Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein Journal Article
| Authors: | Kim, A. S.; Kakalis, L. T.; Abdul-Manan, N.; Liu, G. A.; Rosen, M. K. |
| Article Title: | Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein |
| 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. |
| Keywords: | signal transduction; controlled study; mutation; protein conformation; protein domain; proteins; cell cycle protein; actin; carboxy terminal sequence; protein binding; microfilament proteins; cloning, molecular; amino acid sequence; molecular sequence data; glutathione transferase; magnetic resonance spectroscopy; thermodynamics; binding sites; saccharomyces cerevisiae proteins; protein folding; protein structure; enzyme binding; rho factor; fungal proteins; circular dichroism; guanosine triphosphatase; hydrophobicity; wiskott aldrich syndrome; actin filament; cdc42 gtp-binding protein; wiskott-aldrich syndrome; wiskott-aldrich syndrome protein; humans; human; priority journal; article; vespidae |
| Journal Title: | Nature |
| Volume: | 404 |
| Issue: | 6774 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2000-03-09 |
| Start Page: | 151 |
| End Page: | 158 |
| Language: | English |
| DOI: | 10.1038/35004513 |
| PUBMED: | 10724160 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 18 November 2015 -- Source: Scopus |
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