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Structure and control of the actin regulatory WAVE complex

Author

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  • Zhucheng Chen

    (University of Texas Southwestern Medical Center at Dallas
    Howard Hughes Medical Institute, UT Southwestern Medical Center)

  • Dominika Borek

    (University of Texas Southwestern Medical Center at Dallas)

  • Shae B. Padrick

    (University of Texas Southwestern Medical Center at Dallas
    Howard Hughes Medical Institute, UT Southwestern Medical Center)

  • Timothy S. Gomez

    (Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic)

  • Zoltan Metlagel

    (University of Texas Southwestern Medical Center at Dallas
    Howard Hughes Medical Institute, UT Southwestern Medical Center)

  • Ayman M. Ismail

    (University of Texas Southwestern Medical Center at Dallas
    Howard Hughes Medical Institute, UT Southwestern Medical Center)

  • Junko Umetani

    (University of Texas Southwestern Medical Center at Dallas
    Howard Hughes Medical Institute, UT Southwestern Medical Center)

  • Daniel D. Billadeau

    (Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic)

  • Zbyszek Otwinowski

    (University of Texas Southwestern Medical Center at Dallas)

  • Michael K. Rosen

    (University of Texas Southwestern Medical Center at Dallas
    Howard Hughes Medical Institute, UT Southwestern Medical Center)

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.

Suggested Citation

  • Zhucheng Chen & Dominika Borek & Shae B. Padrick & Timothy S. Gomez & Zoltan Metlagel & Ayman M. Ismail & Junko Umetani & Daniel D. Billadeau & Zbyszek Otwinowski & Michael K. Rosen, 2010. "Structure and control of the actin regulatory WAVE complex," Nature, Nature, vol. 468(7323), pages 533-538, November.
    • Handle: RePEc:nat:nature:v:468:y:2010:i:7323:d:10.1038_nature09623
    DOI: 10.1038/nature09623
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    Cited by:

    1. Bojian Ding & Sheng Yang & Matthias Schaks & Yijun Liu & Abbigale J. Brown & Klemens Rottner & Saikat Chowdhury & Baoyu Chen, 2022. "Structures reveal a key mechanism of WAVE regulatory complex activation by Rac1 GTPase," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Yanan Wang & Giovanni Chiappetta & Raphaël Guérois & Yijun Liu & Stéphane Romero & Daniel J. Boesch & Matthias Krause & Claire A. Dessalles & Avin Babataheri & Abdul I. Barakat & Baoyu Chen & Joelle V, 2023. "PPP2R1A regulates migration persistence through the NHSL1-containing WAVE Shell Complex," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Serena Petracchini & Daniel Hamaoui & Anne Doye & Atef Asnacios & Florian Fage & Elisa Vitiello & Martial Balland & Sebastien Janel & Frank Lafont & Mukund Gupta & Benoit Ladoux & Jerôme Gilleron & Te, 2022. "Optineurin links Hace1-dependent Rac ubiquitylation to integrin-mediated mechanotransduction to control bacterial invasion and cell division," Nature Communications, Nature, vol. 13(1), pages 1-22, December.

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