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Bending forces and nucleotide state jointly regulate F-actin structure

Author

Listed:
  • Matthew J. Reynolds

    (The Rockefeller University)

  • Carla Hachicho

    (The Rockefeller University)

  • Ayala G. Carl

    (The Rockefeller University
    The Rockefeller University)

  • Rui Gong

    (The Rockefeller University)

  • Gregory M. Alushin

    (The Rockefeller University)

Abstract

ATP-hydrolysis-coupled actin polymerization is a fundamental mechanism of cellular force generation1–3. In turn, force4,5 and actin filament (F-actin) nucleotide state6 regulate actin dynamics by tuning F-actin’s engagement of actin-binding proteins through mechanisms that are unclear. Here we show that the nucleotide state of actin modulates F-actin structural transitions evoked by bending forces. Cryo-electron microscopy structures of ADP–F-actin and ADP-Pi–F-actin with sufficient resolution to visualize bound solvent reveal intersubunit interfaces bridged by water molecules that could mediate filament lattice flexibility. Despite extensive ordered solvent differences in the nucleotide cleft, these structures feature nearly identical lattices and essentially indistinguishable protein backbone conformations that are unlikely to be discriminable by actin-binding proteins. We next introduce a machine-learning-enabled pipeline for reconstructing bent filaments, enabling us to visualize both continuous structural variability and side-chain-level detail. Bent F-actin structures reveal rearrangements at intersubunit interfaces characterized by substantial alterations of helical twist and deformations in individual protomers, transitions that are distinct in ADP–F-actin and ADP-Pi–F-actin. This suggests that phosphate rigidifies actin subunits to alter the bending structural landscape of F-actin. As bending forces evoke nucleotide-state dependent conformational transitions of sufficient magnitude to be detected by actin-binding proteins, we propose that actin nucleotide state can serve as a co-regulator of F-actin mechanical regulation.

Suggested Citation

  • Matthew J. Reynolds & Carla Hachicho & Ayala G. Carl & Rui Gong & Gregory M. Alushin, 2022. "Bending forces and nucleotide state jointly regulate F-actin structure," Nature, Nature, vol. 611(7935), pages 380-386, November.
  • Handle: RePEc:nat:nature:v:611:y:2022:i:7935:d:10.1038_s41586-022-05366-w
    DOI: 10.1038/s41586-022-05366-w
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    Cited by:

    1. Sai Shashank Chavali & Steven Z. Chou & Wenxiang Cao & Thomas D. Pollard & Enrique M. Cruz & Charles V. Sindelar, 2024. "Cryo-EM structures reveal how phosphate release from Arp3 weakens actin filament branches formed by Arp2/3 complex," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Kelli L. Hvorecny & Thomas E. Sladewski & Enrique M. Cruz & Justin M. Kollman & Aoife T. Heaslip, 2024. "Toxoplasma gondii actin filaments are tuned for rapid disassembly and turnover," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Qianqian Ma & Wahyu Surya & Danxia He & Hanmeng Yang & Xiao Han & Mui Hoon Nai & Chwee Teck Lim & Jaume Torres & Yansong Miao, 2024. "Spa2 remodels ADP-actin via molecular condensation under glucose starvation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Chisato Tsuji & Marston Bradshaw & Megan F. Allen & Molly L. Jackson & Judith Mantell & Ufuk Borucu & Alastair W. Poole & Paul Verkade & Ingeborg Hers & Danielle M. Paul & Mark P. Dodding, 2024. "CryoET reveals actin filaments within platelet microtubules," Nature Communications, Nature, vol. 15(1), pages 1-8, December.

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