is strongly conserved between all β-thymosins, together with a similar sequence in WH2 domains, is frequently referred to as "the actin-binding motif" of these proteins, although modelling based on X-ray crystallography has shown that essentially the entire length of the β-thymosin sequence interacts with actin in the actin-thymosin complex. [13]

"Moonlighting"

In addition to its intracellular role as the major actin-sequestering molecule in cells of many multicellular animals, thymosin β4 shows a remarkably diverse range of effects when present in the fluid surrounding animal tissue cells. Taken together, these effects suggest that thymosin has a general role in tissue regeneration. This has suggested a variety of possible therapeutic applications, and several have now been extended to animal models and human clinical trials.

It is considered unlikely that thymosin β4 exerts all these effects via intracellular sequestration of G-actin. This would require its uptake by cells, and moreover, in most cases the cells affected already have substantial intracellular concentrations.

The diverse activities related to tissue repair may depend on interactions with receptors quite distinct from actin and possessing extracellular ligand-binding domains. Such multi-tasking by, or "partner promiscuity" of, proteins has been referred to as protein moonlighting. [14] Proteins such as thymosins which lack stable folded structure in aqueous solution, are known as intrinsically unstructured proteins (IUPs). Because IUPs acquire specific folded structures only on binding to their partner proteins, they offer special possibilities for interaction with multiple partners. [15] A candidate extracellular receptor of high affinity for thymosin β4 is the β subunit of cell surface-located ATP synthase, which would allow extracellular thymosin to signal via a purinergic receptor. [16]

Some of the multiple activities of thymosin β4 unrelated to actin may be mediated by a tetrapeptide enzymically-cleaved from its N-terminus, N-acetyl-ser-asp-lys-pro, brand names Seraspenide or Goralatide, best known as an inhibitor of the proliferation of haematopoietic (blood-cell precursor) stem cells of bone marrow.

Tissue regeneration

Work with cell cultures and experiments with animals have shown that administration of thymosin β4 can promote migration of cells, formation of blood vessels, maturation of stem cells, survival of various cell types and lowering of the production of pro-inflammatory cytokines. These multiple properties have provided the impetus for a worldwide series of on-going clinical trials of potential effectiveness of thymosin β4 in promoting repair of wounds in skin, cornea and heart. [17]

Such tissue-regenerating properties of thymosin β4 may ultimately contribute to repair of human heart muscle damaged by heart disease and heart attack. In mice, administration of thymosin β4 has been shown to stimulate formation of new heart muscle cells from otherwise inactive precursor cells present in the outer lining of adult hearts, [18] to induce migration of these cells into heart muscle [19] and recruit new blood vessels within the muscle. [20]

Anti-inflammatory role for sulfoxide

In 1999 researchers in Glasgow University found that an oxidised derivative of thymosin β4 (the sulfoxide, in which an oxygen atom is added to the methionine near the N-terminus) exerted several potentially anti-inflammatory effects on neutrophil leucocytes. It promoted their dispersion from a focus, inhibited their response to a small peptide (F-Met-Leu-Phe) which attracts them to sites of bacterial infection and lowered their adhesion to endothelial cells. (Adhesion to endothelial cells of blood vessel walls is pre-requisite for these cells to leave the bloodstream and invade infected tissue). A possible anti-inflammatory role for the β4 sulfoxide was supported by the group's finding that it counteracted artificially-induced inflammation in mice.

The group had first identified the thymosin sulfoxide as an active factor in culture fluid of cells responding to treatment with a steroid hormone, suggesting that its formation might form part of the mechanism by which steroids exert anti-inflammatory effects. Extracellular thymosin β4 would be readily oxidised to the sulfoxide in vivo at sites of inflammation, by the respiratory burst. [21]

Terminal deoxynucleotidyl transferase

Thymosin β4 induces the activity of the enzyme terminal deoxynucleotidyl transferase in populations of thymocytes (thymus-derived lymphocytes). This suggests that the peptide may contribute to the maturation of these cells. [9]

Clinical significance

Tβ4 has been studied in a number of clinical trials. [22]

In phase 2 trials with patients having pressure ulcers, venous pressure ulcers, and epidermolysis bullosa, Tβ4 accelerated the rate of repair. It was also found to be safe and well tolerated. [23]

In human clinical trials, Tβ4 improves the conditions of dry eye and neurotrophic keratopathy with effects lasting long after the end of treatment. [24]

Doping in Sports

Thymosin beta-4 was allegedly used by some players in various Australian football codes and is under investigation by the Australian Sports Anti-Doping Authority for anti-doping violations. [25] [26]

On 30 March 2015, the Australian Football League anti-doping tribunal initially cleared players of the Essendon Football Club over the use of thymosin beta-4, however after an appeal by the World Anti-Doping Agency, this was overturned on 12 January 2016. [27]

Interactions

TMSB4X has been shown to interact with ACTA1 [28] [29] and ACTG1. [30] [31]

See also

Related Research Articles

Amyloid insoluble protein aggregate

Amyloids are aggregates of proteins characterised by a fibrillar morphology of 7–13 nm in diameter, a β-sheet secondary structure and ability to be stained by particular dyes, such as Congo red. In the human body, amyloids have been linked to the development of various diseases. Pathogenic amyloids form when previously healthy proteins lose their normal structure and physiological functions (misfolding) and form fibrous deposits in plaques around cells which can disrupt the healthy function of tissues and organs.

Actin Family of proteins

Actin is a family of globular multi-functional proteins that form microfilaments. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over 100 μM; its mass is roughly 42-kDa, with a diameter of 4 to 7 nm.

Amylin mammalian protein found in Homo sapiens

Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is cosecreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.

Thymosin family of heat-stable, polypeptide hormones secreted by the thymus gland

Thymosins are small proteins present in many animal tissues. They are named thymosins because they were originally isolated from the thymus, but most are now known to be present in many other tissues. Thymosins have diverse biological activities, and two in particular, thymosins α1 and β4, have potentially important uses in medicine, some of which have already progressed from the laboratory to the clinic. In relation to diseases, thymosins have been categorized as biological response modifiers.

Profilin InterPro Family

Profilin is an actin-binding protein involved in the dynamic turnover and reconstruction of the actin cytoskeleton. It is found in all eukaryotic organisms in most cells. Profilin is important for spatially and temporally controlled growth of actin microfilaments, which is an essential process in cellular locomotion and cell shape changes. This restructuring of the actin cytoskeleton is essential for processes such as organ development, wound healing, and the hunting down of infectious intruders by cells of the immune system.

Beta-catenin mammalian protein found in Homo sapiens

Catenin beta-1, also known as β-catenin, is a protein that in humans is encoded by the CTNNB1 gene.

TGF beta 1 protein-coding gene in the species Homo sapiens

Transforming growth factor beta 1 or TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation, and apoptosis. In humans, TGF-β1 is encoded by the TGFB1 gene.

CXCL7 mammalian protein found in Homo sapiens

Chemokine ligand 7 (CXCL7) is a human gene.

Actin, alpha 1 protein-coding gene in the species Homo sapiens

Actin, alpha skeletal muscle is a protein that in humans is encoded by the ACTA1 gene.

Beta-actin protein-coding gene in the species Homo sapiens

Beta-actin is one of six different actin isoforms which have been identified in humans. This is one of the two nonmuscle cytoskeletal actins. Actins are highly conserved proteins that are involved in cell motility, structure and integrity. Alpha actins are a major constituent of the contractile apparatus.

ACTG1 protein-coding gene in the species Homo sapiens

Gamma-actin is a protein that in humans is encoded by the ACTG1 gene. Gamma-actin is widely expressed in cellular cytoskeletons of many tissues; in adult striated muscle cells, gamma-actin is localized to Z-discs and costamere structures, which are responsible for force transduction and transmission in muscle cells. Mutations in ACTG1 have been associated with nonsyndromic hearing loss and Baraitser-Winter syndrome, as well as susceptibility of adolescent patients to vincristine toxicity.

ACTC1 Protein-coding gene in the species Homo sapiens

ACTC1 encodes cardiac muscle alpha actin. This isoform differs from the alpha actin that is expressed in skeletal muscle, ACTA1. Alpha cardiac actin is the major protein of the thin filament in cardiac sarcomeres, which are responsible for muscle contraction and generation of force to support the pump function of the heart.

ACTG2 protein-coding gene in the species Homo sapiens

Actin, gamma-enteric smooth muscle is a protein that in humans is encoded by the ACTG2 gene.

TMSB10 protein-coding gene in the species Homo sapiens

Thymosin beta-10 is a protein that in humans is encoded by the TMSB10 gene. TMSB10 is a member of the beta-thymosin family of peptides.

Thymosin beta-4, Y-chromosomal protein-coding gene in the species Homo sapiens

Thymosin beta-4, Y-chromosomal is a protein that in humans is encoded by the TMSB4Y gene.

CAP1 gene of the species Homo sapiens

Adenylyl cyclase-associated protein 1 is an enzyme that in humans is encoded by the CAP1 gene.

CAPZB protein-coding gene in the species Homo sapiens

F-actin-capping protein subunit beta, also known as CapZβ is a protein that in humans is encoded by the CAPZB gene. CapZβ functions to cap actin filaments at barbed ends in muscle and other tissues.

Transforming growth factor beta (TGF-β) is a potent cell regulatory polypeptide homodimer of 25kD. It is a multifunctional signaling molecule with more than 40 related family members. TGF-β plays a role in a wide array of cellular processes including early embryonic development, cell growth, differentiation, motility, and apoptosis.

TMSB15A Protein-coding gene in the species Homo sapiens

Thymosin beta-15A is a protein that in humans is encoded by the TMSB15A gene.

Beta thymosins InterPro Family

Beta thymosins are a family of proteins which have in common a sequence of about 40 amino acids similar to the small protein thymosin β4. They are found almost exclusively in multicellular animals. Thymosin β4 was originally obtained from the thymus in company with several other small proteins which although named collectively "thymosins" are now known to be structurally and genetically unrelated and present in many different animal tissues.

References

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Further reading