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Molecular mechanism of Arp2/3 complex inhibition by Arpin

Author

Listed:
  • Fred E. Fregoso

    (University of Pennsylvania)

  • Trevor Eeuwen

    (University of Pennsylvania
    The Rockefeller University)

  • Gleb Simanov

    (Laboratoire de Biologie Structurale de la Cellule, CNRS, Institut Polytechnique de Paris)

  • Grzegorz Rebowski

    (University of Pennsylvania)

  • Malgorzata Boczkowska

    (University of Pennsylvania)

  • Austin Zimmet

    (University of Pennsylvania)

  • Alexis M. Gautreau

    (Laboratoire de Biologie Structurale de la Cellule, CNRS, Institut Polytechnique de Paris
    Skolkovo Institute of Science and Technology)

  • Roberto Dominguez

    (University of Pennsylvania)

Abstract

Positive feedback loops involving signaling and actin assembly factors mediate the formation and remodeling of branched actin networks in processes ranging from cell and organelle motility to mechanosensation. The Arp2/3 complex inhibitor Arpin controls the directional persistence of cell migration by interrupting a feedback loop involving Rac-WAVE-Arp2/3 complex, but Arpin’s mechanism of inhibition is unknown. Here, we describe the cryo-EM structure of Arpin bound to Arp2/3 complex at 3.24-Å resolution. Unexpectedly, Arpin binds Arp2/3 complex similarly to WASP-family nucleation-promoting factors (NPFs) that activate the complex. However, whereas NPFs bind to two sites on Arp2/3 complex, on Arp2-ArpC1 and Arp3, Arpin only binds to the site on Arp3. Like NPFs, Arpin has a C-helix that binds at the barbed end of Arp3. Mutagenesis studies in vitro and in cells reveal how sequence differences within the C-helix define the molecular basis for inhibition by Arpin vs. activation by NPFs.

Suggested Citation

  • Fred E. Fregoso & Trevor Eeuwen & Gleb Simanov & Grzegorz Rebowski & Malgorzata Boczkowska & Austin Zimmet & Alexis M. Gautreau & Roberto Dominguez, 2022. "Molecular mechanism of Arp2/3 complex inhibition by Arpin," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28112-2
    DOI: 10.1038/s41467-022-28112-2
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    References listed on IDEAS

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    1. Florian Fäßler & Georgi Dimchev & Victor-Valentin Hodirnau & William Wan & Florian K. M. Schur, 2020. "Cryo-electron tomography structure of Arp2/3 complex in cells reveals new insights into the branch junction," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
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    Cited by:

    1. Rayane Dibsy & Erwan Bremaud & Johnson Mak & Cyril Favard & Delphine Muriaux, 2023. "HIV-1 diverts cortical actin for particle assembly and release," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Fred E. Fregoso & Malgorzata Boczkowska & Grzegorz Rebowski & Peter J. Carman & Trevor Eeuwen & Roberto Dominguez, 2023. "Mechanism of synergistic activation of Arp2/3 complex by cortactin and WASP-family proteins," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    3. 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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