Allosteric activation of vinculin by talin

Florian Franz, Rafael Tapia-Rojo (), Sabina Winograd-Katz, Rajaa Boujemaa-Paterski, Wenhong Li, Tamar Unger, Shira Albeck, Camilo Aponte-Santamaria, Sergi Garcia-Manyes, Ohad Medalia (), Benjamin Geiger () and Frauke Gräter ()
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Florian Franz: Heidelberg Institute for Theoretical Studies (HITS)
Rafael Tapia-Rojo: King’s College London
Sabina Winograd-Katz: Weizmann Institute of Science
Rajaa Boujemaa-Paterski: University of Zurich
Wenhong Li: Weizmann Institute of Science
Tamar Unger: Weizmann Institute of Science
Shira Albeck: Weizmann Institute of Science
Camilo Aponte-Santamaria: Heidelberg Institute for Theoretical Studies (HITS)
Sergi Garcia-Manyes: King’s College London
Ohad Medalia: University of Zurich
Benjamin Geiger: Weizmann Institute of Science
Frauke Gräter: Heidelberg Institute for Theoretical Studies (HITS)

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract The talin-vinculin axis is a key mechanosensing component of cellular focal adhesions. How talin and vinculin respond to forces and regulate one another remains unclear. By combining single-molecule magnetic tweezers experiments, Molecular Dynamics simulations, actin-bundling assays, and adhesion assembly experiments in live cells, we here describe a two-ways allosteric network within vinculin as a regulator of the talin-vinculin interaction. We directly observe a maturation process of vinculin upon talin binding, which reinforces the binding to talin at a rate of 0.03 s−1. This allosteric transition can compete with force-induced dissociation of vinculin from talin only at forces up to 10 pN. Mimicking the allosteric activation by mutation yields a vinculin molecule that bundles actin and localizes to focal adhesions in a force-independent manner. Hence, the allosteric switch confines talin-vinculin interactions and focal adhesion build-up to intermediate force levels. The ‘allosteric vinculin mutant’ is a valuable molecular tool to further dissect the mechanical and biochemical signalling circuits at focal adhesions and elsewhere.

Date: 2023
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DOI: 10.1038/s41467-023-39646-4

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