The major β-catenin/E-cadherin junctional binding site is a primary molecular mechano-transductor of differentiation .

TitleThe major β-catenin/E-cadherin junctional binding site is a primary molecular mechano-transductor of differentiation .
Publication TypeJournal Article
Year of Publication2018
AuthorsRöper J-C, Mitrossilis D, Stirnemann G, Waharte F, Brito I, Fernandez-Sanchez M-E, Baaden M, Salamero J, Farge E
JournalElife
Volume7
Date Published2018 07 19
ISSN2050-084X
KeywordsAmino Acid Sequence, Animals, Armadillo Domain Proteins, Binding Sites, Cadherins, Cell Differentiation, Drosophila melanogaster, Drosophila Proteins, Fluorescence Resonance Energy Transfer, Mechanotransduction, Cellular, Molecular Dynamics Simulation, Phosphorylation, Protein Binding, Protein Conformation, Proto-Oncogene Proteins pp60(c-src), Sequence Homology, Transcription Factors
Abstract

, the primary molecular mechanotransductive events mechanically initiating cell differentiation remain unknown. Here we find the molecular stretching of the highly conserved Y654-β-catenin-D665-E-cadherin binding site as mechanically induced by tissue strain. It triggers the increase of accessibility of the Y654 site, target of the Src42A kinase phosphorylation leading to irreversible unbinding. Molecular dynamics simulations of the β-catenin/E-cadherin complex under a force mimicking a 6 pN physiological mechanical strain predict a local 45% stretching between the two α-helices linked by the site and a 15% increase in accessibility of the phosphorylation site. Both are quantitatively observed using FRET lifetime imaging and non-phospho Y654 specific antibody labelling, in response to the mechanical strains developed by endogenous and magnetically mimicked early mesoderm invagination of gastrulating embryos. This is followed by the predicted release of 16% of β-catenin from junctions, observed in FRAP, which initiates the mechanical activation of the β-catenin pathway process.

DOI10.7554/eLife.33381
Alternate JournalElife
Citation Key2018|2087
PubMed ID30024850
PubMed Central IDPMC6053302
Grant List11 BSV5014-01 / / Agence Nationale de la Recherche / International
11-LBX-0038 / / Agence Nationale de la Recherche / International
PIEF-GA-2012-332422 / / European Commission / International
ANR-11-LABX-0011-01 / / Agence Nationale de la Recherche / International
ANR-10-INBS-04 / / Agence Nationale de la Recherche / International
DEQ20150331702 / / Fondation pour la Recherche Médicale / International