Kindlin Is Mechanosensitive: Force-Induced Conformational Switch Mediates Cross-Talk among Integrins

Biophysical Journal
Zeinab JahedMohammad R K Mofrad

Abstract

Mechanical stresses directly regulate the function of several proteins of the integrin-mediated focal adhesion complex as they experience intra- and extracellular forces. Kindlin is a largely overlooked member of the focal adhesion complex whose roles in cellular mechanotransduction are only recently being identified. Recent crystallographic experiments have revealed that kindlins can form dimers that bind simultaneously to two integrins, providing a mechanistic explanation of how kindlins may promote integrin activation and clustering. In this study, using the newly identified molecular structure, we modeled the response of the kindlin2 dimer in complex with integrin β1 to mechanical cytoskeletal forces on integrins. Using molecular dynamics simulations, we show that forces on integrins are directly transmitted to the kindlin2 dimerization site, resulting in a shift in an R577-S550/E553 interaction network at this site. Under force, R577 on one protomer switches from interacting with S550 to forming new hydrogen bonds with E553 on the neighboring protomer, resulting in the strengthening of the kindlin2 dimer in complex with integrin β1. This force-induced strengthening is similar to the catch-bond mechanisms that have previous...Continue Reading

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Citations

Jun 13, 2020·Journal of Leukocyte Biology·Vasilios A MorikisScott I Simon
Aug 25, 2020·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Alba ZuidemaArnoud Sonnenberg
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Mar 9, 2021·Frontiers in Immunology·Panagiota BoutiTaco W Kuijpers
Sep 3, 2020·Journal of Chemical Information and Modeling·Yan ZhangJianhua Wu

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