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Nat Commun. 2014 Jul 31;5:4525. doi: 10.1038/ncomms5525.

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

Author information

1
1] Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore [2].
2
1] Department of Physics, National University of Singapore, Singapore 117542, Singapore [2] College of Physics, Chongqing University, No. 55 Daxuecheng South Road, Chongqing 401331, China [3].
3
1] Department of Physics, National University of Singapore, Singapore 117542, Singapore [2] College of Physics, Chongqing University, No. 55 Daxuecheng South Road, Chongqing 401331, China.
4
Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore.
5
1] Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore [2] Singapore-MIT Alliance for Research and Technology, National University of Singapore, Singapore 117543, Singapore.
6
Institut Jacques Monod, CNRS UMR 7592, Université Paris Diderot, Paris 75013, France.
7
1] Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore [2] Department of Bioengineering, National University of Singapore, Singapore 117542, Singapore.
8
1] Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore [2] Institut Jacques Monod, CNRS UMR 7592, Université Paris Diderot, Paris 75013, France.
9
1] Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore [2] College of Physics, Chongqing University, No. 55 Daxuecheng South Road, Chongqing 401331, China [3] Department of Bioengineering, National University of Singapore, Singapore 117542, Singapore [4] Centre for Bioimaging Sciences, National University of Singapore, Singapore 117546, Singapore.

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.

PMID:
25077739
DOI:
10.1038/ncomms5525
[Indexed for MEDLINE]

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