Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein

The Rho-family GTPase, Cdc42, can regulate the actin cytoskeleton through a ctivation of Wiskott-Aldrich syndrome protein (WASP) family members. Activa tion relieves an autoinhibitory contact between the GTPase-binding domain a nd the carboxyterminal region of WASP proteins. Here we report the autoinhi bited structure of the GTPase-binding domain of WASP, which can be induced by the C-terminal region or by organic co-solvents, In the autoinhibited co mplex, intramolecular interactions with the GTPase-binding domain occlude r esidues of the C terminus that regulate the Arp2/3 actin-nucleating complex . Binding of Cdc42 to the GTPase-binding domain causes a dramatic conformat ional change, resulting in disruption of the hydrophobic core and release o f the C terminus, enabling its interaction with the actin regulatory machin ery. These data show that 'intrinsically unstructured' peptides such as the GTPase-binding domain of WASP can be induced into distinct structural and functional states depending on context.