Cadherins can dimerize via asymmetric interactions.

Cadherins are essential cell-cell adhesion proteins that interact in two distinct conformations: X-dimers and strand-swap dimers. Both X-dimers and strand-swap dimers are thought to exclusively rely on symmetric sets of interactions between key amino acids on both cadherin binding partners. Here, we use single-molecule atomic force microscopy and computer simulations to show that symmetry in cadherin binding is dispensable and that cadherins can also interact in a novel conformation that asymmetrically incorporates key elements of both strand-swap dimers and X-dimers. Our results clarify the biophysical rules for cadherin binding and demonstrate that cadherins interact in a more diverse range of conformations than previously understood.

Inside-out regulation of E-cadherin conformation and adhesion.

Cadherin cell-cell adhesion proteins play key roles in tissue morphogenesis and wound healing. Cadherin ectodomains bind in two conformations, X-dimers and strand-swap dimers, with different adhesive properties. However, the mechanisms by which cells regulate ectodomain conformation are unknown. Cadherin intracellular regions associate with several actin-binding proteins including vinculin, which are believed to tune cell-cell adhesion by remodeling the actin cytoskeleton. Here, we show at the single-molecule level, that vinculin association with the cadherin cytoplasmic region allosterically converts weak X-dimers into strong strand-swap dimers and that this process is mediated by myosin II-dependent changes in cytoskeletal tension. We also show that in epithelial cells, ∼70% of apical cadherins exist as strand-swap dimers while the remaining form X-dimers, providing two cadherin pools with different adhesive properties. Our results demonstrate the inside-out regulation of cadherin conformation and establish a mechanistic role for vinculin in this process.

Single-molecule studies of classical and desmosomal cadherin adhesion.

Classical cadherin and desmosomal cadherin cell-cell adhesion proteins play essential roles in tissue morphogenesis and in maintaining tissue integrity. Deficiencies in cadherin adhesion are hallmarks of diseases like cancers, skin diseases and cardiomyopathies. Structural studies and single molecule biophysical measurements have revealed critical similarities and surprising differences between these key adhesion proteins. This review summarizes our current understanding of the biophysics of classical and desmosomal cadherin adhesion and the molecular basis for their cross-talk. We focus on recent single molecule measurements, highlight key insights into the adhesion of cadherin extracellular regions and their relation to associated diseases, and identify major open questions in this exciting area of research.

Combined blunt aortic and bronchial injury.

We report the case of a 29-year-old man with left blunt chest trauma resulting in an intimal tear of the proximal descending aorta, for which he underwent successful thoracic endovascular graft stenting. He subsequently developed progressive left lung collapse, and bronchoscopy revealed left bronchial disruption. A left thoracotomy with end-to-end anastomosis of the left bronchus was performed successfully. The literature from 6 other similar cases of concomitant aortic and bronchial injuries was reviewed.