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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.

Pubmed ID: 10724160

Authors

  • Kim AS
  • Kakalis LT
  • Abdul-Manan N
  • Liu GA
  • Rosen MK

Journal

Nature

Publication Data

March 9, 2000

Associated Grants

None

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