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PMID:10724160

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Citation

Kim, AS, Kakalis, LT, Abdul-Manan, N, Liu, GA and Rosen, MK (2000) Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein. Nature 404:151-8

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.

Links

PubMed Online version:10.1038/35004513

Keywords

Amino Acid Sequence; Binding Sites; Circular Dichroism; Cloning, Molecular; Fungal Proteins/chemistry; Humans; Magnetic Resonance Spectroscopy; Microfilament Proteins/chemistry; Molecular Sequence Data; Mutation; Protein Binding; Protein Conformation; Protein Folding; Proteins/antagonists & inhibitors; Proteins/chemistry; Proteins/genetics; Proteins/metabolism; Saccharomyces cerevisiae Proteins; Signal Transduction; Thermodynamics; Wiskott-Aldrich Syndrome/genetics; Wiskott-Aldrich Syndrome/metabolism; Wiskott-Aldrich Syndrome Protein; cdc42 GTP-Binding Protein/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CDC42

enables

GO:0032427: GBD domain binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P42768

F

Seeded From UniProt

complete

HUMAN:WASP

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P42768

F

Seeded From UniProt

complete

HUMAN:WASP

enables

GO:0031267: small GTPase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P60953

F

Seeded From UniProt

complete


See also

References

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