Force-dependent conformational switch of α-catenin controls vinculin binding

Mingxi Yao, Wu Qiu, Ruchuan Liu, Artem K. Efremov, Peiwen Cong, Rima Seddiki, Manon Payre, Chwee Teck Lim, Benoit Ladoux, René-Marc Mège () and Jie Yan ()
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Mingxi Yao: Mechanobiology Institute, National University of Singapore, Singapore
Wu Qiu: National University of Singapore, Singapore
Ruchuan Liu: National University of Singapore, Singapore
Artem K. Efremov: Mechanobiology Institute, National University of Singapore, Singapore
Peiwen Cong: Mechanobiology Institute, National University of Singapore, Singapore
Rima Seddiki: Institut Jacques Monod, CNRS UMR 7592
Manon Payre: Institut Jacques Monod, CNRS UMR 7592
Chwee Teck Lim: Mechanobiology Institute, National University of Singapore, Singapore
Benoit Ladoux: Mechanobiology Institute, National University of Singapore, Singapore
René-Marc Mège: Institut Jacques Monod, CNRS UMR 7592
Jie Yan: Mechanobiology Institute, National University of Singapore, Singapore

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: Abstract Force sensing at cadherin-mediated adhesions is critical for their proper function. α-Catenin, which links cadherins to actomyosin, has a crucial role in this mechanosensing process. It has been hypothesized that force promotes vinculin binding, although this has never been demonstrated. X-ray structure further suggests that α-catenin adopts a stable auto-inhibitory conformation that makes the vinculin-binding site inaccessible. Here, by stretching single α-catenin molecules using magnetic tweezers, we show that the subdomains MI vinculin-binding domain (VBD) to MIII unfold in three characteristic steps: a reversible step at ~5 pN and two non-equilibrium steps at 10–15 pN. 5 pN unfolding forces trigger vinculin binding to the MI domain in a 1:1 ratio with nanomolar affinity, preventing MI domain refolding after force is released. Our findings demonstrate that physiologically relevant forces reversibly unfurl α-catenin, activating vinculin binding, which then stabilizes α-catenin in its open conformation, transforming force into a sustainable biochemical signal.

Date: 2014
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DOI: 10.1038/ncomms5525

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