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

Nature | Mar 9, 2000

http://www.ncbi.nlm.nih.gov/pubmed/10724160

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.

Pubmed ID: 10724160 RIS Download

Mesh terms: Amino Acid Sequence | Binding Sites | Circular Dichroism | Cloning, Molecular | Fungal Proteins | Humans | Magnetic Resonance Spectroscopy | Microfilament Proteins | Molecular Sequence Data | Mutation | Protein Binding | Protein Conformation | Protein Folding | Proteins | Saccharomyces cerevisiae Proteins | Signal Transduction | Thermodynamics | Wiskott-Aldrich Syndrome | Wiskott-Aldrich Syndrome Protein | cdc42 GTP-Binding Protein

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