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Force-dependent interactions between talin and full-length vinculin

Wang, Yinan, Yao, Mingxi, Baker, Karen, Gough, Rosemarie E., Le, Shimin, Goult, Benjamin T, Yan, Jie (2021) Force-dependent interactions between talin and full-length vinculin. Journal of the American Chemical Society, 143 . pp. 14726-14737. ISSN 1520-5126. (doi:10.1021/jacs.1c06223) (KAR id:89974)

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Talin and vinculin are part of a multi-component system involved in mechanosensing in cell-matrix adhesions. Both exist in auto-inhibited 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 force-dependent talin-vinculin interactions and kinetics 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 auto-inhibited 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
DOI/Identification number: 10.1021/jacs.1c06223
Uncontrolled keywords: talin, vinculin, autoinhibition, mechanical memory, MeshCODE, magnetic tweezers, mechanotransduction
Subjects: Q Science > QH Natural history > QH581.2 Cell Biology
Divisions: Divisions > Division of Natural Sciences > Biosciences
Depositing User: Ben Goult
Date Deposited: 31 Aug 2021 19:42 UTC
Last Modified: 31 Aug 2022 23:00 UTC
Resource URI: (The current URI for this page, for reference purposes)

University of Kent Author Information

Baker, Karen.

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Gough, Rosemarie E..

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Goult, Benjamin T.

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