Force-Dependent Interactions between Talin and Full-Length Vinculin.

Wang, Yinan ORCID: 0000-0003-4111-6707, Yao, Mingxi ORCID: 0000-0002-3905-8475, Baker, Karen B, Gough, Rosemarie E ORCID: 0000-0002-5587-4683, Le, Shimin ORCID: 0000-0003-2359-1897, Goult, Benjamin T ORCID: 0000-0002-3438-2807 and Yan, Jie ORCID: 0000-0002-8555-7291 (2021) Force-Dependent Interactions between Talin and Full-Length Vinculin. Journal of the American Chemical Society, 143 (36). pp. 14726-14737.

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Official URL: http://dx.doi.org/10.1021/jacs.1c06223

Abstract

Talin and vinculin are part of a multicomponent system involved in mechanosensing in cell-matrix adhesions. Both exist in autoinhibited forms, and activation of vinculin requires binding to mechanically activated talin, yet how forces affect talin's interaction with vinculin has not been investigated. Here by quantifying the kinetics of force-dependent talin-vinculin interactions using single-molecule analysis, we show that mechanical exposure of a single vinculin binding site (VBS) in talin is sufficient to relieve the autoinhibition of vinculin, resulting in high-affinity binding. We provide evidence that the vinculin undergoes dynamic fluctuations between an autoinhibited closed conformation and an open conformation that is stabilized upon binding to the VBS. Furthermore, we discover an additional level of regulation in which the mechanically exposed VBS binds vinculin significantly more tightly than the isolated VBS alone. Molecular dynamics simulations reveal the basis of this new regulatory mechanism, identifying a sensitive force-dependent change in the conformation of an exposed VBS that modulates binding. Together, these results provide a comprehensive understanding of how the interplay between force and autoinhibition provides exquisite complexity within this major mechanosensing axis.

Item Type:	Article
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	13 Mar 2024 10:04
Last Modified:	13 Mar 2024 10:04
DOI:	10.1021/jacs.1c06223
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3179293