Abstract
Kindlin proteins are central regulators of integrin-mediated cell adhesion, a process essential for various biological and pathological processes. Although structural studies have proposed that kindlins promote integrin activation and clustering via domain-swapped homodimers, this hypothesis has been challenged by the extremely slow in vitro dimerization kinetics, leaving the physiological regulatory mechanism unresolved. Here we show, via multiscale molecular simulations, that mechanical stress acts as a critical trigger for kindlin activation and homodimerization via mechanical allostery. Force accelerates the rate-limiting closed-to-open conformational transition step involved in dimerization, thereby facilitating homodimer assembly. Our simulations pinpoint specific interactions that underlie the high free-energy barrier of conformational transition, which is supported by analytical gel-filtration experiments. We further demonstrate that the relative lengths of linkers between kindlin subdomains strongly influence the propagation of mechanical allostery. Together, these results clarify how mechanical allostery enables kindlin-mediated integrin mechanoactivation and suggest potential therapeutic strategies for adhesion-related disorders.
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Data availability
The raw data that support this study are available from the corresponding author upon request. The inputfiles for MD simulation and some related files were deposited at https://doi.org/10.6084/m9.figshare.28093673.v2.
Code availability
This study used CafeMol (http://www.cafemol.org/), a non-commercial software for coarse-grained molecular simulations. The source code was minimally modified to apply opposite pair-wise forces in steered simulations. Per the software’s license, neither the original nor modified code may be redistributed. The modified code is available from the corresponding author upon request for verification purposes only.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant Nos. 11974173 and 12347102), the Basic Research Program of Jiangsu Province (BK20253050), the grant of Wenzhou Institute, University of Chinese Academy of Sciences (WIUCASQD2021010), and the Shenzhen Science and Technology Program (Grant No. 20231121095506001 to C.Y.). The authors also thank the partial support of HPC Center of Nanjing University and HPC center of Wenzhou Institute, e-Science center of Nanjing University, Nanjing Kunpeng&Ascend Center of Cultivation, and the Nanjing Key Laboratory for Cardiovascular Information and Health Engineering Medicine (funded by the Nanjing Municipal Health Commission) and its Jiangsu counterpart. C.Y. and Z.W. are investigators of SUSTech Institute for Biological Electron Microscopy.
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W.L. conceived the study, W.Z. conducted the MD simulations, H.Y., Z.Y., Z.W., M.Y., and C.Y. conducted the experiments, W.Z., H.Y., Z.Y., Y.B., J.Z., Z.W., M.Y., W.L., C.Y., and W.W. analyzed the results, W.L., C.Y., and W.W. supervised the project. W.Z., W.L. and W.W. wrote the manuscript with input from all authors. All authors reviewed the manuscript.
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Zhang, W., Yang, H., Yang, Z. et al. Role of mechanical allostery in kindlin-mediated integrin activation. Commun Phys (2026). https://doi.org/10.1038/s42005-026-02557-z
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DOI: https://doi.org/10.1038/s42005-026-02557-z
