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

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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

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Wiskott-Aldrich Syndrome Protein
GTP Phosphohydrolases
Actins
Wiskott-Aldrich Syndrome Protein Family
rho GTP-Binding Proteins
Actin Cytoskeleton
Peptides
Proteins

ASJC Scopus subject areas

  • General

Cite this

Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein. / Kim, Annette S.; Kakalis, Lazaros T.; Abdul-Manan, Norzehan; Liu, Grace A.; Rosen, Michael K.

In: Nature, Vol. 404, No. 6774, 09.03.2000, p. 151-158.

Research output: Contribution to journalArticle

Kim, AS, Kakalis, LT, Abdul-Manan, N, Liu, GA & Rosen, MK 2000, 'Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein', Nature, vol. 404, no. 6774, pp. 151-158. https://doi.org/10.1038/35004513
Kim, Annette S. ; Kakalis, Lazaros T. ; Abdul-Manan, Norzehan ; Liu, Grace A. ; Rosen, Michael K. / Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein. In: Nature. 2000 ; Vol. 404, No. 6774. pp. 151-158.
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