Thymosin β₄

Abstract

The intracellular function of thymosin beta(4) is not limited to simple sequestration of globular actin. Our recent studies revealed that thymosin beta(4) affects actin critical concentration and forms a ternary complex with actin and profilin. The consequences of this complex formation can be very significant. Our new data demonstrate that it is likely that profilin affects binding of thymosin beta(4) to actin in the ternary complex through allosteric changes in actin rather than through competition for the binding site. The N- and C-terminal thymosin beta(4) helices are known to be unstructured in aqueous solution and to adopt helical conformation in organic solvents or upon binding to actin. Osmolytes stabilize protein structure, and TMAO (trimethylamine N-oxide) specifically stabilizes hydrogen bonds. This increases affinity of intact thymosin beta(4) to actin significantly, but the increase is much less for thymosin beta(4) sulfoxide. Our data show that oxidation does not alter binding of profilin to form a ternary complex, and therefore it is very likely that there is no direct steric interference by methionine 6 of thymosin beta(4). Rather, since TMAO has little effect on thymosin beta(4) sulfoxide, this observation is consistent with the hypothesis that methionine oxidation prevents helix transition. The experiment with truncated versions of thymosin beta(4) also supports this hypothesis. Oxidation and formation of the helices are important for both intra- and extracellular properties of thymosin beta(4). We found that actin and, in lesser extent, profilin-actin complex protect thymosin beta(4) from oxidation.

How depolymerization can promote polymerization: the case of actin and profilin

“…Interactions of profilin with different nucleotide forms of actin and formation of a ternary complex between profilin, actin and thymosin b 4 may also be significantly affected by molecular crowding effects changing concentrations of free profilin and monomeric actin available for polymerization. (44,79,80) Both affinity-based and exchange diffusion mechanisms would therefore be affected. Thus profilin function could be spatially regulated by modulation of the nature of crowding molecules and the extent of macromolecular crowding in different locations inside the cells.…”

Multiple fuzzy interactions in the moonlighting function of thymosin-β4

“…Being functionally, but not structurally well-characterized, it is an excellent candidate for studying the conformational underpinning of moonlighting functions. Tß4 was first identified as an actin-sequestring molecule, 14 playing a key role in regulating the formation and modulation of the actin cytoskeleton 15 . As actin-binding is considered its main function, this interaction is well-studied and well characterized, 16 and the structure of Tß4 in complex with G-actin was published in 2004 17 .…”

Neurological functional recovery after thymosin beta4 treatment in mice with experimental auto encephalomyelitis

“…The most prominent physiological function of Tbeta4 is the regulation of actin polymerization which is necessary for cell motility and organogenesis (Crockford, 2007). Recently, studies found that the intracellular function of Tbeta4 is not limited to simple actin-sequestration (Yarmola et al, 2007). The healing properties of Tbeta4 have been found in the skin (Philp et al, 2004a, Philp et al, 2004b) and cornea (Fine, 2007, Guarnera et al, 2007), and more recently it has been shown that Tbeta4 facilitates cardiac repair after infarction by promoting cell migration and myocyte survival (Cavasin, 2006).…”