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Structural mechanism for bi-directional actin crosslinking by T-plastin

View ORCID ProfileLin Mei, View ORCID ProfileMatthew J. Reynolds, View ORCID ProfileDamien Garbett, View ORCID ProfileRui Gong, View ORCID ProfileTobias Meyer, View ORCID ProfileGregory M. Alushin
doi: https://doi.org/10.1101/2021.12.07.471696
Lin Mei
1Laboratory of Structural Biophysics and Mechanobiology
2Tri-Institutional PhD Program in Chemical Biology, The Rockefeller University, New York, NY, USA
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Matthew J. Reynolds
1Laboratory of Structural Biophysics and Mechanobiology
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Damien Garbett
3Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA
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Rui Gong
1Laboratory of Structural Biophysics and Mechanobiology
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Tobias Meyer
3Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA
4Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA
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Gregory M. Alushin
1Laboratory of Structural Biophysics and Mechanobiology
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  • For correspondence: galushin@rockefeller.edu
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Abstract

To fulfill the cytoskeleton’s diverse functions in cell mechanics and motility, actin networks with specialized architectures are built by crosslinking proteins, which bridge filaments to control micron-scale network geometry through nanoscale binding interactions via poorly defined structural mechanisms. Here, we introduce a machine-learning enabled cryo-EM pipeline for visualizing active crosslinkers, which we use to analyze human T-plastin, a member of the evolutionarily ancient plastin/fimbrin family of tandem calponin-homology domain (CHD) proteins. We define a sequential bundling mechanism which enables T-plastin to bridge filaments in both parallel and anti-parallel orientations. Our structural, biochemical, and cell biological data highlight inter-CHD linkers as key structural elements underlying flexible but stable crosslinking which are likely to be disrupted by mutations causing hereditary bone diseases. Beyond revealing how plastins are evolutionary optimized to crosslink dense actin networks with mixed polarity, our cryo-EM workflow will broadly enable analysis of the structural mechanisms underlying cytoskeletal network construction.

One sentence summary Cryo-EM, biochemical, and cellular studies reveal how the crosslinking protein T-plastin bridges actin filaments in two opposing orientations.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • The legend of Supplementary Figure 11 was mis-labelled. This has been corrected, as well as a Figure call in the main text.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 09, 2021.
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Structural mechanism for bi-directional actin crosslinking by T-plastin
Lin Mei, Matthew J. Reynolds, Damien Garbett, Rui Gong, Tobias Meyer, Gregory M. Alushin
bioRxiv 2021.12.07.471696; doi: https://doi.org/10.1101/2021.12.07.471696
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Structural mechanism for bi-directional actin crosslinking by T-plastin
Lin Mei, Matthew J. Reynolds, Damien Garbett, Rui Gong, Tobias Meyer, Gregory M. Alushin
bioRxiv 2021.12.07.471696; doi: https://doi.org/10.1101/2021.12.07.471696

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