Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein.

:The Rho-family GTPase, Cdc42, can regulate the actin cytoskeleton through activation of Wiskott-Aldrich syndrome protein (WASP) family members. Activation relieves an autoinhibitory contact between the GTPase-binding domain and the carboxy-terminal region of WASP proteins. Here we report the autoinhibited 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 complex, intramolecular interactions with the GTPase-binding domain occlude residues of the C terminus that regulate the Arp2/3 actin-nucleating complex. Binding of Cdc42 to the GTPase-binding domain causes a dramatic conformational change, resulting in disruption of the hydrophobic core and release of the C terminus, enabling its interaction with the actin regulatory machinery. 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.

Kim AS ，Kakalis LT ，Abdul-Manan N ，Liu GA ，Rosen MK ... -  《NATURE》

Structure of Cdc42 in complex with the GTPase-binding domain of the 'Wiskott-Aldrich syndrome' protein.

Abdul-Manan N ，Aghazadeh B ，Liu GA ，Majumdar A ，Ouerfelli O ，Siminovitch KA ，Rosen MK ... -  《NATURE》

Direct binding of a fragment of the Wiskott-Aldrich syndrome protein to the C-terminal end of the anaphylatoxin C5a receptor.

Tardif M ，Brouchon L ，Rabiet MJ ，Boulay F ... -  《-》

A conserved amphipathic helix in WASP/Scar proteins is essential for activation of Arp2/3 complex.

Panchal SC ，Kaiser DA ，Torres E ，Pollard TD ，Rosen MK ... -  《-》

Wiskott-Aldrich syndrome (role of WASP).

Nonoyama S 《-》