Autoinhibition and activation mechanisms of the Wiskott–Aldrich syndrome protein

Annette S. Kim, Lazaros T. Kakalis, Norzehan Abdul-Manan, Grace A. Liu and Michael K. Rosen ()
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Annette S. Kim: Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center
Lazaros T. Kakalis: Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center
Norzehan Abdul-Manan: Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center
Grace A. Liu: Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center
Michael K. Rosen: Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center

Nature, 2000, vol. 404, issue 6774, 151-158

Abstract: Abstract 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.

Date: 2000
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DOI: 10.1038/35004513

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