FC0031
Thymosine β4  -  Actin

Biological function
Thymosines are small actin binding proteins, which serve to sequester actin. Thymosin-β4 (Tβ4) is the most abundant and well-studied member of the family, which promotes cell migration. Tβ4 acts also extracellularly with less understood mechanisms to enhance embryonic endothelial cell migration, promote dermal and corneal wound healing or stimulate coronary vasculogenesis.

Domain organization/sequence features
The WH2 domain is present in over 50 modular proteins, in which it might function in association with another domain of the protein to promote actin polymerization. The WH2 domain can also exist in tandem repeats of up to four WH2 motifs, separated by linkers of variable lengths. The length and/or sequence of the linkers have a non- trivial role in enabling each WH2 domain to bind actin, and in the spatial organization and dynamics of the complexes. Despite sequence differences, WH2 domains bind actin identically and possess versatile functions in actin assembly.

Structural evidence
Functionally different βT/WH2 domains differ by distinct dynamics of their C-terminal half interactions with G-actin pointed face. At high ionic strength the C-terminal dynamics increases which contributes to elongation. Low dynamics at normal/weak ionic strength enhances the salt bridge formation and restricts dynamics, corresponding to a structural state relevant for sequestration.

Biochemical evidence
These C-terminal interaction dynamics are controlled by the strength of electrostatic interactions with G-actin. At physiological ionic strength, a single salt bridge with actin located next to their central LKKT/V motif induces G-actin sequestration. A single mutation K14Q however supports actin assembly. This mutation decreases affinity for G-actin by 17-fold.

Mechanism category
competitive binding

Significance
Fuzziness enables two opposite functions (actin polymerization vs disassembly), which is controlled by the ionic strength via screening a single charge-charge interaction.

Further reading
15163409