2. Academic Validation
  3. Structure and control of the actin regulatory WAVE complex

Structure and control of the actin regulatory WAVE complex

  • Nature. 2010 Nov 25;468(7323):533-8. doi: 10.1038/nature09623.
Zhucheng Chen 1,  Dominika Borek,  Shae B Padrick,  Timothy S Gomez,  Zoltan Metlagel,  Ayman M Ismail,  Junko Umetani,  Daniel D Billadeau,  Zbyszek Otwinowski,  Michael K Rosen
Affiliations

Affiliation

  • 1 Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
PMID: 21107423 DOI: 10.1038/nature09623
Abstract

Members of the Wiskott-Aldrich syndrome protein (WASP) family control cytoskeletal dynamics by promoting actin filament nucleation with the Arp2/3 complex. The WASP relative WAVE regulates lamellipodia formation within a 400-kilodalton, hetero-pentameric WAVE regulatory complex (WRC). The WRC is inactive towards the Arp2/3 complex, but can be stimulated by the Rac GTPase, kinases and phosphatidylinositols. Here we report the 2.3-ångstrom crystal structure of the WRC and complementary mechanistic analyses. The structure shows that the activity-bearing VCA motif of WAVE is sequestered by a combination of intramolecular and intermolecular contacts within the WRC. Rac and kinases appear to destabilize a WRC element that is necessary for VCA sequestration, suggesting the way in which these signals stimulate WRC activity towards the Arp2/3 complex. The spatial proximity of the Rac binding site and the large basic surface of the WRC suggests how the GTPase and Phospholipids could cooperatively recruit the complex to membranes.

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