Abstract
Cadherin cell-cell adhesion proteins play critical roles in embryogenesis and in maintaining tissue integrity. Defects in cadherin adhesion occur in metastatic cancers. Cadherins mediate adhesion by binding in two conformations, X-dimers and strand-swap dimers. These binding conformations have distinctly different adhesive properties: while X-dimers form catch bonds that become longer-lived in the presence of a pulling force, strand-swap dimers form slip bonds that weaken upon pulling. It has been proposed that the cell, switches between X-dimer and strand-swap dimer conformations in order to regulate adhesion. However, little is known about the molecular mechanisms for these conformation changes and for cadherin adhesion regulation. Here, we use an integrated approach that couples live-cell, single molecule Atomic Force Microscope force measurements with precise, cell-biological manipulations of cadherin-cytoskeleton interactions, to characterize the biophysical mechanisms by which cadherins switch between alternate conformations on the cell surface and subsequently regulate adhesion. We demonstrate that cadherin interactions with the cytoskeleton tunes ectodomain conformation using an ‘inside-out’ mechanism. Our data also resolves the mechanistic details for mechanosensitive adhesion regulation.
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