title: Lateral assembly of N-cadherin drives tissue integrity by stabilizing adherens junctions.
abstract: Cadherin interactions ensure the correct registry and anchorage of cells during tissue formation. Along the plasma membrane, cadherins form inter-junctional lattices via cis- and trans-dimerization. While structural studies have provided models for cadherin interactions, the molecular nature of cadherin binding in vivo remains unexplored. We undertook a multi-disciplinary approach combining live cell imaging of three-dimensional cell assemblies (spheroids) with a computational model to study the dynamics of N-cadherin interactions. Using a loss-of-function strategy, we demonstrate that each N-cadherin interface plays a distinct role in spheroid formation. We found that cis-dimerization is not a prerequisite for trans-interactions, but rather modulates trans-interfaces to ensure tissue stability. Using a model of N-cadherin junction dynamics, we show that the absence of cis-interactions results in low junction stability and loss of tissue integrity. By quantifying the binding and unbinding dynamics of the N-cadherin binding interfaces, we determined that mutating either interface results in a 10-fold increase in the dissociation constant. These findings provide new quantitative information on the steps driving cadherin intercellular adhesion and demonstrate the role of cis-interactions in junction stability.
authors.affiliation: Department of Synaptic Plasticity, Max Planck Institute for Brain Research, 60438 Frankfurt am Main, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Garg
authors.affiliation: Department of Physical Biology (IZN, FB 15), Buchmann Institute for Molecular Life Sciences (BMLS), Cluster of Excellence Frankfurt Macromolecular Complexes (CEF MC), Goethe Universität Frankfurt am Main, 60438 Frankfurt am Main, Germany sabine.fischer@physikalischebiologie.de.
authors.forename: S C
authors.initials: SC
authors.lastname: Fischer
authors.affiliation: Department of Synaptic Plasticity, Max Planck Institute for Brain Research, 60438 Frankfurt am Main, Germany erin.schuman@brain.mpg.de.
authors.forename: E M
authors.initials: EM
authors.lastname: Schuman
authors.affiliation: Department of Physical Biology (IZN, FB 15), Buchmann Institute for Molecular Life Sciences (BMLS), Cluster of Excellence Frankfurt Macromolecular Complexes (CEF MC), Goethe Universität Frankfurt am Main, 60438 Frankfurt am Main, Germany.
authors.forename: E H K
authors.initials: EH
authors.lastname: Stelzer
mesh_terms: D022005:Adherens Junctions / Q000502:physiology*; D015820:Cadherins / Q000737:chemistry*; D002118:Calcium / Q000737:chemistry; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D003198:Computer Simulation; D016616:Cryoultramicrotomy; D019281:Dimerization; D006801:Humans; D021621:Imaging, Three-Dimensional; D009154:Mutation; D011336:Probability; D011485:Protein Binding; D012984:Software; D018874:Spheroids, Cellular / Q000502:physiology*; D013499:Surface Properties
chemical_list: D015820:Cadherins; D002118:Calcium
keywords: cell adhesion; data analysis; image analysis; long-term live cell imaging; mathematical modelling