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Mechanism of synergistic activation of Arp2/3 complex by cortactin and WASP-family proteins

Author

Listed:
  • Fred E. Fregoso

    (University of Pennsylvania
    University of Pennsylvania)

  • Malgorzata Boczkowska

    (University of Pennsylvania)

  • Grzegorz Rebowski

    (University of Pennsylvania)

  • Peter J. Carman

    (University of Pennsylvania
    University of Pennsylvania)

  • Trevor Eeuwen

    (The Rockefeller University)

  • Roberto Dominguez

    (University of Pennsylvania
    University of Pennsylvania)

Abstract

Cortactin coactivates Arp2/3 complex synergistically with WASP-family nucleation-promoting factors (NPFs) and stabilizes branched networks by linking Arp2/3 complex to F-actin. It is poorly understood how cortactin performs these functions. We describe the 2.89 Å resolution cryo-EM structure of cortactin’s N-terminal domain (Cort1-76) bound to Arp2/3 complex. Cortactin binds Arp2/3 complex through an inverted Acidic domain (D20-V29), which targets the same site on Arp3 as the Acidic domain of NPFs but with opposite polarity. Sequences N- and C-terminal to cortactin’s Acidic domain do not increase its affinity for Arp2/3 complex but contribute toward coactivation with NPFs. Coactivation further increases with NPF dimerization and for longer cortactin constructs with stronger binding to F-actin. The results suggest that cortactin contributes to Arp2/3 complex coactivation with NPFs in two ways, by helping recruit the complex to F-actin and by stabilizing the short-pitch (active) conformation, which are both byproducts of cortactin’s core function in branch stabilization.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42229-y
    DOI: 10.1038/s41467-023-42229-y
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    References listed on IDEAS

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    1. Siyang Guo & Olga S. Sokolova & Johnson Chung & Shae Padrick & Jeff Gelles & Bruce L. Goode, 2018. "Abp1 promotes Arp2/3 complex-dependent actin nucleation and stabilizes branch junctions by antagonizing GMF," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    2. Katerina Naydenova & Christopher J. Russo, 2017. "Measuring the effects of particle orientation to improve the efficiency of electron cryomicroscopy," Nature Communications, Nature, vol. 8(1), pages 1-5, December.
    3. 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.
    4. Malgorzata Boczkowska & Grzegorz Rebowski & David J. Kast & Roberto Dominguez, 2014. "Structural analysis of the transitional state of Arp2/3 complex activation by two actin-bound WCAs," Nature Communications, Nature, vol. 5(1), pages 1-12, May.
    5. 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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