The β-Thymosin/WH2 Domain: Structural Basis for the Switch from Inhibition to Promotion of Actin Assembly

• Published in: Cell 2004-05, Vol.117 (5), p.611-623
• Main Authors: Hertzog, Maud, van Heijenoort, Carine, Didry, Dominique, Gaudier, Martin, Coutant, Jérôme, Gigant, Benoı̂t, Didelot, Gérard, Préat, Thomas, Knossow, Marcel, Guittet, Eric, Carlier, Marie-France
• Format: Article
• Language: English
• Subjects: Actins; Actins - biosynthesis; Actins - chemistry; Animals; Crystallography, X-Ray; Drosophila; Drosophila - chemistry; Drosophila - genetics; Drosophila - metabolism; Drosophila Proteins; Life Sciences; Magnetic Resonance Spectroscopy; Microfilament Proteins; Microfilament Proteins - chemistry; Microfilament Proteins - metabolism; Mutation; Nerve Tissue Proteins; Neurons and Cognition; Protein Structure, Tertiary; Thymosin; Thymosin - genetics; Thymosin - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(04)00403-9

The widespread β-thymosin/WH2 actin binding domain has versatile regulatory properties in actin dynamics and motility. β-thymosins (isolated WH2 domain) maintain monomeric actin in a “sequestered” nonpolymerizable form. In contrast, when repeated in tandem or inserted in modular proteins, the β-thymosin/WH2 domain promotes actin assembly at filament barbed ends, like profilin. The structural basis for these opposite functions is addressed using ciboulot, a three β-thymosin repeat protein. Only the first repeat binds actin and possesses the function of ciboulot. The region that shows the strongest interaction with actin is an amphipathic N-terminal α helix, present in all β-thymosin/WH2 domains, which recognizes the ATP bound actin structure and uses the shear motion of actin linked to ATP hydrolysis to control polymerization. Crystallographic ( 1H, 15N), NMR, and mutagenetic data reveal that the weaker interaction of the C-terminal region of β-thymosin/WH2 domain with actin accounts for the switch in function from inhibition to promotion of actin assembly.