E-cadherin is the major adhesion receptor in epithelial adherens junctions, which connect cells to form tissues and are essential for morphogenesis and homeostasis. The mechanism by which E-cadherin monomers cluster and become organized in adherens junctions remains poorly understood. Here, using superresolution microscopy techniques in combination with structure-informed functional mutations, we found that loosely organized clusters of approximately five E-cadherin molecules that form independently of cis or trans interactions, and that are delimited by the cortical F-actin meshwork, are the precursors of trans-ligated adhesive clusters that make up the adherens junction. The density of E-cadherin clusters was wide ranged, and notably, we could detect densities consistent with the crystal lattice structure at the core of adhesive clusters, which were dependent on extracellular domain interactions. Thus, our results elucidate the nanoscale architecture of adherens junctions, as well as the molecular mechanisms driving its assembly.
Multicellularity in animals requires dynamic maintenance of cell-cell contacts. Intercellularly ligated cadherins recruit numerous proteins to form supramolecular complexes that connect with the actin cytoskeleton and support force transmission. However, the molecular organization within such structures remains unknown. Here we mapped protein organization in cadherin-based adhesions by superresolution microscopy, revealing a multi-compartment nanoscale architecture, with the plasma membrane-proximal cadherin-catenin compartment segregated from the actin cytoskeletal compartment, bridged by an interface zone containing vinculin. Vinculin position is determined by α-catenin, and upon activation, vinculin can extend ˜30 nm to bridge the cadherincatenin and actin compartments, while modulating the nanoscale positions of the actin regulators, zyxin and VASP. Vinculin conformational activation requires tension and tyrosine
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