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Thymosin



thymosin, beta 4, X-linked
Identifiers
Symbol TMSB4X
Alt. Symbols TMSB4
Entrez 7114
HUGO 11881
OMIM 300159
RefSeq NM_021109
UniProt P62328
Other data
Locus Chr. X q21.3-q22

Thymosin is a an actin-binding protein in cells.

Additional recommended knowledge

The predominant form of thymosin, thymosin β4, is a member of a highly conserved family of actin monomer-sequestering proteins. β-thymosins are the primary regulators of unpolymerized actin, and are essential for maintaining the small cytoplasmic pool of free G-actin monomers required for rapid filament elongation and allowing for the flux of monomers between the thymosin-bound pool and F-actin (Dedova et.al., 2006).

Thymosin β4 sequesters actin, holding it in a form that is unable to polymerize. Due to its profusion in the cytosol and its ability to bind ATP G-actin but not F-actin, thymosin β4 is regarded as the principal actin-sequestering protein. Tβ4 binds ATP G- monomeric actin in a 1:1 complex where G-actin cannot polymerize. Thymosin β4 (Tβ4) functions like a buffer for monomeric actin as represented in the following reaction (Lodish et al., 2000):

F-actin <-> G-actin + Tβ4 <-> G-actin/Tβ4

Increase in cytosolic concentrations of thymosin β4 increases the concentration of sequestered actin subunits and correspondingly decreases F-actin due to actin filaments being in equilibrium with actin monomers (Lodish et al., 2000).

Furthermore, the inhibitory thymosin which sequesters the actin competes for monomers with profilin.

Actin monomers preferentially bind to either ATP or ADP and both forms of G-actin are capable of polymerization. The affinities of ATP-G-actin and ADP-G-actin monomers for thymosin and profilin vary significantly. Both profilin and thymosin β4 bind ATP monomers with higher affinity than ADP monomers; however, binding by thymosin is preferred over profilin-binding. This affinity for ATP monomers ensures that the pool of unpolymerized actin consists almost entirely of ATP-G-actin with no significant amount of ADP-G-actin in the thymosin-sequestered pool (Atkinson et al., 2004).

Release of ATP-actin monomers from thymosin β4 occurs as part of the mechanism that drives rapid actin polymerization in the normal function of the cytoskeleton in cell morphology and cell motility. Thymosin maintains the bulk of the monomer pool due to its abundance and high affinity for ATP monomers. Maintenance of a high concentration of available monomers at nuclei or filament barbed ends is necessary for rapid actin polymerization. The low affinity of the interaction between ADP monomers and thymosin is necessary to allow monomers to be handed on so that catalysis of nucleotide exchange by profilin regenerates ATP monomers for rapid addition onto filament barbed ends (Atkinson et al., 2004).


In Figure 1, thymosin β4 and profilin serve complementary roles in regulating the polymerization of G-actin. (a) Profilin is bound to PIP2, a membrane lipid, at the cell membrane while the majority of G-actin is bound in a complex with thymosin β4 and thus unable to polymerize. (b) In response to an extracellular signal, such as chemotactic molecules that stimulate actin assembly, profilin is released from the membrane by the hydrolysis of PIP2. The released profilin displaces thymosin β4, forming profilin G-actin complexes that can assemble into filaments. (c) The profilin-actin complexes interact with proline-rich proteins in the membrane, where profilin adds actin monomers to the (+) end of actin filaments. (d) Eventually, the incorporation of monomers into filaments depletes the pools of profilin-actin and thymosin β4 actin complexes. ADP G-actin subunits that have dissociated from a filament are converted into ATP G-actin by profilin, thus helping to replenish the cytoplasmic pool of ATP G-actin (Lodish et al., 2000).


In Figure 2, the effect of thymosin and profilin on actin polymerization is shown. When thymosin binds to an actin monomer it sterically prevents further binding to and elongation of the plus end of the actin filament. In contrast, when profilin binds to an actin monomer the filament is still capable of elongating. As thymosin and profilin cannot both bind to a single actin monomer at the same time, there is competition between the inhibitory thymosin and the profilin. Generally a majority of actin monomer is thymosin-bound, thus the activation of a small amount of profilin produces rapid filament assembly. Profilin binds to actin monomers that are temporarily released from the thymosin-bound monomer pool, shuttles them onto the plus ends of actin filaments, and is then released and recycled for further rounds of filament elongation (Alberts et al., 2002).

Therefore, the polymerization of actin is controlled by the give and take between thymosin and profilin. Thymosin basically acts in an inhibitory fashion and interacts with the G-actin monomer and interferes with conformations (ATP and ADP bound forms) to control the assembly of microfilaments.

The promise of repairing sun parched aging skin is alluring, especially if damage control may be attained by applying a substance that is abundant in our body. Thymosin beta 4 (Tb4), a molecule that accelerates wound healing in animals and cultured cells, "may be valuable in repairing skin damage caused by sun or even by the wear and tear of aging?" This hopeful message of Tb4's potential to restore damaged human skin was voiced at the 5th International Symposium on Aging Skin, in California (May 2001), by Dr. Allan Goldstein, Chairman of the Biochemistry Department at George Washington University and founder of RegeneRX Biopharmaceuticals. RegeneRX is carrying out preclinical research on Tb4 as a wound healer, in collaboration with scientists at the National Institutes of Health.

Skin is the largest organ of the body, which makes up 16% of total body weight. It is also the largest organ that provides immune protection and plays a role in inflammation. Composed of specialized epithelial and connective tissue cells, skin is our major interface with the environment, a shield from the outside world and a means of interacting with it. As such, the skin is subjected to insults and injuries: burns from the sun’s ultraviolet radiation that elicit inflammatory reactions, damage from environmental pollutants and wear and tear that comes with aging.

Thymosin beta 4 accelerated skin wound healing in a rat model of a full thickness wound where the epithelial layer was destroyed. When Tb4 was applied topically to the wound or injected into the animal, epithelial layer restoration in the wound was increased 42% by day four and 61% by day seven, after treatment, compared to untreated. Furthermore, Tb4 stimulated collagen deposition in the wound and angiogenesis. Tb4 accelerated keratinocyte migration, resulting in the wound contracting by more than 11%, compared to untreated wounds, to close the skin gap in the wound. An analysis of skin sections (histological observations) showed that the Tb4 treated wounds healed faster than the untreated. Proof of accelerated cell migration was also seen in vitro, where Tb4 increased keratinocyte migration two to threefold, within four to five hours after treatment, compared to untreated keratinocytes.

A critical step in wound healing is angiogenesis. New vessels are needed to supply nutrients and oxygen to the cells involved in repair, to remove toxic materials and debris of dead cells and generate optimal conditions for new tissue formation. Another important step is the directional migration of cells into the injured area, joining up to repair the wound. This requires an attractant that will direct the cells to the wound and propel them to the site. These critical steps in wound healing are regulated by beta 4, as seen in the following experiments.


References

  • Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K. and P. Walter (2002). Molecular Biology of the Cell IV: Chapter 16. Internal Organization of the Cell. The Cytoskeleton: How Cells Regulate Their Cytoskeletal Filaments. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.3008, accessed 060218.
  • Atkinson S, Hosford M, Molitoris B (2004). "Mechanism of actin polymerization in cellular ATP depletion". J Biol Chem 279 (7): 5194-9. PMID 14623892.
  • Dedova I, Nikolaeva O, Safer D, De La Cruz E, dos Remedios C (2006). "Thymosin beta4 induces a conformational change in actin monomers". Biophys J 90 (3): 985-92. PMID 16272441.
  • Lodish, H., Berk, A., Zipursky, L. S., Matsudaira, P., Baltimore, D. and J. Darnell (2000). Molecular Cell Biology: Chapter 18. Cell Motility and Shape I: Microfilaments. 18.2. The Dynamics of Actin Assembly. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.section.5145, accessed 060218.
  • Lodish, H., Berk, A., Zipursky, L. S., Matsudaira, P., Baltimore, D. and J. Darnell (2000). Molecular Cell Biology: Chapter 18. Cell Motility and Shape I: Microfilaments. 18.2. The Dynamics of Actin Assembly. Figure 18-15. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.figgrp.5157, accessed 060218.
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Thymosin". A list of authors is available in Wikipedia.
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