1. Structural Biology and Molecular Biophysics

Structural basis of αE-catenin-F-actin catch bond behavior

  1. Xiao-Ping Xu
  2. Sabine Pokutta
  3. Megan Torres
  4. Mark F Swift
  5. Dorit Hanein  Is a corresponding author
  6. Niels Volkmann  Is a corresponding author
  7. William I Weis  Is a corresponding author
  1. Scintillon Institute, United States
  2. Stanford University, United States
  3. Stanford University School of Medicine, United States
https://doi.org/10.7554/eLife.60878
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  1. Xiao-Ping Xu
  2. Sabine Pokutta
  3. Megan Torres
  4. Mark F Swift
  5. Dorit Hanein
  6. Niels Volkmann
  7. William I Weis
(2020)
Structural basis of αE-catenin-F-actin catch bond behavior
eLife 9:e60878.
https://doi.org/10.7554/eLife.60878
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Abstract

Cell-cell and cell-matrix junctions transmit mechanical forces during tissue morphogenesis and homeostasis. α-Catenin links cell-cell adhesion complexes to the actin cytoskeleton, and mechanical load strengthens its binding to F-actin in a direction-sensitive manner. Specifically, optical trap experiments revealed that force promotes a transition between weak and strong actin-bound states. Here, we describe the cryo-electron microscopy structure of the F-actin-bound αE-catenin actin-binding domain, which in solution forms a 5-helix bundle. In the actin-bound structure, the first helix of the bundle dissociates and the remaining four helices and connecting loops rearrange to form the interface with actin. Deletion of the first helix produces strong actin binding in the absence of force, suggesting that the actin-bound structure corresponds to the strong state. Our analysis explains how mechanical force applied to αE-catenin or its homolog vinculin favors the strongly bound state, and the dependence of catch bond strength on the direction of applied force.

Data availability

The coordinates and cryo-EM map of the aE-catenin-F-actin complex have been deposited in the Protein Data Bank, identifiers 6WVT and EMD-21925, respectively

Article and author information

Author details

  1. Xiao-Ping Xu

    Scintillon Institute, Scintillon Institute, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Sabine Pokutta

    Department of Structural Biology, Stanford University, Stanford, CA, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Megan Torres

    Structural Biology and Molecular & Cellular Physiology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Mark F Swift

    Scintillon Institute, Scintillon Institute, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Dorit Hanein

    Scintillon Institute, Scintillon Institute, San Diego, United States
    For correspondence
    dorit@scintillon.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6072-4946

  6. Niels Volkmann

    Scintillon Institute, Scintillon Institute, San Diego, United States
    For correspondence
    niels@sbpdiscovery.org
    Competing interests
    The authors declare that no competing interests exist.

  7. William I Weis

    Departments of Structural Biology and of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States
    For correspondence
    weis@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5583-6150

Funding

National Institutes of Health (GM118326)

  • Dorit Hanein
  • Niels Volkmann
  • William I Weis

National Institutes of Health (GM131747)

  • William I Weis

National Institutes of Health (S10-OD012372)

  • Dorit Hanein

National Institutes of Health (S10-OD026926)

  • Dorit Hanein

Pew Charitable Trusts (864K625)

  • Dorit Hanein

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2020, Xu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Xiao-Ping Xu
  2. Sabine Pokutta
  3. Megan Torres
  4. Mark F Swift
  5. Dorit Hanein
  6. Niels Volkmann
  7. William I Weis
(2020)
Structural basis of αE-catenin-F-actin catch bond behavior
eLife 9:e60878.
https://doi.org/10.7554/eLife.60878

Share this article

https://doi.org/10.7554/eLife.60878

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Further reading

    1. Structural Biology and Molecular Biophysics

    Mechanism of the cadherin–catenin F-actin catch bond interaction

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    Mechanotransduction at cell–cell adhesions is crucial for the structural integrity, organization, and morphogenesis of epithelia. At cell–cell junctions, ternary E-cadherin/β-catenin/αE-catenin complexes sense and transmit mechanical load by binding to F-actin. The interaction with F-actin, described as a two-state catch bond, is weak in solution but is strengthened by applied force due to force-dependent transitions between weak and strong actin-binding states. Here, we provide direct evidence from optical trapping experiments that the catch bond property principally resides in the αE-catenin actin-binding domain (ABD). Consistent with our previously proposed model, the deletion of the first helix of the five-helix ABD bundle enables stable interactions with F-actin under minimal load that are well described by a single-state slip bond, even when αE-catenin is complexed with β-catenin and E-cadherin. Our data argue for a conserved catch bond mechanism for adhesion proteins with structurally similar ABDs. We also demonstrate that a stably bound ABD strengthens load-dependent binding interactions between a neighboring complex and F-actin, but the presence of the other αE-catenin domains weakens this effect. These results provide mechanistic insight to the cooperative binding of the cadherin–catenin complex to F-actin, which regulate dynamic cytoskeletal linkages in epithelial tissues.

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    Molecular mechanism for direct actin force-sensing by α-catenin

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    The actin cytoskeleton mediates mechanical coupling between cells and their tissue microenvironments. The architecture and composition of actin networks are modulated by force; however, it is unclear how interactions between actin filaments (F-actin) and associated proteins are mechanically regulated. Here we employ both optical trapping and biochemical reconstitution with myosin motor proteins to show single piconewton forces applied solely to F-actin enhance binding by the human version of the essential cell-cell adhesion protein αE-catenin but not its homolog vinculin. Cryo-electron microscopy structures of both proteins bound to F-actin reveal unique rearrangements that facilitate their flexible C-termini refolding to engage distinct interfaces. Truncating α-catenin’s C-terminus eliminates force-activated F-actin binding, and addition of this motif to vinculin confers force-activated binding, demonstrating that α-catenin’s C-terminus is a modular detector of F-actin tension. Our studies establish that piconewton force on F-actin can enhance partner binding, which we propose mechanically regulates cellular adhesion through α-catenin.