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Structures reveal a key mechanism of WAVE regulatory complex activation by Rac1 GTPase

Author

Listed:
  • Bojian Ding

    (Stony Brook University)

  • Sheng Yang

    (Iowa State University
    Target & Protein Sciences, Janssen R&D, Johnson & Johnson)

  • Matthias Schaks

    (Technische Universität Braunschweig
    Helmholtz Centre for Infection Research
    Soilytix GmbH, Dammtorwall 7 A)

  • Yijun Liu

    (Iowa State University)

  • Abbigale J. Brown

    (Iowa State University)

  • Klemens Rottner

    (Technische Universität Braunschweig
    Helmholtz Centre for Infection Research
    Braunschweig Integrated Centre of Systems Biology (BRICS))

  • Saikat Chowdhury

    (Stony Brook University
    CSIR-Centre for Cellular and Molecular Biology
    Academy of Scientific and Innovative Research (AcSIR))

  • Baoyu Chen

    (Iowa State University)

Abstract

The Rho-family GTPase Rac1 activates the WAVE regulatory complex (WRC) to drive Arp2/3 complex-mediated actin polymerization in many essential processes. Rac1 binds to WRC at two distinct sites—the A and D sites. Precisely how Rac1 binds and how the binding triggers WRC activation remain unknown. Here we report WRC structures by itself, and when bound to single or double Rac1 molecules, at ~3 Å resolutions by cryogenic-electron microscopy. The structures reveal that Rac1 binds to the two sites by distinct mechanisms, and binding to the A site, but not the D site, drives WRC activation. Activation involves a series of unique conformational changes leading to the release of sequestered WCA (WH2-central-acidic) polypeptide, which stimulates the Arp2/3 complex to polymerize actin. Together with biochemical and cellular analyses, the structures provide a novel mechanistic understanding of how the Rac1-WRC-Arp2/3-actin signaling axis is regulated in diverse biological processes and diseases.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33174-3
    DOI: 10.1038/s41467-022-33174-3
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    References listed on IDEAS

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    1. 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.
    2. Annette S. Kim & Lazaros T. Kakalis & Norzehan Abdul-Manan & Grace A. Liu & Michael K. Rosen, 2000. "Autoinhibition and activation mechanisms of the Wiskott–Aldrich syndrome protein," Nature, Nature, vol. 404(6774), pages 151-158, March.
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    Cited by:

    1. 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.

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