Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein

Annette S. Kim, Lazaros T. Kakalis, Norzehan Abdul-Manan, Grace A. Liu, Michael K. Rosen

Research output: Contribution to journalArticle

563 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)151-158
Number of pages8
JournalNature
Volume404
Issue number6774
DOIs
StatePublished - Mar 9 2000

ASJC Scopus subject areas

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