Nanoscale architecture of cadherin-based cell adhesions

Abstract

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

Correlative three-dimensional super-resolution and block face electron microscopy of whole vitreously frozen cells

“…6C) and found that the density of heavy metal staining at the PM was also nonuniform ( While the smooth nature of the adhesion as defined by JAM-C is expected because of the mechanical tension induced by the juxtacrine interaction (72)(73)(74), the fact that the adhesion does not comprise the whole contact area between these two cells is not. A further surprise is the enrichment of drebrin in the regions adjacent to JAM-C, rather than the laminar stacking of adhesion-associated cytoskeletal adaptor proteins found in focal or cadherin-based adhesions to glass (62,63).…”

“…Cell-to-cell adhesions are of central importance in tissue morphogenesis because they mediate cell migration, nucleate cell polarity and spur communication between individual cells in multicellular organisms (60,61). While the molecular context and ultrastructure of cellular adhesions to rigid artificial substrates are well characterized (62,63) those between cells in complex 3D environments are not. Neuronal adhesions are particularly interesting because they are crucial for brain development, playing an integral role in sorting neurons based on their maturation status (64,65), forming the laminar structure of the brain (66,67), and ultimately promoting the complex neuronal interactions that drive circuit morphogenesis (68).…”

A central role for cadherin signaling in cancer

“…Through these interactions catenins regulate AJ function and stability. For example, β-catenin links cadherins to α-catenin, to promote the re-organization of the actin cytoskeleton 8–12 . Whether this reorganization is due to direct binding of actin filaments via α-catenin, via the regulation of monomeric versus dimeric α-catenin pools, tension-induced activation of α-catenin and vinculin, and/or via other actin binding β-catenin partners, like EPLIN, or ZO1, is still a mater of active investigation.…”

A weak link with actin organizes tight junctions to control epithelial permeability

“…Bundles of actin filaments stabilize the AJ and lend integrity to epithelial sheets (Yonemura, 2011). At the molecular level, actin is connected to the membrane at the AJ indirectly through a protein hierarchy that extends perpendicular to the lipid bilayer, beginning with membrane proteins, which are linked to cytoplasmic adaptors that are coupled to cytoskeletal proteins (Bertocchi et al, 2017). One critical complex that spans this space is that between the adhesive transmembrane protein E-cadherin, the cytoplasmic adaptors β-and α-catenin, and filamentous actin (F-actin) .…”