PMID- 25077739
OWN - NLM
STAT- MEDLINE
DCOM- 20151102
LR  - 20140801
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 5
DP  - 2014 Jul 31
TI  - Force-dependent conformational switch of alpha-catenin controls vinculin binding.
PG  - 4525
LID - 10.1038/ncomms5525 [doi]
AB  - Force sensing at cadherin-mediated adhesions is critical for their proper 
      function. alpha-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 alpha-catenin adopts a stable auto-inhibitory conformation that 
      makes the vinculin-binding site inaccessible. Here, by stretching single 
      alpha-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 
      alpha-catenin, activating vinculin binding, which then stabilizes alpha-catenin in its 
      open conformation, transforming force into a sustainable biochemical signal.
FAU - Yao, Mingxi
AU  - Yao M
AD  - 1] Mechanobiology Institute, National University of Singapore, Singapore 117411, 
      Singapore [2].
FAU - Qiu, Wu
AU  - Qiu W
AD  - 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].
FAU - Liu, Ruchuan
AU  - Liu R
AD  - 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.
FAU - Efremov, Artem K
AU  - Efremov AK
AD  - Mechanobiology Institute, National University of Singapore, Singapore 117411, 
      Singapore.
FAU - Cong, Peiwen
AU  - Cong P
AD  - 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.
FAU - Seddiki, Rima
AU  - Seddiki R
AD  - Institut Jacques Monod, CNRS UMR 7592, Universite Paris Diderot, Paris 75013, 
      France.
FAU - Payre, Manon
AU  - Payre M
AD  - Institut Jacques Monod, CNRS UMR 7592, Universite Paris Diderot, Paris 75013, 
      France.
FAU - Lim, Chwee Teck
AU  - Lim CT
AD  - 1] Mechanobiology Institute, National University of Singapore, Singapore 117411, 
      Singapore [2] Department of Bioengineering, National University of Singapore, 
      Singapore 117542, Singapore.
FAU - Ladoux, Benoit
AU  - Ladoux B
AD  - 1] Mechanobiology Institute, National University of Singapore, Singapore 117411, 
      Singapore [2] Institut Jacques Monod, CNRS UMR 7592, Universite Paris Diderot, 
      Paris 75013, France.
FAU - Mege, Rene-Marc
AU  - Mege RM
AD  - Institut Jacques Monod, CNRS UMR 7592, Universite Paris Diderot, Paris 75013, 
      France.
FAU - Yan, Jie
AU  - Yan J
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140731
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (alpha Catenin)
RN  - 125361-02-6 (Vinculin)
SB  - IM
EIN - Nat Commun. 2015;6:6568. PMID: 25735633
MH  - Actin Cytoskeleton/chemistry/metabolism
MH  - Animals
MH  - Binding Sites
MH  - Gene Expression Regulation
MH  - Magnetic Fields
MH  - Mechanotransduction, Cellular
MH  - Mice
MH  - Optical Tweezers
MH  - Protein Binding
MH  - Protein Structure, Secondary
MH  - Protein Structure, Tertiary
MH  - Recombinant Fusion Proteins/*chemistry/genetics/metabolism
MH  - Stress, Mechanical
MH  - Vinculin/*chemistry/genetics/metabolism
MH  - alpha Catenin/*chemistry/genetics/metabolism
EDAT- 2014/08/01 06:00
MHDA- 2015/11/03 06:00
CRDT- 2014/08/01 06:00
PHST- 2014/02/04 00:00 [received]
PHST- 2014/06/25 00:00 [accepted]
PHST- 2014/08/01 06:00 [entrez]
PHST- 2014/08/01 06:00 [pubmed]
PHST- 2015/11/03 06:00 [medline]
AID - ncomms5525 [pii]
AID - 10.1038/ncomms5525 [doi]
PST - epublish
SO  - Nat Commun. 2014 Jul 31;5:4525. doi: 10.1038/ncomms5525.